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The frequency of pathogenic/likely pathogenic (P/LP) germ line variants in patients with myelodysplastic syndrome (MDS) diagnosed at age 40 years or less is 15% to 20%. However, there are no comprehensive studies assessing the frequency of such variants across the age spectrum. We performed augmented whole-exome sequencing of peripheral blood samples from 404 patients with MDS and their related donors before allogeneic hematopoietic stem cell transplantation. Single-nucleotide and copy number variants in 233 genes were analyzed and interpreted. Germ line status was established by the presence of a variant in the patient and related donor or for those seen previously only as germ line alleles. We identified P/LP germ line variants in 28 of 404 patients with MDS (7%), present within all age deciles. Patients with P/LP variants were more likely to develop higher-grade MDS than those without (43% vs 25%; P = .04). There was no statistically significant difference in outcome parameters between patients with and without a germ line variant, but the analysis was underpowered. P/LP variants in bone marrow failure syndrome genes were found in 5 patients aged less than 40 years, whereas variants in DDX41 (n = 4), telomere biology disorder genes (n = 2), and general tumor predisposition genes (n = 17) were found in patients aged more than 40 years. If presumed germ line variants were included, the yield of P/LP variants would increase to 11%, and by adding suspicious variants of unknown significance, it would rise further to 12%. The high frequency of P/LP germ line variants in our study supports comprehensive germ line genetic testing for all patients with MDS regardless of their age at diagnosis.

There is a lack of large comparative study on the outcomes of reduced intensity conditioning (RIC) in acute myeloid leukemia (AML) transplantation using fludarabine/busulfan (FB) and fludarabine/melphalan (FM) regimens. Adult AML patients from Center for International Blood and Marrow Transplant Research who received first RIC allo-transplant between 2001 and 2015 were studied. Patients were excluded if they received cord blood or identical twin transplant, total body irradiation in conditioning, or graft-versus-host disease (GVHD) prophylaxis with in vitro T-cell depletion. Primary outcome was overall survival (OS), secondary end points were leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and GVHD. Multivariate survival model was used with adjustment for patient, leukemia, and transplant-related factors. A total of 622 patients received FM and 791 received FB RIC. Compared with FB, the FM group had fewer transplant in complete remission (CR), fewer matched sibling donors, and less usage of anti-thymocyte globulin or alemtuzumab. More patients in the FM group received marrow grafts and had transplantation before 2005. OS was significantly lower within the first 3 months posttransplant in the FM group (hazard ratio [HR] = 1.82, P < .001), but was marginally superior beyond 3 months (HR = 0.87, P = .05). LFS was better with FM compared with FB (HR = 0.89, P = .05). NRM was significantly increased in the FM group during the first 3 months of posttransplant (HR = 3.85, P < .001). Long-term relapse was lower with FM (HR = 0.65, P < .001). Analysis restricted to patients with CR showed comparable results. In conclusion, compared with FB, the FM RIC showed a marginally superior long-term OS and LFS and a lower relapse rate. A lower OS early posttransplant within 3 months was largely the result of a higher early NRM.

We examined the risk of subsequent neoplasms (SNs) and late mortality in children and adolescents undergoing allogeneic hematopoietic cell transplantation (HCT) for nonmalignant diseases (NMDs). We included 6028 patients (median age, 6 years; interquartile range, 1-11; range

Allogeneic hematopoietic cell transplantation (HCT) is the only curative therapy for myelofibrosis (MF). In this large multicenter retrospective study, overall survival (OS) in MF patients treated with allogeneic HCT (551 patients) and without HCT (non-HCT) (1377 patients) was analyzed with Cox proportional hazards model. Survival analysis stratified by the Dynamic International Prognostic Scoring System (DIPSS) revealed that the first year of treatment arm assignment, due to upfront risk of transplant-related mortality (TRM), HCT was associated with inferior OS compared with non-HCT (non-HCT vs HCT: DIPSS intermediate 1 [Int-1]: hazard ratio [HR] = 0.26, P < .0001; DIPSS-Int-2 and higher: HR, 0.39, P < .0001). Similarly, in the DIPSS low-risk MF group, due to upfront TRM risk, OS was superior with non-HCT therapies compared with HCT in the first-year post treatment arm assignment (HR, 0.16, P = .006). However, after 1 year, OS was not significantly different (HR, 1.38, P = .451). Beyond 1 year of treatment arm assignment, an OS advantage with HCT therapy in Int-1 and higher DIPSS score patients was observed (non-HCT vs HCT: DIPSS-Int-1: HR, 2.64, P < .0001; DIPSS-Int-2 and higher: HR, 2.55, P < .0001). In conclusion, long-term OS advantage with HCT was observed for patients with Int-1 or higher risk MF, but at the cost of early TRM. The magnitude of OS benefit with HCT increased as DIPSS risk score increased and became apparent with longer follow-up.

BACKGROUND GVHD and non-relapse mortality (NRM) remain frequent complications of HLA-matched HSCT despite the use of standard immunosuppression like tacrolimus and methotrexate. Alternative GVHD prophylaxis (PPX) strategies like T-cell depletion and post-transplant cyclophosphamide negatively impact relapse, infection, and organ toxicity, and no strategy has yet demonstrated a clear benefit for GVHD-free survival. Orca-T is an investigational cellular product comprising stem and immune cells that leverages highly purified donor regulatory T cells to control alloreactive immune responses. Unlike point-of-care graft engineering approaches, Orca-T is produced in a central GMP laboratory and has been successfully distributed to multiple centers across in the U.S. Early clinical trials using Orca-T showed a good safety profile, promising GVHD control, and potentially improved immune reconstitution. Here, we present trial results from both a single-institution Phase 1/2 trial that has completed enrollment and an ongoing multicenter Phase 1b trial. METHODS As of 28 July 2021, 113 patients aged 18-72 have received Orca-T for AML, ALL, MDS, lymphoma, or myelofibrosis. We present here data from 80 patients that have ≥90 days follow-up. 28 and 52 patients, respectively, received Orca-T followed by single-agent GVHD prophylaxis on a single-center Phase 2 study (NCT01660607) and a multicenter Phase Ib (NCT04013685). Orca-T products were derived from HLA-matched related (n=46) or unrelated (n=34) donors. Patients received a variety of myeloablative conditioning regimens (e.g., non-TBI, n=66; TBI-based, n=14) followed by single-agent PPX with either tacrolimus (n=73) or sirolimus (n=7). Median follow-up for these patients is 541 days (single-center) and 248 days (multicenter). We identified a contemporaneous SOC cohort, and we reported on their clinical outcomes at Stanford (n=95) with both matched related (n=52) and unrelated (n=43) transplant recipients who received unmanipulated PBSC products (median f/u 546) and methotrexate plus tacrolimus prophylaxis. RESULTS The Orca-T investigational cell therapy was manufactured reliably, delivered in less than 72 hours for all patients, and every patient enrolled received Orca-T. The Treg drug product was characterized by high Treg purity of 93.8% +/- 3.1% and a dose of 2.6 +/- 0.4 x 106 per kg (equivalent between trials). An Orca-T product was produced and infused for all patients, and there were no logistics failures or infusion reactions. All patients engrafted and Orca-T patients showed earlier neutrophil (median of 12 days vs. 14 days, p On the single-center, Phase 2 clinical trial study at Stanford there is evidence of improved 1-year GVHD and relapse-free survival (GRFS) which was 77% (CI 51-88%) for Orca-T patients vs 34% (CI 25-44%) with SOC (Figure 1A). We observed improved rates of >grade 2 acute GVHD at Day +180 (aGVHD, 14% versus 33%), moderate-to-severe chronic GVHD at 1 year (4% versus 42%) and NRM at 1 year (0% versus 13%). Relapse-free (RFS) and overall survival (OS) trended upwards for Orca-T. Severe infectious complications were rare. Key clinical results from both Orca-T trials are summarized in Table 1; 23 of 80 patients had ≥1 year follow-up. Consistent with findings from the single-institution study, on the multicenter study, rates of moderate-to-severe cGVHD and non-relapse mortality were low at 1-year post-transplant at 3% and 4%, respectively. For all patients who received Orca-T across both studies, we observed GRFS of 72% (Figure 1B), RFS of 78%, and OS of 91% at 1 year. These survival rates compare favorably to the contemporaneous SOC control (33%, 71% and 78%, respectively). Immune reconstitution in Orca-T patients with single agent tacrolimus appears similar to SOC except for observable differences in the IL-2 pathway. CONCLUSIONS Manufacture of high precision Orca-T investigational cell therapy drug products was scaled in a central GMP with reliable distribution to centers. Patients that received Orca-T and single-agent PPX showed significantly reduced aGVHD, cGVHD and NRM. Orca-T shows promise to improve GRFS and other transplant outcomes. Orca-T has been granted Regenerative Medicine Advanced Therapy status by the FDA, and a phase 3 prospectively, randomized study is planned. Figure 1 Figure 1. Disclosures Gandhi: Gamida Cell: Consultancy, Membership on an entity's Board of Directors or advisory committees; CareDx Inc: Honoraria. Muffly: Pfizer, Amgen, Jazz, Medexus, Pfizer: Consultancy; Astellas, Jasper, Adaptive, Baxalta: Research Funding; Adaptive: Honoraria, Other: fees for non-CME/CE services: , Research Funding. Shiraz: Kite Pharma-Gilead: Research Funding. Mehta: Kadmon: Research Funding; Incyte: Research Funding; CSLBehring: Research Funding; Syndax: Research Funding. McGuirk: Allovir: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Gamida Cell: Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Juno Therapeutics: Consultancy, Honoraria, Research Funding; EcoR1 Capital: Consultancy; Bellicum Pharmaceuticals: Research Funding; Pluristem Therapeutics: Research Funding; Fresenius Biotech: Research Funding; Astelllas Pharma: Research Funding; Novartis: Research Funding. Waller: Verastem Oncology: Consultancy, Research Funding; Cambium Oncology: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Arai: Magenta Therapeutics: Research Funding. Rezvani: US Department of Justice: Consultancy; Nohla Therapeutics: Other: One-time scientific advisory board; Pharmacyclics-Abbvie: Research Funding; Kaleido: Other: One-time scientific advisory board. Weng: Kite Pharma: Research Funding. Miklos: Adaptive Biotechnologies, Novartis, Juno/Celgene-BMS, Kite, a Gilead Company, Pharmacyclics-AbbVie, Janssen, Pharmacyclics, AlloGene, Precision Bioscience, Miltenyi Biotech, Adicet, Takeda: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics, Amgen, Kite, a Gilead Company, Novartis, Roche, Genentech, Becton Dickinson, Isoplexis, Miltenyi, Juno-Celgene-Bristol Myers Squibb, Allogene, Precision Biosciences, Adicet, Adaptive Biotechnologies: Research Funding; Kite, a Gilead Company, Amgen, Atara, Wugen, Celgene, Novartis, Juno-Celgene-Bristol Myers Squibb, Allogene, Precision Bioscience, Adicet, Pharmacyclics, Janssen, Takeda, Adaptive Biotechnologies and Miltenyi Biotechnologies: Consultancy; Pharmacyclics: Patents & Royalties. Frank: Kite-Gilead: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Research Funding; Allogene Therapeutics: Research Funding. Fernhoff: Orca Bio: Current Employment. Putnam: Orca Bio: Current Employment. McClellan: Orca Bio: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Shaw: Orca bio: Consultancy; mallinkrodt: Other: payments. Abedi: Seattle Genetics: Speakers Bureau; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Speakers Bureau. Meyer: Triursus Therapeutics: Current holder of stock options in a privately-held company; GigaImmune: Current holder of stock options in a privately-held company; Orca Biosystems: Research Funding; Indee, Jura: Consultancy.

Background: Relapsed or refractory acute myeloid leukemia (R/R AML) portends a poor prognosis, thus salvage chemotherapy is commonly used as a bridge to HSCT, however the optimal salvage regimen remains unknown. For decades cytarabine (Ara-C) has served as the backbone of regimens frequently used in the R/R setting. MEC is among the most studied regimens for R/R AML; up to 66% of patients achieve complete remission (CR), with a median survival of 36 weeks (Arcese et al., J Clin Oncol. 1991). The Ara-C couplets regimen was shown to have a similar overall response rate (ORR) of 55%, in a single study (Larson et al., Leukemia & Lymphoma. 2012). Currently, there are no studies directly comparing these regimens. Here, in a multi-institution retrospective analysis we assessed the efficacy and toxicity of MEC and Ara-C couplets therapy. Methods: We analyzed the records of 136 patients treated between 1998 and 2017. There were 87 patients (15 from University of Illinois and 72 from Indiana University) treated with MEC (mitoxantrone 8 mg/m2 IV, etoposide 80 mg/m2 IV and Ara-C 1 g/m2 x 5 days) and 49 patients (36 from University of Illinois and 13 from University of Chicago) treated with Ara-C couplets (mitoxantrone 30 mg/m2 daily and Ara-C dosed at 2 g/m2 twice daily or 3 g/m2 daily; both drugs given on days 1 and 5). The primary endpoint was comparison of response rates. Secondary endpoints included progression free survival (PFS), overall survival (OS), duration of hospitalization, hematologic and non-hematologic toxicities, and success in proceeding to HCT. Results: The median age of the MEC group was 52 years (yr) (range: 20-75 yr) vs 55 yr (22-75 yr) in the Ara-C couplets group. There were significantly more white patients in the MEC group (72% vs 41%; p = 0.004). The incidence of unfavorable cytogenetics was similar between groups; 32 in the MEC group (36.8%) and 19 in the Ara-C couplets group (38.7%). High-risk patients, as defined by Charlson Comorbidity Index (CCI) ≥4, comprised 29 of 87 (33.3%) of MEC, and 26 of 49 (53.1%) of Ara-C couplets patients (p = 0.03). Time from initial diagnosis to diagnosis of R/R AML was similar between groups, 303 days (MEC) and 306 days, respectively (p = 0.10). CR or CRi (ORR) was achieved in 44% of MEC, and 55% of the Ara-C couplets patients. OS was 159 days and 186 days, respectively (p = 0.055). PFS was 66 days in the MEC group and 113 days in the Ara-C couplets group (p = 0.56). In total, 27 (31%) of the MEC patients and 24 (49%) Ara-C couplets patients underwent HCT (p = 0.04). Within the MEC group, the median number of days to ANC and platelet recovery was 34 days and 35 days, respectively. ANC and platelet recovery was slightly longer within the Ara-C couplets group, at 41 days and 55 days, respectively (p = 0.02 for platelet recovery). The median duration of hospitalization was similar, 29 days for MEC and 30 days for Ara-C couplets. The most common adverse event was febrile neutropenia (FN), occurring in 93% of the MEC and 78% of the Ara-C couplets patients (p = 0.01). Notably, grade 3/4 GI toxicity occurred in 15 MEC (17.2%) and one (2.0%) of the Ara-C couplets patients (p = 0.01). There were no significant differences between groups in terms of pulmonary, liver, renal, cardiac or neurologic toxicities. Conclusions: This is the first large multi-institutional retrospective study directly comparing salvage regimens in a racially diverse population of R/R AML patients. While matched for a number of variables (including the incidence of unfavorable cytogenetics), patients receiving Ara-C couplets did have a significantly higher CCI. Despite this, use of the Ara-C couplets regimen resulted in improved ORR, significantly improved efficacy as a bridge to HCT, and led to a significant comparative decrease in the incidence of FN and grade 3/4 GI toxicities. Our retrospective analysis suggests that this regimen should be considered as an effective, safe salvage regimen in this population. Disclosures Patel: Janssen: Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Khan:Teva: Speakers Bureau. Stock:Jazz Pharmaceuticals: Consultancy. Odenike:ABBVIE: Honoraria, Research Funding; Pfizer: 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; CTI/Baxalta: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Dava Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncotherapy Science: Research Funding; Agios: Research Funding; Celgene: Research Funding; NS Pharma: Research Funding; Janssen: Research Funding; Astex: Research Funding; Gilead Sciences: Research Funding.

Background: The optimal setting to treat AYA patients remains a complex decision involving access to different treatment regimens, clinical trial availability, and appropriate psychosocial support. There are data to support that AYA patients with acute lymphoblastic leukemia (ALL) have better outcomes and improved overall survival when treated on pediatric inspired treatment protocols. However, limited data exist for similar patients with AML. We, therefore, sought to assess the variation in outcomes between AML patients within the AYA population treated in our pediatric setting versus adult setting. Methods: A retrospective review of patients with newly diagnosed AML aged 17-25 years old (n=33) treated at either the Indiana University Simon Cancer Center (n=20) or Riley Hospital for Children at Indiana University Health (n=13) between 2006 and 2018 was completed. All patients in the adult setting received standard induction therapy with the 7+3 (standard-dose cytarabine, anthracycline) regimen, while patients in the pediatric setting received an ADE (daunorubicin, cytarabine, etoposide) backbone +/- investigational agents per clinical trial protocols. Data were analyzed with t-tests using IBM SPSS v25 software. This study was approved by the Indiana University Institutional Review Board. Results: Median age was 23 years in patients treated in the adult setting (range 19-25) compared with 17 years (range 17-20) in the pediatric setting. As per the most recent NCCN risk classification for AML, patients in the adult setting were classified as 55% poor risk, 35% intermediate risk, and 10% favorable risk; in the pediatric setting, risk classification was 15% poor risk, 62% intermediate risk, and 23% favorable risk. The incidence of FLT3 mutations was n=4 (20%) in the adult setting and none in the pediatric setting. Clinical trial enrollment was markedly lower in the adult setting with no patients enrolled compared with 54% (7/13) enrolled in the pediatric setting. Complete response (CR) was achieved in 85% of patients treated in the adult setting, but only 62% of patients treated in the pediatric setting. Relapse post induction was higher in the pediatric setting (n=6, 46%) compared to the adult setting (n=5, 40%), and median time to relapse was shorter in the pediatric setting (275 days vs. 344 days). During induction, no statistically significant differences in toxicities were found as measured by ICU interventions (dialysis, mechanical ventilation/NIPPV, and/or use of vasopressors) and identified infections (bacteremia, pneumonia, and/or clostridium difficile). Clostridium difficile infections were increased in the adult setting (15% vs. 0%), but identified bacteremia was higher in the pediatric setting (38% vs. 20%). The median time to allogeneic stem cell transplantation in the adult setting was 117.5 days compared to a median of 223 days seen in the pediatric setting. Incidence of relapse post stem cell transplantation was higher in the adult setting (36% vs. 17%). Proportion of overall survival was 50% (n=10) in the adult setting and 28% (n=8) in the pediatric setting. The highest mortality was seen in poor-risk patients (90%) in the adult setting and intermediate risk patients (62.5%) in the pediatric setting. A trend was seen towards improved overall survival in the adult setting with median overall survival of 739.5 days in the adult setting compared to 415 days in the pediatric setting (p=0.11). In both settings, patients that proceeded to stem cell transplantation had conferred survival benefit: median 1128 vs. 414.5 days in the adult setting and median 530.5 vs. 486.5 days in the pediatric setting. Conclusion: Despite having a higher risk population and lower clinical trial enrollment, we found a trend towards higher complete response rate after induction, reduced relapse rate after induction, shorter time to transplant, longer time to relapse post-transplant, improved survival in the transplant population, and improved median overall survival without a clear increase in toxicity in patients treated in our adult setting. This is in contrast to data in ALL, which suggests improved patient outcomes in AYA patients treated with pediatric based regimens. Our data is limited by a small sample size and a single institution experience. Larger, multicenter studies are needed to understand the optimal AML treatment strategy in the AYA population. Table. Table. Disclosures No relevant conflicts of interest to declare.

Introduction: Chemotherapy induced peripheral neuropathy (CIPN) is a recognized clinical outcome of vinca alkaloid based therapy that frequently results in dose reduction or therapy discontinuation, but the determinants of interpatient variability remain unpredictable. Previous pharmacogenetics studies have demonstrated that vincristine is metabolized through the CYP3A system with the CYP3A5*3 variant (GG allele at rs776746) having the least efficacy in metabolizing vincristine to its inactive metabolite M1 and conferring higher risk of neurotoxicity. Similarly, a single nucleotide polymorphism (SNP) in the promoter of the CEP72 gene (TT allele at rs924607) has been described as being significantly associated with increased risk and severity of vincristine-associated peripheral neuropathy in the pediatric population. Our recent studies have further studied the incidence of this risk allele and its correspondence with CIPN in the adult population treated with vincristine. This study aimed to investigate if an additive SNP analysis, both for CYP3A5*3 and CEP72, would determine increased predictability of CIPN in patients treated with vinca alkaloids. Methods: A retrospective case-control study of patients was completed in patients that were exposed to vinca alkaloids (vincristine, vinorelbine, and vinblastine) at Geisinger Medical Center from 2007-2015. Available samples of these patients were identified in the Geisinger MyCode bio banking project and the SNP of interest was genotyped using the TaqMan® SNP Genotyping Assay, with genotypic discrimination performed using SDS software (Applied Biosystems). Cases of CIPN were confirmed with retrospective chart review. Statistical analysis was conducted using SAS (SAS Institute Inc.) software, version 9.4. All genotyping and chart review was conducted by personnel blinded to sample identity. Results: A total of 121 patients had genotype mapping completed, of which 60 patients received vincristine, 33 received vinblastine, and 28 received vinorelbine. CIPN was detected in 35.5% of the study population. The CEP72 risk allele (TT) was detected in 14.9% (n=18) of the cohort and the CYP3A5*3 risk allele (GG) was detected in 89.2% (n=108) of the cohort, with similar incidence in each drug class. The median age of this population was 61 years of age with 52.9% (n=64) being males. Multivariate logistic regression analysis, controlling for age and sex, did not demonstrate a significant model for the recessive genetic model of both SNPs with all vinca alkaloids (p=0.33), vincristine alone (p=0.26), vinorelbine alone (p=0.98), or vinblastine alone (p=0.97). The incidence of the inactive G/G allele for CYP3A5*3 was seen in 87.5% (n=21) of the vincristine cohort with neuropathy, The incidence of neuropathy was higher in patients with the TT genotype (75%) in patients receiving vincristine therapy than with the CT or CC genotype (35.7%). As consistent with prior findings, a similar dominant effect was not detected in vinorelbine or vinblastine groups. In the vincristine population (n=60), diseases that were treated included diffuse large B-cell lymphoma (n=29), acute lymphoblastic leukemia (n=6), oligoastrocytoma (n=5), and Ewing's sarcoma (n=2). No disease specific variation in neuropathy incidence and association with TT genotype was detected. Patients received a median three doses of vincristine at 2 mg each (total 6 mg) before detection of CIPN. Four patients (6.67%) of the patients required dose adjustment of chemotherapy, including dose reduction (n=2) or early discontinuation (n=2). Conclusions: This study demonstrates that the CEP72 genotype confers predictive modeling for patients receiving vincristine-based therapy and that including CYP3A5*3 analysis in an additive model is not associated with an increased predictive model for CIPN in patients receiving vinca alkaloid based therapy. In our population, the high incidence of the inactive G/G allele of CYP3A5*3 made it difficult to discern a significant effect in patients that experienced neuropathy. Larger studies are needed to include a more diverse population to confirm this predictive association and to understand if this can help guide precision-based chemotherapy administration and favorably impact disease prognosis. Disclosures No relevant conflicts of interest to declare.