Search

Introduction While clonal hematopoiesis (CH) can precede the development of AML, preleukemic CH can persist after attaining remission. In rare cases, non-leukemic CH can also emerge after remission. Long-term clonal dynamics of persistent CH or emerging CH (together, post-remission CH) in AML patients during consolidation therapies or maintenance therapies is not well understood. Furthermore, the clinical implications of post-remission CH have not been systematically studied. Since AML patients receive various types of post-remission consolidation therapies, including allogeneic stem cell transplant (allo-SCT), analysis of clonal dynamics of post-remission CH offers unique opportunity to study the response of CH to therapies. Such knowledge may be translated into the development of therapeutic strategy targeting CH. Here, we analyzed multiple longitudinal samples from AML patients after remission and analyzed clonal behavior of post-remission CH during consolidation and maintenance therapies. Methods We studied 164 AML patients who attained complete remission (CR) after induction therapies and analyzed baseline and CR marrow by targeted deep sequencing of 295 genes (median 403x depth). Among the patients who were identified to have post-remission CH, we analyzed multiple longitudinal marrows and tracked clonal dynacmis of post-remission CH. We defined “persistent CH” when patients had mutations that were originally detected in AML and persisted after CR with variant allele frequency (VAF) > 2.5%. On the other hand, we defined “ emerging CH” when the patients had new mutations arising after attaining CR. Results Among the 164 AML patients, 79 (48%) patients were found to have post-remission CH at first CR. Of those, we were able to analyze multiple post-remission marrows in 54 patients (median 6 samples/patient, IQR 4-7.75),of which 44 (66%) had persistent CH and 1 (1.9%) had emerging CH, and 9 (17%) had both. The median age of these 54 patients cohort was 59 (IQR: 51-68). 34 (63%) patients attained CR after intensive chemotherapies (IC, idarubicin with high-dose cytarabine based), whereas 20 (37%) patients received low-intensity chemotherapies as induction (hypomethylating agent [HMA]-based N=3, low dose cytarabine-based N=17). All 34 patients treated with IC induction subsequently received consolidation chemotherapies with high-dose cytarabine (HDAC) regimens for median 2 cycles (IQR 2-3.25). Among the 20 patients treated with low-intensity chemotherapies, all patients received consolidation therapies with HMA-based regimen. A subset of patients received maintenance therapies under clinical trials: lenalidomide (N = 1), venetoclax (N = 2), and nivolumab (N = 1). 29 patients underwent allo-SCT (23 with myeloablative conditioning [MAC], and 6 with reduced-intensity conditioning [RIC]). The most frequently mutated genes for persistent CH were DNMT3A (N = 23), followed by TET2 (N = 17), IDH2 (N = 10), and SRSF2 (N = 10). For emerging CH, we observed emergence of JAK2 (N = 2), RUNX1 (N = 2), TET2 (N = 2), BRAF (N = 1), BCOR (N = 1), TP53 (N = 1), KDM6A (N = 1), and NRAS (N = 1). Longitudinal clonal analysis revealed that post-remission CH persisted in 52 of 54 (96%) patients during consolidation and maintenance therapies. Neither cytarabine based chemotherapies, HMA, venetoclax, lenalidomide, and nivolumab, reduced the VAF of post-remission CH, except in 2 (4%) patients, in which post-remission CH (IDH2 and TET2 mutations) were cleared with high dose cytarabine regimen. Although consolidation or maintenance therapies did not reduce post-remission CH, 17 out of 19 (89.4%) patients who underwent for allo-SCT had clearance of post-remission CH with both MAC and RIC. Overall, post-remission CH did not impact the risk of relapse or overall survival. Furthermore, post-remission CH did not affect long-term blood counts (neutrophil counts, hemoglobin, and platelet counts). Conclusion Post-remission CH persisted long-term in AML patients during consolidation and maintenance therapies without having significant impact on blood counts, relapse, and survival. Therapies with cytarabine-based chemotherapies and HMA did not affect the clonal size of post-remission CH, suggesting that these therapies may not be useful to treat CH in pre-leukemic context either. The novel therapeutic approach is warranted to target CH. Disclosures DiNardo: celgene: Consultancy, Honoraria; abbvie: Consultancy, Honoraria; syros: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; daiichi sankyo: Honoraria; agios: Consultancy, Honoraria; medimmune: Honoraria; jazz: Honoraria. Kadia: Bioline RX: Research Funding; Celgene: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; AbbVie: Consultancy, Research Funding. Ravandi: Selvita: Research Funding; Macrogenix: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Consultancy, Research Funding; Menarini Ricerche: Research Funding; Cyclacel LTD: Research Funding. Konopleva: Astra Zeneca: Research Funding; Agios: Research Funding; Ablynx: Research Funding; Kisoji: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Genentech: Honoraria, Research Funding; Ascentage: Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Eli Lilly: Research Funding; Forty-Seven: Consultancy, Honoraria; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Calithera: Research Funding. Kantarjian: Takeda: Honoraria; AbbVie: Honoraria, Research Funding; BMS: Research Funding; Jazz Pharma: Research Funding; Pfizer: Honoraria, Research Funding; Ariad: Research Funding; Amgen: Honoraria, Research Funding; Cyclacel: Research Funding; Daiichi-Sankyo: Research Funding; Immunogen: Research Funding; Astex: Research Funding; Agios: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Champlin: Johnson and Johnson: Consultancy; Sanofi-Genzyme: Research Funding; Actinium: Consultancy. Garcia-Manero: Onconova: Research Funding; H3 Biomedicine: Research Funding; Astex: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Amphivena: Consultancy, Research Funding; Merck: Research Funding. Takahashi: Symbio Pharmaceuticals: Consultancy.

Introduction Molecular MRD assays targeting NPM1 mutant (mut) transcripts have an established role for monitoring treatment efficacy in patients with NPM1mut AML. Approximately 25% of NPM1mut patients show persistent MRD level in the bone marrow (BM) at the end of treatment (EOT), which is associated with a higher risk of relapse (Ivey, NEJM 2016; Kronke, JCO 2011). Molecular persistence at low copy number (MP-LCN) is defined by the European LeukemiaNet (ELN) as MRD positivity in patients in morphological complete remission (CR) with Methods Consecutive patients with newly diagnosed NPM1mut AML receiving at least 2 cycles of intensive chemotherapy were included if MRD remained detectable at EOT. UK patients were all enrolled in the NCRI AML17 and AML19 studies. Australian patients were retrospectively identified. BM samples were analyzed by either RT-qPCR (n=75) (Ivey, NEJM 2016) or ultra-deep next-generation sequencing (UD-NGS, n=5, excluded from Cox model). We applied the ELN definitions for molecular progression or relapse (considered together as molecular failure [MF]), MP-LCN and complete molecular remission (CRMRD-). Kaplan Meier survival estimates were calculated from EOT to death (OS), and/or morphologic relapse (RFS), and/or MF (EFS). The optimal NPM1mut expression threshold was pre-determined by recursive partitioning. Variables with p Results A total of 80 patients had NPM1mut detectable at a median of 37 days (range 19-90; 12 [15%] were >60 days) from last course of chemotherapy; characteristics summarized in Table 1. The majority of patients (89%) had received 3-4 cycles of chemotherapy. At EOT, the median NPM1mut transcript level by RT-qPCR was 11 copies (range 0.3-8699; 3 were >2000) and median reduction from baseline was 4.7 log (range 2.1-6.0). A total of 34 patients (45%; 4 not monitored) fulfilled the criteria for MP-LCN. With a median follow-up time of 24 mo (range 8-77), 27 (34%) spontaneously achieved a sustained CRMRD- for >6 months, 31 (39%) had MF and 13 (16%) had morphologic relapse without preceding MF (due to rapid relapse [n=8], lack of monitoring [n=3], extramedullary or NPM1 wild-type relapse [n=1 each]) (Figure 1). Nine patients (11%) had persisting MP-LCN (included transient MRD negativity): median interval between EOT to the last known positive sample was 12 mo (range 3-32), and all patients currently remain alive and without morphologic relapse by the data cut-off date July 13, 2020. Next, we examined the variables associated with MF and/or morphologic relapse. In univariate analysis, factors associated (p Conclusions We describe the natural history of patients with NPM1 mutated AML who remain MRD positive after completing intensive chemotherapy. Almost half either spontaneously achieve MRD-negativity or have stable low-level expression without relapse with minimum follow up of 8 mo. Patients with both FLT3-ITD and Disclosures Tiong: Pfizer: Consultancy; Servier: Consultancy; Amgen: Consultancy, Honoraria. Dillon:Abbvie: Honoraria, Research Funding; Novartis: Honoraria; Menarini: Honoraria; Astellas: Honoraria; Pfizer: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria; Amgen: Honoraria, Research Funding. Bajel:Abbvie: Honoraria; Pfizer: Honoraria; Amgen: Honoraria, Speakers Bureau; Novartis: Honoraria; Astellas: Honoraria. Russell:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees; Jazz: Research Funding, Speakers Bureau. Wei:MacroGenics: Consultancy, Honoraria; Pfizer: Honoraria; Servier: Consultancy, Honoraria, Research Funding; Walter and Eliza Hall Institute: Other: former employee and receives a fraction of its royalty stream related to venetoclax; Celgene: Consultancy, Honoraria, Research Funding; AbbVie Inc.: Consultancy, Honoraria, Research Funding; Genentech: Honoraria; Astra Zeneca: Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding.

Introduction: Allogeneic hematopoietic cell transplantation (HCT) in first complete remission (CR1) is the standard of care for adult patients with Philadelphia Chromosome Positive (Ph+) Acute Lymphoblastic Leukemia (ALL). The addition of tyrosine kinase inhibitors (TKI) to therapy have resulted in significantly higher rates of complete molecular remissions (CMR) and better overall outcomes. Given the increased toxicity associated with HCT, we aimed to study the benefit of HCT in adult patients with Ph+ ALL in CR1 in CMR. Methods: We performed a multi-institutional, retrospective analysis of 186 patients ≥18 years of age who received induction therapy including TKI for Ph+ ALL from January 2001 through December 2018 and achieved a CMR CR1. Patients achieving CMR within 3 months of diagnosis were included. Sixty-six patients underwent HCT consolidation (HCT group) and 120 patients did not receive HCT in CR1 (no HCT group). Primary outcomes of interest were overall survival (OS), relapse free survival (RFS), cumulative incidence of relapse (CIR), non-relapse mortality (NRM), and GVHD free relapse free survival (GRFS). GRFS was defined as being alive without grade III-IV acute GVHD, extensive or systemic chronic GVHD requiring therapy, or relapse. Although GRFS in no HCT group should be exactly as RFS, GRFS comparison was done to compare the composite outcome of quality of life in addition to survival in two groups. Landmark analysis was performed at 3 months to ensure CMR in all subjects at time 0. Survival end points were estimated using Kaplan-Meier method and analyzed with the log-rank test and Cox proportional hazard regression models. Gray's test was used for the comparison of cumulative incidence between cohorts. Results: Patient characteristics at diagnosis are summarized in Table 1. Compared to the non-transplanted patients, HCT patients were younger (median age 45 years vs. 56 years, p 90% in 90% of patients vs. 60%, p In both univariate and multivariate analysis, there was no statistically significant difference in OS or RFS between the two treatment groups (Figure 1A and 1B). Compared to the non-transplanted patients, HCT patients had higher rates of NRM (HR: 3.57; 95% CI: 1.62-7.85), lower rates of CIR (Figure 1C), and a trend toward lower GRFS (Figure 1D). Five-year estimates of the probabilities of OS, RFS, CIR, and GRFS were 65%, 59%, 21%, and 38% for allo-HCT group and 58%, 54%, 28%, and 54% for no allo-HCT group, respectively. Conclusions: Comparing transplant versus chemotherapy only consolidation in CR1, this multicenter retrospective study shows that adult patients with Ph+ ALL in CMR have similar estimates of OS and RFS. Lower CIR in the HCT group was offset by higher NRM, resulting in similar RFS. Results of this study need to be confirmed in a prospective randomized trial. Disclosures Ghobadi: Kite: Consultancy, Research Funding; BMS: Consultancy; Amgen: Consultancy, Research Funding; EUSA: Consultancy; WUGEN: Consultancy. Kantarjian:Janssen: Honoraria; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Jazz: Research Funding; Immunogen: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Honoraria, Research Funding; Sanofi: Research Funding; Oxford Biomedical: Honoraria; BMS: Research Funding; Amgen: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Ascentage: Research Funding; BioAscend: Honoraria; Aptitute Health: Honoraria; Adaptive biotechnologies: Honoraria; Delta Fly: Honoraria. Jabbour:AbbVie: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding. Short:Astellas: Research Funding; Amgen: Honoraria; AstraZeneca: Consultancy; Takeda Oncology: Consultancy, Honoraria, Research Funding. Uy:Daiichi Sankyo: Consultancy; Astellas Pharma: Honoraria; Agios: Consultancy; Pfizer: Consultancy; Jazz Pharmaceuticals: Consultancy; Genentech: Consultancy. DiPersio:Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Champlin:Actinium: Consultancy; Johnson and Johnson: Consultancy; DKMS America: Membership on an entity's Board of Directors or advisory committees; Genzyme: Speakers Bureau; Takeda: Patents & Royalties; Cytonus: Consultancy; Omeros: Consultancy. Ravandi:Macrogenics: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding. Kebriaei:Amgen: Other: Research Support; Jazz: Consultancy; Pfizer: Other: Served on advisory board; Kite: Other: Served on advisory board; Novartis: Other: Served on advisory board; Ziopharm: Other: Research Support.

Platelet (PLT) recovery after chemotherapy is associated with the prognosis in patients with acute myeloid leukemia (AML); however, its predictive value is yet controversial. A total of 206 de novo non-M3 AMLs treated at the Second Affiliated Hospital of Shanxi Medical University from January 2014 to December 2020 and achieved complete remission (CR) were analyzed in this retrospective study. The overall survival (OS) and relapse-free survival (RFS) were assessed using Kaplan-Meier and Cox regression analyses.According to receiver operating characteristic (ROC) curve analysis, 312×10 9/L was confined as the cutoff of the PLT count, and hence, we divided patients into high PLT group (≥312×10 9/L) and low PLT group (100≤PLT Disclosures No relevant conflicts of interest to declare.

Introduction: Myelodysplastic syndromes (MDS) are characterized by ineffective malignant hematopoiesis; current treatments may provide symptomatic improvement and prolong life but are not curative without allogeneic transplant. Hypomethylating agents (HMAs) may prolong survival but have heterogeneous bone marrow blast and hematologic responses. Prior studies have shown the IWG response to HMA is associated with survival, with patients achieving complete remission (CR) having the best OS. It is not clear to what degree other responses may also be associated with survival and therefore may be meaningful outcomes with prognostic significance. The 2006 IWG response criteria include CR, partial remission (PR), marrow complete remission (mCR), stable disease (SD), and progressive disease (PD), as well as hematologic improvement (HI). Recently, CR with incomplete hematologic improvement (CRh, blasts < 5%, ANC > 500, Plt > 50) has been evaluated as a response in acute leukemias, but its relevance is unknown in MDS. We therefore sought to assess what MDS clinical characteristics and patient outcomes are associated with a CRh response following HMA. Methods: We retrospectively identified adult patients (18+) with MDS ( 500 cells/uL, Plt > 50k/uL), and recoded responses according to modified criteria (CR, PR, CRh, mCR, SD, PD). We assessed patient and disease characteristics associated with CRh. We evaluated the duration of HMA therapy according to modified response criteria, from the time of HMA start until treatment cessation. We also assessed overall survival according to response, starting at the time of treatment start, and until death or censored at last known alive using the method of Kaplan and Meier. Results: We identified a total of 311 patients with MDS who received treatment between 2007 and 2018. The median age at the time of HMA therapy was 69 years (range 23-91). The median ANC was 1.3 (range 0 - 22.3), hemoglobin was 9.5 (4.0-14.0), and platelets were 76 (7-868). Median bone marrow blasts were 5% (0-19%). Most patients had excess blasts (n=181; 58%) and 71% had intermediate or higher risk MDS by IPSS-R (Table 1). Most received azacitidine chemotherapy (n=238, 77%). Median follow up was 60 months. According to IWG 2006, responses to HMA included CR (n=43, 14%), PR (n=2, 1%), mCR (n=57, 18%), SD (n=149, 48%) and PD (n=60, 19%). A total of 79 patients (25% of total) achieved some form of HI. When adding CRh as a response, a total of 62 patients (20%) met CRh criteria, with concordant decreases in the number classified as mCR (n=26, 8%), and SD (n=118, 38%). The duration of time on HMA therapy was assessed according to modified response. Patients achieving CR had the longest duration of time on HMA therapy (median 8.1mo) compared to CRh (6mo, HR 1.4, 95%CI 0.9-2.0), mCR (4.7mo, HR 1.9 [1.2-3.1]), SD (4mo, HR 2.0 [1.4-2.9]), PR (4.1mo, HR 3.3 [0.8-13.8]) or PD (2.9mo, HR 5.0 [3.3-7.7]) (p Overall survival confirmed prior studies showing patients with CR had improved OS compared to other IWG 2006 response outcomes (Figure 1A, median 23.3mo, p Discussion: Although CR has been the most robust clinical response metric for prediction of OS, MDS patients who achieve a CRh equivalent response had similar survival to those with CR and improved duration on therapy compared to other responses. These data support further evaluation of CRh or other combined marrow/blood count endpoints into future response criteria iterations. These data also suggest new endpoints which could be evaluated in ongoing prospective studies, such as those evaluating novel HMA doublets. Figure 1 Figure 1. Disclosures Brunner: Aprea: Research Funding; AstraZeneca: Research Funding; Janssen: Research Funding; GSK: Research Funding; Keros Therapeutics: Consultancy; Agios: Consultancy; Acceleron: Consultancy; Takeda: Consultancy, Research Funding; BMS/Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Komrokji: BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; Acceleron: Consultancy; Jazz: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy. Zeidan: Cardiff Oncology: Consultancy, Other: Travel support, Research Funding; Astellas: Consultancy; BMS: Consultancy, Other: Clinical Trial Committees, Research Funding; Janssen: Consultancy; Kura: Consultancy, Other: Clinical Trial Committees; Pfizer: Other: Travel support, Research Funding; Genentech: Consultancy; Astex: Research Funding; Epizyme: Consultancy; Ionis: Consultancy; Geron: Other: Clinical Trial Committees; Amgen: Consultancy, Research Funding; ADC Therapeutics: Research Funding; Aprea: Consultancy, Research Funding; BioCryst: Other: Clinical Trial Committees; BeyondSpring: Consultancy; Agios: Consultancy; Acceleron: Consultancy, Research Funding; Gilead: Consultancy, Other: Clinical Trial Committees; Incyte: Consultancy, Research Funding; Jazz: Consultancy; Jasper: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Loxo Oncology: Consultancy, Other: Clinical Trial Committees; Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding; AstraZeneca: Consultancy; AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding. Sallman: Incyte: Speakers Bureau; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Agios: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Background In myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML) achievement of complete remission (CR) is a prerequisite for potential cure. In AML, CR/CR with incomplete recovery (CRi) is deemed the major outcome associated with improved overall survival (OS); patients (pts) without CR/CRi are considered non-responders, and hematologic improvement (HI) without (assessment of) bone marrow (BM) blast clearance is considered treatment (trt) failure. Achievement of CR may not be necessary for prolonged OS in pts treated with azacitidine (AZA) (Pleyer L, Annals Hematol 2014, 1825; Schuh AC, ASH 2015, P575). Outside of clinical trials, BM evaluations (BME) are only performed in ~50% of pts (Dinmohamed, Leuk Res 2015, 177) when either response or progression are obvious from peripheral blood (PB) values, or when pts are unable or unwilling to have BME. Aims To assess of the impact of response type on AZA trt outcomes in multivariate adjusted analyses (MVA). Methods 1441 pts included in the Austrian Azacitidine Registry were analyzed (NCT01595295). Data cut-off was 1 July 21. Marrow response was assessed for MDS/CMML and AML at each BME; HI was assessed on day 1 of each AZA cycle (Döhner H, Blood 2017, 424; Cheson BD, Blood 2006, 419; Pleyer L, ASH 2019, P3821); peripheral blood complete remission (PB-CR) was defined as hemoglobin ³11 g/dL, platelet count ≥100 G/L, neutrophil count ³1.0 G/L, white blood cell count Results In total, 521, 135, and 785 pts had MDS, CMML and AML. Median year of initial diagnosis was 2012, median time to AZA start was 3·0 (IQR 1·0-13·2) months (mo), median follow-up time from AZA start was 10.6 (IQR 4·0-21·1) mo, 894 pts received AZA as first line trt, median age at AZA start was 73 (range 23-99) years. In total, 13956 AZA cycles were applied, median duration of AZA trt was 5·0 (IQR 1·9-12·1) mo, median AZA dose was 875 (IQR 700-1000) mg/cycle, AZA was applied for a median of 7 (IQR 5-7) days. Median time to best response was 3·7 (IQR 2·0-5·9) months. Early mortality was 5.5% within 30 days. During AZA trt 1225 BM evaluations (BME) were performed in 697 (48·4%) of pts. Of these, 204 achieved CR/CRi. Irrespective of BME, 622 (43%) of 1441 pts achieved an HI and 264 (18·3%) of 1441 pts achieved a PB-CR. Pts achieving CR had longer adjusted OS (23·7 vs 19·7 mo, p=0·0227; HR=0·621 [0·413-0·936]) and TTNT (19·4 vs 15·7 mo, p=0·0262; HR=0·644 [0·436-0·949]) than pts achieving CRi. Among pts achieving CR, those additionally achieving PB-CR had longer adjusted OS (24·8 vs 16·3; p=0·0040; HR=0·256 [0·101-0·647]; Fig 1A) and TTNT (21·2 vs 11·0; p=0·0005; HR=0·219 [0·094-0·513]; Fig 1B) than those who did not. Among pts not achieving CR, those additionally achieving PB-CR had longer adjusted OS (20·8 vs 14·1; p Among all pts, irrespective of BM blast count, achievement of PB-CR resulted in longer adjusted OS (21·7 vs 10·0 mo; p Among all response types and after MVA, the highest prognostic impact on both OS and TTNT was observed when achieving PB-CR or CR/CRi by cycle 9 or 10 (Fig 2A-B). Conclusions Above data indicate that achievement of PB-CR is a strong predictor of OS and TTNT that provides additional information to current response criteria. Inclusion of PB-CR in updated response criteria of pts with MDS, CMML or AML receiving non-intensive trt should be considered. The greatest advantage of PB-CR is that it can be easily, nearly painlessly and quickly assessed. Inclusion of PB-CR as an endpoint in clinical trials would be desirable for validation of these results. Figure 1 Figure 1. Disclosures Pleyer: AbbVie, BMS, Novartis: Honoraria, Other: Travel Sport. Pfeilstocker: BMS: Honoraria. Stauder: Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Heibl: BMS: Honoraria. Sill: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Hartmann: Celgene, Amgene, Janssen, AbbVie: Honoraria. Petzer: Kite-Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Saegen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene-BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Geissler: BMS: Honoraria. Sperr: AbbVie, BMS-Celgene, Daiichi Sankyo, Deciphera, Incyte, Jazz, Novartis, Pfizer, StemLine, Thermo Fisher: Honoraria, Research Funding. Leisch: Honoraria from BMS, Celgene, Gilead, Takeda and Novartis; Travel support: Celgene and Novartis: Honoraria, Other: Travel support. Melchardt: Abbvie, Celgene, Novartis: Honoraria. Zebisch: Novartis: Consultancy; AbbVie: Consultancy; Celgene: Consultancy, Honoraria. Machherndl-Spandl: AbbVie, Celgene, BMS, Pfizer: Honoraria. Wolf: Roche: Honoraria, Research Funding; MSD: Honoraria, Research Funding; BMS-Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Takeda: Honoraria; Gilead: Honoraria; Incyte: Honoraria; GEMOAB: Honoraria. Greil: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Daiichi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Sandoz: Honoraria, Research Funding. OffLabel Disclosure: Azacitidine is approved for all types of MDS and CMML as well as low blast count AML by FDA, but not for all subtypes of MDS and CMML by EMA.

Background: Post-transplant cyclophosphamide (PTCy) has been shown to significantly reduce transplant related mortality (TRM) post hematopoietic stem cell transplantation (HSCT) and is being increasingly used for acute myelogenous leukemia (AML) patients (pts) undergoing HSCT including from unrelated donors (UD). These publications mainly include pts transplanted in first complete remission (CR1). We recently reported outcome in 1879 AML pts transplanted in second CR (CR2) with conventional graft-versus-host disease (GVHD) prophylaxis (Leukemia 2020). Results may differ in transplantation with PTCy as GVHD prophylaxis, eliminating proliferating alloreactive T cells, and upregulating T regulatory cells while suppressing host natural killer (NK) cells immediately after transplantation, changing the biology and characteristics of the transplantation. Methods: The study aim was to assess outcome of adult AML pts, aged ≥18 years in CR2 undergoing HSCT from a 9-10/10 UD with PTCy, in 2010-2019.Statistics included multivariate analysis (MVA) adjusting for potential confounding factors was performed using a Cox's proportional-hazards regression model for main outcomes. Results: In total, 127 pts were included. Median follow-up was 19.2 (95% CI, 14.7-28) months (mos). Median age was 45.5 (range, 18.2-71.3) years. 54.3% were male. Cytogenetic risk (MRC classification) was favorable, intermediate, and adverse in 15.7%, 55.9%, and 5.5% of pts, respectively (missing data-22.8percentage) Median year of transplantation was 2017. Time from diagnosis to transplantation was 20.4 (range, 4.1-182.4) months. All pts were at CR2 at time of transplantation. Donors were 10/10 and 9/10 UD in 60.6% and 39.4% of pts, respectively. 77.8% and 47.2% of the pts and donors, respectively, were cytomegalovirus (CMV) seropositive. Conditioning was myeloablative in 50.4% and reduced intensity in 49.6%. The most frequent (61.4%) conditioning consisted of busulfan and fludarabine. All pts received PTCy as anti GVHD prophylaxis in combination with immunosuppression, which was cyclosporine A /mycophenolate mofetil (MMF) in 21.3% and MMF/tacrolimus in 23.6%. 33.9% of the pts received In vivo T-cell depletion. Grafts were peripheral blood in 93.7% and bone marrow in 6.3% of transplants. Karnofsky performance score (KPS) was > 90 in 71.2% and the hematopoietic cell transplantation-specific comorbidity index (HCT-CI) was zero in 61.5% of the pts. Engraftment was achieved by 97.6% with day (d) 60 absolute neutrophil count (ANC) > 0.5 x 10 9/L in 96.8%, and d 180 incidence of acute (a) GVHD II-IV and III-IV was 26.2% and 9.2%, respectively. The 2-year total and extensive chronic (c) GVHD was 34.3% and 13.8 %, respectively. The 2-year non-relapse mortality (NRM) was 17.2%. The 2-year relapse incidence (RI) was 21.1%. RI was the main cause of death in 41% of pts who died, followed by infections (23.1%) and GVHD (20.5%). The 2-year leukemia-free survival (LFS), overall survival (OS) and GVHD-free, relapse-free survival (GRFS) was 61.7%, 65.2% and 49.3%, respectively (Figure). In MVA time from diagnosis to transplant was significant prognostic factor for RI, LFS, OS and GRFS hazard ratio (HR) =0.19 (95% CI 0.07-0.48, p Conclusions: Outcome of AML pts undergoing HSCT from a 9-10/10 MUD in CR with PTCy as GVHD prophylaxis, are similar to previous reports using conventional GVHD prophylaxis with 26% of pts developing aGVHD ,34% cGVHD and NRM of 17%. These results are also similar to those we previously observed in pts undergoing HSCT from UD with PTCy while in CR1. Figure 1 Figure 1. Disclosures Labopin: Jazz Pharmaceuticals: Honoraria. Kulagin: X4 Pharmaceuticals, Alexion, Apellis, Biocad: Research Funding; Novartis, Generium, Sanofi, Roche, Johnson & Johnson, Pfizer: Speakers Bureau. Blaise: Jazz Pharmaceuticals: Honoraria. Yakoub-Agha: Jazz Pharmaceuticals: Honoraria. Ciceri: IRCCS Ospedale San Raffaele: Current Employment. Mohty: Sanofi: Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Astellas: Honoraria; Amgen: Honoraria; Adaptive Biotechnologies: Honoraria.

The therapeutic landscape for acute myeloid leukemia (AML) has evolved in recent years with the introduction of hypomethylating agents (HMA) and venetoclax in patients previously deemed unfit for curative - intent treatment. Some of these patients undergo allogeneic hematopoietic cell transplant (alloHCT), yet there are scarce data regarding transplantation outcomes. We conducted a multicenter nationwide retrospective cohort study to evaluate outcomes of patients with AML who underwent alloHCT in first CR (CR1) after frontline treatment with 5-azacitidine plus venetoclax (aza-ven group). In addition, we collected a historical control group of patients who achieved CR1 following first line intensive chemotherapy followed by alloHCT (intensive group). 24 patients in the aza-ven group were transplanted between 2019 and 2021. Compared to the intensive group, patients in the aza-ven group were older (median age 71.7 vs. 58.4 years, p Median follow up was 8 (range, 0 to 25) months in the aza-ven group and 23 (range, 4 to 56) months in the intensive group. Estimated 12 months non relapse mortality was 19.1% in the aza-ven group and 11.8% in the intensive group (p=0.492). The estimated median relapse free survival (RFS) was not reached in the aza-ven group and was 19.3 months (CI 95% 1-38) in the intensive group. There was no difference between the two groups in 12 months RFS (58% and 54% in the aza-ven group and intensive group, respectively, p = 0.892). The estimated median survival of the aza-ven group was not reached and the 12 months overall survival (OS) rate was 63.2%. The estimated median survival of the intensive group was 50 months (CI 95% 5 - 96) and the 12 months OS rate was 70.8%. There was no statistical differences between the two groups regarding OS (p = 0.58). In a subgroup Cox regression analysis of the aza-ven group, adverse ELN 2017 risk category and HCT-CI score ≥3 were predictive of decreased RFS, both in univariate analysis (UVA) and in multivariate analysis (MVA) (HR 10.56, CI 95%1.64-68.1, p=0.013 and HR 6.43, CR 95% 1.34-30.75, p=0,02, respectively). Graft source (alternative vs. matched donor) and HCT-CI score ≥3 were predictive of decreased OS in UVA (HR 19.45, CI 95% 1.66-228.13, p= 0.018 and HR 5.93, CI 95% 1.13-31.05, p=0.03], yet in MVA neither of these factors retained their predictive value. The cumulative incidence of acute GVHD at 6 months was similar between groups: 58% in the aza-ven group vs. 62% in the intensive group (p=0.39). Likewise, there was no difference in the cumulative incidence of chronic GVHD at 12 months: 40% vs 42%, respectively (p=0.747) In conclusion, our data suggests that alloHCT for AML patients achieving first CR with aza-ven appears feasible, with short term post-transplant outcomes comparable to those expected after traditional intensive chemotherapy. Our results were collected in the real world setting, and patients in the aza-ven group were older and had inherently worse leukemia characteristics, including more secondary AML and more adverse cytogenetic features. Future research is warranted to decipher the true spectrum of AML patients who could benefit from remission induction with this less intensive regimen prior to alloHCT. Figure 1 Figure 1. Disclosures Ram: Gilead: Honoraria; Novartis: Honoraria. Wolach: Janssen: Consultancy; Abbvie: Consultancy, Honoraria, Research Funding; Astellas: Consultancy; Amgen: Research Funding; Novartis: Consultancy; Neopharm: Consultancy. Yeshurun: Astellas: Consultancy; Janssen: Consultancy.

Background: Achieving a first complete remission (CR1) is the primary goal in the treatment of AML and is an important prognostic factor for transplantation outcome in general and even more so for autologous transplantation (AutoSCT). However, there are no data for AutoSCT indicating whether the number of chemotherapy courses (1 vs 2) needed to achieve CR1 is of prognostic significance for transplantation outcome. Methods: Using the EBMT/ALWP registry, we compared transplantation outcomes of adult patients (pts) aged ≥18 years with de novo AML that underwent a peripheral blood AutoSCT in 2000-2019 in CR1 achieved following one vs two chemotherapy courses. The primary outcome was the Leukemia Free Survival (LFS). Multivariate analysis (MVA) adjusting for differences between the groups and knowns factors were performed using Cox's proportional- hazards regression model for outcomes. Results: 1825 pts were included: 1532 (84%) with one and 293 (16%) with two induction chemotherapies courses. Time from diagnosis to AutoSCT was 4.7 (3.9-5.8) vs 5.7 (4.7-7.1) months, respectively (p 90 was higher in pts receiving 1 vs 2 inductions, 71% and 58% of pts, respectively (p Day 30 neutrophil engraftment incidence was 96% and 96.5%. Five -year non-relapse mortality (NRM) was 6.2% vs 6.0% for pts achieving CR1 with 2 vs 1 chemotherapy courses, respectively, and did not differ significantly (HR=1.31 (95% CI: 0.81-2.10), p=0.27). Five -year relapse incidence (RI) was higher :67.2% vs 52.3%, (HR=1.46 (95% CI: 1.25-1.72), p Conclusions: The five -year RI was higher and transplantation outcomes significantly inferior in pts with AML undergoing AutoSCT but who received two lines of chemotherapy to achieve CR1. Such pts may benefit from additional novel therapies in the conditioning or post-AutoSCT or be considered for allogeneic transplantation in an attempt to reduce their high RI and improve outcomes. Figure 1 Figure 1. Disclosures Labopin: Jazz Pharmaceuticals: Honoraria. Blaise: Jazz Pharmaceuticals: Honoraria. Huynh: Jazz Pharmaceuticals: Honoraria. Mohty: Takeda: Honoraria; Jazz: Honoraria, Research Funding; Astellas: Honoraria; Janssen: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Novartis: Honoraria; Celgene: Honoraria, Research Funding; Amgen: Honoraria; Gilead: Honoraria; Pfizer: Honoraria; Adaptive Biotechnologies: Honoraria; Sanofi: Honoraria, Research Funding. Pigneux: Amgen: Consultancy; Sunesis: Consultancy, Research Funding; BMS Celgene: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.

Introduction KMT2A-rearranged (KMT2A-r) acute myeloid leukemia (AML) is a heterogeneous genetic subgroup with a frequency of about 25% in children with AML. At the 62 nd ASH annual meeting last year, we reported on the differences in outcome of various KMT2A subgroups based on translocation partner and the significance of minimal residual disease (MRD) status during and after induction as a follow-up study of Balgobind et al., Blood 2009. The impact of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR1) and the presence of additional cytogenetic aberrations (ACAs) on prognosis have not yet been described for our cohort. Methods Data on allo-HSCT in CR1 and the presence of ACAs of 1256 KMT2A-r de novo pediatric AML patients from 15 AML study groups affiliated with the I-BFM Study Group, diagnosed between 2005 and 2016, were retrospectively collected and studied. Karyotypes were reviewed and classified by two of the authors (RW&CH). Based on translocation partners, patients were classified to the KMT2A high-risk subgroup (6q27, 10p11.2, 10p12, 4q21, and 19p13.3) or non-high-risk subgroup (9p22, 19p13, 19p13.1, 1q21, Xq24, 17q21, 1p32, and 17q12). These two categories have been used to estimate a Cox model. Patients with unknown translocation partners were excluded from these analyses (n=126). Flow cytometry MRD levels at the end of induction course 1 (EOI1) and 2 (EOI2) Results Of 1256 pediatric patients with KMT2A-r AML, data on HSCT in CR1 and ACAs were available for 1186 (94.4%) and 1204 patients (95.9%), respectively; 211 (17.8%) patients received HSCT in CR1 and ACAs were present in 601 (49.9%) patients. Compared with the KMT2A non-high-risk subgroup, patients in the KMT2A high-risk subgroup underwent HSCT in CR1 more often (23.8% vs 15.0%; P < .001). ACAs were borderline significantly more common in the KMT2A high-risk subgroup (54.1% vs 46.4%; P = .015). Univariate analysis of the probability of DFS (Table 1) showed that the KMT2A high-risk subgroup (HR 2.1; 95% CI, 1.7-2.5), age ≥10 years (HR 1.4; 95% CI, 1.2-1.7), and MRD ≥0.1 at EOI1 (HR 1.5; 95% CI, 1.1-1.9) were associated with DFS. HSCT in CR1 was a borderline significant prognostic factor (HR 0.7; 95% CI, 0.6-0.9). In a multivariate analysis for DFS (n=515) (Table 1), the KMT2A high-risk subgroup (HR 2.0; 95% CI, 1.6-2.6), MRD ≥0.1 at EOI1 (HR 1.7; 95% CI, 1.2-2.3), and HSCT in CR1 (HR 0.6; 95% CI, 0.4-0.9) were associated with DFS. Univariate analysis of the probability of OS (Table 1) showed that the KMT2A high-risk subgroup (HR 1.8; 95% CI, 1.5-2.2), age ≥10 years (HR 1.6; 95% CI 1.3-2.0), WBC ≥100 x10 9/L (HR 1.4; 95% CI, 1.1-1.7), the presence of ACAs (HR 1.4; 95% CI, 1.2-1.7), and MRD ≥0.1 at EOI1 (HR 2.1; 95% CI, 1.6-2.7) were associated with OS. HSCT in CR1 was not associated with OS. The effect of HSCT in CR1 was not significantly different between the KMT2A high-risk and non-high-risk subgroups. In a multivariate analysis for OS (n=557) (Table 1), the KMT2A high-risk subgroup (HR 1.9; 95% CI, 1.4-2.5), age ≥10 years (HR 1.5; 95% CI, 1.1-1.9), the presence of ACAs (HR 1.6; 95% CI, 1.2-2.1), and MRD positivity at EOI1 (HR 1.9; 95% CI, 1.4-2.5) were associated with OS. Conclusions In this cohort of KMT2A-r pediatric AML patients, the presence of ACAs at diagnosis was independently associated with inferior OS, but not with DFS. This may be due to the exclusion of refractory patients in DFS analysis, who were significantly more common in the group of patients with ACAs. Analysis has yet to be performed to distinguish karyotype complexity. In addition, allo-HSCT in CR1 was an independent predictor of improved DFS, but was not a prognostic factor for OS. Figure 1 Figure 1. Disclosures Abrahamsson: wedish Children´s Cancer Foundation. Research grants and 50% senior research position for clinical research on pediatric leukemia: Research Funding. Locatelli: Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Miltenyi: Speakers Bureau; Medac: Speakers Bureau; Jazz Pharamceutical: Speakers Bureau; Takeda: Speakers Bureau.

Achievement of complete remission (CR) signifies a crucial milestone in the therapy of acute myeloid leukemia (AML) while refractory disease is associated with dismal outcomes. Hence, accurately identifying patients at risk is essential to tailor treatment concepts individually to disease biology. Machine Learning (ML) is a branch of computer science that can process large data sets for a plethora of purposes. The underlying mechanism does not necessarily begin with a manually drafted hypothesis model. Rather the ML algorithms can detect patterns in pre-processed data and derive abstract information. We used ML to predict CR and 2-year overall survival (OS) in a large multi-center cohort of 1383 AML patients who received intensive induction therapy using clinical, laboratory, cytogenetic and molecular genetic data. To enable a customizable and reusable technological approach and achieve optimal results, we designed a data-driven platform with an embedded, automated ML pipeline integrating state-of-the-art software technology for data management and ML models. The platform consists of five scalable modules for data import and modelling, data transformation, model refinement, machine learning algorithms, feature support and performance feedback that are executed in an iterative manner to approach step-wisely the optimal configuration. To reduce dimensionality and the the risk of overfitting, dynamic feature selection was used, i.e. features were selected according to their support by feature selection algorithms. To be included in an ML model, a feature had to pass a pre-determined threshold of overall predictive power determined by summing the normalized scores of the feature selection algorithms. Features below the threshold were automatically excluded from the ML models for the respective iteration. In that way, features of high redundancy or low entropy were automatically filtered out. Our classification algorithms were completely agnostic of pre-existing risk classifications and autonomously selected predictive features both including established markers of favorable or adverse risk as well as identifying markers of so-far controversial relevance. De novo AML, extramedullary AML, double-mutated (dm) CEBPA, mutations of CEBPA-bZIP, NPM1, FLT3-ITD, ASXL1, RUNX1, SF3B1, IKZF1, TP53, U2AF1, t(8;21), inv(16)/t(16;16), del5/del5q, del17, normal or complex karyotypes, age and hemoglobin at initial diagnosis were statistically significant markers predictive of CR while t(8;21), del5/del5q, inv(16)/t(16;16), del17, dm CEBPA, CEBPA-bZIP, NPM1, FLT3-ITD , DNMT3A, SF3B1, U2AF1, TP53, age, white blood cell count, peripheral blast count, serum LDH and Hb at initial diagnosis as well as extramedullary manifestations were predictive for 2-year OS. For prediction of CR and 2-year OS, AUROCs ranged between 0.77 - 0.86 and 0.63 - 0.74, respectively. We provide a method to automatically select predictive features from different data types, cope with gaps and redundancies, apply and optimize different ML models, and evaluate optimal configurations in a scalable and reusable ML platform. In a proof-of-concept manner, our algorithms utilize both established markers of favorable or adverse risk and also provide further evidence for the roles of U2AF1, IKZF1, SF3B1, DNMT3A and bZIP mutations of CEBPA in AML risk prediction. Our study serves as a fundament for prospective validation and data-driven ML-guided risk assessment in AML at initial diagnosis for the individual patient. Image caption: Patient features were automatically selected by machine learning to predict complete remission (CR) and 2-year overall survival (OS) after intensive induction therapy. Based on a continuous feature support metric with a predefined cut-off of 0.5 (determined by optimal classification performance), 27 and 25 features were automatically selected for prediction of CR (A) and 2-year OS (C), respectively. For each of these features predicted by machine learning, odds ratios and 95% confidence intervals (CI) were calculated for CR (B) and 2 year OS (D). BMB: bone marrow blast count; FLT3h/low: FLT3-ITD ratio, h=high>0.5; Hb: hemoglobin; karyotype, c: complex aberrant karyotype (≥ 3 aberrations); karyotype, n: normal karyotype (no aberrations); LDH: lactate dehydrogenase; PBB: peripheral blood blast count; PLT: platelet count; WBC: white blood cell count. Figure 1 Figure 1. Disclosures Schetelig: Roche: Honoraria, Other: lecture fees; Novartis: Honoraria, Other: lecture fees; BMS: Honoraria, Other: lecture fees; Abbvie: Honoraria, Other: lecture fees; AstraZeneca: Honoraria, Other: lecture fees; Gilead: Honoraria, Other: lecture fees; Janssen: Honoraria, Other: lecture fees . Platzbecker: Janssen: Honoraria; Celgene/BMS: Honoraria; AbbVie: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Geron: Honoraria. Müller-Tidow: Pfizer: Research Funding; Janssen: Consultancy, Research Funding; Bioline: Research Funding. Baldus: Celgene/BMS: Honoraria; Amgen: Honoraria; Novartis: Honoraria; Jazz: Honoraria. Krause: Siemens: Research Funding; Takeda: Honoraria; Pfizer: Honoraria; art-tempi: Honoraria; Kosmas: Honoraria; Gilead: Other: travel support; Abbvie: Other: travel support. Haenel: Bayer Vital: Honoraria; Jazz: Consultancy, Honoraria; GSK: Consultancy; Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Amgen: Consultancy; Celgene: Consultancy, Honoraria. Schliemann: Philogen S.p.A.: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Other: travel grants; Astellas: Consultancy; AstraZeneca: Consultancy; Boehringer-Ingelheim: Research Funding; BMS: Consultancy, Other: travel grants; Jazz Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy; Roche: Consultancy; Pfizer: Consultancy. Middeke: Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Jazz: Consultancy; Astellas: Consultancy, Honoraria; Sanofi: Honoraria, Research Funding; Novartis: Consultancy; Gilead: Consultancy; Glycostem: Consultancy; UCB: Honoraria.

Background: Additional cytogenetic abnormalities (ACA), the most frequent form of cytogenetic changes, are considered as a result of genetic instability and clonal evolution of leukemia cells. Recently, we described that ACA at the first relapse was associated with the significantly lower second complete remission (CR2) rate and poor survival in adult acute myeloid leukemia (AML) patients (Hematol Oncol. 2018;36:252-257). However, the prognostic impact of ACA after allogeneic stem cell transplant (allo-SCT) has not been elucidated in adult AML patients. Patients and methods: Of the 145 adult AML patients who underwent the first allo-SCT in CR2 between 1997 and 2019, 98 patients whose cytogenetic abnormality data both at diagnosis and at the first relapse were available were included in this study. Cytogenetic changes between at diagnosis and the first relapse were classified into four groups: (1) no change, (2) ACA was acquired at the first relapse, (3) cytogenetic abnormalities observed at diagnosis were reduced or had disappeared at the first relapse, and (4) cytogenetic abnormalities observed at diagnosis were reduced or had disappeared, and completely different ACA was acquired at the first relapse. In this study, groups 2 and 4 were defined as ACA acquisition. Overall survival (OS) was defined as the interval from the date of transplant to the date of death. Fisher's exact test was used to compare binary variables. The cumulative incidence (CI) of non-relapse mortality (NRM) and relapse were evaluated with Gray's test, considering relapse and NRM as a competing risk, respectively. OS was estimated with the Kaplan-Meier method and compared using the log-rank test. Factors associated with at least borderline significance (p < 0.20) in univariate analyses were subjected to multivariate analysis. The Cox and Fine-Gray proportional hazard model were used for multivariate analysis of prognostic and risk factors, respectively. Values of p < 0.05 were considered to indicate statistical significance. Results: Of the 98 patients included in this study, 57 were male, and 41 were female. The median age at transplant was 45 years (range, 17-71 years). The median duration of CR1 was 12.4 months (range, 1.3-70.3 months) and cytogenetic risk groups were good, intermediate, and poor in 26 (27%), 70 (71%), and two patients (2%), respectively. Donor types were related, unrelated, and cord blood in 23 (24%), 59 (60%), and 16 patients (16%), respectively, and 86 (87%) and 61 patients (62%) were conditioned with myeloablative and total body irradiation-containing regimens, respectively. According to the definition described above, 20 patients (20%) acquired ACA at the first relapse. There was no significant difference in baseline characteristics and transplant procedures between patients with and without ACA acquisition. The OS rates were not significantly different between two groups (55% vs. 72% at three years after transplant; p = 0.28). The CI of relapse was significantly higher in patients with ACA acquisition than those without ACA acquisition (59% vs. 15%; p < 0.01), while the CI of NRM were not significantly different between two groups (5% vs. 19%; p = 0.17). Multivariate analysis for OS revealed that age over 50 years (hazard ratio [HR] = 2.4; p < 0.01), but not ACA acquisition, was identified as an independent prognostic factor. ACA acquisition (HR = 4.7; p < 0.01) was extracted as an independent risk factor of relapse, while use of reduced intensity conditioning regimens (HR = 3.1; p = 0.03) and more than or equal to 1 of performance status at transplant (HR = 2.7; p = 0.04) showed independent risks of NRM. The similar OS rates between two groups might resulted from an offset of the lower relapse rate with the higher NRM rate in patients without ACA acquisition despite not reaching statistical significance. This increasing NRM rates in those without ACA acquisition was potentially associated with use of reduced intensity conditioning regimens in larger proportion (0% vs. 15%; p = 0.12). Conclusion: These findings suggested that ACA acquisition at the first relapse was associated with a higher risk of relapse even after allo-SCT in CR2 in adult AML patients. As AML cells with ACA acquisition was resistant to not only chemotherapy but also graft-versus-leukemia effect, innovative therapeutic strategy is warranted. Disclosures Handa: Janssen: Honoraria; Kyowa Kirin: Research Funding; Takeda: Honoraria, Research Funding; BMS: Honoraria; Chugai: Research Funding; Ono: Honoraria; Sanofi: Honoraria, Research Funding; Abbvie: Honoraria; MSD: Research Funding; Shionogi: Research Funding; Celgene: Honoraria, Research Funding; Daiichi Sankyo: Research Funding.

Allogeneic hematopoietic cell transplantation (allo-HCT) is a promising therapeutic option for hematological malignancies, but relapse resulted predominantly from residual disease in bone marrow (BM) remains the major cause of treatment failure. Using immunodeficient mice grafted with laboratory-generated human B-ALL, our previous study suggested that leukemia cells within the BM were resistant to graft-versus-leukemia (GVL) effects, and mobilization with CXCR4 antagonist may dislodge leukemia cells from BM, rendering them destroyed by GVL effects. In this study, we extended this approach to patient-derived xenograft (PDX) and murine T-ALL and AML models for determining its clinical relevance and effects on GVHD and donor hematopoietic engraftment. We found that post-transplant treatment with CXCR4 antagonist AMD3100 significantly improved eradication of leukemia cells in the BM in PDX mice grafted with B-ALL cells from multiple patients. AMD3100 also significantly improved disease-free remission rates in murine T-ALL and AML models, and promoted donor hematopoietic engraftment in mice following non-myeloablative allo-HCT. Furthermore, post-transplant treatment with AMD3100 had no detectable deleterious effect on acute or chronic GVHD. These findings provide important preclinical data supporting the initiation of clinical trials exploring combination therapy with CXCR4 antagonist and allo-HCT. Disclosures No relevant conflicts of interest to declare.

Introduction: Patients (pts) with primary refractory or relapsed high-grade lymphoma (HGL) including Burkitt lymphoma (BL) and high-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6 (double-hit lymphoma, DHL) have a dismal prognosis with patients almost never achieving a meaningful remission to second line therapy. No standard second line therapeutic approach exists, particularly for BL. The characteristic hallmark of these diseases is a dysregulated MYC oncogene with both downstream effects on proliferation and a high metabolic fluxes which use tricarboxylic acid (TCA) cycle intermediates as biosynthetic precursors. CPI-613 (devimistat) is a non-redox active analogue of lipoic acid, a required cofactor for two key mitochondrial enzymes of the TCA cycle, pyruvate dehydrogenase and alpha ketoglutarate dehydrogenase. Disruption of mitochondrial function by CPI-613 results in a shutdown of ATP and biosynthetic-intermediate production, leading to cancer cell death by apoptosis or necrosis. In the initial phase I trial (n=26) one patient with multiply refractory BL had a partial remission sustained for over one year and then consolidated by surgical resection. She remains alive 7 years later. As of July 2021, 20 clinical studies for various cancers have been conducted (ongoing/completed) with devimistat with over 700 patients having received study drug. We initiated a phase II trial to further explore efficacy in HGL. Devimistat has FDA orphan status for BL and 4 other cancers. Methods: NCT03793140 is a multicenter study aiming to enroll 17 patients on each of two cohorts, BL and DHL, with a Simon's 2-stage design for each cohort, requiring one response among the first 9 treated patients to expand to 17. Patients must have had at least one prior line of therapy or are refusing standard of care and must be more than 3 months after a prior stem cell transplant. Active central nervous system (CNS) parenchymal disease is excluded, but prior leptomeningeal disease is allowed if the CSF is negative for more than 4 weeks at enrollment and maintenance intrathecal therapy is ongoing. Devimistat is given by central line over 2 hours daily x 5 days for two 14-day cycles and then as maintenance x5 days every 21 days. Pts were evaluable for response if they received at least 4 infusions over 5 days of the first cycle. Results: 9 pts were enrolled in the DHL/THL arm. Mediannumber of prior therapies were 3 (range, 1-6). No responses were seen, with only 1 patient achieving stable disease as best response, resulting in cohort closure. Thus far, 8 BL pts were enrolled. Median number of prior therapies was 3 (range, 2-4). Two patients were inevaluable for response. 1/6 patients had stable disease through cycle 7 and one had a complete response (CR). This CR patient (HIV+) with 4 prior therapies entered the study with only a biopsy proven thigh mass. He was not a transplant candidate for social reasons. He had a near complete metabolic remission after 4 cycles of devimistat and a CR after cycle 7. (Table and Figure) As of July 2021, he is in cycle 11, having had a 4-week treatment delay of cycle 5 due to CoVID 19 infection. ECOG improved from 3 to 0. Adverse events (AE): As of July30, 2021, no patient experienced a serious adverse event related to study drug. Four patients had grade 3 events at least possibly related: 2 neutropenia, 1 thrombocytopenia and 1 elevated bilirubin. 1 patient had a dose reduction for grade 2 alanine aminotransferase increase. Conclusions: Although our results are preliminary, the complete remission in this patient is promising in a disease where no viable treatment options exist in the relapsed, refractory BL. Enrollment to the BL cohort is ongoing. Figure 1 Figure 1. Disclosures Nikolaenko: Pfizer: Research Funding; Rafael Pharmaceuticals: Research Funding. Pardee: Celgene/BMS: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees; CBM Biopharma: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Research Funding; Rafael Pharmaceuticals: Research Funding. Abramson: Genentech: Consultancy; Kymera: Consultancy; Karyopharm: Consultancy; AbbVie: Consultancy; Seagen Inc.: Research Funding; Allogene Therapeutics: Consultancy; Astra-Zeneca: Consultancy; Incyte Corporation: Consultancy; BeiGene: Consultancy; Bluebird Bio: Consultancy; Genmab: Consultancy; EMD Serono: Consultancy; Bristol-Myers Squibb Company: Consultancy, Research Funding; C4 Therapeutics: Consultancy; Morphosys: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy. Horwitz: Vividion Therapeutics: Consultancy; Shoreline Biosciences, Inc.: Consultancy; Tubulis: Consultancy; Verastem: Research Funding; ONO Pharmaceuticals: Consultancy; Myeloid Therapeutics: Consultancy; SecuraBio: Consultancy, Research Funding; Trillium Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Millennium /Takeda: Consultancy, Research Funding; Kura Oncology: Consultancy; Janssen: Consultancy; Kyowa Hakko Kirin: Consultancy, Research Funding; Forty Seven, Inc.: Research Funding; Daiichi Sankyo: Research Funding; C4 Therapeutics: Consultancy; Celgene: Research Funding; Aileron: Research Funding; Affimed: Research Funding; Acrotech Biopharma: Consultancy; ADC Therapeutics: Consultancy, Research Funding. Matasar: GlaxoSmithKline: Honoraria, Research Funding; Teva: Consultancy; Janssen: Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Genentech, Inc.: Consultancy, Honoraria, Research Funding; Merck Sharp & Dohme: Current holder of individual stocks in a privately-held company; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; IGM Biosciences: Research Funding; Merck: Consultancy; Juno Therapeutics: Consultancy; TG Therapeutics: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding; Memorial Sloan Kettering Cancer Center: Current Employment; Pharmacyclics: Honoraria, Research Funding; Daiichi Sankyo: Consultancy; ImmunoVaccine Technologies: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Rocket Medical: Consultancy, Research Funding. Noy: Rafael Parhma: Research Funding; Morphosys: Consultancy; Targeted Oncology: Consultancy; Medscape: Consultancy; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Epizyme: Consultancy. OffLabel Disclosure: CPI-613 (devimistat) is a non-redox active analogue of lipoic acid, a required cofactor for two key mitochondrial enzymes of the TCA cycle, pyruvate dehydrogenase and alpha ketoglutarate dehydrogenase. Disruption of mitochondrial function by CPI-613 results in a shutdown of ATP and biosynthetic-intermediate production, leading to cancer cell death by apoptosis or necrosis

Background: Treosulfan has been increasingly used in reduced toxicity regimens, especially in older or frail patients. Different doses of treosulfan plus fludarabine have shown an advantage over reduced intensity regimens, confirmed by a randomized phase 3 trial utilizing treosulfan 30 g/m² (or FT10) in the majority of patients. However, data comparing fludarabine with higher doses of treosulfan (FT14) to fludarabine combined with myeloablative doses of busulfan are limited. Aims: We compared outcomes between treatment alternatives of similar conditioning intensity: FT14 (fludarabine 150 or 160 mg/m 2 and treosulfan 42g/m 2, or FT14) over FB4 (fludarabine 150 or 160 mg/m 2 and busulfan 12.8 mg/kg). Methods: We retrospectively studied consecutive patients from the European Society for Blood and Marrow Transplantation (EBMT) registry, meeting the following inclusion criteria: a) adults diagnosed with acute myeloid leukemia (AML), b) recipients of first allogeneic hematopoietic stem cell transplantation (HSCT) from a matched unrelated or sibling donor between 2010-2020, c) HSCT at first or second complete remission (CR), d) conditioning regimen with either FT14 or FB4. Patients with ex vivo manipulated grafts were excluded. A sub-group analysis was performed according to age ( Results: In total, 2703 patients were included in the analysis comprising 2025 (75%) transplanted with FB4, and 678 (25%) with FT14. In the sub-group of patients younger than 55 years (n=1676), FT14 recipients (n=236) had a significantly increased age (p Similar differences in patient characteristics were observed in patients aged ≥55 years (n=1027). FT14 recipients (n=442) had a significantly increased age (p Conclusion: With the limitations of a retrospective analysis, our large real-world multicenter study suggests that FB4 is associated with better outcomes compared to FT14 in younger patients with AML transplanted in first or second CR. The same was not true for older patients (≥55 years). It should also be noted that FT14 has been selected by treating physicians for higher risk HSCT, including patients who are older, have secondary disease, adverse cytogenetics, and unrelated donors. Therefore, further studies are needed to determine the optimal conditioning regimen for such patient populations. Figure 1 Figure 1. Disclosures Gavriilaki: Alexion, Omeros, Sanofi Corporation: Consultancy; Gilead Corporation: Honoraria; Pfizer Corporation: Research Funding. Labopin: Jazz Pharmaceuticals: Honoraria. Yakoub-Agha: Jazz Pharmaceuticals: Honoraria. Hilgendorf: Novartis: Honoraria; AbbVie: Honoraria; Jazz Pharmaceuticals: Honoraria, Other: Travel Support; Celgene: Other: Travel Support; SanofiGenzyme: Other: Travel Support. Kröger: Novartis: Research Funding; Riemser: Honoraria, Research Funding; Sanofi: Honoraria; Neovii: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Gilead/Kite: Honoraria; Celgene: Honoraria, Research Funding; AOP Pharma: Honoraria. Mielke: Gilead/KITE: Other: Travel support, Expert panel ; Novartis: Speakers Bureau; Immunicum: Other: Data safety monitoring board; Miltenyi: Other: Data safety monitoring board; DNA Prime SA: Speakers Bureau; Celgene/BMS: Speakers Bureau. Zuckerman: AbbVie: Honoraria; Orgenesis Inc.: Honoraria; Janssen: Honoraria; BioSight Ltd: Honoraria; Novartis: Honoraria; Gilead Sciences: Honoraria, Speakers Bureau; Cellect Biotechnology: Honoraria. Giebel: Janssen: Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau. Bazarbachi: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Hikma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees. Spyridonidis: Menarini: Current Employment. Mohty: Astellas: Honoraria; Amgen: Honoraria; Celgene: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Takeda: Honoraria; Jazz: Honoraria, Research Funding; Adaptive Biotechnologies: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Bristol Myers Squibb: Honoraria; Janssen: Honoraria, Research Funding; Gilead: Honoraria.

Background: Pediatric patients younger than two years of age with acute myeloid leukemia (AML) commonly receive a chemotherapy-based myeloablative conditioning regimen before allogeneic hematopoietic stem cell transplantation (HSCT). The optimal choice of cytotoxic agents is still controversial. Methods: A retrospective EBMT-registry based study was conducted to investigate the impact of different chemotherapy-based conditionings on the outcomes in young children. Children younger than two years of age receiving a first HSCT of bone marrow (BM), peripheral blood stem cells (PBSC) or cord blood (CB) from matched siblings (MSD) or unrelated donors (UD) in first complete remission (CR1) between 2000 and 2019 were included. Busulfan/Cyclophosphamide (BuCy) and BuCy/Melphalan (BuCyMel) were the most frequent combinations on which this analysis focused. The primary endpoint was leukemia-free survival (LFS). Multivariate analysis adjusting for differences between the conditioning regimens and risk factors influencing outcome was performed using the Cox's proportional hazards regression model. Results: 289 patients (56% male) transplanted at a median age of 1.2 years (IQR 0.9-1.6) after BuCy (164, 57%) or BuCyMel (125, 43%) were included. 184 (64%) patients received BM, 71 (24%) CB and 34 (12%) PBSC from UD (201, 70%) and MSD (88, 30%). In-vivo T-cell-depletion (TCD) was performed in 160 (58%, missing data 14) of the HSCTs with anti-thymocyte-globulin (ATG, 153) or alemtuzumab (7). Ex-vivo TCD was performed in 13 (5%, missing data 3) of the HSCTs. Graft-versus-host-disease (GvHD)-prophylaxis was Cyclosporin-A-based in 90% of the HSCTs. Median follow-up (FU) was 4.9 years (95% CI 3.9-5.5). After a median FU of 4 years, 4-y-LFS after BuCyMel (74.3%, 95% CI 65.1-81.4) was significantly better compared to BuCy (59.7%, 95% CI 51.2-67.2), hazard ratio (HR) 0.56 (95% CI 0.35-0.90, P=0.02). Overall survival (4-y-OS) after BuCyMel (77.2%, 95% CI 68.1-84.0) was significantly better compared to BuCy (66.6%, 95% CI 58.0-73.8), HR=0.58 (95% CI 0.35-0.97, P=0.04). No significant differences were found in the probability of relapse (4-y-RI (whole cohort) 26.2% (95% CI 21.0-31.7), HR of BuCyMel 0.59 (95% CI 0.34-1.02), P=0.06), non-relapse mortality (4-y-NRM (whole cohort) 7.8% (95% CI 5.0-11.4), HR of BuCyMel 0.49 (95% CI 0.19-1.24), P=0.13) and incidence of acute grade II-IV GvHD at day 100 (day-100-aGvHD II-IV (whole cohort) 36.8% (95% CI 31.2-42.5), HR of BuCyMel 0.59 (95% CI 0.35-1.01), P=0.06). Incidence of chronic GvHD (4-y-cGvHD (whole cohort)) was 9.8% (95%-CI 6.3-14.2). The donor type had no significant influence on the outcome. Conclusion: Bu-based conditionings of HSCT for infants with AML at high risk of relapse offer a high probability of cure. Conditioning with three alkylators (BuCyMel) resulted in better LFS and OS compared with two alkylators (BuCy) without significantly increasing the risk of both NRM and aGvHD. Future trials will evaluate the impact of the more recently introduced alkylator Treosulfan within the conditioning of HSCT in pediatric AML. Disclosures Peters: Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants. Locatelli: Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Miltenyi: Speakers Bureau; Medac: Speakers Bureau; Jazz Pharamceutical: Speakers Bureau; Takeda: Speakers Bureau. Moraleda: Pfizer: Other: Educational Grants, Research Funding; Sanofi: Other: Educational Grants, Research Funding; MSD: Other: Educational Grants, Research Funding; ROCHE: Consultancy, Honoraria, Other: Educational Grants, Research Funding; Takeda: Consultancy, Honoraria, Other: Educational Grants, Research Funding; Sandoz: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Educational Grants, Research Funding; Gilead: Consultancy, Honoraria, Other: Educational Grants, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Educational Grants, Research Funding; NovoNordisk: Other: Educational Grants, Research Funding; Janssen: Other: Educational Grants, Research Funding; Celgene: Other: Educational Grants, Research Funding; Amgen: Other: Educational Grants, Research Funding. Biffi: BlueBirdBio: Consultancy, Other: Advisory Board. Corbacioglu: Gentium/Jazz Pharmaceuticals: Consultancy, Honoraria.

Introduction Several studies reported that AML patients who remain in long-term remission after allogeneic transplant (allo-HCT) or autologous transplant (auto-HCT) have a shorter life expectancy, compared to the general population. However, little is known about the life expectancy of adult long-term survivors of AML who were treated with chemotherapy without HCT and, there have been no comparisons with survival among the general population. The current study reports on the life expectancy of AML patients who survived 3 years in complete remission (CR) after treatment without HCT, and compared this to the gender- and age-matched normal population. At 3 years in CR, the incidence of recurrence is exceedingly low (3%; Watts JM, Leuk Res 2014) minimizing the impact of relapse on the long-term survival. Methods Between 1984 and 2008, 3,012 patients, aged 15 years and older, with untreated AML entered 9 consecutive, phase II and III, ECOG-ACRIN trials (E3483, PC486, E3489, E1490, E3993, E4995, E3997, E3999, E1900). Patients in CR and relapse-free at 3 years are included in the analysis . Minimal cytogenetic information was available in the early protocols (E1490, E3483, PC486). A Kaplan-Meier plot was generated for the three groups, allo, auto and no HCT, censoring for patients alive at last contact. Univariate and multivariate cox proportional hazard regression models were generated, considering death as an event. For comparison of long-term outcomes, patients were grouped together by age and matched to a normative population mortality rate. Subjects were also grouped by gender and treatment allowing for separate analysis of these groups with the no HCT group as the main group of interest. The normative population comparator of expected deaths was derived using mortality rates from United State CDC life table data. The median year was derived by calculating the person-years for each calendar year that patients were followed. To calculate the expected deaths for each age group, person-years was calculated by tabulating the years lived in each age group for all subjects. Each year of follow-up for AML patient was counted as one person year, and the tabulated bin corresponded with their age at the time. Person-years was then multiplied by the matching mortality rate. Chi-square statistics were derived using expected and observed deaths and then summed for each gender and treatment. The final comparison was of mortality rates since diagnosis in the 3-year alive and relapse-free AML patient population vs the normative population. To produce plots of mortality from diagnosis, person-years was tabulated for every year since diagnosis by treatment. The person-years were tabulated into 2-year bins. The US life tables from the CDC were used to generate a population mortality rate from diagnosis. Results A total of 503 adult AML patients in 3 year CR with a mean age of 42.9 years (15-79) were identified; 78 underwent allo, 110 auto and 315 did not undergo transplantation. The patients in the groups differed in age (p Observed deaths and person-years were given by age group, gender, and treatment group and each were matched to a mortality rate from the United State CDC life table data that matched the median year of each treatment group. A chi square test for each group compared the derived expected to observed deaths. In every treatment group, patients had a shorter survival compared to their age- and gender- matched general population (p-value of 0.004 for the auto-HCT and Figure 1 indicates that AML patients who have survived relapse-free for at least 3 years continue to have higher mortality rates compared to the normative population for up to 14 years. This finding is not altered even if the very small number of patients who die from late relapse (>3 years from diagnosis) are removed from the analysis (data not shown) Conclusions Patients with AML who remain in CR at 3 years, do not have a normal life expectancy, even if they do not undergo HCT. The shorter life expectancy observed following an HCT may, at least in part, be related to the prior intensive therapy or other predisposing factors (e.g. CHIP) of the leukemia, rather than the transplant procedure itself. Figure 1 Figure 1. Disclosures Luger: Syros: Honoraria; Agios: Honoraria; Daiichi Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria; Brystol Myers Squibb: Honoraria; Acceleron: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Onconova: Research Funding; Celgene: Research Funding; Biosight: Research Funding; Hoffman LaRoche: Research Funding; Kura: Research Funding. Lazarus: Bristol Myer Squibb: Membership on an entity's Board of Directors or advisory committees. Douer: Amgen: Consultancy, Speakers Bureau; Servier: Consultancy, Speakers Bureau; Adaptive: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Speakers Bureau; Jazz: Consultancy. Tallman: Syros: Membership on an entity's Board of Directors or advisory committees; Kura: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Biosight: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Oncolyze: Membership on an entity's Board of Directors or advisory committees; KAHR: Membership on an entity's Board of Directors or advisory committees; Orsenix: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Rafael Pharmaceuticals: Research Funding; Glycomimetics: Research Funding; Biosight: Research Funding; Orsenix: Research Funding; Abbvie: Research Funding; NYU Grand Rounds: Honoraria; Mayo Clinic: Honoraria; UC DAVIS: Honoraria; Northwell Grand Rounds: Honoraria; NYU Grand Rounds: Honoraria; Danbury Hospital Tumor Board: Honoraria; Acute Leukemia Forum: Honoraria; Miami Leukemia Symposium: Honoraria; New Orleans Cancer Symposium: Honoraria; ASH: Honoraria; NCCN: Honoraria. Litzow: Pluristem: Research Funding; Biosight: Other: Data monitoring committee; AbbVie: Research Funding; Actinium: Research Funding; Astellas: Research Funding; Omeros: Other: Advisory Board; Jazz: Other: Advisory Board; Amgen: Research Funding.

Introduction Philadelphia positive (Ph+) acute lymphoblastic leukemia (ALL) presents with an aggressive clinical course and carries a high risk for relapse. The addition of tyrosine kinase inhibitors (TKI) has revolutionized the induction and maintenance treatment for this disease and has increased the patients achieving and maintaining complete remission. Allogeneic hematopoietic stem cell transplantation (HSCT) is the standard of care at this time for patients who achieve first complete remission (CR1); however, its impact on outcomes is debated. This systematic review and meta-analysis aimed to compare the outcomes of TKI maintenance therapy with or without HSCT in Ph+ ALL patients in CR1. Methods Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, a comprehensive literature search was conducted on PubMed, Cochrane, and Clinical trials.gov using MeSH terms and keywords for " Philadelphia chromosome ", "hematopoietic stem cell transplantation" and " protein kinase inhibitors " from date of inception to May 01, 2021. A total of 1691 records were discovered using database searching. All search results were imported into the Endnote X9.0 reference manager, and duplicates were removed. The primary and secondary screening was performed, and after excluding irrelevant and review articles, a total of 6 (3 retrospectives, 3 phase II randomized controlled trials) original articles were included reporting separate outcomes of TKI maintenance therapy (TKI cohort) and HSCT followed by TKI maintenance therapy (HSCT-TKI cohort) for Ph+ ALL in CR1. Quality evaluation was done using the NIH quality assessment tool. The inter-study variance was calculated using the Der Simonian-Laird Estimator. Proportions along with a 95% Confidence Interval (CI) were extracted to compute pooled analysis using the 'meta' package by Schwarzer et al. in the RevMan (version 5.4-1). RESULTS: A total of 413 patients from 6 studies were included for this systematic review and meta-analysis. Out of these, 222 (53.8%) had TKI maintenance after consolidation therapy and 191 (46.2%) patients had HSCT followed by TKI maintenance in CR1. The median age of the whole cohort was 49.3 (17-84) years, while the median age for HSCT-TKI patients was 47 (14-84) years. The proportion of males was 26.2% (n=90) in TKI group versus 37.5% (n=137) in the HSCT-TKI group, as reported by 5 studies. The median follow-up was 28 (0.6-149) months. Imatinib mesylate (first-generation TKI) was used in 55.6% (n=125) patients and Dasatinib (second-generation TKI) was given to 44.4% (n=100) patients. (Table 1) Overall survival (OS) was reported from 100% and 93.3% at 1 year to 49% and 33% at 5 years for TKI and HSCT-TKI cohorts, respectively. At median follow-up time of 4 (3-5) years, a trend towards poor OS was seen with TKI group as compared to HSCT-TKI group (OR 0.46, 95% CI 0.17-1.23, I 2=70%); however, the association was not statistically significant. Disease-free survival (DFS) was reported from 49.3% and 71.3% at 4 years to 38.1% and 50.5% at 5 years for TKI and HSCT-TKI cohorts, respectively. At a median follow-up time of 4 (3-5) years, the pooled analysis showed poor DFS for TKI as compared to HSCT-TKI cohort (OR 0.30, 95% CI 0.17-0.53, I 2=0%). Four studies (n=292) reported separate outcomes for relapse, it was 59.1% (87/147) for TKI versus 14.5% (n=21/145) for HSCT-TKI patients, and odds of developing relapse were higher among patients receiving TKI as compared to HSCT-TKI (OR=8.08, 95% CI=3.81-17.14, I 2=0%). Conclusion: Hematopoietic stem cell transplant in Philadelphia positive acute lymphoblastic leukemia in first complete remission followed by tyrosine kinase inhibitor maintenance therapy confers disease-free and overall survival benefit compared to tyrosine kinase inhibitors maintenance alone. Our findings confirm HSCT as a standard of care in Ph+ ALL in CR1 followed by TKI maintenance and the need for a prospective randomized clinical trial to validate these findings. Figure 1 Figure 1. Disclosures Lin: AbbVie, Aptevo Therapeutics, Astellas Pharma, Bio-Path Holdings, Celgene, Celyad, Genentech-Roche, Gilead Sciences, Incyte, Jazz Pharmaceuticals, Novartis, Ono Pharmaceutical, Pfizer, Prescient Therapeutics, Seattle Genetics, Tolero, Trovagene: Research Funding. Abhyankar: Incyte/Therakos: Consultancy, Research Funding, Speakers Bureau. McGuirk: Astelllas Pharma: Research Funding; Fresenius Biotech: Research Funding; EcoR1 Capital: Consultancy; Novartis: Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Allovir: Consultancy, Honoraria, Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Pluristem Therapeutics: Research Funding; Bellicum Pharmaceuticals: Research Funding; Novartis: Research Funding; Gamida Cell: Research Funding.

Introduction Allogenic hematopoietic cell transplant (HCT) for acute myeloid leukemia (AML) is a curative option in patients with intermediate/high risk disease who achieve morphologic complete remission (CR) after induction chemotherapy. Patients in CR but with positive measurable residual disease (pMRD) prior to HCT had high relapse risk(RR) (67% vs 65%) and low 3 year overall survival (OS) (26% vs 23%),similar to those with active disease in a single institution study (Araki et.al; Volume 34, Feb 1,2016, JCO). However, this study included only patients who received myeloablative conditioning (MAC) and included both peripheral blood and marrow grafts. A single institution retrospective study showed that use of MAC compared to reduced intensity conditioning (RIC) improved 3 year RR(19% v 67%; P < .001) and OS( 61% v 43%; P = .02) in patients with pMRD/CR(determined by molecular analysis of limited gene mutational panel)(Hourigan et.al. Volume 38, April 20,2020, JCO). We analyzed a cohort of AML patients that underwent either MAC or RIC followed by peripheral blood stem cell grafts and post-transplant cyclophosphamide (PTCy) based GVHD prevention regimen at our institution to determine the effect of pMRD on transplant outcomes. Methods: To evaluate the impact of pMRD on transplant outcomes, we analyzed AML patients who underwent HCT at Levine Cancer Institute between June 2014 and April 2020 with MRD testing performed within 1 month prior to HCT. MRD testing was performed at University of Washington by using multiparametric flow cytometry (MPC). The overall sensitivity of the assay is conservatively estimated as 0.1%. In our institution, all patients received MAC (Bu/Flu) or RIC (Bu/Flu or Flu/Cy/TBI) regimens followed by peripheral blood stem cell grafts and identical PTCy-based GVHD prophylaxis regimens that included tacrolimus and mycophenolate. Patient and transplant related characteristics were presented via descriptive statistics. Corresponding P-values were determined using Fisher's exact test for categorical variables and nonparametric Mann-Whitney U test for continuous variables. Relapse-free survival (RFS) and OS were estimated using the Kaplan Meier method. All statistical tests were two sided, and a P-value < 0.05 was considered statistically significant. Results From June 2014 to April 2020, 105 patients with AML underwent HCT. Eighty-three patients with MRD results were included in the final analysis - 52 (63%) with negative MRD (nMRD)/CR, 16 (19%) with pMRD/ CR and 15 (18%) with active disease (no CR). Baseline characteristics were similar except for presence of significantly greater number of high risk patients, based on ASTCT disease classification in the active disease group compared to pMRD/CR and nMRD/CR cohorts( 87% vs 19% vs 0%, P =< 0.001). Median follow up for the entire cohort was 32.7 months. RFS was superior in patients with nMRD/ CR compared to pMRD/ CR or active disease (56.4% vs 19.4% vs 35%, P= 0.005). In addition, OS was superior in nMRD/ CR compared to pMRD/CR or active disease (56.7% vs 35.2% vs 40%, P= 0.014). The use of MAC compared to RIC did not improve RFS (0% vs 32%, P= 0.018) and OS (0% vs 44%, P= 0.071) in pMRD/CR cohort. The use of MAC or RIC did not significantly impact RFS (69% vs 52%, P=0.729) or OS (61% vs 53%, P=0.739) in nMRD/CR patients. Conclusion: Our study validates the previous data that prognosis of patients with pMRD/CR (determined by MPC) prior to HCT is not significantly better than those having active disease. The outcomes were poor regardless of conditioning regimen intensity and PTCy based GVHD prophylaxis used at our institution. These patients might benefit from additional chemotherapy or targeted treatments to achieve nMRD prior to HCT and/or maintenance therapy post HCT. Patients with nMRD/CR disease had similar outcomes with MAC or RIC. This finding suggests that less aggressive conditioning regimens incorporating PTCy could be considered in a subset of patients with nMRD/CR, thereby sparing them from complications associated with MAC. Prospective trials are needed to further study these findings. Figure 1 Figure 1. Disclosures Copelan: Amgen: Consultancy. Grunwald: Astellas: Consultancy; Karius: Consultancy; PER: Other; Gilead: Consultancy; Incyte: Consultancy, Research Funding; Amgen: Consultancy; PRIME: Other; Daiichi Sankyo: Consultancy; Bristol Myers Squibb: Consultancy; AbbVie: Consultancy; Trovagene: Consultancy; Stemline: Consultancy; Pfizer: Consultancy; Janssen: Research Funding; Blueprint Medicines: Consultancy; Sierra Oncology: Consultancy; Med Learning Group: Other; Cardinal Health: Consultancy; MDEdge: Other; Agios: Consultancy.

Introduction: Consolidation of first-line induction treatment in myeloma (MM) patients (pts) with 200 mg/m2 melphalan chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) was established as standard of care three decades ago. However, definite cure in myeloma patients remains exceptional due to residual disease escaping intensive treatment, and almost all patients will ultimately relapse at earlier or later time points following ASCT. Thus, improving efficacy of HDCT in MM remains an unresolved issue. Methods: We performed a phase-II randomized trial comparing standard 200 mg/m2 Melphalan (Mel) HDCT to experimental HDCT treatment with 200 mg/m2 bendamustine, a bifunctional alkylating agent, given at days -4 and -3, combined with 200 mg/m2 melphalan split on days -2 and -1 at 100 mg/m2 (BenMel) before ASCT in MM pts. Patients had up to four cycles of first-line induction treatment with bortezomib, lenalidomide and dexamethasone. After ASCT, pts received lenalidomide maintenance treatment for two years. The primary endpoint was to show a 15% improvement of the rate of complete remission (sCR+CR) after HDCT with BenMel compared to Mel alone. MRD assessment from the bone marrow was performed by multiparameter flow cytometry after hematological engraftment following HDCT/ASCT. MRD negativity was defined as clonal plasma cells below 10(-5). Results: We randomized 120 myeloma pts (60 patients in each arm), with high-risk genetic abnormalities present in 21.3% of the patients. The median age was 63 years (range 35-74). The sCR/CR rate after ASCT before initiation of lenalidomide maintenance treatment was better in the BenMel arm compared to Mel alone (70.0% vs 51.7%; p=.039). The post-ASCT remission rates in detail were sCR 40.0% vs 31.7% (p=.341); CR 30.0% vs 20.0% (p=.205); VGPR 16.7% vs 33.3% (p=.035); and PR 13.3% vs 15.0% (p=.793). MRD negativity assessed in the bone marrow by flow cytometry was observed in 26 (45.6%) of the BenMel treated pts compared to 22 (37.9%) of the Mel pts. Median time until neutrophil engraftment was 11 days after BenMel vs 12 days after Mel (p=.096), and median time until platelet engraftment was 13 days in both arms (p=0.367); all pts had full engraftment of both cell lineages. Prolonged hospitalization duration was seen in BenMel pts (median 19 vs 18 days; p=.006) due to the longer BenMel treatment administration. Fully reversible acute renal insufficiency occurred in three (5%) BenMel pts compared to none of the Mel pts (p=.250). No treatment-related mortality was seen in both groups. ICU admissions were necessary in 3 pts (5%) in the BenMel group (ARDS, septic shock, pulmonary failure), and 2 Mel treated pts (3.3%; due to pulmonary failure and decompensated cardiomyopathy). The PFS rates at 12 months were 95% in BenMel pts and 91% in Mel treated pts (p=.551). OS at 12 months was 96% for both groups (p=.262), and median PFS and OS were not reached in both groups. Conclusions: Our data confirm that high-dose bendamustine combined with melphalan HDCT before ASCT in MM patients is safe and well tolerated. In particular, bendamustine-associated renal toxicity was manageable and reversible in all patients, and hematopoietic engraftment was comparable to standard melphalan HDCT. HDCT with BenMel improves the sCR/CR rate compared to standard melphalan alone. Thus, BenMel HDCT before ASCT warrants further investigation aiming to improve the long-term survival rates of MM patients, eventually combined with new maintenance strategies in the post-transplant period. Figure 1 Disclosures No relevant conflicts of interest to declare.

The histone-lysine-N-methyltransferase 2A (KMT2A) gene (formerly known as mixed-lineage leukemia (MLL)) plays an essential role in regulating gene expression including homeobox (HOX) and MEIS1 genes. In 5-10% of AML cases, specific KMT2A gene perturbations can occur which result in an aggressive and poor prognostic group of blood cancers. The KMT2A complex also appears to play a central role in the epigenetic dysregulation in AMLs with co-mutations such as NPM1, IDH1/2, EZH2, and DNMT3A. Therefore, there is strong rationale for targeting these AML subsets which may be exquisitely sensitive to inhibition of the menin-KMT2A chromatin complex. KO-539 is a novel, once daily, oral investigational drug candidate targeting the menin-KMT2A protein-protein interaction. KOMET-001 (NCT04067336) is an ongoing Phase 1/2A open-label study evaluating KO-539 in adult patients (pts) with relapsed and/or refractory AML agnostic to oncogenic mutational type. The Phase 1 dose-escalation objectives are to assess safety and tolerability, characterize the pharmacokinetics (PK), and determine a recommended Phase 2 dose. The Phase 2A dose expansion portion will assess anti-leukemic activity, PK, safety and tolerability in select genetic subtypes of AML. Preclinically, the drug is shown to be highly protein bound (>99%) across animal species. Using physiologically-based PK (PBPK) modeling, the estimated human efficacious dose was estimated to be 600 mg po qd. As of data cutoff on August 10, 2020, 6 pts with relapsed and/or refractory AML have been enrolled in the trial. Dose escalation began with single pt cohorts at 50 mg po qd in 28 day cycles and has proceeded through to 200 mg dosing cohorts. An expansion of 3 pts at 200 mg was initiated to better characterize the PK and exposure of KO-539. To date, 3 enrolled pts have been studied for safety and have not experienced any dose-limiting toxicities (DLTs) within the 28 day DLT-assessment window. Grade 3 (G3) or higher drug related adverse events have included G3 tumor lysis syndrome (TLS) at 50 mg and a G3 embolic event at 100 mg. KO-539 has been well tolerated with no dose interruptions or discontinuations due to drug related adverse events. There were no treatment-related deaths, and two pts discontinued treatment due to disease progression. Peak drug concentrations were attained between 2-3 hours after daily oral dosing with an elimination half-life of greater than 24 hours. KO-539 has demonstrated evidence of biologic activity in pts in the first 3 dose levels treated to date. The 50 mg pt with a KMT2A-r and the 200 mg pt with a p53 mutation and PICALM-AF10 fusion exhibited evidence of tumor lysis syndrome and markedly decreased hydroxyurea requirements with blood count stabilization, respectively. A third pt (100 mg dose level) with SETD2 and RUNX1 co-mutations achieved a complete remission with confirmed negative MRD by flow cytometry after two cycles of therapy and continues on treatment. The biologic activity of KO-539 at lower doses may be explained by inhibition of the CYP3A4 enzyme by concomitantly administered azole antifungals. KO-539 is metabolized into at least two metabolites with comparable activity to KO-539; total drug concentrations (i.e., KO-539 plus active metabolites) exhibited a dose-dependent increase. Although KO-539 is a CYP3A4 substrate, preclinical data suggest both KO-539 and its metabolites act as inhibitors, potentially providing an advantage in overcoming drug resistance attributable to CYP3A4 metabolism by bone marrow stroma. The physiology of the bone marrow sinusoids also allows both unbound and protein-bound drug to reach the sites of leukemic involvement. The high level of protein binding may therefore provide an opportunity for organ-specific targeted action while possibly limiting off target effects. The potential advantage associated with the CYP3A4 inhibitory characteristics of KO-539 to overcome drug-resistance in the bone marrow stroma also continues to be investigated. In conclusion, the early biologic activity of KO-539 in relapsed AML is encouraging, and its unique PK characteristics may be advantageous for clinical benefit. In addition to the above, any updated safety, PK, and efficacy data will be presented at the time of the conference. Disclosures Wang: Abbvie: Consultancy; Jazz Pharmaceuticals: Consultancy; Bristol Meyers Squibb (Celgene): Consultancy; Genentech: Consultancy; Pfizer: Speakers Bureau; Stemline: Speakers Bureau; PTC Therapeutics: Consultancy; Macrogenics: Consultancy; Astellas: Consultancy. Altman:BioSight: Other: No payment but was reimbursed for travel , Research Funding; Kura Oncology: Other: Scientific Advisory Board - no payment accepted, Research Funding; Daiichi Sankyo: Other: Advisory Board - no payment but was reimbursed for travel; Bristol-Myers Squibb: Consultancy; Boehringer Ingelheim: Research Funding; Celgene: Research Funding; Kartos: Research Funding; Fujifilm: Research Funding; France Foundation: Consultancy; PrIME Oncology: Consultancy; Novartis: Consultancy; Theradex: Other: Advisory Board; Agios: Other: advisory board, Research Funding; Glycomimetics: Other: Data safety and monitoring committee; Janssen: Consultancy; ASH: Consultancy; Amphivena: Research Funding; Immune Pharmaceuticals: Consultancy; Syros: Consultancy; Amgen: Research Funding; ImmunoGen: Research Funding; Genentech: Research Funding; Aprea: Research Funding; AbbVie: Other: advisory board, Research Funding; Astellas: Other: Advisory Board, Speaker (no payment), Steering Committee (no payment), Research Funding; Cancer Expert Now: Consultancy; PeerView: Consultancy. Pettit:PharmaEssentia: Other: advisory board; Kura Oncology: Other: advisory board; CTI Biopharma: Other: advisory board. Walter:Kite: Consultancy; Race Oncology: Consultancy; Pfizer: Consultancy, Research Funding; Macrogenics: Research Funding; New Link Genetics: Consultancy; Selvita: Research Funding; Seattle Genetics: Research Funding; StemLine: Research Funding; Agios: Consultancy, Research Funding; Aptevo: Consultancy, Research Funding; Daiichi: Consultancy; Celgene: Consultancy, Research Funding; Boston Biomedical: Consultancy; BiVictriX: Consultancy; BioLineRx: Consultancy, Research Funding; Astellas: Consultancy; Jazz: Consultancy, Research Funding; ImmunoGen: Research Funding; Genentech: Consultancy; Arog: Research Funding; Argenx: Consultancy; Amphivena: Current equity holder in publicly-traded company; Amgen: Consultancy, Research Funding. Fenaux:Novartis: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. Burrows:Kura Oncology: Current Employment, Current equity holder in publicly-traded company. Tomkinson:Kura Oncology: Current Employment. Martell:Kura Oncology: Current Employment, Current equity holder in publicly-traded company. Fathi:Daiichi Sankyo: Consultancy; Amphivena: Consultancy, Honoraria; Astellas: Consultancy; Celgene: Consultancy, Research Funding; PTC Therapeutics: Consultancy; TrovaGene: Consultancy; Takeda: Consultancy; Kura: Consultancy; Pfizer: Consultancy; Seattle Genetics: Consultancy, Research Funding; Trillium: Consultancy; Agios: Consultancy, Research Funding; AbbVie: Consultancy; Novartis: Consultancy; Kite: Consultancy, Honoraria; NewLink Genetics: Consultancy, Honoraria; Amgen: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Blue Print Oncology: Consultancy; Boston Biomedical: Consultancy; Forty Seven: Consultancy; Jazz: Consultancy, Honoraria.

Allogeneic hematopoietic cell transplant (HCT) improves survival in patients with relapsed or high risk acute myeloid leukemia (AML). Complete remission (CR) is typically a pre-requisite for transplantation, though many do not achieve a formal CR. The traditional AML treatment starts with induction chemotherapy, followed by assessment of response to guide next steps. Response criteria definitions differ between that of the National Comprehensive Cancer Network (NCCN), utilized by the majority of clinicians, and the Center for International Blood and Marrow Research (CIBMTR) data registry utilized by transplant centers, making interpretation of the impact of HCT difficult. Definitions for morphologic complete remission (CR) are the same, however complete remission with incomplete hematologic recovery (CRi) differs and the CIBMTR does not recognize the morphologic leukemia-free state (MLFS), thus mis-identifying such patients and preventing clear treatment guidelines for this population. We conducted a retrospective study, identifying a cohort of 35 AML patients at our center who underwent allogeneic HCT while in MLFS, to evaluate characteristics in patient demographics, disease status, treatment(s), and outcomes. From our cohort, the median overall survival (OS) was 14 months, however 37% were alive and in remission with median follow-up of survivors of five years. Twenty three percent had progression of disease following transplant. Non-relapse mortality (NRM) was 35% with leading cause of death being infection. Our study reveals that transplant can induce long-term survival in patients with acute leukemia who are in MLFS at the start of induction, similar to data for patients with high risk disease in early relapse or in later remissions. Early transplantation while in MLFS and not waiting for full count recovery may protect patients from toxicities of further chemotherapeutic agents or prevent unnecessary delays that may allow for infections or other barriers to arise, and requires further study. Disclosures Leblanc: American Cancer Society, BMS, Duke University, NINR/NIH, Jazz Pharmaceuticals, Seattle Genetics: Research Funding; UpToDate: Patents & Royalties: Royalties; Agios, AbbVie, and Bristol Myers Squibb/Celgene: Speakers Bureau; AstraZeneca: Research Funding; AbbVie, Agios, Amgen, AstraZeneca, CareVive, BMS/Celgene, Daiichi-Sankyo, Flatiron, Helsinn, Heron, Otsuka, Medtronic, Pfizer, Seattle Genetics, Welvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Rizzieri:Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Honoraria, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Mustang: Membership on an entity's Board of Directors or advisory committees; Celltrion: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AROG: Membership on an entity's Board of Directors or advisory committees; abbvie: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Acrobiotech: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees.

Introduction: Racial disparities in pediatric acute myeloid leukemia (AML) outcomes have consistently demonstrated inferior event-free survival (EFS) and overall survival (OS) in minority populations with the worst outcomes in Black children. However, AML is a heterogenous disease classified by recurrent genetic aberrations, and these disparities have not been thoroughly investigated within specific cytogenetic groups. In addition, race-based response to individual chemotherapy agents in AML has not been explored. Here, we use data from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database to describe the effects of race on outcomes and response to gemtuzumab ozogamicin (GO) therapy in core binding factor (CBF) AML, a favorable risk AML subtype. Methods: CBF AML patient data was extracted from the online TARGET database. Race and ethnicity were self-reported. Estimates of 2-year OS and EFS were calculated using the Kaplan-Meier method and analyzed via log-rank statistic. Pearson's Chi-squared test and Fisher's exact test were used to analyze patient variables. Results: The OS in CBF AML differed significantly based on race/ethnicity at 87% (95% CI, 82-93%) for White non-Hispanic (WNH), 77% (95% CI, 67-89%) for Hispanic, and 71% (95% CI, 58-88%) for Black children (p=0.005). EFS was also significantly lower in Black (46%; 95% CI, 32-66%) compared to non-Black children (66%; 95% CI, 60-73%)(p=0.023). When assessed by CBF AML subtype, EFS and OS in t(8;21) AML varied significantly based on ethnicity at 50% (95% CI, 34-75%) and 67% (95% CI, 50-88%) in Black patients, 63% (95% CI, 49-82%) and 69% (95% CI, 55-87%) in Hispanic patients, and 82% (95% CI, 72-92%)(p=0.01) and 90% (95% CI, 93-98%)(p=0.006) in WNH patients. In inv(16) AML, Hispanic patients experienced the highest EFS (71%; 95% CI, 55-92%) followed by WNH (54%; 95% CI, 43-66%) and Black (36%; 95% CI, 17-79%) patients though this did not reach statistical significance (p=0.12). There was no impact of race/ethnicity on OS in inv(16) AML. The use of GO did not alter OS in any subset of CBF AML. EFS appeared to be slightly improved but was not statistically significant. However, Black children with any type of CBF AML had preferential improvement with GO with significantly higher EFS (69% v. 26%, p=0.03) and a trend toward improved OS (81% v. 63%, p=0.19) with GO therapy. These improvements were primarily driven by a significant increase in EFS in inv(16) AML when treated with GO (80% v. 50%, p=0.01) and a similar but non-significant improvement in OS in this group. In Hispanic children there was a trend toward inferior EFS with the use of GO (63% v. 73%, p=0.37) in CBF AML, particularly in t(8;21) patients with a 1-year EFS of 56% (95% CI, 37-87%) compared to 81% (95% CI, 64-100%)(p=0.23). WNH children were more likely to achieve Complete Remission (CR) after course 1 (OR 2.36, 95% CI 1.09-5.10, p=0.03), and Black children were more likely to have persistent Minimal Residual Disease (MRD) after course 2 (OR 9.64, 95% CI 2.48-37.43, p Conclusion: Children with CBF AML represent a favorable cytogenetic risk group with an EFS of 70% and OS of 85%. However, the impact of race/ethnicity on outcome is significant with Black children experiencing the lowest EFS and OS at 46% and 71%, respectively, with this trend persisting across cytogenetic subtypes. Black children were also more likely to remain MRD positive after Induction II and less likely than WNH patients to achieve CR. However, while the addition of GO to standard therapy did not improve outcomes in CBF AML overall, Black children selectively benefited from GO therapy. Black children trended toward improved EFS and OS with GO with the most pronounced effect on EFS in inv(16) which was improved from 50% to 80% at 1 year. These results demonstrate that Black children with CBF AML are disproportionately at risk for poor outcomes compared to other ethnicities, but these risks may be mitigated by the use of GO which increase EFS and OS primarily in this group. Conversely, Hispanic patients trended toward worse EFS with GO, particularly in t(8;21) AML, possibly due to treatment-related toxicity. As CD33 expression and certain ABCB1 SNPs are known to predict response to GO therapy, our ongoing work investigates racial differences in these variables as a potential explanation for the differing responses to GO. Disclosures Rau: Jazz Pharmaceuticals, Inc.: Consultancy, Other: Travel Fees.

Background: Therapy options for pts with HR-MDS or AML who are not candidates for intensive chemotherapy (IC) or hematopoietic stem cell transplantation (HSCT) are limited, and clinical outcomes are poor. Novel, effective and tolerable therapies are urgently needed. TIM-3 is an inhibitory receptor that regulates both adaptive and innate immune responses. It is expressed on immune cells and on leukemic stem cells (LSCs) and blasts, but not on normal hematopoietic stem cells, making it a promising target in MDS and AML. Sabatolimab is a high-affinity, humanized, anti-TIM-3 IgG4 (S228P) antibody that simultaneously targets TIM-3 on immune and myeloid cells; this may restore immune function while also directly targeting LSCs and blasts. In preclinical studies, sabatolimab enhanced immune cell-mediated killing of AML cells in vitro. In early results from a ph 1b study (NCT03066648), sabatolimab + hypomethylating agents (HMAs; decitabine [Dec] or azacitidine [Aza]) demonstrated encouraging overall response rates in pts with high-/very high-risk MDS (+ Dec, 61%; + Aza, 57%) and newly diagnosed AML (+ Dec, 47%; + Aza, 29%), and a favorable safety profile. Study Design and Methods: The STIMULUS clinical trial program currently includes 3 trials evaluating the efficacy and safety of sabatolimab combination therapy in pts with HR-MDS or AML who are ineligible for IC or HSCT: STIMULUS-MDS1 (NCT03946670; ph 2) in pts with HR-MDS, STIMULUS-MDS2 (NCT04266301; ph 3) in pts with HR-MDS or chronic myelomonocytic leukemia-2 (CMML-2), and STIMULUS-AML1 (NCT04150029; ph 2) in pts with AML. STIMULUS-MDS1 is a randomized, double-blind, placebo-controlled ph 2 study evaluating the addition of sabatolimab to HMA in pts with HR-MDS. The 2 primary endpoints are complete remission (CR) rate and/or progression-free survival. Secondary endpoints include overall survival (OS), event-free survival (EFS), leukemia-free survival, duration of CR, transfusion independence, safety, pharmacokinetics (PK), and immunogenicity. Approximately 120 pts will be randomized 1:1 to receive sabatolimab 400 mg or placebo IV Q2W (D8 and D22 of each 28-d cycle), + Dec 20 mg/m2 IV on D1-D5 or Aza 75 mg/m2 IV/SC on D1-D7, or D1-D5 + D8 and D9, of each 28-d cycle. STIMULUS-MDS2 is a randomized, double-blind, placebo-controlled ph 3 study of sabatolimab in combination with Aza in pts with HR-MDS or CMML-2; the primary endpoint is OS. Secondary endpoints include measures related to pt quality of life, such as time to definitive deterioration of fatigue, improvement of fatigue, transfusion-free intervals, and physical/emotional functioning, as well as additional efficacy and safety parameters. Approximately 500 pts will be randomized 1:1 to sabatolimab 800 mg or placebo IV Q4W at D8 of each 28-d cycle + Aza using the same Aza dosing schedule as in STIMULUS-MDS1. Eligible pts for STIMULUS-MDS1 or -MDS2 are treatment-naïve adults with HR-MDS (Revised International Prognostic Scoring System [IPSS-R] intermediate-/high-/very high-risk MDS). Pts with intermediate-risk MDS enrolling in STIMULUS-MDS1 are also required to have ≥5% bone marrow blasts at baseline. Pts with CMML-2 are eligible for STIMULUS-MDS2 only. STIMULUS-AML1 is a single-arm ph 2 study evaluating the safety and efficacy of sabatolimab in combination with Aza and venetoclax in pts with AML who are not candidates for IC or HSCT. Primary endpoints are incidence of dose-limiting toxicities (safety run-in) and CR rate. Secondary endpoints include safety and tolerability, CR/CRi rate, measurable residual disease-negative rate, durability of CR, relapse-free survival, EFS, OS, PK, transfusion independence, and immunogenicity. Eligible pts for STIMULUS-AML1 are adults with newly diagnosed AML who are not candidates for IC or HSCT, based on comorbidities (including renal and hepatic impairments, cardiac and pulmonary comorbidities), age (≥75 years old), or Eastern Cooperative Oncology Group performance status of 2 or 3. STIMULUS-AML1 will enroll approximately 86 pts. Part 1 consists of a safety run-in (≈18 pts) across 2 escalating sabatolimab dose levels (400/800 mg IV Q4W on D8 of each 28-d cycle) in combination with Aza (75 mg/m2 IV/SC on D1-D7, or D1-D5 + D8 and D9) and venetoclax 400 mg PO QD. If this triple combination is assessed to be safe, part 2 (expansion) will open and enroll approximately 68 additional pts who will receive sabatolimab 800 mg Q4W in combination with Aza and venetoclax. Disclosures Zeidan: Incyte: Consultancy, Honoraria, Research Funding; Trovagene: Consultancy, Honoraria, Research Funding; Astex: Research Funding; Celgene / BMS: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; CCITLA: Other; Taiho: Consultancy, Honoraria; Cardinal Health: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Acceleron: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria; MedImmune/Astrazeneca: Research Funding; Leukemia and Lymphoma Society: Other; Epizyme: Consultancy, Honoraria; Ionis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Cardiff Oncology: Consultancy, Honoraria, Other; BeyondSpring: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Aprea: Research Funding; ADC Therapeutics: Research Funding. Giagounidis:AMGEN: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Kim:SL VaxiGen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AML Global Portal: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Hanmi: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Yuhan: Consultancy, Honoraria; Chugai: Consultancy, Honoraria; BL&H: Research Funding; Sanofi Genzyme: Honoraria; Abbvie: Honoraria. Miyazaki:Novartis Pharma KK: Honoraria; NIPPON SHINYAKU CO.,LTD.: Honoraria; Astellas Pharma Inc.: Honoraria; Otsuka Pharmaceutical: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Kyowa Kirin Co., Ltd.: Honoraria; Celgene: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria. Platzbecker:Amgen: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Geron: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Sekeres:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda/Millenium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Malek:Novartis: Current Employment. Scott:Novartis: Current Employment. Niolat:Novartis: Current Employment. Peyrard:Novartis: Current Employment. Ma:Novartis: Current Employment. Kiertsman:Novartis: Current Employment. Stegert:Novartis AG: Current Employment, Current equity holder in publicly-traded company. Hertle:Novartis Pharma AG: Current Employment, Current equity holder in publicly-traded company. Fenaux:BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. Santini:Takeda: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria; Novartis: Consultancy, Honoraria; Acceleron: Consultancy; Takeda: Consultancy, Honoraria; Menarini: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria.

Introduction: Patients with Acute Myeloid Leukemia (AML) and positive Minimal Residual Disease (MRD) prior to allogeneic transplant are currently considered to be a group at high risk of relapse. Multiparameter flow cytometry is a standard technique to measure MRD, and generally we use a 0.1% threshold for positivity. The clinical significance of those patients with an MRD levels >0% but Material and methods: We performed a single-center retrospective analysis of 88 patients transplanted between 2012 and 2020. All patients achieved complete remission (CR) with or without hemoperipheral recovery prior to allogeneic transplant. We have divided our cohort into three groups according to MRD state by flow cytometry: Group 1 patients with negative MRD, Group 2 patients with MRD level >0% but Results: The baseline characteristics of our cohort are reflected in Table 1. We did not find statistical significant differences except for the response to induction. The median follow-up of the entire cohort was 13.5 months (range 6-43.5). The 4-year RFS (4y-RFS) was 47% and the 4-year OS (4y-OS) 50%. The 4y-RFS was 52.5% in Group 1 vs 59% in Group 2 vs 30% in Group 3. The 4y-OS was 60% in Group 1 vs 60% in Group 2 vs 31% in Group 3 (Image 1). The Hazard Ratio (HR) for RFS and OS comparing Group 1 vs Group 2 was 0.9 [95% CI ((0.3-2.5)] and 1.1 [95% CI (0.4-3)] respectively. The HR for the RFS and OS comparing Group 1 vs 3 was 1.2 [95% CI (0.9-1.7)] and 1.2 [95% CI (0.8-1.6)]. We have stratified patients according to the European LeukemiaNet risk classification. In Group 1, the 4y-RFS was 79% in patients with Favorable Risk (FR) vs 55% in those with Intermediate Risk (IR) and 53% in patients with Adverse Risk (AR) [HR 1.2, 95% CI (0.6-2.3)] and the 4y-OS was 79% vs 54% vs 53% respectively [HR 1.3, 95% CI (0.6-2.5)]. In Group 2, the 4y-RFS was 100% in those with FR vs 83% in IR vs 33% in AR [HR 3.9, 95% CI (0.4-30)] and the 4y-OS was 100% vs 82% vs 36% respectively [HR 4, 95% CI (0.5-32%)]. In Group 3, the 4y-RFS in patients with FR was 82% vs 0% in IR vs 0% in AR [HR 2.1, 95% CI (1.1-4.1)] and the 4y-OS was 82% vs 0% vs 0% respectively [HR 1.6, 95% CI (0.8-3.3)] (Image 2). Conclusions: In our cohort, positive MRD >0.1% prior to transplant identified a group with worse RFS and OS compared to those with negative MRD or positive MRD level >0% but 0.1% is especially relevant in the IR and AR groups of the European LeukemiaNet risk classification. In the AR subgroup even any detectable level of positive MRD could identify patients with unfavorable post-transplant OS and RFS outcomes. We must establish post-transplant strategies in these patients to improve survival. Disclosures Garcia-Gutiérrez: Pfizer: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding; Incyte: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding; Bristol-Myers Squibb: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding; Novartis: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding.

Introduction. In the absence of an HLA-identical sibling or a matched unrelated donor, whether to prefer a Haploidentical (Haplo) or a one antigen mismatched unrelated donor (MMUD) for allogeneic hematopoietic cell transplantation (HCT) remains an unanswered question. Implementation of graft-versus-host disease (GVHD) prophylaxis with post-transplant cyclophosphamide (PTCY) was initially pioneered in the Haplo and then also extended to MMUD setting, resulting in low rates of GVHD. Methods. This was a retrospective study from the EBMT registry. Included were adults undergoing either Haplo- or MMUD-HCT for acute myeloid leukemia during the period 2010-2018 and who were in first or second complete remission at allo-HCT. Only patients receiving unmanipulated grafts with PTCY as GVHD prophylaxis were included. Ex vivo and in vivo T-cell depletion were exclusion criteria. Comparisons were made among three groups: MMUD-HCT with peripheral blood as stem cell source (PBSC; n=124); Haplo-HCT with bone marrow (Haplo-BM; n=560); Haplo-HCT with PBSC (Haplo-PB; n=769). Results. Patients in Haplo-PB were older (median age of 55 years versus (vs) 52 and 51 years in MMUD-HCT and Haplo-BM, respectively; p Conclusion. According to our results, use of MMUD is associated to significantly higher LFS. However, our results highlight that both MMUD- and Haplo-HCT are valid options for transplant candidates, with no differences in GRFS. On the other hand, when choosing Haplo over MMUD, one should consider BM as stem cell source in order to better prevent GVHD. Further strategies to better prevent NRM are needed, particularly in Haplo-HCT. Disclosures Labopin: Jazz Pharmaceuticals: Honoraria. Blaise:Jazz Pharmaceuticals: Honoraria. Sica:F. Hoffmann-La Roche Ltd: Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland., Research Funding. Pane:Amgen: Consultancy, Other: Travel Expenses, Speakers Bureau; AbbVie: Consultancy, Other: Travel Expenses, Speakers Bureau; Daiichi Sankyo: Consultancy, Other: Travel Expenses; Jazz Pharmaceuticals: Consultancy, Other: travel expenses, Speakers Bureau; Novartis pharma SAS: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Other: Travel Expenses; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mohty:BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Stemline: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau.

In spite of CR rates of 75-80% currently achieved with anthracycline-cytarabine regimens in younger patients with favorable and intermediate-risk AML, relapse remains a major issue. The French AML intergroup launched the BIG-1 trial in 2015 in order to test different strategies aiming at reducing relapse rate and improving survival. All patients with previously untreated non-APL and non-CBF AML aged 18-60 years are eligible for trial participation which is still ongoing. The trial design includes several randomizations (R): Idarubicin vs daunorubicin for induction (R1), HDAC vs IDAC for consolidation (R2), post-transplant GVHD prophylaxis modalities (R3). R4 consists of nested randomized phase 2-3 trials testing the addition of new drugs to the IDAC or HDAC backbones during the consolidation phase. The protocol was designed to allow the sequential evaluation of several new agents over the trial period. Vosaroxin (VOS) has shown antileukemic activity (Advani, Clin Cancer Res 2010). The combination of VOS and IDAC showed higher CR rate and a non-significant OS benefit as compared to a placebo-IDAC arm in a large phase 3 trial in patients with refractory/relapsed AML (Ravandi Lancet Oncol 2015). We hypothesized that the addition of VOS to IDAC would improve LFS as compared to IDAC alone when given during the consolidation phase. Methods. Eligibility criteria in the BIG-1 trial include: previously untreated AML according to WHO 2016 classification (AML secondary to an untreated myelodysplastic syndrome allowed), age 18-60, ECOG PS 0-2, no cardiac contra-indication to anthracyclines. Patients with APL and patients with CBF-AML are excluded. Eligibility criteria for R4 randomization were: Patients in first CR/CRp/CRi following 1 or 2 courses of induction chemotherapy according to the BIG-1 protocol; ELN2010 favorable- and intermediate-risk groups; ECOG PS ≤ 3; Absence of severe uncontrolled infection. Patients were scheduled to receive Cytarabine: 1.5 gr/m² twice daily on D1, 3, 5 with or without Vosaroxin: 70 mg/m² on D1 and D4 per cycle for a maximum of three cycles at 4-6 weeks intervals. Patients scheduled for allo-SCT or those who had reached CR after 2 induction cycles were to receive only 2 cycles of VOS-IDAC/IDAC. R4-VOS sub-trial was designed to detect an increase of the 18-month LFS from 55% to 75% using a two-step phase 2-3 study. With type I and II errors set at 20% and using a one-sided test, 70 patients had to be randomized. If the predefined statistical objectives were met, study would resume recruiting 130 additional patients in the phase 3 part for a total of 200 patients. Results. 70 patients (35 in each arm), median age 47, ELN 2010 favorable and intermediate risk groups, have been included. 94% had de novo AML with NPM1 mutations in 46% and FLT3-ITD in 20%. As shown in the Table, patients and disease characteristics were not different between the 2 arms except for slightly more patients in CRi in the VOS-IDAC arm. Patients received a median of 4 chemotherapy cycle (including induction; range 3-4) without difference between the treatment arms. 13 patients (18.5%) received an alloSCT (VOS-IDAC: 5, IDAC: 8). Time between cycle 1 and cycle 2 was significantly longer in the VOS-IDAC arm (p= 0.017). Hematologic toxicity was higher in the VOS-IDAC group with a significantly longer neutropenia duration after each cycle, a greater number of RBC and Platelet transfusions, a significantly greater number of days with antibiotics and antifungal therapies and days with fever (during cycle 1). There were also significantly more cutaneous toxicity, mild nausea/vomiting and diarrhea in the VOS-IDAC arm. With a median follow-up of 19 months, 14 and 15 patients relapse in the VOS-IDAC vs IDAC arms respectively. The study primary endpoint has not been reached and LFS was not significantly higher in the VOS-IDAC arm (18-month LFS of 51% vs 46% for VOS-IDAC vs IDAC respectively; see Figure) even after accounting for allo-SCT as a time-dependent variable (p-value=.49). The 2-year CIR was 51% vs 46% (p=NS) and 2-year OS was 88% vs 68% (p=NS). Conclusion, the study's primary endpoint has not been met and results fail to show a significant improvement of 18-month LFS with the addition of VOS to IDAC consolidation of favorable/intermediate-risk AML in first CR. The phase 3 part of the trial will not open. The BIG-1 trial is still ongoing and uses the same design to tests addition of other drugs to the IDAC/HDAC consolidation backbone. Disclosures Guieze: abbvie: Honoraria, Other: advisory board, travel funds; janssen cilag: Honoraria, Other: advisory board, travel funds; roche: Other: travle funds; gilead: Honoraria, Other: travel funds; astrazanecka: Honoraria, Other: advisory board. Dombret:Pfizer: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Nova: Consultancy, Research Funding; Celgene: Consultancy; Jazz Pharma: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Sunesis: Consultancy; Servier: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Menarini: Consultancy; Janssen: Consultancy; Cellectis: Consultancy; Shire-Baxalta: Consultancy; Immunogen: Consultancy; Otsuka: Consultancy; Abbvie: Consultancy. Hunault:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Diachi: Membership on an entity's Board of Directors or advisory committees; Jansen: Honoraria; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees.

BACKGROUND: The progress in the understanding of pathophysiology of AML has allowed the identification of genetic and immune abnormalities with prognostic impact on outcome and suitable as therapeutic targets. The genetic abnormalities are essential for risk allocation and risk-adapted treatment included the indication of hematopoietic cell transplantation. In the last decade, several studies have shown that persistence of measurable residual disease (MRD) after chemotherapy increases relapse incidence and the probability of leukemia recurrence and survival. Therefore, MRD has been progressively incorporated in prognosis estimation. In the last 25 years the CETLAM cooperative group has promoted 4 consecutive trials for AML patients fit for intensive chemotherapy and eventually HCT. Post-remission treatment was based on genetics of the disease and more recently on MRD. The aim of this study has been to investigate if the survival of patients has improved and, if so, to identify the factors that have influenced on the better outcome. METHODS: We included all patients with primary AML up to the age of 60 years enrolled in 4 consecutive Spanish CETLAM group trials. In brief, induction chemotherapy included idarubicin, cytarabine and etoposide in AML-94, AML-99 and AML-03 protocols and without etoposide in the AML-12. G-CSF priming was allowed in the two more recent trials. Post remission therapy included 1 to 3 consolidations including intermediate or high dose cytarabine. Hematopoietic transplantation indication was based on availability of an HLA-compatible donor, genetic findings and more recently MRD. Follow-up was extended to June 2020. The survival and relapse incidence analyses were censored at 5 years. Informed consent was obtained in all cases and the institutional review boards approved the protocols. RESULTS: Between 1994 and 2019, 1755 primary AML patients between 18 and 60 years-old fulfilled the inclusion criteria. The main characteristics of patients appear in table 1. Median age of the whole group was 46 years old. Overall survival (OS) in the whole group was 45% at 5 years, being significantly better in AML-03 and AML-12 than in AML-94 and AML-99 (image 1). Event free survival (EFS) in the whole group was 37% at 5 years, with also significant differences between trials. Also, the cumulative incidence of relapse (CIR) was 39% in the whole group with less relapses in the two more recent trials (image 2). To understand these findings, we analyzed first the CR rate over time that was higher in the AML-03 and AML-12 protocols (table 2). The results were different depending on genetics of AML with highest CR rate in patients with CBF AML and in those with intermediate-risk cytogenetics and favorable molecular findings; in contrast, patients with adverse cytogenetics had the lowest CR rate mainly because frequent refractoriness to therapy. According to outcomes in each MRC cytogenetic group 5y-OS was: 69±3% (63-76) in favorable group, 46±2% (43-49) in intermediate and 21±3% (16-27) in adverse group (p Referent to feasibility of allogeneic HCT, there was an increased access to the procedure over the years. A higher proportion of patients allografted in AML-03 and AML-12, 32% and 41% of patients in CR, respectively, compared to 16% in AML-94 and 19% in AML-99. A shortening of the interval between CR and transplantation has been observed in recent years; 3.9 months (mo) in AML-94, 2.7 mo in AML-99, 2.9 mo in AML-03 and 2.2 mo in AML-12. CONCLUSIONS: In adults with primary AML and age up to 60 years-old have improved over the last 25 years. During this period, the CETLAM group has refined the biological characterization of AML patients and tailored the post-remission therapy based on genetic markers with prognostic impact. The increased feasibility of allogeneic HCT may also justify the better results in more recent trials. Even though, there is substantial room for improvement, particularly in patients with AML and adverse genetic features. Disclosures Salamero: Pfizer: Consultancy; Jazz Pharmaceuticals: Consultancy, Honoraria; Daichii Sankyo: Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Moraleda:Takeda: Consultancy, Other: Travel Expenses; Sandoz: Consultancy, Other: Travel Expenses; Novartis: Consultancy, Other: Travel Expenses; Gilead: Consultancy, Other: Travel Expenses; Jazz Pharmaceuticals: Consultancy, Research Funding. Tormo:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; MSD: Honoraria; Daiichi Sankyo: Honoraria; Servier: Honoraria; Roche: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Ribera:Pfizer, Amgen: Research Funding; Pfizer, Amgen, Ariad, Novartis: Consultancy, Speakers Bureau. Sureda Balari:Roche: Honoraria; Incyte: Consultancy; Janssen: Consultancy, Honoraria; Gilead/Kite: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Merck Sharpe and Dohme: Consultancy, Honoraria, Speakers Bureau; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; BMS: Speakers Bureau; Celgene: Consultancy, Honoraria. Sierra:Jazz Pharmaceuticals: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead-Kite: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Introduction Outcome of KMT2A-rearranged (KMT2A-r) pediatric AML (pAML) is in general poor with a 5-year probability of event-free survival (5y-pEFS) and overall survival (5y-pOS) of 44% and 56%, respectively (Balgobind et al., 2009). However, over the past decades, the heterogeneity of KMT2A-r pAML has emerged, showing differences in outcome between subgroups based on translocation partners. The predictive value of MRD in KMT2A-r pAML is undefined. This retrospective study aimed to confirm the outcome of pediatric KMT2A subgroups (Balgobind et al., 2009) in a more recent era and to study the significance of MRD status during and after induction. Methods Outcome and MRD data of 1257 KMT2A-rde novo pAML patients from 15 AML groups affiliated with the I-BFM-AML study group, diagnosed between 2005 and 2016 were retrospectively collected. Patients were assigned to KMT2A subgroups, or to the KMT2A-other group in case of unknown translocation partner. Flow cytometry MRD levels Results The 1257 patients were assigned to 13 KMT2A subgroups, or the KMT2A-other group. Two novel subgroups were identified: t(X;11)(q24;q23) (n=21, 2%) and t(1;11)(p32;q23) (n=12, 1%). The median age was 2.5 years (range, 0-18.9). The median WBC was 21.4 x 109/L (range, 0.2-727). Overall complete remission rate was 91%. The 5y-pEFS was 46% [SE, 2%] and the 5y-pOS was 62% [SE, 2%]. Differences across subgroups in 5y-pEFS (Figure 1) ranged from 24% [SE, 5%] to 76% [SE, 9%], and in 5y-pOS from 25% [SE, 13%] to 92% [SE, 8%] (both p The subgroups t(10;11)(p12;q23) (HR 1.7, p100 x 10^9/L (HR 1.3, p=.006), and age >10y (HR 1.3, p=.005) were revealed as independent predictors of poor EFS. These factors also predicted OS. MRD data after induction course one were available for n=635 (MRD-positivity (range, 0.1-94) n=126, 20%) and after course two for n=527 (MRD-positivity (range, 0.1-88) n=51, 10%). In the four KMT2A poor-risk subgroups, MRD-positivity was not significantly more common after induction course one (p=.0232) or two (p=.066), compared with the other subgroups. MRD-positivity was associated with inferior 5y-pDFS after both induction course one (36% [SE, 4%] vs 48% [SE, 2%]; p=.002) and course two (28% [SE, 6%] vs 49% [SE, 2%]; p10y (HR 1.5, p=.002) were revealed as independent predictors of poor DFS. Within the group of patients with MRD-negativity after induction course two, the subgroups t(10;11)(p12;q23) and t(10;11)(p11.2;q23) were independent predictors of poor EFS (5y-pEFS 35%, HR 1.7, p=.003 and 5y-pEFS 18%, HR 2.7, p=.004, respectively). Conclusion Outcome for KMT2A-r pAML patients has improved slightly, but similar subgroups were identified as poor risk (Balgobind et al., 2009), including t(10;11)(p12;q23), t(10;11)(p11.2;q23) and t(6;11)(q27;q23). In our study, t(4;11)(q21;q23) was poor risk as well. These subgroups should be considered for high-risk pAML therapy protocols. The favorable risk of t(1;11)(q21;q23) could not be confirmed in our cohort. MRD status is highly predictive of outcome within KMT2A subgroups. In MRD-negative patients after induction course two, both t(10;11) KMT2A subgroups were associated with poor outcome. Disclosures Guest: Syndax Pharmaceuticals: Consultancy. Locatelli:Medac: Speakers Bureau; Miltenyi: Speakers Bureau; Bellicum Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceeutical: Speakers Bureau. Rubnitz:AbbVie Inc.: Research Funding. Kaspers:Helsinn Healthcare: Ended employment in the past 24 months; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Janssen R&D: Ended employment in the past 24 months; AbbVie: Ended employment in the past 24 months.

Background: Many studies have evaluated the impact of cytomegalovirus (CMV) reactivation after allogeneic hematopoietic stem cell transplantation (allo-HSCT) showing a significant association with reduced risk of relapse while other studies failed to show the same results. On the other hand, other frequent viral infections or reactivations like Epstein-Barr virus (EBV), Human Herpesvirus 6 (HHV6) and BK virus (BK-V) have not been evaluated in the same context and/or together with CMV. The aim of this study is to evaluate the impact of CMV, EBV, HHV6 and BK-V reactivation in acute leukemia (AL) patients receiving allo-HSCT in complete remission (CR) and evaluate their impact alone or associated on disease relapse. Patients and methods: We evaluated 158 consecutive AL patients who received allo-HSCT at our center between January 2008 and June 2015; 95 (60%) were males, median age was 46 years (range: 18-67), 101 (64%) had acute myeloid leukemia (AML) and 57 (36%) had acute lymphoblastic leukemia (ALL). At transplantation, 114 (72%) patients were in first complete response (CR1) and 44 (28%) were in second CR (CR2). Conditioning regimen was myeloablative for 97 (61%) patients and of reduced intensity in 61 (39%) patients. DNA levels of CMV, EBV, HHV6 and BK-V were detected by quantitative RQ-PCR after weekly monitoring up to 3 months after allo-HSCT. CMV-DNA, EBV-DNA, HHV6-DNA or BK-V-DNA was considered positive when the copies exceeded 1000 copies/ml. Results: Among 158 patients, 45 (28%) patients had CMV reactivation after a median time of 40 days (6-72) after allo-HSCT; 53 (34%) patients had EBV reactivation after a median time of 42 days (18-91) after allo-HSCT; 33 (21%) patients had HHV6 reactivation after a median time of 24 days (6-69) and 30 (19%) patients had BK-V reactivation after a median time of 32 days (6-60) after allo-HSCT. There was 61 (39%) patients who did not have any viral reactivation, 46 (29%) patients who had only one reactivation (no matter the type), and 51 (32%) patients who had at least two or more co-reactivations (group 1). When evaluating relapse incidence, we found that patients who had only one reactivation were not significantly different from those who did not have any reactivation, with a comparable relapse incidence, thus, we analyzed those patients as one group (group 2, n=107). The cumulative incidence of relapse at 6 months for group 1 and group 2 was 2% (95% CI: 0.2-9.4) and 15.9 % (95%CI: 9.7-23.5) respectively, this result remained significantly different when stratifying on the type of conditioning, in RIC: 15.8% (95%CI: 3.7-35.7) vs 21.4% (95%CI: 10.5-35) respectively; and in MAC: 0 % vs 15.4% (95%CI: 7.8-25.3) respectively, p=0.04. This finding was confirmed independently of the presence of GVHD or not. Conclusion: We demonstrate here for the first time, in this homogeneous population, that co-reactivation of multiple viruses after allo-HSCT could lead to a lower incidence of relapse in AL patients in CR; this can be explained as a stimulation of the immune system via both the functional activation and amplification of NK compartment. This could also explain some conflicting results in studies evaluating single viral reactivation alone without consideration of other reactivations. These encouraging results should be validated at a larger multicenter level. Disclosures No relevant conflicts of interest to declare.

Background: Minimal residual disease (MRD) diagnostics in multiple myeloma (MM) are gaining increasing importance to determine response depth beyond complete remission (CR) since novel agents have shown to induce high rates of deep clinical responses. Moreover, recent reports indicated combining functional imaging with next generation flow cytometry (NGF) could be beneficial in predicting clinical outcome. This applies in particular to the subset of patients suffering from relapsed/refractory multiple myeloma (RRMM) who tend to show a higher incidence of residual focal lesions despite serological response. Here, we report our institutions experience with implementing both functional imaging and NGF-guided MRD diagnostics in clinical practice. Methods: Our study included patients with newly diagnosed multiple myeloma (NDMM) and RRMM achieving VGPR, CR or sCR. Bone marrow aspirates were obtained for MRD-testing according to IMWG 2016 criteria. Samples were collected between July 2019 and July 2020 and analyzed with NGF (according to EuroFlowTM guidelines) at a sensitivity level of 10-5. Results were compared to functional imaging obtained with positron emission tomography (PET) and diffusion-weighted magnetic resonance imaging (DW-MRI). High-risk disease was defined as presence of deletion 17p, translocation (14;16) or (4;14). Results: We included 66 patients with NDMM (n=39) and RRMM (n=27) who achieved VGPR or better. In patients with RRMM the median number of treatment lines was 2 (range 2-11). Fifteen patients suffered from high-risk disease. Median age at NGF diagnostics was 64 years (range 31-83). Among patients achieving VGPR (n=27), CR (n=10) and sCR (n=29) seventeen (26%) were MRD-negative by NGF testing. CR or better was significantly associated NGF MRD-negativity (p=0.04). Notably, rates of NGF MRD-negativity were similar among patients with NDMM (28%) and RRMM (26%). Even some heavily pretreated patients who underwent ≥ 4 lines of therapy achieved MRD-negativity on NGF (2 of 9). Functional imaging was performed in 46 (70%) patients with DW-MRI (n=22) and PET (n=26). Median time between NGF and imaging assessment was 2 days (range 0-147). Combining results from imaging and NGF, 12 out of 46 (26%) patients were MRD-negative with both methods (neg/neg). Three patients displayed disease activity as measured with both, imaging and NGF (pos/pos). Twenty-nine of the remaining patients were MRD-positive only according to NGF (pos/neg), while two patients were positive on imaging only (neg/pos). More patients demonstrated combined MRD-negativity on NGF and imaging (neg/neg) in the NDMM setting than in RRMM (32% versus 19%). We also observed that 30% of the patients with high-risk genetics showed MRD-negativity on both imaging and NGF. Of note, none of the patients with very advanced disease (≥4 previous lines) was MRD-negative on both techniques. Conclusion In the clinical routine, MRD diagnostics could be used to tailor maintenance and consolidation approaches for patients achieving deep responses by traditional IMWG criteria. Our real-world experience highlights that MRD-negativity can be achieved in patients suffering from high-risk disease and also in late treatment lines, supporting its value as endpoint for clinical trials. However, our data also support MRD diagnostics to be combined with functional imaging at least in the RRMM setting to rule out residual focal lesions. Future studies using MRD for clinical decision-making are highly warranted. Disclosures Einsele: Takeda: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; GlaxoSmithKline: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau. Rasche:Celgene/BMS: Honoraria; GlaxoSmithKline: Honoraria; Oncopeptides: Honoraria; Skyline Dx: Research Funding; Janssen: Honoraria; Sanofi: Honoraria.

Background: IMGN632 is a CD123-targeting ADC, comprised of a high affinity anti-CD123 antibody coupled to a DNA-alkylating payload of the novel IGN (indolinobenzodiazepine pseudodimer) class. An ongoing Phase I trial in patients with CD123-positive AML or BPDCN (NCT03386513) has reported encouraging efficacy and manageable tolerability with IMGN632 monotherapy. Preclinical data from AML mouse models demonstrate synergy in combinations with azacitidine and/or venetoclax1,2, supporting the clinical exploration of these combinations. Here we describe the ongoing Phase 1b/2 study actively enrolling patients to determine the safety, tolerability, and preliminary anti-leukemia activity of IMGN632 when administered in combination with azacitidine and/or venetoclax to patients with relapsed and frontline CD123-positive AML, and the single-agent activity of IMGN632 in patients with minimal residual disease (MRD)-positive AML after frontline treatment. M ethods and s tudy d esign : Adult patients with CD123-positive relapsed or refractory (R/R) AML, who are deemed appropriate for experimental therapy, are eligible to enroll as part of the dose escalation phase. Key exclusion criteria for all regimens include active central nervous system disease, and history of sinusoidal obstruction syndrome/venous occlusive disease of the liver. Three different combination regimens are being evaluated: Regimen A, IMGN632 plus azacitidine (632+AZA); Regimen B, IMGN632 plus venetoclax (632+VEN); and Regimen C, IMGN632 plus azacitidine and venetoclax (632+AZA+VEN). For each regimen, a Phase 1b dose escalation cohort in R/R patients will determine the recommended Phase 2 dose (RP2D) of IMGN632 for the specific combination. Escalation will follow a standard 3+3 design, with a starting dose for IMGN632 of 0.015 mg/kg administered intravenously on Day 7 of a 21- (632+VEN) or 28-day cycle (632+AZA, 632+AZA+VEN). Regimens A and B (the doublets) were initially explored to evaluate safety at increasing doses of IMGN632. Escalation of IMGN632 on Regimen C (the triplet) was allowed once the corresponding dose of IMGN632 was evaluated in each doublet combination (Figure). This will be followed by a Phase 2 dose expansion stage to further characterize the safety profile and assess antileukemia activity in frontline or relapsed AML patients, depending on the combination regimen. In addition, IMGN632 monotherapy is being explored in expansion cohorts of MRD-positive patients to assess conversion rate from MRD-positivity to MRD-negativity, in fit and unfit AML subpopulations. NCT04086264 Figure Disclosures Daver: Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sweet:Incyte: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Stemline: Honoraria; Novartis: Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Montesinos:Celgene, Pfizer, Abbvie: Consultancy; Pfizer, Abbvie, Daiichi Sankyo: Research Funding; Astellas, Novartis, Janssen: Speakers Bureau. Wang:Genentech: Consultancy; PTC Therapeutics: Consultancy; Pfizer: Speakers Bureau; Abbvie: Consultancy; Jazz Pharmaceuticals: Consultancy; Bristol Meyers Squibb (Celgene): Consultancy; Stemline: Speakers Bureau; Astellas: Consultancy; Macrogenics: Consultancy. Aribi:Seattle Genetics: Consultancy. DeAngelo:Jazz: Consultancy; Shire: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Abbvie: Research Funding; Incyte Corporation: Consultancy; Forty-Seven: Consultancy; Glycomimetics: Research Funding; Autolos: Consultancy; Amgen: Consultancy; Agios: Consultancy; Blueprint Medicines Corporation: Consultancy, Research Funding; Takeda: Consultancy. Walter:Pfizer: Consultancy, Research Funding; Macrogenics: Research Funding; Amgen: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; ImmunoGen: Research Funding; Celgene: Consultancy, Research Funding; StemLine: Research Funding; BioLineRx: Consultancy, Research Funding; Genentech: Consultancy; Seattle Genetics: Research Funding; New Link Genetics: Consultancy; Agios: Consultancy, Research Funding; BiVictriX: Consultancy; Boston Biomedical: Consultancy; Amphivena: Current equity holder in publicly-traded company; Aptevo: Consultancy, Research Funding; Argenx: Consultancy; Arog: Research Funding; Astellas: Consultancy; Daiichi: Consultancy; Race Oncology: Consultancy; Kite: Consultancy; Selvita: Research Funding. Altman:Biosight: Research Funding; PrIME Oncology: Consultancy; France Foundation: Consultancy; PeerView: Consultancy; Fujifilm: Research Funding; Kartos: Research Funding; Celgene: Research Funding; ASH: Consultancy; Bristol-Myers Squibb: Consultancy; Immune Pharma: Consultancy; Janssen: Consultancy; Syros: Consultancy; Novartis: Consultancy; Genentech: Research Funding; Amphivena: Research Funding; Aprea: Research Funding; Amgen: Research Funding; ImmunoGen: Research Funding; Boehringer Ingelheim: Research Funding; Kura: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees, Research Funding; Theradex: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Glycomimetics: Other: DSMC; Daiichi Sanko: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cancer Expert Now: Consultancy. Advani:Immunogen: Research Funding; Seattle Genetics: Other: Advisory board/ honoraria, Research Funding; Abbvie: Research Funding; Takeda: Research Funding; OBI: Research Funding; Amgen: Consultancy, Other: steering committee/ honoraria, Research Funding; Kite: Other: Advisory board/ honoraria; Pfizer: Honoraria, Research Funding; Novartis: Consultancy, Other: advisory board; Glycomimetics: Consultancy, Other: Steering committee/ honoraria, Research Funding; Macrogenics: Research Funding. Sloss:ImmunoGen, Inc.: Current Employment. Malcolm:ImmunoGen, Inc.: Current Employment. Zweidler-McKay:ImmunoGen, Inc.: Current Employment. OffLabel Disclosure: Phase 1b/2 trial of experimental therapy

To the editor: Here we present a case of a patient with JAK2V617F- and IDH2-mutation–positive myelofibrosis (MF) with elevated blasts on ruxolitinib therapy for 8 years with a complete hematologic, histomorphologic, cytogenetic, and molecular remission. MF is a rare Philadelphia chromosome–

Introduction: Serum M-protein levels, measured by serum immunoelectrophoresis, have been one of the major tests that determine the type of response to therapy in Multiple Myeloma. Achieving an M-protein of zero is one of the criteria determining complete remission which in turn translates into longer progression-free survival and overall survival. Triplet therapy tends to be the standard therapeutic approach in younger, fit, and transplant candidates. However, in older non-fit patients many oncologists start with doublets and only escalate to triplet combinations upon less optimal response. The predictive value of the velocity of the M-spike decline (VMD) has not been adequately studied. We conducted this study to find the optimal VMD that predicts a serum M-protein of zero. Methods: A sample of mostly non-fit older Multiple Myeloma patients was identified. All patients had regular serum protein electrophoresis with M-protein levels documented every 4-8 weeks until they achieved M-protein levels of zero, plateauing without attaining the target of zero, or rebounding with progression. Best-fit line or curve was constructed and the slope of the decline was calculated. VMD was defined as the slope of the best fit-curve/line. VMD values corresponding to the binary outcomes of achieving or failing to achieve an M-protein value of zero were collected. A ROC curve was constructed to determine the cut-off VMD value that best predicts the outcome of M-protein of zero. Results: A total of 47 patients of mostly non-fit older Multiple Myeloma patients were included in our final sample. The median age of the sample was 71 years. Thirteen percent had triplet therapy. Thirty four percent had proteasome inhibitor based combinations while 64% had IMiD based combinations. Fifty seven percent achieved the target M-protein level of zero while 43% failed. The area under the ROC curve, AUC, was 0.98 (p Conclusions: This exploratory study established the VMD value that best predicts the outcome of M-protein of zero in response to Multiple Myeloma therapy. This may be potentially used by oncologists to make early decisions regarding the need for further optimization or intensification of their therapeutic combinations as they treat their older non-fit Multiple Myeloma patients. Disclosures No relevant conflicts of interest to declare.

Background: In the context of a haploidentical stem cell transplantation (Haplo-SCT) platform with post transplantation cyclophosphamide (PT-Cy) for acute myeloid leukemia (AML) patients, the optimal conditioning regimen remains unknown. A non-myeloablative conditioning (NMAC) regimen (cyclophosphamide + fludarabine + 2Gy TBI [CyFluTBI]) was initially reported by the Johns Hopkins group as a safe approach in this setting, notably to treat patients of advanced age and/or with comorbid conditions. However, relapse incidence after NMAC Haplo-SCT remains high in AML where it can reach 45%. Alternatively, a reduced intensity conditioning (RIC) regimen containing an antileukemic drug combination like thiotepa and reduced-dose busulfan in addition to fludarabine (TBF) may decrease AML relapse. However, this anticipated benefit may be counterbalanced by a higher incidence of toxicity, graft-versus-host disease (GVHD) and non-relapse mortality (NRM). To date, no study comparing TBF vs. CyFluTBI has been published in complete remission (CR) AML. We performed this retrospective comparison on behalf of the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT). Methods: We retrospectively analyzed 398 patients from the EBMT registry database with the following inclusion criteria: 1) adult patient in CR1 or CR2 AML; 2) T-replete Haplo-SCT with PT-Cy; 3) no in vivo depletion using antithymocyte globulin or alemtuzumab; and 4) receiving either TBF RIC (equivalent of 2-day iv busulfan dose) or CyFluTBI NMAC regimen. We compared separately TBF vs. CyFluTBI in patients younger (n=170, 82 TBF vs. 88 CyFluTBI) and older (n=228, 141 TBF vs. 87 CyFluTBI) than 60 years. Results: In patients younger than 60 years, the 2-year cumulative incidence of relapse (CIR) was significantly lower in the TBF group compared with the CyFluTBI group (TBF vs. CyFluTBI: 14% vs. 43%, p In patients older than 60 years, univariate analysis did not show any significant difference in outcome according to the type of conditioning regimen (2-year NRM: TBF vs. CyFluTBI: 33% vs. 25%, p=0.23; 2-year CIR: TBF vs. CyFluTBI: 23% vs. 28%, p=0.20; 2-year LFS: TBF vs. CyFluTBI: 44% vs. 47%, p=0.96). Multivariate analysis showed a significant reduction in the risk of NRM after CyFluTBI (HR 0.5, 95%CI [0.2-0.9], p=0.04), while a non-significant increase in the risk of relapse was observed (HR 1.9, 95%CI [0.8-4.2], p=0.13). Finally, there was no significant difference in LFS (HR 0.9, 95%CI [0.5-1.5], p=0.67) and OS (HR 0.9, 95%CI [0.5-1.5], p=0.67). Conclusion: Our study suggests that in CR AML patients aged younger than 60 years, the use of TBF RIC provides better outcomes than NMAC CyFluTBI due to lower incidence of relapse, without significant increase in the risk of NRM. Conversely, it seems that older patients do not benefit from such conditioning intensification, due to a significantly higher risk of NRM after TBF RIC. Thus, in CR AML patients who will not receive a truly myeloablative regimen prior to PT-Cy Haplo-SCT, age could be used for determining the conditioning intensity from the wide variety of reduced toxicity conditioning regimens. Beyond the patient age, further prospective trials should assess patient-based parameters that may be useful for a fine tuning of conditioning intensity in a more individualized approach. Disclosures Labopin: Jazz Pharmaceuticals: Honoraria. Blaise:Jazz Pharmaceuticals: Honoraria. Bug:Sanofi: Other: Travel; Neovii: Other: Travel; Jazz: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel; Hexal: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Eurocept: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel. Mohty:Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Stemline: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Introduction Current risk stratification of Acute Lymphoblastic Leukemia (ALL) approach has significantly improve the outcome for pediatric and adolescent ALL. However, the outcome for adult ALL remains poor. With the emerging technologies that could drastically increase the parameters and scales of clinical data for treatment strategy formulation and more new therapeutic agents approved for ALL treatment, a better integrated and more systematic risk stratification method is needed for ALL. In our study, we propose to use artificial intelligence to develop an integral outcome prediction models that include all clinical exam and treatment history, aiming to further improve current risk stratification strategies. Method Retrospective clinical data of patients with ALL, including demographic (age & gender), laboratory results including complete blood count (CBC), white blood count (WBC), molecular genetics, cytogenetics, flow cytometry (FC) and treatment history at National Taiwan University Hospital were collected. A total of 513 newly diagnosed ALL from 2005 to 2017 were enrolled this study. The median age at diagnosis was 20 years and the median follow up duration was 49.1 months, 78.9% of them achieved complete remission (CR), 27.5% had relapsed, 31.6% had received HSCT (Table 1). In total, 243,464 CBC & WBC records, 32 types of anti-neoplastic medications in L01, L03 and L04 ATC code category with a total of 20,043 medication records from these 513 patients were utilized in developing the ALL outcome prediction model. A vectorized representation that captures the static-dynamic clinical aspects of an ALL patient can be learned directly from the collected data. The representation includes both static personal attributes (demographic, and genetic) and time-varying progression of patient's clinical assessment across time (laboratory results, HSCT, and medication). The time-dependent representation was derived from training a deep network architecture of bi-directional long short-term memory network (BLSTM). By taking 7 days as a time step, the BLSTM took the input of Fisher-vector encoded time series of a patient's CBC and WBC, medication, and HSCT records separately. The last output layer, which summarized the relapse/mortality risk exhibited in the measurements of patient's clinical conditions over time, of each separately-learned BLSTM was used as the encoded dynamic clinical representation. The concatenation of the ALL patient's static features and the time-dependent representations were fed into a deep neural network followed by a support vector machine to carry out the final prediction. The prediction models were conducted in 5-fold cross-validation experiments and further evaluated using metrics of accuracy (ACC). Results The median leukemia free survival and median overall survival of these 513 ALL patients are 29.3 months and 61.9 months respectively. The outcome prediction models developed achieved accuracy of next 3-month relapse, relapse or mortality, and mortality prediction reached 86.2%, 74.9% and 64.3% respectively (Table 2). Conclusions Our team has demonstrated the BLSTM-DNN model's potential that is capable in taking multiple and longitudinal clinical measurements into integrated relapse or mortality prediction in AML in 2018 (ASH 2018 #2811) and we have observed the same potential in ALL relapse and mortality prediction. More external and multi-national center studies are needed to further improve the performance of such integrated outcome prediction models. Disclosures Ko: Roche: Honoraria.

In this issue of Blood , Statler et al report the incidence and outcomes of patients who were treated on leukemia clinical trials conducted by Southwest Oncology Group (SWOG) from 2005 to 2015, but who were retrospectively deemed ineligible. The primary finding is that patients labeled as ineligible for the included clinical trials have similar outcomes as eligible patients. 1

Anti-CD22 moxetumomab pasudotox achieved 46% complete remissions (CRs) in previously reported phase 1 testing in relapsed/refractory hairy cell leukemia (HCL; n = 28). The importance of minimal residual disease (MRD) after CR in HCL is unknown. A 21-patient extension cohort received 50 µg/kg every other day for 3 doses in 4-week cycles. These patients plus 12 previously reported at this upper dose level received 143 cycles without dose-limiting toxicity. The combined 33-patient cohort achieved 64% CR and 88% overall response rates, with median CR duration of 42.4 months. Of 32 50-µg/kg patients evaluable for MRD by bone marrow aspirate flow cytometry (most stringent assessment), median CR duration was 13.5 (4.9-42.4) months in 9 MRD-positive CRs vs 42.1 (24.0-69.2) months in 11 MRD-negative CRs (P < .001). Among MRD-negative CRs, 10 patients had ongoing CR, 9 without MRD, at end of study. To our knowledge, moxetumomab pasudotox is the only nonchemotherapy regimen that can eliminate MRD in a significant percentage of HCL patients, to enhance CR duration. Repeated dosing, despite early neutralizing antibodies, increased active drug levels without detectable toxicity from immunogenicity. The activity and safety profiles of moxetumomab pasudotox support ongoing phase 3 testing in HCL. This trial was registered at www.clinicaltrials.gov as #NCT00586924.

Measurable residual disease (MRD; previously termed minimal residual disease) is an independent, postdiagnosis, prognostic indicator in acute myeloid leukemia (AML) that is important for risk stratification and treatment planning, in conjunction with other well-established clinical, cytogenetic, and molecular data assessed at diagnosis. MRD can be evaluated using a variety of multiparameter flow cytometry and molecular protocols, but, to date, these approaches have not been qualitatively or quantitatively standardized, making their use in clinical practice challenging. The objective of this work was to identify key clinical and scientific issues in the measurement and application of MRD in AML, to achieve consensus on these issues, and to provide guidelines for the current and future use of MRD in clinical practice. The work was accomplished over 2 years, during 4 meetings by a specially designated MRD Working Party of the European LeukemiaNet. The group included 24 faculty with expertise in AML hematopathology, molecular diagnostics, clinical trials, and clinical medicine, from 19 institutions in Europe and the United States.

Background:The small molecule BCL-2 inhibitor Venetoclax (VEN) has emerged as a promising frontline therapy in combination with low dose cytarabine (LDAC) or hypomethylating agents in older patients with acute myeloid leukemia (AML)(DiNardo et al, Lancet Oncol 2018, Blood 2019; Wei et al,JCO 2019). The anti-leukemic activity of single agent VEN as monotherapy in newly diagnosed AML is unknown. This information would be useful for studies considering VEN as a maintenance therapy. We have previously presented preliminary outcomes from a phase 1b/2 study: Chemotherapy and Venetoclax in Elderly AML Trial (CAVEAT), which incorporated a 7-day single agent VEN run-in phase prior to combination with chemotherapy (Wei et al, ASH 2018). The study procedures incorporated a bone marrow assessment performed at study screening and on day 8, prior to commencement of chemotherapy (Figure 1A). This allowed us to explore the single agent activity of venetoclax on bone marrow blasts in treatment naïve patients with AML and to assess molecular dynamics of response. Methods:The CAVEAT trial included 51 de novo or secondary patients with AML aged ≥65 years and considered fit for intensive chemotherapy. The study enrolled patients to 5 VEN dose cohorts (50-100-200-400-600mg). VEN was administered on days 1-14 during induction. Chemotherapy commenced on day 8, with a 7-day VEN monotherapy pre-phase. Molecular studies:a 54-gene myeloid NGS panel (Illumina TruSight) and MassARRAY MALDI-TOF mass spectrometry was performed on DNA extracted from bone marrow aspirates. FLT3-ITD testing was by fragment analysis, PCR and capillary electrophoresis. Minimal residual disease (MRD) testing was performed by digital droplet PCR for IDH mutations (assay sensitivity: 10-4-10-5). Results: A total of 46 patients had paired BM assessments at screening and on day 8 for comparison. A ≥50% relative reduction in BM blasts was recorded in 13/46 (28%) patients. Figure 1B shows the relative BM blast reduction stratified by molecular subgroups. Patients with NPM1(n=9) or IDH2 (n=8) mutation achieved greater BM blast reductions (median of 56% and 55%, respectively) than IDH1 (n=6), TP53 (n=10) or FLT3-ITD (n=5) mutant cases (median of 37%, 17% and 7%, respectively). Three NPM1 mutant cases with Clinically, complete remission (CR) and CR with incomplete count recovery (CRi) rates after chemotherapy were seen for the following mutations: NPM1(80%), IDH2 (100%), IDH1 (62%) and TP53 (36%) (Figure 1D). Despite all four response-evaluable patients with FLT3-ITD achieving CR/CRi, 3/4 relapsed with detectable FLT3-ITD (at 0.8, 1.5 and 12.3 months respectively). Median survival for each genomic sub-group were NPM1 (12.5m), IDH2 (not reached), IDH1 (6.1m),TP53 (3.8m), FLT3-ITD (5.5m). CyTOF analyses for changes in BCL-2 family expression are underway and results will be presented at the meeting. Conclusion: Treatment naïve NPM1 and IDH2 mutant AML blasts are highly sensitive to VEN alone and combination with cytarabine and anthracycline chemotherapy results in a high clinical response rate. TP53 and FLT3-ITD mutant cases were more resistant and outcomes were poor despite VEN combined with chemotherapy. Figure 1 Disclosures Reynolds: Alfred Health: Employment, Other: Biostatistician for trials funded by the Australian government and Abbvie, Amgen, Celgene, GSK, Janssen-Cilag, Merck, Novartis, Takeda, but sponsored by Alfred Health.; AUSTRALASIAN LEUKAEMIA & LYMPHOMA GROUP (ALLG): Consultancy; Novartis AG: Equity Ownership; Novartis Australia: Honoraria. Fong:Pfizer: Consultancy, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau; Astellas: Consultancy; Novartis: Speakers Bureau. Ting:NHMRC: Research Funding. Fleming:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Pfizer: Honoraria; Ariad: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Moujalled:Walter and Eliza Hall Institute of Medical Research: Patents & Royalties: Share in venetoclax royalties . Ivey:Novartis: Honoraria. Roberts:AbbVie: Research Funding; Janssen: Research Funding; Walter and Eliza Hall Institute: Employment, Patents & Royalties: receives a fraction of its royalty stream related to venetoclax. Wei:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: AHW is a former employee of the Walter and Eliza Hall Institute and receives a fraction of its royalty stream related to venetoclax, Research Funding, Speakers Bureau; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Honoraria, Research Funding; Janssen: Honoraria. OffLabel Disclosure: Venetoclax is a BCL-2 inhibitor that is FDA-approved in some indications. This presentation will focus on correlative study results in the CAVEAT trial which combines venetoclax with modified intensive chemotherapy in AML, which is not an approved indication.

Background: The use of midostaurin in combination with standard induction chemotherapy has been shown to improve the outcomes in patients with newly diagnosed FLT3 mutated (FLT3m) AML (Stone et al) and allogeneic transplant is often recommended in first remission. While likely to achieve remission with standard induction, the majority of these patients will relapse and die of their disease. Gilteritinib, a potent FLT3 inhibitor, has been approved for use in patients with relapsed or refractory FLT3 mutated AML. In Phase I/II studies, when used as part of induction therapy, gilteritinib has shown promising CR rates. We have designed a trial comparing the outcomes of induction therapy with gilteritinib to those with midostaurin. The hypothesis is that gilteritinib, when added to induction chemotherapy, will produce more FLT3m negative composite complete remission (CRc). The Ratify trial combined midostaurin with daunorubicin 60 mg/m2/d X 3 days and cytarabine X 7 days Daunorubicin 90 mg/m2/d has however been shown to be superior during induction in patients with newly diagnosed FLT3 ITD mutated AML (Luskin et al, Burnett et al) While improved survival is the ultimate goal of any leukemia regimen, it is known that AML patients who proceed to allogeneic transplant with measurable residual disease (MRD) positive disease fare worse than those with MRD negative disease. As such, our goal is to increase the likelihood of an MRD negative state after induction. Study Design This is a randomized, open-label, multicenter phase II study comparing gilteritinib to midostaurin in combination with cytarabine 100 mg/m2 and daunorubicin 90 mg/m2 in newly diagnosed FLT3 mutated AML patients ages 18-65. Central confirmation of FLT3 mutation and other pretreatment studies are required. In order to identify patients without delay, all patients with suspected AML will be able to be prescreened without enrollment to the randomized treatment trial. Patients will be stratified according to TKD vs. ITD FLT3 mutation. Patients with FLT3-ITD mutation will undergo further stratification with NPM1 mutation status (positive vs. negative) and FLT3 ITD to FLT3 wild type signal ratio (high [≥ 0.5] vs. low [ Key Eligibility: Newly diagnosed FLT3m AML Primary Objective To evaluate the FLT3m negative (evaluated by polymerase chain reaction [PCR] and capillary electrophoresis) composite complete response (CRc) (includes CR or CRi)rate of patients with FLT3 mutated AML who receive gilteritinib compared to those who receive midostaurin in addition to standard therapy with cytarabine and daunorubicin during induction. Sample Size and Statistical design The accrual goal of this study will be 179 patients. Patients who achieve remission will be followed for survival and relapse. With an allocation ratio of 1:1 to the two arms, the study will have 80% power to detect an improvement of 20% in the FLT3 mutation negative CRc rate in the gilteritinib arm (i.e. from 40% to 60%) at the one-sided significance level of 0.05 based on Fisher's exact test. This study is conducted through PrECOG and is funded by Astellas Pharma. The study is slated to open in the summer of 2019 at 30 US sites. References: Stone R.M., Mandrekar S.J., Sanford B.L., et al. N Engl J Med 2017; 377:454-464 Luskin MR, Lee JW, Fernandez HF et al. Blood 2016 :blood-2015-07-657403; doi: https://doi.org/10.1182/blood-2015-07-657403 Burnett AK, Russell NH, Hills RK et al. Blood 2016; Blood 2016 128:449-452; doi: https://doi.org/10.1182/blood-2016-04-712091 Figure Disclosures Luger: Genetech: Research Funding; Jazz: Honoraria; Celgene: Research Funding; Pfizer: Honoraria; Kura: Research Funding; Onconova: Research Funding; Agios: Honoraria; Ariad: Research Funding; Biosight: Research Funding; Seattle Genetics: Research Funding; Cyslacel: Research Funding; Daichi Sankyo: Honoraria. Loghavi:MDACC: Employment; GLG Consultants: Consultancy; AlphaSights: Consultancy. Lazarus:Genentech: Speakers Bureau; Pluristem Therapeutics, Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Adaptive Biotechnologies: Consultancy, Honoraria; CSL Behring: Consultancy; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Honoraria, Speakers Bureau; Actinium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Biosight: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Speakers Bureau; Teva Pharmaceuticals: Speakers Bureau. Rowe:BioSight: Consultancy. Tallman:Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biosight: Research Funding; ADC Therapeutics: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellerant: Research Funding; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties. Pratz:Astellas Pharma: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Millenium/Takeda: Research Funding; Boston Biomedical: Consultancy. OffLabel Disclosure: In this study gilteritinib is being studies in newly diagnosed AML.

Introduction:Acute Myeloid Leukemia (AML) predominantly affects the older population, with a median age at diagnosis of 67 years (yrs). In the last decades, Overall Survival (OS) has not changed meaningfully for these patients (pts). This worse outcome is explained by the poor-risk biological profile of the disease but also by the scarce propensity in administering curative treatments in this age category. Despite this general attitude, there is consensus that age alone should not be representative of the functional profile of older pts and that making decisions based on the sole age parameter can compromise possible therapeutic attempts. Therefore, a panel of experts from SIE (Italian Society of Hematology),SIES (Italian Society of Experimental Hematology) and GITMO (Italian Group for Bone Marrow Transplantation) summarized a list of operational criteria to be used in the process of treatment allocation, identifying 3 fitness categories of patients to address to differentiated strategies: 1)Fit pts (FP), eligible to intensive chemotherapy (IC) with the aim to achieve complete remission (CR); 2)Unfit pts (UP), eligible to non-intensive chemotherapy (NIC) with the aim to prolong survival; 3)Frail pts (FP) for whom, since the natural course of disease cannot be altered, supportive therapy (ST) is the best option in the attempt to preserve an acceptable quality of life (Ferrara et. al, Leukemia 2013). Aim: We retrospectively applied the operational SIE, SIES, GITMO criteria to a series of 180 consecutive non-APL AML pts diagnosed at our institution from 2013 to 2018 to investigate (1) the degree of concordance between the "operational criteria derived categories" and the actual treatment received; (2) the impact of this evaluation on long-term OS. Methods: We analyzed 180 consecutive pts with AML (median age 66 yrs, range 21-91) diagnosed at our institution from January 2013 to December 2018. We mainly focused on 125 pts older than 60 yrs (median 70 yrs, range 61-91). For the purpose of comparison, 55 younger pts, submitted to IC (51/55, 93%), were also analyzed. Results: SIE, SIES, GITMO operational criteria were retrospectively applied through medical files backtracking. One-hundred-48 out of 181 pts were stratified according to ELN 2010 as follow: 24 (16%) low risk, 59 (40%) intermediate-I, 25 (17%) intermediate-II and 40 (27%) high risk. This risk stratification did not differ between younger and older pts, suggesting that risk distribution may not be always an age-related factor. Overall, according to physician choice, 98 pts were submitted to IC, 40 to NIC, 42 to ST (54%, 22%, 24%, respectively). When focusing on pts older than 60 yrs, 47/125 were submitted to IC, 39/125 to NIC, 39/125 to ST (38% vs. 31% vs. 31%, respectively). A high concordance between treatment actually given and the one derived from the application of the "operational criteria" (165/180, 92%) was observed. The highest concordance was observed for the association of ST with FrP (39/40, 98%), whereas the associations IC with FP (96/107, 90%) and NIC with UP (30/33, 91%) showed a lower level of concordance. Overall, by applying the "operational criteria" the 3 categories differed significantly in terms of OS: 15,3 mos (range 0,4-78) for FP, 8,6 mos (range 2,2-47,9) for UP and 1 mos (range 0,1-29,9) for FrP, respectively (p Conclusions: In our real-life analysis, we confirmed that SIE, SIES, GITMO "operational criteria" represent a powerful tool to discriminate categories of older pts with different outcome.In pts older than 60 years, it was observed a high degree of concordance (>90%) between the "operational criteria" and the actual treatment delivered. However, long-term OS was longer when plotted according to the 3 fitness categories rather than to treatment intensity stratification (Fig.1 A and B). Such a discrepancy can be explained by a higher incidence of toxicity/early mortality in the IC group and also by a suboptimal application of treatment selection criteria. Reproducibility of operational criteria applications in a prospective fashion is currently underway. Disclosures Venditti: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy. Buccisano:Janssen: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Background: Although BCP-ALL patients can achieve complete remission (CR) after induction chemotherapy, about 40% of them have residual leukemia cells in the bone marrow which is called minimal residual disease (MRD). Complete MRD response is defined as lack of MRD with an assay sensitivity of >= 10-4, which, if sustained for more than five years, may be regarded as a functional cure for ALL. On the contrary, presence of MRD is a signal of high risk of relapse leading to poor health outcomes. Blinatumomab is the only drug approved for BCP-ALL patients with MRD based on the results from BLAST, a single-arm phase 2 study conducted to assess the efficacy and safety of blinatumomab in adult BCP-ALL patients in CR with MRD. Currently, there is limited evidence on the relationship between MRD response and functional cure in ALL and life years gained. Objectives: The objective of this study was to assess the relationship between complete MRD response after blinatumomab treatment and 1) functional cure; 2) life years and quality adjusted life years (QALYs) gained among BCP-ALL patients with MRD. Methods: The relationship between MRD response, and clinical outcomes was analyzed using an existing cost-effectiveness analysis (CEA) based on combined decision tree and Markov cohort model over a lifetime horizon (50 years). The model includes survival conditional on treatment and MRD status for time to stem transplant, relapse and death. In the CEA, blinatumomab was compared to standard of care (SOC, defined as conventional maintenance chemotherapy). Clinical probabilities were derived primarily from blinatumomab clinical trial data and a non-interventional cohort study (used as a historical control). Life years gained were adjusted for quality based on utility values from trial EQ-5D scores. An annual discount rate of 3.5% was applied to estimate future outcomes. Results: In the base case, the complete MRD response rate was 83.6%, and blinatumomab yielded more life years gained (8.26 vs. 5.68) and more QALYs (6.56 vs. 4.44) compared with SOC. The proportion of patients achieving a functional cure was 43.59% in blinatumomab group vs. 26.78% in the SOC group. Clinical response varied with variations in MRD response rate at 75%, 78%, 80%, 85%. Specifically, when the complete MRD response rate increased from 75% to 85%, the total life years gained in the blinatumomab group increased by 0.51, QALYS increased by 0.42, and the proportion of patients cured increased by 3.05%. Conclusion: Achieving complete MRD response is associated with longer life expectancy, higher probability of being cured, and more QALYs among patients with BCP-ALL and MRD. Disclosures Shao: Amgen: Employment. Tiwana:Amgen: Employment, Equity Ownership. Despiegel:Amgen: Employment, Equity Ownership. Dirnberger:Amgen: Employment, Equity Ownership.

Background: More than 45 mutations have been identified in association with HR-MDS. In the majority of patients with MDS (80%) co-mutations are present and the prognostic contribution of each individual mutation remains elusive, especially after adjusting for clinical variables such as IPSS-R score. N-RAS and K-RAS mutations as well as regulators of the Ras pathway (e.g. PTPN11, NF1) are frequently observed (15-20%) in HR-MDS, however their clinical impact is unclear, especially in de novo MDS. Rigosertib (RGS) is a non-ATP-competitive small molecule RAS mimetic that has the potential to block RAS-RAF-MEK-ERK and PI3K-AKT-mTOR signaling pathways (Athuluri-Divakar 2016). Rigosertib has the potential to also inhibit wildtype upregulation of RAS. We report here genomic profiling at the time of study entry in the ongoing phase 3 randomized global study (known as INSPIRE) in patients with HR-MDS after failure of HMA therapy. Methods: INSPIRE (NCT02562443) is a global randomized Ph3 trial in pts with HR-MDS after HMA failure with an overall target enrollment of 360 pts with currently 298 pts randomized. Pts are randomized 2:1 to rigosertib or physician's choice of treatment. The primary endpoint is overall survival (OS). All pts failed to respond or progressed on HMA therapy. Key inclusion criteria includes: age < 82 years, RAEB-1, RAEB-2 or RAEB-t; intermediate risk (IR), high risk (HR) and very high risk (VHR) per IPSS-R; ≥ 1 cytopenia; duration of prior HMA ≤ 9 cycles within 12 months; last dose of HMA ≤ 6 months before enrollment; baseline blast counts between 5-29% and one of the following: progression any time after initiation of HMA treatment, intolerance to HMA, failure to achieve complete remission (CR), partial remission (PR), or hematologic improvement (HI) after six 4-week cycles of AZA or either four 4-week or four 6-week cycles of DAC, or relapse after initial CR, PR or HI. Bone marrow samples were collected at study baseline and throughout the study for mutational analysis as an exploratory endpoint. Baseline blast counts are described as % reported in bone marrow aspirate at screening. Genomic DNA was extracted from diagnostic bone marrow or peripheral blood samples and targeted capture deep sequencing of 295 genes were performed (median sequencing depth 500x) using Agilent's SureSelect custom panel. Modified Mutect and Pindel were used to identify high-confidence somatic mutations. Results: All data is presented as blinded aggregate results for both arms of the study. Baseline mutations are presented for 114 pts; 92 pts were randomized and 22 pts were screen failures. Median age is 72 years (59-81). The IPSS-R scores for the pts randomized were: Intermediate 5(5%), High 30 (32%) and VHR 56 (60%). In total 48 different mutations were identified at baseline prior to pts receiving study treatment. The most common mutations identified in pts were ASXL1 40%, STAG2 26%, TP53 24%, RUNX1 22%, SRSF2 and TET2 each 18%. Average number of mutations per pt was 3.06. At baseline, 4 pts (4%) had no mutations, 17 pts (18%) had only 1 mutation while 17 pts (18%) had between 6-8 mutations. N-RAS and K-RAS mutations occurred in 4 pts each (7% of pts) and all in the presence of other mutations. Mutations involving regulators of the Ras pathway (N-RAS, K-RAS, PTPN11, NF1) occurred in 12 (13%) of patients. Of note, 23 pts (25%) had IDH1 (6 pts) or IDH2 (17 pts) and the majority of these pts (68%) were High/VHR with an average blast count of 15% (range 5-27%) at study entry. The high proportion of IDH1/2 mutations observed is most likely due to inclusion of patients with RAEB-t. These results will be updated at the meeting with blinded baseline mutational analyses for all pts randomized into the study. Conclusion: The baseline mutational analyses from the INSPIRE study provides important initial insights into the genomic profile of pts with HMA failure, especially for the subset with VHR. Following analysis of the primary endpoint, it is anticipated that correlation of overall survival and clinical response with mutational status will be possible, including changes in mutations following therapy. Given the number of mutations involving the Ras pathway the efficacy of rigosertib in patients with this group of mutations will also be examined. Figure Disclosures Garcia-Manero: Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Luger:Agios: Honoraria; Jazz: Honoraria; Kura: Research Funding; Onconova: Research Funding; Pfizer: Honoraria; Seattle Genetics: Research Funding; Daichi Sankyo: Honoraria; Genetech: Research Funding; Cyslacel: Research Funding; Ariad: Research Funding; Biosight: Research Funding; Celgene: Research Funding. Al-Kali:Astex Pharmaceuticals, Inc.: Research Funding. Jedrzejczak:Amgen: Consultancy, Other: travel support for hematology meetings (ASH, EBMT, EHA) ; Celgene: Other: travel support for hematology meetings (ASH, EBMT, EHA) ; Takeda: Consultancy; Novartis: Research Funding; Roche: Other: travel support for hematology meetings (ASH, EBMT, EHA) . Díez-Campelo:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Zbyszewski:Onconova Therapeutics, Inc.: Employment. Cavanaugh:Onconova Therapeutics, Inc.: Employment. Woodman:Onconova Therapeutics, Inc.: Employment. Fruchtman:Onconova Therapeutics, Inc.: Employment. Takahashi:Symbio Pharmaceuticals: Consultancy.

Introduction: Clinical outcomes of acute myeloid leukemia (AML) in adolescents and young adults (AYA) are rarely reported as an isolated subgroup. Treatments vary little across age groups, and treatment intensity depends upon comorbid conditions and performance status. Optimal treatment strategies focused on disease behavior, biological factors, and the distinct needs of this subset of AML patients remain elusive. The purpose of this retrospective analysis is to determine the characteristics and outcomes of AYA AML patients treated at a specialized adult leukemia cancer center in comparison to older adults with AML (40-60 years). Methods: A retrospective analysis was performed on all patients treated at Princess Margaret Cancer Center from 2008-2018. Patients with acute promyelocytic leukemia were excluded. Clinical characteristics, treatment strategies, and survival outcomes were recorded for all patients. Overall survival (OS) and disease-free survival (DFS) rates were calculated using the Kaplan-Meier product-limit method and the impact of covariates were assessed using the Log-rank test. Finally, we compared the outcomes of AYA patients treated at our centre between 2015-2018 with older patients. Results: A total of 175 patients aged 18-39 were identified. Patient characteristics are shown in (Table 1). Cytogenetic were available in 163 patients. Based on MRC criteria, 27 (16%) were favorable risk, intermediate in 95 (54%), adverse in 39 (22%), and missing/failed in 14(8%). NPM1 status was available in 110 patients of whom 38 (35%) were positive. FLT3-ITD was available in 67 patients with 24 (36%) positive. Both mutations were present in 13 (54%) patients. There were no significant differences in terms of risk stratification based on cytogenetic and molecular markers based on age (18-29 vs.30-39) (P= 0.98). Most patients 172 (98%) received induction, 157 (91%) with 3+7, and 15 (9%) with FLAG-IDA. Complete remission (CR) was achieved in 133 (77%) after first induction [120 (76%) after 3+7 and 11 (73%) after FLAG-IDA]. Induction related mortality was low (2%). Of the 39 who did not achieve CR, thirty-four patients received re-induction (13 FLAG-IDA, 16 NOVE-HiDAC, 5 others) with CR in 21 (62%). Overall, 154 (89.5%) achieved CR1. Sixty-four (42%) proceeded to hematopoietic stem cell transplantation (HSCT) in CR1. 59 (38%) patients relapsed in CR1 with 8 (12%) relapsing post HSCT. Fifty-five (5 post HSCT) patients received reinduction with 30 (51%) (2 after HSCT) achieving CR2. Fifteen patients received HSCT in CR2. OS and DFS at 2 years were 62% (95% CI 0.53-0.69) and 50% (95% CI 0.41-0.57), respectively. Stratified by cytogenetic risk, OS was 81% for favorable risk, 61% for intermediate, and 50% for adverse risk (P=0.0001), respectively. DFS in these groups was 85%, 57%, and 46 % (P=0.0025), respectively. We further compared outcomes in the 18-29y and 30-39y age groups. The OS was 61.9% compared to 62.5% (P=0.91) and DFS of 52.1% compared to 47% (P=0.65) respectively. On univariate analysis for OS and DFS, cytogenetic risk stratification was the only significant variable (P=0.0004 and P=0.0042). We then compared the outcomes 67 sequential patients aged I8-39 treated from 2014-2018, with those of 176 sequential patients aged 40-60 treated during the same period (table 2). OS at 2 years was not statistically higher in the younger group compared to the older group (66.7% vs. 61.2%, P=0.372). While relapse rate was lower in older patients (15.5% vs. 22.6%, P=0.093), NRM was higher in older patients (29.7% vs. 18.8%,P=0.094). Conclusion: AYA pts. occupy a unique niche amongst AML as a whole. While treatment responses have improved in general, there may be potential for further gains in these patients. Increased tolerance for more intense treatment strategies as well as the incorporation of novel agents into standard treatment protocols may provide a means to optimize care in AYA patients. Finally, research is needed to elucidate biological mechanisms and predictors of disease behavior instead of arbitrary, age-stratified treatment schema. Disclosures McNamara: Novartis Pharmaceutical Canada Inc.: Consultancy. Schimmer:Jazz Pharmaceuticals: Consultancy; Medivir Pharmaceuticals: Research Funding; Novartis Pharmaceuticals: Consultancy; Otsuka Pharmaceuticals: Consultancy. Schuh:Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Teva Canada Innovation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees. Maze:Pfizer Inc: Consultancy; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yee:Astellas: Membership on an entity's Board of Directors or advisory committees; Millennium: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MedImmune: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Hoffman La Roche: Research Funding. Minden:Trillium Therapetuics: Other: licensing agreement. Gupta:Incyte: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sierra Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Background In myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML), achievement of morphologic complete response (CR) is a prerequisite for potential cure. In AML, CR is deemed the major outcome associated with improved overall survival (OS); patients (pts) without CR are considered non-responders, and hematologic improvement (HI) without bone marrow blast (BMB) clearance is considered treatment (trt) failure (Cheson 2003). Evidence suggests that these definitions may not be applicable to older pts treated with hypomethylating agents (HMA), and that achievement of CR may not be necessary for prolonged OS (Pleyer 2013, 2014, 2015; Schuh 2015; Bloomfield 2018). IWG response criteria for HI do not differentiate between pts who qualify for response (QFR) vs those that do not. Pts with 'normal' blood counts at trt start are per definition HI non-responders. This may obscure potential survival benefits of responding pts. Aims 1) Assess the impact of HI irrespective of BMB clearance and excluding immortal time bias via landmark analyses. 2) Differentiate between pts who QFR, and those with 'normal' baseline values (not-QFR) defined according to IWG prerequisites for CR. 3) Introduce 3 new categories of HI: peripheral blood blasts (PBB), elevated white blood cells (WBC), and PB-CR (defined as Hb ≥11 g/dl, ANC ≥1.0 G/l, WBC Methods 1301 consecutive pts with azacitidine (AZA) trt were analyzed (NCT01595295). Data cut-off 26.07.19. HI was assessed according to IWG criteria (Cheson 2006) and the definitions specified in 3) above. More recent proposals of revision for low-risk MDS pts included in trials (Platzbecker 2018) remain largely idem. Human errors in HI assessment for each AZA cycle and lineage were excluded by automated computational calculation from electronic case report form (eCRF) data. Landmark analyses were performed at 3 months (mo) (HI requires ≥8 weeks response duration) and 6 mo (91, 92 and 88% of MDS, CMML and AML pts respond by cycle 6 [Silverman 2011; Pleyer 2013, 2014]). Statistics were performed by Unidata Geodesign GmbH using DeployR Open 8.0.0. Results In total, 462, 113, and 720 pts had MDS, CMML and AML (n=6 unknown). At AZA start, median age was 73 (range 23-93) years. One, 2 or 3 cytopenias were present in 25, 41 and 29% of pts and 46% were transfusion dependent. 55% received AZA 1st line (26% of whom received prior growth factors or iron chelators). Median AZA dose was 889 mg/cycle and 73 mg/m2/day. Median time to 1st response was 3.0 mo and 95% of pts responded by cycle 6. During AZA trt 1091 BM evaluations (BME) were performed in 599 (46%) pts. At the 3 (6) mo landmark, 44% (47%) of pts with BME achieved CR or CR with incomplete blood count recovery (CRi). Early mortality was 5.6 and 10.3% at 30 and 60 days. Of 932 (598) pts that met the 3 (6) mo landmark, a total of 39% (25%) had no BME. The impact of HI on OS became smaller the later the landmark (Tables 1 and 2). The impact of response on OS was 0.4-4.4 mo longer and significance at the 6 mo landmark was retained using IWG criteria with (Table 1) vs without (Table 2) differentiating between pts who did or did not QFR. Pts who did not QFR had similar or better OS compared with responders. At the 3 mo landmark, proposed additional response parameters HI-PBB, HI-elevated WBC and PB-CR were assoc. with a survival benefit of +7.4, +5.0 and +12.9 mo (Table 1, Fig 1A-C). Conclusions 1) The impact of HI on OS is overestimated without landmark analyses. Median time to 1st response was 3.0 mo and ≥8 weeks response duration required. We therefore suggest using a 3 mo landmark when assessing HI. 2) Using IWG criteria for HI assessment underestimates the impact of response, as non-responders are diluted by pts who do not QFR. Distinguishing QFR/not-QFR seems necessary. 3) Proposed additional HI categories (HI-PBB, HI-elevated WBC, PB-CR) add value to current response criteria. It is often the case that BME are not performed in elderly pts in real-world settings (Dinmohamed 2015; current study). Achievement of HI in any lineage and especially PB-CR might be used as a surrogate for response in pts unable or unwilling to undergo BME for response assessment. This large and growing database is suitable to allow future validation of potential novel response criteria. Disclosures Pleyer: Celgene: Other: Advisory board; Novartis: Other: Advisory board; Inflection Point Biomedical Advisors: Other: Advisory board; Agios: Other: Advisory board; Abbvie: Other: Advisory board. Pfeilstocker:Novartis: Consultancy, Honoraria; Janssen-Cilag: Honoraria; Celgene: Consultancy, Honoraria. Stauder:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Teva (Ratiopharm): Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board, Research Funding. Heibl:Daiichi Sankyo: Honoraria; Pfizer: Honoraria; Mundipharma: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AOP Orphan Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sill:Astex: Other: Advisory board; Novartis: Other: Advisory board; AbbVie: Other: Advisory board; Astellas: Other: Advisory board. Girschikofsky:Pfizer: Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria. Petzer:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Personal fees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Vallet:MSD: Honoraria; Pfizer: Honoraria; Roche Pharmaceuticals: Consultancy. Geissler:Abbvie: Honoraria; Pfizer: Honoraria; Amgen: Honoraria; AstraZeneca: Honoraria; AOP: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Roche: Honoraria; Ratiopharm: Honoraria. Sperr:Novartis: Honoraria; Celgene: Consultancy, Honoraria. Leisch:Novartis: Honoraria, Other: Travel support; Celgene: Other: Travel support; Bristol-Myers-Squibb: Honoraria. Egle:Celgene: Honoraria, Other: Advisory board and Travel support. Melchardt:MSD: Honoraria; Merck: Honoraria, Research Funding; Takeda: Honoraria; Janssen-Cilag: Honoraria; Roche: Honoraria; Novartis: Honoraria; Cephalon: Research Funding. Piringer:Amgen: Research Funding; Roche: Other: Travel support; Merck: Other: Travel support; Bayer: Research Funding. Zebisch:Roche: Honoraria; Novartis: Honoraria, Other: Advisory board; Celgene: Honoraria; AbbVie: Other: Advisory board. Machherndl-Spandl:Celgene: Other: Advisory board. Wolf:Celgene: Honoraria, Research Funding; Abbvie: Honoraria. Keil:Bionorica: Honoraria, Research Funding; Roche: Honoraria; Pfizer: Honoraria; Celgene: Honoraria; AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Daiichi Sankyo: Honoraria; Novartis: Honoraria; Merck: Honoraria, Research Funding; Takeda: Honoraria, Research Funding. Greil:Ratiopharm: Research Funding; MSD: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Cephalon: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Gilead: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Pfizer: Honoraria, Research Funding; Bristol-Myers-Squibb: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Genentech: Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Eisai: Honoraria; Mundipharma: Honoraria, Research Funding; Sanofi Aventis: Honoraria; Takeda: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; GSK: Research Funding; Sandoz: Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Janssen-Cilag: Honoraria; Amgen: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Roche: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Boehringer Ingelheim: Honoraria. OffLabel Disclosure: Azacitidine is not approved for the treatment of MP-CMML, CMML with