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OBJECTIVE ABO mismatch between donor and recipient occurs in 40% of allogeneic hematopoietic stem cell transplantations (HCT). Different strategies have been described to reduce isohemagglutinins (IHA) before HCT. We describe the effect of selective ABO immunoadsorption (ABO IA) on erythrocyte transfusion rate and the development of post-transplant pure red cell aplasia (ptPRCA). METHODS 63 patients with major ABO incompatibility were retrospectively analyzed. Nine patients with major ABO incompatibility and high-IHA titer were treated by ABO IA before HCT. We analyzed the need for transfusion and the occurrence of ptPRCA. We compared the outcome with patients treated by other methods to reduce IHA. RESULTS In all nine patients treated by ABO IA, IHA decreased in a median four times. PtPRCA occurred in one patient. The median number of transfusions was 8 (range: 0-36) between d0 and d100. In 25 patients with high-IHA titer without treatment or treated by other methods to reduce IHA, the need for transfusions was comparable. No difference in the incidence of ptPRCA was observed. CONCLUSIONS Selective ABO IA is a feasible, safe, and effective method to reduce IHA before HCT in major ABO incompatibility. No effect on transfusion rate or ptPRCA compared to other strategies could be observed.

The ideal post-remission strategy in patients with intermediate-risk (IR) acute myeloid leukemia (AML) in first complete remission (CR) has been a matter of debate. To address this question, one hundred and forty-three patients with AML, IR cytogenetics in first CR or CRi, aged ≤ 60 years with an available HLA-matched sibling or unrelated donor were randomized 1:1 to either receive allogeneic HCT or high-dose cytarabine for consolidation and salvage HCT only in case of relapse. According to the intent-to-treat analysis, the probability of survival at 2 years was 71% (95%-CI 60-81%) and 84% (95%.CI 73-92%) in Arm A (Primary allogeneic HCT) and Arm B (Chemo-consolidation), respectively (p=.120). Disease-free survival after HCT in CR1 at 2 years was 69% (95%-CI 57-80%) compared to 41% (95%-CI 29-54%; p=.001). The cumulative incidence of relapse was 20% (95% CI 13-31%) and 57% (95%-CI 46-71%; p

Higher doses of cytarabine appear to improve long-term outcome in acute myeloid leukemia (AML), in particular for younger patients. To this end, the optimal dosage of single agent cytarabine in consolidation therapy remains elusive. Here, we assessed the impact of different dosages of cytarabine consolidation after 7 + 3 induction on outcome in a large real-world data set from the German Study Alliance Leukemia-Acute Myeloid Leukemia (SAL-AML) registry. Patients below 65 years of age, registered between April 2005 and September 2020, who attained complete remission after intensive induction and received at least one consolidation cycle with intermediate (IDAC) or high dose cytarabine (HiDAC) were selected. To account for differences in patient and disease characteristics between both groups, the average treatment effect was estimated by propensity score weighting. Six-hundred-forty-two patients received HiDAC consolidation with median dosage of median 17.6 (IQR, 16.5–18.0) g/m² for a median number of 3 cycles (IQR, 2–3), whereas 178 patients received IDAC consolidation with 5.9 (IQR, 5.7–8.6) g/m² for a median of 2 cycles (IQR, 1–3). Both groups differed significantly in some important characteristics (age, sex, cytogenetic risk group, ECOG performance status, disease status, HCT-CI, number of induction cycles). After propensity score weighting for differences in patient and disease characteristics, relapse-free survival after 2 years was comparable between HiDAC-treated (55.3%) and IDAC-treated (55.6%) patients. Moreover, no significant differences in overall survival were observed after 2 years (84.7 vs. 80.6%). Notably, more patients treated with IDAC received allogeneic hematopoietic cell transplantation in first remission (37.6 vs. 19.8%, p

BACKGROUND: Fiberoptic bronchoscopy (FOB) with broncho-alveolar lavage (BAL) is frequently performed in patients with hematological malignancies and pulmonary opacities. While the safety of the procedure in this patient population has been shown, data about the diagnostic yield widely differ between studies. Furthermore, data comparing diagnostic yield and safety of flexible bronchoscopy to narrow sources of pulmonary infections in patients with and without underlying hematological malignancy are lacking. METHODS: We carried out a retrospective analysis of bronchoscopies done for the diagnostic work-up of pulmonary infections. Diagnostic yield and the occurrence of complications in patients with and without hematological disease were compared. RESULTS: In total n=268 bronchoscopies were done in patients suffering from a hematological malignancy (HM) compared to n=408 bronchoscopies in patients without hematological malignancy (NHM). The overall diagnostic yield was similar and did not differ between the groups (HM: 67.2% vs. NHM: 64.7%; P=0.5622). However, when cultures positive for Candida were not considered as clinically relevant diagnostic yield was higher in the HM group (HM: 62.7% vs. NHM: 53.9%; P=0.0261) due to a higher detection rate of fungi and viruses (both P0.05). There was no difference in the complication rate between the groups and most complications were considered as minor. CONCLUSIONS: In summary, our data demonstrate similar diagnostic yield and safety of flexible bronchoscopy for diagnosing pulmonary infection in patients with and without underlying hematological malignancy.

Background: Trisomy 4 is a recurrent but rare cytogenetic abnormality reported in patients with acute myeloid leukemia (AML). The prognostic significance of this abnormality in AML patients is not clear. Prognosis of AML patients with trisomy 4 seems to be poor as compared to that of patients with intermediate-risk cytogenetics. Allogeneic hematopoietic stem cell transplantation (allo-HCT) may improve survival if applied early in first complete remission (CR). However, neither prospective clinical nor larger retrospective cohort studies are available to support these results from small series. Aims: To characterize AML patients with trisomy 4 and compare outcomes according to different treatment strategies. Methods: We retrospectively studied 123 AML patients with trisomy 4 (median age at diagnosis, 58 years; range, 16-76 years) treated between 2000 and 2019 within 2 large study groups. Standard statistical methods were applied. Results: Median white blood cell count at diagnosis was 4.8/nl (range, 0.4-255/nl) and platelets 46/nl (range, 2-330/nl). Type of AML was de novo in 97 (79%), secondary after myelodysplastic syndrome/myeloproliferative neoplasm in 18 (15%), and therapy-related in 8 (6%) patients. Sixty-two (50%) patients were female. Cytogenetic analysis revealed trisomy 4 as the sole abnormality in 28 (23%), additional abnormalities in 95 (77%) patients, most frequently ≥3 (n=66) abnormalities, trisomy 8 (n=41), karyotypes characterized by trisomies only (n=21) and t(8;21) or inv(16) (CBF; n=10). A total of 98 patients (80%) had NPM1 and FLT3-ITD mutation testing. Of those, 21 (21%) and 15 (15%) harbored NPM1 and FLT3-ITD mutations. Only 2 (3%) of 72 patients were CEBPA double mutated. Data on response to intensive anthracycline-based induction therapy were available in 117 patients. Early death rate was 5% (n=6). CR was achieved in 68% (n=79) with 22 (19%) requiring an intensive salvage treatment cycle. Notably, patients with trisomy 4 as sole abnormality had a CR rate of 89% (n=25/28). There was no difference in the CR rate in FLT3-ITD positive (n=10/15) as compared to FLT3 wild type (n=56/83) patients (67% each, P=0.99). Univariable analysis revealed trisomy 4 as sole abnormality (OR, 5.76; P=0.007) and NPM1 (OR, 12.08; P=0.02) as favorable factors. An allo-HCT was performed in 40 (34%) patients, of whom 19 patients were transplanted in first CR after induction therapy. Nine patients achieved CR after salvage chemotherapy and went on to allo-HCT; another 12 patients received allo-HCT with active disease. Type of donor was matched-related in 8, matched-unrelated in 30, and unknown in 2 of the 40 patients, respectively. Median follow-up of the intensively treated cohort was 73 months (95%-CI, 36-91 months). Five-year overall survival (OS) and relapse-free survival (RFS) were 31% (95%-CI, 23-42%) and 27% (95%-CI, 18-42%). OS rates were significantly higher in patients with CBF leukemia or patients with trisomy 4 as compared to all other abnormalities (Figure 1; P Conclusions: Clinically, patients with trisomy 4 are very heterogeneous in particular with respect to cytogenetic and molecular abnormalities. In our cohort, patients with trisomy 4 as a sole abnormality had a high CR rate and favorable clinical outcome. In the total cohort, allo-HCT did not improve RFS. Figure 1 Figure 1. Disclosures Krause: Siemens: Research Funding; Takeda: Honoraria; Pfizer: Honoraria; art-tempi: Honoraria; Kosmas: Honoraria; Gilead: Other: travel support; Abbvie: Other: travel support. 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. Haenel: Takeda: Consultancy, Honoraria; Bayer Vital: Honoraria; Jazz: Consultancy, Honoraria; GSK: Consultancy; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy; Celgene: Consultancy, Honoraria. Crysandt: Incyte: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees. Fransecky: Medac: Honoraria; Amgen: Honoraria; Abbvie: Honoraria, Research Funding; Novartis: Honoraria; Takeda: Honoraria. Martinez-Lopez: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: 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; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: 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; Janssen: 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; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Einsele: Janssen, Celgene/BMS, Amgen, GSK, Sanofi: Consultancy, Honoraria, Research Funding. Platzbecker: AbbVie: Honoraria; Celgene/BMS: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Geron: Honoraria; Takeda: Honoraria. Baldus: Novartis: Honoraria; Amgen: Honoraria; Celgene/BMS: Honoraria; Jazz: Honoraria. Müller-Tidow: Pfizer: Research Funding; Janssen: Consultancy, Research Funding; Bioline: Research Funding. Levis: Astellas and FujiFilm: Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Honoraria; Amgen, Astellas Pharma, Daiichi-Sankyo, FujiFilm, and Menarini: Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria; Takeda: Honoraria. Montesinos: Stemline/Menarini: Consultancy; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Forma Therapeutics: Consultancy; Glycomimetics: Consultancy; Tolero Pharmaceutical: Consultancy; Agios: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau. Röllig: Roche: Honoraria, Research Funding; Bristol-Meyer-Squibb: Honoraria, Research Funding; Janssen: Honoraria; Jazz: Honoraria; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Amgen: Honoraria; AbbVie: Honoraria, Research Funding. Schlenk: Novartis: Honoraria; Pfizer: Honoraria, Research Funding, Speakers Bureau; Hexal: Honoraria; Neovio Biotech: Honoraria; Daiichi Sankyo: Honoraria, Research Funding; Celgene: Honoraria; Astellas: Honoraria, Research Funding, Speakers Bureau; Abbvie: Honoraria; Agios: Honoraria; Roche: Honoraria, Research Funding; AstraZeneca: Research Funding; Boehringer Ingelheim: Research Funding.

Leukemia : normal and malignant hemopoiesis ; a peer-reviewed journal 36, 80-89 (2022). doi:10.1038/s41375-021-01316-z, Published by Springer Nature, London

Background Double induction using two subsequent 7+3 regimens of cytarabine plus anthracycline is commonly performed in AML patients with an adequate performance status in order to maximize dose intensity upfront. However, for patients with a good early response at day 15 of first induction, there is no prospective randomized evidence on the necessity or value of a second induction cycle. Aims In order to answer the question if good responders of the first 7+3 induction could be spared a second induction cycle, we set up randomized-controlled SAL DaunoDouble trial. The study prospectively assesses the outcome of patients with a good early response with respect to the number of induction cycles (single versus double). We assumed non-inferiority of single induction in terms of complete remission (CR/CRi) rate, based on a margin of 7.5%. Here, we present the results of the planned interim analysis. Methods Patients (pts) 18-65 years with newly diagnosed AML, normal cardiac and organ function received a first induction cycle with seven days of cytarabine plus three days of daunorubicin ("7+3"). Response assessment in bone marrow was done on day 15 after the initiation of chemotherapy and confirmed by central review. A blast count Results Between 2014 and 2020, 624 evaluable pts were enrolled and received the first induction cycle with 7+3. A marrow blast clearance below 5% on day 15 was achieved in 298 pts (48%), providing eligibility for randomization. Of these patients, 150 were randomized into arm S and 148 into arm D, respectively. Median age was 52 years, 92% had de novo AML, NPM1 mutation was present in 53%, FLT3-ITD in 25% of pts. Favorable, intermediate and adverse risk (ELN 2017) were present in 56%, 34% and 10% of pts, respectively. CR/CRi rates at the end of induction were 86% after single induction and 85% after double induction. The CR/CRi rates in 224 pre-defined per-protocol pts were 88% versus 91%, resulting in a CR difference of 3% (95%-CI -0.047-0.111; p for non-inferiority test 0.145). After a median follow-up time of 24 months, RFS was slightly but not significantly lower after single induction with a 3-year RFS of 53% versus 64% (HR 1.4, p=0.125), whereas no differences were seen in 3-year OS, with a of rate of 74% versus 75% (HR 1.1, p=0.645) after single versus double induction. Conclusion The interim analysis results show that in good responders, the difference between CR rates after single versus double induction was even smaller than the predefined 7.5% margin, suggesting a trend for non-inferiority of single induction, although statistical significance was not reached. The trial continued recruitment. These findings suggest that in good responders, it may be safe to omit a second induction cycle if a second cycle poses a high risk. Figure. CR + CRi, RFS and OS after randomization to single versus double induction. Disclosures Alakel: Pfizer: Consultancy. Jost:Pfizer: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; JAZZ: Other: travel support; Celgene: Other: travel support. Novak:Roche: Consultancy; Janssen: Other: Travel expenses; Takeda: Consultancy; Amgen: Consultancy, Other: Travel expenses; Pfizer: Consultancy; Novartis: Consultancy. Krause:Takeda: Honoraria; Celgene: Other: Travel Support; MSD: Honoraria; Pfizer: Honoraria; Siemens: Research Funding; Gilead: Other: Travel Support. Held:Roche: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; BMS: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; MSD: Consultancy; Acrotech: Research Funding; Spectrum: Research Funding; Amgen: Research Funding. Platzbecker:AbbVie: Consultancy, Honoraria; Amgen: Honoraria, Research Funding; Geron: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria. Thiede:AgenDix GmbH: Other: Co-owner and CEO. Müller-Tidow:Daiichi Sankyo: Research Funding; Pfizer: Research Funding, Speakers Bureau; BiolineRx: Research Funding; Janssen-Cilag GmbH: Speakers Bureau.

Resume La greffe allogenique de cellules souches hematopoietiques (CSH) est une therapeutique usuelle pour de nombreuses maladies hematologiques. Au cours des dernieres decennies, des progres importants ont ete realises dans les domaines de la prise en charge des patients. La selection des donneurs, les conditionnements de greffe et les soins de support des patients ont contribue a l’amelioration de la survie des patients. La plupart des procedures en rapport avec la greffe allogenique de CSH ont ete standardisees par des recommandations nationales ou internationales amenant a des certifications telles que Joint Accreditation Committee ISCT-Europe & EBMT (JACIE). Mais tous ces standards et ces recommandations ne definissent pas de facon precise les moyens minimums humains et materiels necessaires a la realisation de telles procedures. En plus, les unites dans lesquelles sont places ces patients sont soumises a des regles architecturales et procedurales non uniformisees. Lors de cet atelier, nous avons tente de definir une trame minimale concernant le personnel, l’infrastructure architecturale et des pratiques d’hygiene generales pour les patients, le personnel et les visiteurs.

Background Venetoclax (VEN)-based combination therapy with hypomethylating agents (HMA) has been approved for first-line treatment in patients ineligible for intensive treatment based on two randomized trials. There is some evidence for efficacy also in the in relapsed/ refractory setting (R/R), but comparative controlled data is lacking. Here, we report our experience of VEN-Azacitidine (AZA) in R/R AML salvage treatment and bridge to allogeneic cell transplantation (allo-HCT) in fit patients compared to historical data from the Study Alliance Leukemia (SAL) registry (ClinicalTrials.gov Identifier: NCT03188874). Design/Methods We analyzed all patients with R/R AML after initial intensive therapy, who started VEN-AZA salvage treatment at the University Hospital Heidelberg, between October 2018 and October 2020. Patients, who were bridged to allo-HCT were compared in a multivariable analysis to data of R/R AML patients from the SAL registry receiving an allo-HCT. Results: A total of 26 patients (median age 60 years, range 23 to 79) were included. All patients initially received intensive therapy, 16 patients (62%) had been refractory to intensive induction therapy with DA (daunorubicin, cytarabine) (11 patients)/ CPX-351 (2 patients) or to an intensive salvage therapy regime with HAM (2 patients)/ Cytarabin-Bortezomib (1 patient). Ten patients (38%) had morphologic (7 patients) or molecular relapse (3 patients) after intensive first line therapy. The distribution of AML according to WHO-2016 classification was n=10 recurrent genetic abnormalities (n= 7, mutated NPM1; n=1, biallelic CEBPA mutations; n=1, mutated RUNX1; n=1, CBFB-MYH11), n=10 AML with MRC, n=6 AML NOS. According to the 2017 ELN classification, 9 patients (34,5%) had low risk, 8 (31%) intermediate risk and 9 (34,5%) adverse risk disease. All patients received AZA 75mg/m² for 7 days combined with VEN 400mg/day after initial ramp up or a reduced dose of 100mg/day in case of co-medication with azoles in 28 days cycles. Best response was CR/CRi in 58% (n=15), PR in 23% (n=6) patients. Day 30-mortality was 0%, day 60-mortality was 4% (n=1). Allo-HCT was performed in 20 patients (77%). Pre-Allo-HCT remission status was CR/CRi in 11 (55%), PR in 4 (20%) patients and MLFS in 1 patient and 4 patients had active disease (n=3, relapse after achieving CR/CRi on VEN-AZA, n=1 refractory to VEN-AZA.). At the time of analysis 15 (75%) of the 20 bridged patients were alive and 11 (55%) are still in CR resulting in a median relapse-free survival in bridged patients of 406 days, whereas all patients not proceeding to allo-HCT died after a median of 139 days. In total, 63 patients with R/R AML were identified in the SAL-registry proceeding to allo-HCT with non VEN-based salvage attempt. Pre-Allo-HCT remission status was CR/CRi in 18 (28%), PR in 15 (24%), unknown in 13 patients (21%) and 17 (27%) patients had active disease (n=9 relapsed, n=8 refractory). Patients of the SAL registry were younger (median, 55 years; range, 22-75 years) and more patients were ELN-int (low risk, 32%, n=20; int, 52%, n=33, adv, 16%, n=10). Median follow-up in the VEN-AZA and the SAL cohorts were 1.4 years and 4.6 years, respectively. Cox-regression modeling of survival measured from the date of being refractory/relapsed revealed a non-significant effect of the cohorts favoring the VEN-AZA salvage therapy (HR, 0.87, p=0.73). However, stratified univariable survival analysis revealed in trend better survival (p=0.10) in the VEN-AZA compared to the SAL cohort with 77% (95%-CI, 62-95%) and 74% (95%-CI, 57-97%) as well as 84% (95%-CI, 76-94%) and 52% (95-CI, 41-68%) 1- and 2-years survival, respectively. Conclusion: Our data confirms the efficacy of VEN-AZA in patients with R/R AML and underlines its potential as an effective strategy for bridging to successful allo-HCT. Disclosures Unglaub: JazzPharma: Consultancy, Other: travel costs/ conference fee; Novartis: Consultancy, Other: travel costs/ conference fee. Schlenk: Boehringer Ingelheim: Research Funding; AstraZeneca: Research Funding; Roche: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria; Neovio Biotech: Honoraria; Hexal: Honoraria; Daiichi Sankyo: Honoraria, Research Funding; Celgene: Honoraria; Astellas: Honoraria, Research Funding, Speakers Bureau; Abbvie: Honoraria; Agios: Honoraria. Middeke: Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Gilead: Consultancy; Abbvie: Consultancy, Honoraria; Jazz: Consultancy; Pfizer: Consultancy, Honoraria; Sanofi: Honoraria, Research Funding; Astellas: Consultancy, Honoraria; Novartis: Consultancy; Glycostem: Consultancy; UCB: Honoraria. Krause: Siemens: Research Funding; Takeda: Honoraria; Pfizer: Honoraria; art-tempi: Honoraria; Kosmas: Honoraria; Gilead: Other: travel support; Abbvie: Other: travel support. 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. Haenel: GSK: Consultancy; Jazz: Consultancy, Honoraria; Bayer Vital: Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy; Celgene: Consultancy, Honoraria. Crysandt: Pfizer: Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria. Fransecky: Medac: Honoraria; Abbvie: Honoraria, Research Funding; Amgen: Honoraria; Takeda: Honoraria; Novartis: Honoraria. Einsele: Janssen, Celgene/BMS, Amgen, GSK, Sanofi: Consultancy, Honoraria, Research Funding. Seggewiss-Bernhardt: Astra-Zeneca: 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; Celgene: 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; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; ipsen: 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; 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; EusaPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. Platzbecker: AbbVie: Honoraria; Celgene/BMS: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Geron: Honoraria; Takeda: Honoraria. Baldus: Amgen: Honoraria; Celgene/BMS: Honoraria; Jazz: Honoraria; Novartis: Honoraria. Dreger: Bluebird Bio: Consultancy; AstraZeneca: Consultancy, Speakers Bureau; BMS: Consultancy; AbbVie: Consultancy, Speakers Bureau; Janssen: Consultancy; Gilead Sciences: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Riemser: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Speakers Bureau. Müller-Tidow: Pfizer: Research Funding; Janssen: Consultancy, Research Funding; Bioline: Research Funding. Sauer: Takeda: Consultancy, Other: DSMB/SAB Member; Matterhorn Biosciences AG: Consultancy, Other: DSMB/SAB Member; Abbvie: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau. OffLabel Disclosure: off-label use of Venetoclax-based combination therapy in relapsed or refractory AML

Allogeneic hematopoietic cell transplantation (HCT) offers the highest chance for cure in patients with adverse-risk acute myeloid leukemia (AML) when performed in first remission (CR1). In contrast, patients in CR1 with favorable risk do not seem to benefit from allogeneic HCT due to the inherent risk of transplant-related mortality. Donor vs. no donor comparisons as well as prospective matched-pair analyses have suggested that allogeneic HCT performed in intermediate-risk AML may provide a higher probability of overall survival or relapse-free survival in patients ≤ 60 years of age with an acceptable risk for transplant-related mortality. On the other hand, many intermediate-risk patients relapsing after conventional chemotherapy may be successfully salvaged by allogeneic HCT. The role of allogeneic HCT in cytogenetically defined intermediate-risk AML patients in CR1 was addressed by a prospective randomized trial performed in 16 centers in Germany. Key inclusion criteria were: AML with intermediate-risk cytogenetics, first CR or CRi after conventional induction therapy, age of 18-60 years, and availability of an HLA-matched sibling or unrelated donor. For unrelated donors, a 9 out of 10 HLA allelic match was acceptable except for patients with an NPM1 mutation, for whom full 10/10 allele matching was required. Randomization was stratified according to age (< 40 vs. 40-60), NPM1/FLT3, and CEBP-alpha mutational status and unrelated vs. related donor availability. Endpoints included overall-survival as primary outcome and relapse-free survival (RFS), cumulative incidence of relapse, treatment-related mortality, and quality of life measured according to the short form (36) health status. From 2010 - 2018, 143 patients in CR1 were randomized into Arm A (n=76, allogeneic HCT) and Arm B (n=67, conventional consolidation and allo-HCT only in case of relapse). In July 2018, the trial was stopped prematurely due to slow accrual (143 out of 356 pts. randomized). Median age of the trial cohort was 51 years (range, 19-60), with 42% exhibiting an NPM1 and 25% a FLT3 mutation. A normal karyotype was reported in 84% of the included patients. All mentioned characteristics did not differ between both treatment arms. Sibling donors were available for 44 (31% of patients), matched unrelated donors for 99 (69%) patients. According to the intent-to-treat analysis, the probability of survival at 2 years was 71% (95% CI 60-81%) and 84% (95% CI 73-92%) in Arm A (Transplant) and Arm B (conventional consolidation), respectively (p=0.120, Figure 1A). RFS after allogeneic HCT was 69% (95% CI 57-80%) compared to 41% (95% CI 29-54%) after conventional consolidation (p=0.001, Figure 1B). Primary allogeneic HCT reduced the cumulative incidence of relapse at 2 years from 57% [95%-CI 46-71%] after conventional consolidation to 20% [95%-CI 13-31%] after HCT (p SF (36) scoring suggested a trend towards a lower physical functioning throughout the first 3 months after randomization in the primary HCT arm. No significant differences in vitality, mental health, social and emotional functioning could be documented between both treatment arms. In summary, the results of this first prospective randomized trial did not show that allogeneic HCT performed immediately after achievement of CR1 in patients with cytogenetically defined intermediate-risk AML ≤ 60 years of age conveys an overall survival advantage. However, allogeneic HCT in CR1 significantly reduced the relapse risk and was not associated with relevant impairments in quality of life. Although the limited statistical power of the trial does not allow definitive conclusions, delayed allogeneic transplantation seems to be a potential treatment algorithm in CR1 intermediate-risk AML with an available donor. Figure 1 Figure 1. Disclosures Schliemann: Jazz Pharmaceuticals: Consultancy, Research Funding; Roche: Consultancy; Philogen S.p.A.: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; AstraZeneca: Consultancy; Boehringer-Ingelheim: Research Funding; Novartis: Consultancy; Abbvie: Consultancy, Other: travel grants; Astellas: Consultancy; BMS: Consultancy, Other: travel grants. 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 . Glass: Riemser: Research Funding; Roche: Consultancy, Research Funding, Speakers Bureau; Kite: Consultancy; BMS: Consultancy; Novartis: Consultancy; Helios Klinik Berlin-Buch: Current Employment. Platzbecker: Janssen: Honoraria; Celgene/BMS: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Geron: Honoraria; AbbVie: Honoraria. Burchert: Novartis: Honoraria, Research Funding; AOP Orphan: Honoraria, Research Funding; Pfizer: Honoraria; Incyte: Honoraria; Gilead: Honoraria; BMS: Honoraria. Haenel: Jazz: Consultancy, Honoraria; GSK: Consultancy; Bayer Vital: Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy; Celgene: Consultancy, Honoraria. Mueller: Amgen: 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, Other: Travel Support; CTI: Membership on an entity's Board of Directors or advisory committees; Gentium: Other: Travel Support; Gilead: Other: Travel Support; Janssen: Other: Travel Support; Novartis: Other: Travel Support; Pfizer: Other: Travel Support; Sanofi: Other: Travel Support. Berdel: Philogen S.p.A.: Consultancy, Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees. Stelljes: Novartis: Consultancy, Speakers Bureau; MSD: Consultancy, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; Kite/Gilead: Consultancy, Speakers Bureau; Celgene/BMS: Consultancy, Speakers Bureau; Medac: Speakers Bureau; Amgen: Consultancy, Speakers Bureau.

COVID‐19 carries a high risk of severe disease course, particularly in patients with comorbidities. Therapy of severe COVID‐19 infection has relied on supportive intensive care measures. More specific approaches including drugs that limit the detrimental “cytokine storm”, such as Janus‐activated kinase (JAK) inhibitors, are being discussed. Here, we report a compelling case of a 55‐yo patient with proven COVID‐19 pneumonia, who was taking the JAK1/2 inhibitor ruxolitinib in‐label for co‐existing primary myelofibrosis for 15 months prior to coronavirus infection. The patient had significant comorbidities, including chronic kidney disease, arterial hypertension, and obesity, and our previous cohort suggested that he was thus at high risk for acute respiratory distress syndrome (ARDS) and death from COVID‐19. Since abrupt discontinuation of ruxolitinib may cause fatal cytokine storm and ARDS, ruxolitinib treatment was continued and was well tolerated, and the patient´s condition remained stable, without the need for mechanical ventilation or vasopressors. The patient became negative for SARS‐CoV‐2 and was discharged home after 15 days. In conclusion, our report provides clinical evidence that ruxolitinib treatment is feasible and can be beneficial in patients with COVID‐19 pneumonia, preventing cytokine storm and ARDS.

In fit patients with newly diagnosed acute myeloid leukemia (AML), immediate treatment start is recommended due to the poor prognosis of untreated acute leukemia. We explored the relationship between time from diagnosis to treatment start (TDT) and prognosis in a large real-world data set from the German Study Alliance Leukemia–Acute Myeloid Leukemia (SAL-AML) registry. All registered non–acute promyelocytic leukemia patients with intensive induction treatment and a minimum 12 months of follow-up were selected (n = 2263). We analyzed influence of TDT on remission, early death, and overall survival (OS) in univariable analyses for each day of treatment delay, in groups of 0 to 5, 6 to 10, 11 to 15, and >15 days of TDT, adjusted for influence of established prognostic variables on outcomes. Median TDT was 3 days (interquartile range, 2-7). Unadjusted 2-year OS rates, stratified by TDT of 0 to 5, 6 to 10, 11 to 15, and >15 days, were 51%, 48%, 44%, and 50% (P = .211). In multivariable Cox regression analysis accounting for established prognostic variables, the TDT hazard ratio as a continuous variable was 1.00 (P = .617). In OS analyses, separately stratified for age ≤60 and >60 years and for high vs lower initial white blood cell count, no significant differences between TDT groups were observed. Our study suggests that TDT is not related to survival. As stratification in intensive first-line AML treatment evolves, TDT data suggest that it may be a feasible approach to wait for genetic and other laboratory test results so that clinically stable patients are assigned the best available treatment option. This trial was registered at www.clinicaltrials.gov as #NCT03188874.

Background: Acute myeloid leukemia (AML) is characterized by a high relapse rate, indicating insufficient clearance of leukemia-initiating cells. Depending on genetic risk stratification, consolidating chemotherapy proves to significantly reduce the risk of relapse. In particular, in younger AML patients higher dosage of cytarabine appears to improve long-term outcome, while there is no apparent benefit of multiagent combination, compared to cytarabine monotherapy. However, to this end the optimal dosage of single agent cytarabine in consolidation therapy after 7+3 remission induction remains elusive. Methods: Here, we retrospectively assessed the impact of different dosages of cytarabine consolidation on outcome in a large real-world data set from the German Study Alliance Leukemia-Acute Myeloid Leukemia (SAL-AML) registry. Patients below 65 years of age, registered between April 2005 and September 2020 with non-acute promyelocytic leukemia, who attained complete remission after intensive induction and received at least one consolidation cycle with intermediate (IDAC) or high dose cytarabine (HiDAC) were selected. To account for differences in patient and disease characteristics between both groups, the average treatment effect was estimated by propensity score weighting. Results: 642 patients received HiDAC consolidation with a median dosage of 5794.88 (IQR, 4745.48-5971.56) mg/m 2/d with a median number of 3 cycles (IQR, 2-3), whereas 178 patients received IDAC consolidation with 1946.16 (IQR, 1869.51-2469.15) mg/m 2/d with a median of 2 cycles (IQR, 1-3). IDAC-treated patients showed in average a higher age (median (IQR) 58.5 (49-62) years vs. 50 (41-56) years) and more comorbidities with 43.8% having an HCT-CI score of 2-4, compared to 22.3% among HiDAC-treated patients. Alongside, significantly more secondary (5.1% vs. 3.1%) and therapy-related (12.4% vs. 4.1%) AML as well as more adverse (14.5% vs. 6.5%) and less favorable (40.6% vs. 56%) genetic risk features according to ELN 2017 risk classification were found among IDAC-treated patients. After propensity score weighting for differences in patient and disease characteristics, overall survival after 5 years was comparable between HiDAC-treated (71.1 %) and IDAC-treated (67.7%) patients. Moreover, no significant differences in relapse-free survival were observed after 5 years (47.4 vs. 45.2%). Notably, more patients treated with IDAC received allogeneic stem cell transplantation in first remission (37.6 vs. 19.8%) while significantly more HiDAC-treated patients underwent allogeneic stem cell transplantation in relapse (30.8 vs. 20.2%). Censoring for allogeneic stem cell transplantation in first remission revealed no significant survival difference with regard to cytarabine dosage. Considering only ELN favorable risk AML patients, there was no difference in 5-years overall (80.5% vs. 83.9%) nor relapse-free (57.7% vs. 56.8%) survival. Of note, significantly more patients treated with HiDAC suffered from ≥3 CTCAE infectious complications (56.7 vs. 44.1%), which was more striking in patients above 50 years of age. The rate of other ≥3 CTCAE non-hematological toxicities and secondary malignancies was comparable in both treatment groups. Conclusion: This retrospective analysis suggests no significant benefit of high dose cytarabine compared to intermediate dosages in consolidation for AML patients under 65 years of age, independent of ELN risk group. Disclosures Krause: Siemens: Research Funding; Takeda: Honoraria; Pfizer: Honoraria; art-tempi: Honoraria; Kosmas: Honoraria; Gilead: Other: travel support; Abbvie: Other: travel support. 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. Haenel: Jazz: Consultancy, Honoraria; GSK: Consultancy; Bayer Vital: Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy; Celgene: Consultancy, Honoraria. Brummendorf: Takepart Media: Honoraria; Repeat Diagnostics: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Patents & Royalties, Research Funding; Janssen: Honoraria; Bristol Myers: Research Funding. Fransecky: Abbvie: Honoraria, Research Funding; Medac: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Einsele: Janssen, Celgene/BMS, Amgen, GSK, Sanofi: Consultancy, Honoraria, Research Funding. Held: MSD: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Roche: Research Funding; Acortech Biopharma: Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Platzbecker: Janssen: Honoraria; Celgene/BMS: Honoraria; AbbVie: Honoraria; Geron: Honoraria; Takeda: Honoraria; Novartis: Honoraria. Baldus: Amgen: Honoraria; Celgene/BMS: Honoraria; Novartis: Honoraria; Jazz: Honoraria. Mueller-Tidow: Janssen Cilag: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Bioline: Consultancy, Research Funding.

Introduction: The unfolded protein response (UPR) is a stress sensing signaling network that is activated upon endoplasmic reticulum (ER) stress, a condition characterized by an accumulation of mis- and unfolded proteins in the ER. To retain a functional cell metabolism, UPR activation increases protein folding and degradation. Acute myeloid leukemia (AML) stem cells are prone to develop ER stress, due to their oncogene-driven metabolism and the bone marrow niche, where they face stressors like hypoxia or nutrient fluctuations. Our preliminary work showed enhanced UPR gene expression levels, especially of IRE1α and XBP1, in different AML subtypes. Patients with high XBP1 mRNA expression had an inferior overall survival rate compared to patients with low XBP1 mRNA expression. Aims: We studied the role of elevated UPR signaling in AML therapy resistance and assessed the therapeutic potential of IRE1α-XBP1 inhibitor STF-083010 (STF) as a new strategy in different AML subtypes, including FLT3-ITD + AML. Methods: Human MV4-11 (FLT3-ITD), RS4-11 (FLT3 wildtype; WT), NB-4 (PML-RARα), THP-1 (MLLr) cells, and murine 32D cells transduced with FLT3-ITD or FLT3 WT were analyzed via western blot and RT-PCR. Metabolic activity was assessed by MTT assay, cell death and apoptosis were measured with propidium iodide (PI) or Annexin V staining using flow cytometry. FLT3 cell surface expression was measured via flow cytometry. The clonogenic potential was determined in CFU assays, using patient-derived mononuclear and CD34 + cells. For hypoxic experiments, MV4-11 cells were cultivated under hypoxia (3 % O 2) and cells were subjected to phosphoproteomic analysis, which was performed by mass spectrometry. Conditional Mx1-Cre/XBP1 fl/fl knockout mice were generated and deletion of XBP1 was induced by IP injection of Polyinosinic-polycytidylic acid (Poly(I:C)). Bone marrow and spleen cells were analyzed via flow cytometry and RT-PCR. Results: Treatment with FLT3 TKI AC220 specifically enhanced IRE1α mRNA (9.3-fold, p0.05). Analysis of phosphoproteomics revealed a less active FLT3 signaling under hypoxia. Intriguingly, the combination of IRE1α and FLT3 inhibition overcame the resistance towards AC220 under hypoxia and significantly induced cell death. Conclusion: IRE1α-XBP1 signaling is activated in different AML subtypes including FLT3-ITD + and is further enhanced by hypoxia present in the bone marrow niche. Targeting IRE1α in FLT3-ITD + cells effectively decreases clonogenic growth and induces apoptosis. Our data demonstrate that hypoxia-mediated resistance against AC220 can be overcome by simultaneous IRE1α inhibition. Genetic deletion of XBP1 does not harm steady-state murine hematopoiesis, rendering XBP1 an excellent therapeutic target. Disclosures Koschmieder: CTI: Membership on an entity's Board of Directors or advisory committees, Other; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); Baxalta: Membership on an entity's Board of Directors or advisory committees, Other; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); AOP Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support), Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); Shire: Honoraria, Other; Image Biosciences: Other: Travel support; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support), Research Funding; Geron: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support), Research Funding; Karthos: Other: Travel support; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); Alexion: Other: Travel support; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Abbvie: Other: Travel support; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Brümmendorf: Bristol Myers: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; Novartis: Honoraria, Patents & Royalties, Research Funding; Repeat Diagnostics: Research Funding; Takepart Media: Honoraria.

Acute myeloid leukemia (AML) is a hematologic malignancy that is treated in medically fit patients with intensive induction chemotherapy (IT) and postremission therapy to achieve a complete and long-term remission. The incidence of obesity in the general population is steadily increasing and has been identified as a major risk factor for all-cause mortality. Despite previous studies assessing the role of obesity in AML patients undergoing IT, there is an ongoing debate on the impact of obesity on patient outcome as well as the optimal dosing strategy in obese AML patients. We conducted a retrospective registry study assessing 1677 AML patients who were treated with IT for newly diagnosed AML. The primary endpoint was overall survival (OS) while event-free survival (EFS), the rate of first complete remission (CR1), relapse/refractory disease and non-relapse/refractory-related mortality (NRRrM), treatment-related toxicities, patient comorbidities and chemotherapy dosing strategies were analyzed as secondary endpoints. Obese patients (body mass index, BMI ≥ 30) displayed a significant inferior median OS (29.44 vs. 47.94 months, p = 0.015) without a significant difference in median EFS (7.8 vs. 9.89 months, p = 0.3) compared to non-obese patients (BMI < 30). The cumulative incidence (CI) of NRRrM was significantly increased in obese patients compared to non-obese patients while no differences could be observed regarding the CI of relapsed or refractory disease. Obesity was identified as an independent risk factor for death (HR 1.27, [95% CI 1.07-1.51], p = 0.005) in a multivariable Cox regression analysis. When the cohort was stratified by age (≥/< 60 years), the difference in OS as well as the significantly increased CI of NRRrM was only observed in patients ≥ 60 years. Notably, obese patients demonstrated higher rates of cardiovascular and metabolic comorbidities regardless of their age. No disparities for OS, EFS, CR1 rate or treatment-related toxicities were observed when the entire study population was stratified for the used dosing strategy (dose calculation using total body weight, idealized body weight, adjusted idealized body weight or capped at body surface area of 2 m 2). In conclusion, the present study identifies obesity as a major independent risk factor for worse overall survival and increased CI of non-relapse/refractory-related mortality in older (≥60 years) AML patients undergoing curative IT. These findings may be most likely attributed to obesity related comorbidities and not to dose adaption of chemotherapy in obese AML patients. Disclosures Schliemann: Boehringer-Ingelheim: Research Funding; Abbvie: Consultancy, Other: travel grants; Philogen S.p.A.: Consultancy, Honoraria, Research Funding; Astellas: Consultancy; AstraZeneca: Consultancy; BMS: Consultancy, Other: travel grants; Jazz Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy; Roche: Consultancy; Pfizer: Consultancy. Krause: Siemens: Research Funding; Takeda: Honoraria; Pfizer: Honoraria; art-tempi: Honoraria; Kosmas: Honoraria; Gilead: Other: travel support; Abbvie: Other: travel support. Haenel: Jazz: Consultancy, Honoraria; GSK: Consultancy; Bayer Vital: Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy; Celgene: Consultancy, Honoraria. Fransecky: Amgen: Honoraria; Abbvie: Honoraria, Research Funding; Novartis: Honoraria; Medac: Honoraria; Takeda: Honoraria. Burchert: Novartis: Honoraria, Research Funding; AOP Orphan: Honoraria, Research Funding; Pfizer: Honoraria; Incyte: Honoraria; Gilead: Honoraria; BMS: Honoraria. Crysandt: Incyte: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees. Müller-Tidow: Janssen: Consultancy, Research Funding; Bioline: Research Funding; Pfizer: Research Funding. Platzbecker: Celgene/BMS: Honoraria; AbbVie: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Geron: Honoraria. Baldus: Jazz: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Celgene/BMS: Honoraria.

Background TP53 mutations are associated with adverse outcome of AML treated with cytarabine-based regimens. Interestingly, DNA-hypomethylating agents (HMAs) induce a higher response rate in TP53-mutated (MUT) compared to TP53 wildtype (WT) AML (Welch et al., N. Engl. J. Med. 2016, Döhner et al., Leukemia 2018). We conducted a randomized phase II trial (NCT00867672, 2x2 factorial design) asking whether the in vitro cooperativity of DAC with VPA or ATRA translates into clinical benefit. While VPA added to DAC affected neither objective response rate (ORR) nor overall survival (OS), ATRA significantly improved ORR and OS, without added toxicity (Lübbert et al., J. Clin. Oncol. 2020). Preclinical data suggest that HMAs and ATRA have cooperative effects also in TP53 MUT AML. We therefore performed a post-hoc analysis to determine the predictive impact of TP53 status. Patients and Methods Key inclusion criteria: newly diagnosed AML pts >60 yr (non-M3) unfit for induction, ECOG performance status (PS) 0-2. Treatment: DAC 20 mg/m 2 day 1-5 (arms A/B/C/D), VPA p.o. from day 6 (arms B/D), ATRA p.o. day 6-28 (arms C/D) of each 28-day course. For TP53 mutation analyses, the Illumina TruSight Myeloid Sequencing Panel was used for library preparation and an Illumina MiSeq device for sequencing. Key endpoints: ORR (CR/CRi/PR, ELN 2010 criteria) and OS. Original sample size calculation of a total of 200 patients (pts) was based on the primary endpoint ORR (Lübbert et al., Haematologica 2012). ORR was analyzed with logistic regression, OS with Cox regression. Odds ratios (OR) for the effect on ORR and hazard ratios (HR) for the effect on death with 95% confidence intervals (CI) are presented in the genetic subgroups TP53 MUT and TP53 WT including tests for interactions (TFI) between treatment and TP53. These are post-hoc exploratory analyses, hence p-values have to be interpreted in a descriptive sense. Results Between 12/2011 and 2/2015, 200 pts were randomized and treated. Information on TP53 status was available for 168 of 200 pts (84%); 155 of them (92%) had died at last follow-up (June 2021). 61% of pts were aged >75 years (range 61-92), ECOG PS 0/1/2: 19/62/19% (a single pt had a PS of 3); 53% had an HCT-CI >3, 19% WBC >30.000/µl, 30% adverse genetics (ELN 2010), 51% an antecedent hematologic disorder. TP53 aberrations were detected in 42 pts (25%), with 1 (n=27) or 2 mutations (n=12, median variant allele frequency 44%, range, 1.3-99%) in 39 pts, and TP53 deletions in 3 additional pts. The 42 pts with TP53 MUT showed a higher ORR (23.8%) than the 126 pts with TP53 WT (ORR 15.1%), with an OR of 2.04 (95% CI 0.83-4.98), p=0.12. OS (irrespective of treatment) in the TP53 MUT v WT pts was not different (HR, adjusted for treatment: 1.14 [95% CI 0.78-1.66], p=0.51; Fig. A). In both genetic groups, the addition of ATRA had a favorable effect on ORR (ATRA v no ATRA in TP53 MUT: 31.3% v 19.2%, OR 1.91 [95% CI 0.45-8.03]; ATRA v no ATRA in TP53 WT: 18.8% v 10.5%, OR 1.98 [95% CI 0.70-5.61]), TFI p=0.97 (Fig. B). A positive effect of ATRA on OS in both genetic groups was reflected by a median OS of 6.0 v 4.5 months (ATRA v no ATRA in TP53 MUT: HR 0.75 [95% CI 0.38-1.48]), and a median OS of 8.9 v 4.7 months (ATRA v no ATRA in TP53 WT: HR 0.58 [95% CI 0.39-0.86], all results adjusted for VPA, ECOG, HCT-CI, sLDH, Hb), TFI p=0.49 (Fig. C). VPA did not affect ORR in either of the 2 genetic groups (VPA v no VPA in TP53 MUT: 21.7% v 26.3%, OR 0.76 [95% CI 0.18-3.21]; VPA v no VPA in TP53 WT: 16.7% v 13.3%, OR 1.34 [95% CI 0.5-3.61]), TFI p=0.53. The impact of VPA on OS differed between TP53 MUT pts (VPA v no VPA: median OS of 4.2 v 5.3 months, HR 1.31 [95% CI 0.69-2.48], and TP53 WT pts (VPA v no VPA: median OS of 8.4 v 4.8 months, HR 0.67 [95% CI 0.46-0.99], all results adjusted for ATRA, ECOG, HCT-CI, sLDH, Hb; TFI p=0.08, Fig. C). Conclusions Our results confirm the reported higher response rate to DAC in pts with TP53 MUT compared to TP53 WT; the addition of ATRA led to a higher ORR. Improved OS with ATRA was observed particularly in TP53 WT pts. In contrast, VPA did not affect the ORR in either genetic group; TP53 WT pts may benefit from VPA regarding OS. Our exploratory post-hoc results need confirmation in other trials, e.g. in the DECIDER-2 study (adding ATRA or placebo to the recently approved dual treatment of a HMA combined with venetoclax). Cooperative effects of HMAs and retinoids deserve a deeper mechanistic understanding, which may have implications not only for AML but also for other malignancies with impaired TP53. Figure 1 Figure 1. Disclosures Becker: BMS: Honoraria; Pierre Fabre Pharma: Honoraria; Servier: Honoraria; MSD: Honoraria; Novartis: Honoraria. Crysandt: Incyte: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees. Thol: Abbvie: Honoraria; Pfizer: Honoraria; Astellas: Honoraria; Novartis: Honoraria; BMS/Celgene: Honoraria, Research Funding; Jazz: Honoraria. Heuser: Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolremo: 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; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; BergenBio: Research Funding; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer Pharma AG: Research Funding; Astellas: Research Funding. Goetze: Abbvie: Other: Advisory Board; BMS/Celgene: Other: Advisory Board, Research Funding. Schlenk: Agios: Honoraria; Astellas: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria; Daiichi Sankyo: Honoraria, Research Funding; Abbvie: Honoraria; Hexal: Honoraria; Neovio Biotech: Honoraria; Novartis: Honoraria; Pfizer: Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria, Research Funding; AstraZeneca: Research Funding; Boehringer Ingelheim: Research Funding. Salih: Synimmune GmbH: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Celgene: Honoraria; BMS: Honoraria. Schittenhelm: Takeda: Other: advisory board; Astellas: Other: advisory board; BMS: Other: advisory board; University of Tuebingen: Patents & Royalties: patent for ASPP2k. Müller-Tidow: Pfizer: Research Funding; Janssen: Consultancy, Research Funding; Bioline: Research Funding. Germing: Novartis: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria, Other: advisory activity, Research Funding. Giagounidis: Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Wäsch: Amgen: Consultancy, Honoraria; Pfizer: Consultancy; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Novartis: Consultancy; BMS/Celgene: Consultancy; Gilead: Consultancy. Döhner: Jazz Roche: Consultancy, Honoraria; Celgene/BMS: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Other: Advisory Board; Agios and Astex: Research Funding; Abbvie: Consultancy, Honoraria; Janssen: Honoraria, Other: Advisory Board; Astellas: Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Ganser: Novartis: Honoraria; Jazz Pharmaceuticals: Honoraria; Celgene: Honoraria. Döhner: Astellas: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Oxford Biomedicals: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Helsinn: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Berlin-Chemie: Consultancy, Honoraria; Astex: Consultancy, Honoraria; Agios: Consultancy, Honoraria, Research Funding; Ulm University Hospital: Current Employment; Jazz: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Roche: Consultancy, Honoraria; GEMoaB: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Pfizer: Research Funding. Hackanson: Roche: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Boehringer-Ingelheim: Consultancy, Honoraria; MSD: Consultancy, Honoraria. Lübbert: Cheplapharm: Other: study drug (ATRA); TEVA: Other: study drug (valproic acid); Janssen: Consultancy, Other: study drug (decitabine), Research Funding; Syros: Consultancy, Honoraria; Aristopharm: Other: study drug ; Imago BioSciences: Consultancy, Other: study support with study drug; AbbVie: Consultancy, Honoraria; Astex: Consultancy, Honoraria. OffLabel Disclosure: ATRA, in non-M3 AML valproic acid, in non-M3 AML

Introduction Recent studies indicate that particularly in a subgroup of younger patients, acute myeloid leukemia (AML) develops due to an inherited genetic predisposition linked to mutations in genes such as ANKRD26, SAMD9, SAMD9-L, GATA-2, genes causing telomere biology disorders or Shwachman-Diamond syndrome. However, the prevalence of so-called "AML predisposition syndromes" (APS) underlying newly diagnosed cases with AML is unknown. Actual screening strategies for APS are based on the family history and clinical/genetic features. There is growing evidence that APS frequently manifest themselves with an oligosymptomatic phenotype or are lacking specific symptoms altogether. Furthermore, molecular analysis of the clonal population without additional analysis of non-clonal cells do not allow the discrimination between inherited and acquired changes. Thus, new approaches to identify the subset of patients with underlying APS in adult newly diagnosed AML patients are needed. One frequent feature observed in APS is younger age at the time of diagnosis and the initial presence of an aberrant karyotype. Along this line, we retrospectively screened the German SAL-AML registry using age and the presence of an aberrant karyotype as pre-defining parameters to analyze the prevalence of APS in this selected cohort. Patients and methods The database of the German SAL-AML registry includes over 5207 patients with AML. We screened for patients below 35 years of age and with any type of numerical or structural chromosomal aberration at first diagnosis. DNA samples of patients achieving cytological remission (CR) and available samples of peripheral blood or bone marrow were selected. CR samples were chosen to reduce potential contamination by malignant AML blasts. Patients were screened for pathogenic variants using a self-designed NGS panel containing the entire coding sequences of ACD, ANKRD26, CTC1, DDX41, DKC1, ERCC6, ETV6, GATA1, GATA2, LIG4, NHP2, NOP10, PARN, POT1, RPA1, RPL11, RPL15, RPL26, RPL35A, RPL5, RPS10, RPS17, RPS19, RPS24, RPS26, RPS7, RTEL1, SAMD9, SAMD9L, SBDS, SRP72, TERC, TERF1, TERF2, TERT, TINF2, TPP1 and WRAP53. An inherited variant was considered in all patients with a variant allele frequency between 40-60% for heterozygous variants and >90% for homozygous ones. To analyze the functional consequence of SAMD9 variants, proliferation assays with HEK293 cells transfected with the respective identified variant was carried out. Results and discussion On the basis of the inclusion criteria mentioned above, we were able to identify 41 patients. All cases except one were considered de novo AML by the treating physicians and received an anthracycline/cytarabine based induction chemotherapy. Mean age of the 41 patients was 26 ± 5 years (mean ± S.D.). Predominant karyotypic aberration were abnormalities of chromosome 8 (18/41) as well as a complex aberrant karyotype (29/41). NGS analysis revealed five different heterozygous mutations in approx. 10% (4/41) of patients: GATA2 c.1009C>T p.(Arg337Ter), SBDS c.183_184delInsCT and c.258+2T>C (both mutations in the same patient), TINF2 c.848C>A p.(Pro283His), SAMD9 c.2854G>C p.(Gly952Arg). The variants in GATA2, SBDS and TINF2 are known to be pathogenic. For SAMD9, in vitro experiments showed increased inhibition of cell growth compared to wild-type supporting the pathogenicity of the mutation. Focusing on the clinical outcome, 50% (2/4) of the identified APS patients received allogeneic transplantation during follow-up compared to 65% (24/37) in the group without detectable mutations. Median survival in the APS group was significantly shorter with 3.2 months compared to 105.3 months in the remaining 37 AML patients (p Conclusions Using age and karyotype as selection criteria, we were able to identify an inherited APS in 10% of newly diagnosed AML patients below 35 years with chromosomal aberrations reaching CR. Obviously, our study is limited by rather stringent inclusion criteria not allowing overall conclusions on the incidence of APS in newly diagnosed AML. However, age and karyotype might provide simple clinical parameters to trigger genetic screening for inherited APS in addition to the actual recommendations. Given the significant difference in survival in patients with and without underlying APS, our study clearly supports inclusion of screening for APS in this cohort pending prospective validation. Figure Disclosures Röllig: Amgen, Astellas, BMS, Daiichi Sankyo, Janssen, Roche: Consultancy; Abbvie, Novartis, Pfizer: Consultancy, Research Funding. Müller-Tidow:Daiichi Sankyo: Research Funding; Pfizer: Research Funding, Speakers Bureau; Janssen-Cilag GmbH: Speakers Bureau; BiolineRx: Research Funding. Panse:Blueprint Medicines: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Chugai: Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees; Grunenthal: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Apellis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Brümmendorf:Pfizer: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Novartis: Consultancy, Other: travel, accommodation, expenses, Research Funding; Janssen: Consultancy; Merck: Consultancy; Takeda: Consultancy. Jost:Roche: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Celgene: Other: travel support; JAZZ: Other: travel support.

Background: DNA-hypomethylating agents are providing a very well-accepted backbone for non-intensive combination treatment of AML/MDS patients (pts), and an in vivo synergism has been demonstrated for the azacitidine+venetoclax combination in the VIALE-A trial (DiNardo et al., EHA 2020). The DAC+ATRA combination also resulted in an improved response rate and survival compared to DAC without ATRA (DECIDER trial, Lübbert et al., J. Clin. Oncol. 2020), also in pts with prior hematologic disorder (mostly MDS); no benefit was seen when valproic acid (VPA) was added to DAC (2x2 factorial design). In a previous study, we had investigated the outcome of elderly pts with oligoblastic AML (i.e. with 20-30% bone marrow blasts, defined as MDS RAEBt according to the French-American-British classification) treated with either DAC or best supportive care within the EORTC 06011 phase III trial (Becker et al., Ann. Hematol. 2015), observing a median overall survival (OS) of 8.0 months (mths) in DAC-treated RAEBt pts. We now hypothesized that the outcome of pts with oligoblastic AML may be improved by the addition of ATRA to DAC. Therefore, in the present exploratory subgroup analysis, pts from the DECIDER cohort with 20-30% bone marrow blasts were analyzed for clinical outcome. Patients and Methods: Key inclusion criteria: newly diagnosed pts >60 years (yr), unfit for induction with non-M3 AML (WHO, de novo or after antecedent hematologic disorder [AHD], therapy-associated [t]AML), ECOG performance status (PS) 0-2. Treatment: DAC 20 mg/m2 day 1-5 (treatment arms A/B/C/D), ATRA p.o. day 6-28 (arms C/D), VPA p.o. continuously from day 6 (arms B/D), of each 28-day course (repeated until relapse/progression, prohibitive toxicity, withdrawal or death). Key endpoints: objective response rate (ORR): CR/CRi/PR, overall (OS) and event-free survival (EFS). Sample size calculation was based on the primary endpoint ORR, assuming an ORR of 25% in arm A (Lübbert et al., Haematologica 2012). For a power of 80% (test in this phase II study at 1-sided alpha=0.1) for an increase of ORR to 40% with ATRA or VPA, 176 pts were necessary, planned sample size 200. Between 12/2011 and 2/2015, 200 pts were randomized and treated. Efficacy analyses were performed in the intention-to-treat (ITT) population. ATRA was investigated by comparing arms C+D vs arms A+B, VPA by comparing arms B+D vs arms A+C, ORR was analyzed with logistic regression estimating odds ratios (OR), OS/EFS with Cox regression estimating hazard ratios (HR), each with 95% confidence intervals (CI), and presented with descriptive two-sided p values of the tests of no treatment effect. Central hematopathologic review (blinded as to treatment arms) was conducted by an independent morphologist. Results: In 56/200 pts of the DECIDER cohort, bone marrow blasts were 20-30% (median, 25%). The number of pts in the randomized arms were: 13 in arm A, 21 in arm B, 9 in arm C, 13 in arm D. Baseline pt characteristics were as follows: male 77%, median age: 75 yr (range 61-88), median WBC: 3400/µl (range 500-52,600), adverse genetics (ELN 2010) present in 25%, ECOG 2 in 13%, comorbidities (HCT-CI) ≥ 3 in 48%, AHD in 68%, tAML in 11% (only slight random imbalances across randomized treatment arms). A median of 5 DAC courses were administered (per arm: 2/5/11/4). Six pts attained a CR, 7 pts a CRi, and 1 pt a PR, resulting in an ORR of 25% (arm A: 7.7%, arm B: 28.6%, arm C: 33.3%, arm D: 30.8%, respectively). Effect on ORR of ATRA vs no ATRA (31.8 vs 20.6%): OR 1.85, CI [0.54,6.37], p=0.33; and of VPA vs no VPA (29.4 vs 18.2%): OR 1.93, CI [0.51,7.24], p=0.33. With 40 deaths out of 56 pts, median OS was 9.5 mths (arm A: 7.6 mths, arm B: 8.9 mths, arm C: 37.2 mths, arm D: 11.2 mths, respectively). Effect on OS of ATRA vs no ATRA (12.5 vs 7.6 mths median OS): HR 0.47, CI [0.24,0.94], p=0.032 (after adjustment for PS, HCT-CI, WBC, LDH, genetic risk: HR 0.42, CI [0.19,0.90], p=0.025); and of VPA vs no VPA (10.0 vs 8.4 mths median OS): HR 0.99, CI [0.51,1.92], p=0.98: A comparable benefit on EFS of ATRA vs no ATRA (but not VPA vs no VPA) was observed. Conclusion: In elderly pts with oligoblastic AML ineligible for induction chemotherapy, the addition of ATRA, but not VPA, to DAC resulted in a clinically meaningful survival benefit; OS of pts receiving DAC without ATRA was very similar to that observed in a previous study. It is tempting to speculate that the combination of an HMA with a retinoid such as ATRA may also be active in MDS pts with excess of blasts. Disclosures Jost: JAZZ: Other: travel support; Roche: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Celgene: Other: travel support. Thol:Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Heuser:Amgen: Research Funding; Bayer: Consultancy, Research Funding; BerGenBio ASA: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Stemline Therapeutics: Consultancy; Janssen: Consultancy; PriME Oncology: Honoraria; Karyopharm: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy; Astellas: Research Funding; Roche: Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Götze:Celgene: Research Funding. Schlenk:Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses, Research Funding, Speakers Bureau; Novartis: Speakers Bureau; Roche: Research Funding; AstraZeneca: Research Funding; PharmaMar: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Döhner:Sunesis Pharmaceuticals: Research Funding; Abbvie: Consultancy; Agios: Consultancy; Amgen: Consultancy, Research Funding; Astellas Pharma: Consultancy; Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Arog: Research Funding; Roche: Consultancy; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Astex Pharmaceuticals: Consultancy; Janssen: Consultancy, Honoraria; Daiichi Sankyo: Honoraria; Celgene: Consultancy, Honoraria; Novartis: Honoraria, Research Funding. Salih:Synimmune: Consultancy, Research Funding; Philogen: Consultancy; Medigene: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Schittenhelm:Pfizer: Consultancy; Astellas: Consultancy. Mueller-Tidow:Jose-Carreras-Siftung: Research Funding; Wilhelm-Sander-Stiftung: Research Funding; BMBF: Research Funding; Deutsche Krebshilfe: Research Funding; Deutsche Forschungsgemeinschaft: Research Funding; Janssen-Cilag Gmbh: Membership on an entity's Board of Directors or advisory committees; BiolineRx: Research Funding; Daiichi Sankyo: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer AG: Research Funding. Brugger:MorphoSys: Current Employment. Bug: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; Sanofi: Other: Travel; Neovii: Other: Travel. Wäsch:Pfizer: Consultancy; Amgen: Consultancy; Janssen: Consultancy. Ganser:Celgene: Consultancy; Novartis: Consultancy. Döhner:AstraZeneca: Consultancy, Honoraria; Sunesis: Research Funding; Roche: Consultancy, Honoraria; Pfizer: Research Funding; Oxford Biomedicals: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Helsinn: Consultancy, Honoraria; Jazz: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Astex: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Research Funding; AROG: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; GEMoaB: Consultancy, Honoraria. OffLabel Disclosure: ATRA is approved for APL treatment but not for non-APL AML

Introduction: The most common cause of treatment failure after allogeneic hematopoetic stem cell transplantation (aHSCT) is relapse. The combination of venetoclax and the hypomethylating agents (HMA) azacitidine (AZA) or decitabine (DAC) have shown promising efficacy in elderly patients with AML. We here present clinical data on 32 patients, who were treated with an HMA/venetoclax combination therapy (HMAClax) for relapse of a myeloid malignancy after aHSCT, collected retrospectively from 11 German centers. Results: Sixteen patients (50%) were male, median age was 54 years (30.8-71.5). Diagnoses at aHSCT were 25 AML (17 primary, 8 emerging from MDS, CMML or OMF), 5 MDS, 1 CMML and one atypical CML. Twenty six patients were treated for relapse after their 1st and 6 after their 2nd aHSCT. Only 9 patients were in CR at aHSCT. The majority received a graft of a matched unrelated donor (21), 4 from an HLA-identical sibling and 7 from a haploidentical relative. Conditioning was myeloablative in 15 and RIC in 17patients. Median time from aHSCT to last relapse was 5.7ms (1.1-67.8). Five patients had molecular (MR) and 23 had hematologic relapses (HR), 4 patients had extramedullary manifestations 3 with concurrent HR and 1 with MR. Twenty-one patients were treated for 1st and 5 for 2nd relapse after 1st aHSCT. Four patients were treated for 1st and 2 for 2nd relapse after 2nd aHSCT. HMAClax was first line therapy for relapse in 8, 2nd line in 22, 3rd line 1 and 4th line in 1 patient. In 21 patients relapse had been refractory to HMA (+/- DLI, +/- lenalidomide). Median time from relapse to HMAClax was 1.8 ms (0.3-42.9). Twelve patients received AZA and 19 DAC with venetoclax. One patient was switched from AZAClax to DAClax because of rising MRD after 6 cycles and back to AZAClax after another 7 cycles. Six patients received DLI. Median number of cycles was 2 (1-15). Six patients are still on therapy. In total 75 cycles were given. Three patients had non-fatal tumor lysis syndrome. All but one patient had grade 3/4 neutropenia and 25 patients (78%) had grade 3/4 thrombocytopenia. Hospital admission for grade 3/4 infections was necessary in 23 patients (72%), 5 of these infections (22%) were fatal. Overall response rate was 43% (12/28, 2 CR MRD-, 4 CR, 2 CRi, 3 PR, 1 MLFS). Two patients died of infection before first response evaluation and in another 2 response has not been evaluated yet. ORR for patients who received first line HMAClax was 80% (4/5) and 35% (8/23) for salvage treatment. Three of 5 patients with MR reached CR, 2 received HMAClax first line. Time to best response was 1.2ms (0.7-3.8). Six patients lost best response after 1ms (0.4-3.3.) 2 underwent second transplant in remission, 4 have ongoing responses (0.4, 0.7, 3.1 and 8.8ms at last follow up). On July 25th 2019, median follow up was 3.3 ms (0.9-17.3), 20 patients (63%) had died and 12 were alive. Six were continuing HMAClax. One patient developed cGvHD and 4 underwent second aHSCT (2 in remission). Estimated median overall survival was 3.7ms (CI 2.9-4.7). Four responders are continuing treatment with HMAClax. Patients, who responded had an estimated OS of 11.1ms (2 underwent second aHSCT in remission). Median survival of patients with HMAClax first line therapy was 5.8ms and of patients with HMAClax salvage therapy 3.7ms. Conclusion: For patients relapsing after aHSCT, venetoclax plus AZA or DAC seems to be an effective, but also highly hematotoxic therapy. Responses occurred fast and were more frequently seen during 1st line treatment for relapse. Duration of response was short, especially in patients receiving HMAClax as 2nd, 3rd or 4th line therapy. Therefore HMAClax should be explored as 1st line therapy for relapse after aHSCT in combination with DLI or as a bridge to 2nd transplant. Disclosures Schuler: Celgene: Other: travel grants; Novartis: Honoraria, Other: travel grants; Alexion: Other: travel grants. Bug:Gilead Sciences: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Hexal: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants; 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; Sanofi: Other: travel grants; Celgene Neovii: Other: travel grant. Crysandt:Incyte: Membership on an entity's Board of Directors or advisory committees; Amgem: Other: travel grant; celgene: Other: travel grant; Pfizer: Other: travel grant; Gilead: Other: travel grant. Jost:Jazz Pharmaceuticals: Honoraria; Sanofi: Honoraria; Gilead: Other: travel grants; Daiichi: Honoraria. Kaivers:Jazz Pharmaceuticals: Other: Travel Support. Mueller:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; CTI Life Sciences: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Financing of Scientific Research; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Gentium: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Jazz: Honoraria; Pharmaceuticals: Honoraria; Neovii: Honoraria; Novartis: Honoraria; Sanofi: Honoraria. Rautenberg:Jazz Pharmaceuticals: Other: Travel Support; Celgene: Honoraria, Other: Travel Support. Wolff:Takeda: Honoraria; Mallinckrodt: Honoraria; Novartis: Honoraria; Neovi: Honoraria. Schroeder:Celgene Corporation: Consultancy, Honoraria, Research Funding. Off Label Use: Venetoclax was used in combination with azacitidine or decitabine. The combination is not approved in the EU so far.. Kobbe:Pfizer: Honoraria, Other: Travel support; Abbvie: Honoraria, Other: Travel support; Biotest: Honoraria, Other: Travel support; Roche: Honoraria, Other: Travel support; Jazz: Honoraria, Other: Travel support; MSD: Honoraria, Other: Travel support; Celgene: Honoraria, Other: Travel support, Research Funding; Takeda: Honoraria, Other: Travel support; Amgen: Honoraria, Other: Travel support, Research Funding; Neovii: Honoraria, Other: Travel support; Medac: Honoraria, Other: Travel support; Novartis: Honoraria, Other: Travel support. OffLabel Disclosure: Venetoclax was used in combination with azacitidine or decitabine. The combination is not approved in the EU so far.

Hematopoiesis is a highly regulated and complex process involving hematopoietic stem cells (HSCs), cell surface adhesion molecules, and cytokines as well as cells of the hematopoietic niche in the bone marrow (BM). Myeloproliferative neoplasms (MPNs) are characterized by clonal expansion of HSCs involving one or more blood cell lineages. Philadelphia-negative MPNs (Ph-neg MPNs) comprise polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). In nearly all patients with Ph-neg MPN, mutations in the genes encoding janus kinase 2 (JAK2), calreticulin (CALR), or the thrombopoietin receptor (MPL) can be detected and, together with additional mutations in epigenetic modifier genes, these genetic aberrations contribute to the clonal expansion of the cells. In addition to these intracellular changes in the malignant clone, inflammatory processes involving both the clonal and the non-clonal cells contribute to the signs and symptoms of the patients, as well as to progression of the disease to myelofibrosis (MF) or acute leukemia, and to thrombotic complications. This contribution has been corroborated in preclinical studies including mouse models and patient-derived iPS cells, and in clinical trials, using anti-inflammatory drugs such as JAK inhibitors and steroids, or immunomodulatory drugs such as IMiDs and interferon-alpha (IFNa), all of which change the (im)balance of circulating inflammatory factors (e.g., TNFa, IL-1b, and TGFβ) in MPN. Currently, allogeneic hematopoietic (stem) cell transplantation (allo-HCT) remains the only curative treatment for Ph-neg MPN and is the treatment of choice in intermediate-2 and high-risk MF. HCT can reverse inflammatory changes induced by MPN as well as fibrosis in a large proportion of patients, but it also induces itself profound changes in inflammatory cells and cytokines in the patient, which may help to eradicate the disease but also in part cause significant morbidity (e.g., by graft-versus-host disease). In this review, we focus on the contribution of aberrant inflammation to disease pathogenesis in Ph-neg MPN as well as the current understanding of its alterations after allogeneic HCT.

Thede novoDNA methyltransferase 3A (DNMT3A) plays pivotal roles in hematopoietic differentiation. In this study, we followed the hypothesis that alternative splicing ofDNMT3Ahas characteristic epigenetic and functional sequels. SpecificDNMT3Atranscripts were either downregulated or overexpressed in human hematopoietic stem and progenitor cells and this resulted in complementary and transcript-specific DNA methylation and gene expression changes. Functional analysis indicated that particularly transcript 2 (coding for DNMT3A2) activates proliferation and induces loss of a primitive immunophenotype, whereas transcript 4 interferes with colony formation of the erythroid lineage. Notably, in acute myeloid leukemia (AML) expression of transcript 2 correlates with itsin vitroDNA methylation and gene expression signatures and is associated with overall survival, indicating thatDNMT3Avariants impact also on malignancies. Our results demonstrate that specificDNMT3Avariants have distinct epigenetic and functional impact. Particularly DNMT3A2 triggers hematopoietic differentiation and the corresponding signatures are reflected in AML.

The occurrence of TERT promoter mutations has been well described in soft tissue sarcomas (STS). However, the biological role of these mutations as well as their impact on telomere length in STS is still unclear. We analyzed 116 patient samples diagnosed with 22 distinct histological subtypes of bone and STS for the occurrence of TERT promoter mutations by Sanger sequencing. We observed TERT promoter mutations at an overall frequency of 9.5% distributed over 7 different sarcoma subtypes. Except for one chondrosarcoma case harboring a C250T mutation, all other mutations were detected at location C228T. By far the far highest frequency of TERT promoter mutations was found in myxoid liposarcoma (MLS) (4 out of 9 cases studied, i.e., 44%). Assessment of telomere length from tumor biopsies revealed that TERT promoter-mutated MLSs had significantly fewer shortened telomeres in comparison to TERT wildtype MLSs. Based on the frequency of TERT promoter mutations and the elongated telomere length in mutated compared to wildtype MLS, we hypothesize that occurrence of TERT promoter mutations has a pivotal role in the disease progression as a secondary genetic event at a time when tumor cells face the need for telomere elongation to allow further proliferation.

Modulation of DNMT3A splice variants causes transcript-specific DNA methylation and gene expression changes and affects differentiation. Particularly, transcript 2 is relevant in acute myeloid leukemia., De novo DNA methyltransferase 3A (DNMT3A) plays pivotal roles in hematopoietic differentiation. In this study, we followed the hypothesis that alternative splicing of DNMT3A has characteristic epigenetic and functional sequels. Specific DNMT3A transcripts were either down-regulated or overexpressed in human hematopoietic stem and progenitor cells, and this resulted in complementary and transcript-specific DNA methylation and gene expression changes. Functional analysis indicated that, particularly, transcript 2 (coding for DNMT3A2) activates proliferation and induces loss of a primitive immunophenotype, whereas transcript 4 interferes with colony formation of the erythroid lineage. Notably, in acute myeloid leukemia expression of transcript 2 correlates with its in vitro DNA methylation and gene expression signatures and is associated with overall survival, indicating that DNMT3A variants also affect malignancies. Our results demonstrate that specific DNMT3A variants have a distinct epigenetic and functional impact. Particularly, DNMT3A2 triggers hematopoietic differentiation and the corresponding signatures are reflected in acute myeloid leukemia.

Introduction: Most patients with FLT3-ITD-positive AML, who relapse after allogenic stem cell transplantation (allo-SCT) die from their disease. Whether prophylactic FLT3-ITD inhibition with sorafenib can prevent AML relapse and improve outcome of patients in complete hematological remission (CHR) after allo-SCT is unknown and was tested in the SORMAIN trial. Methods: This randomized, double blind, placebo-controlled study was done at 14 centers in Germany and Austria. Patients with FLT3-ITD+ AML, aged 18 years or older, who had undergone allogenic stem cell transplantation from a HLA-matched sibling donor, 10/10 or 9/10 HLA-matched unrelated donor, and who were in confirmed CHR at the time of screening between day +30 and day +100 post allo-SCT, were included. Patients were randomly assigned (1:1) to receive either sorafenib (starting dose: 2 x 1 tbl. [2 x 200mg] qd, increasing every 14d to up to 2 x 2 tbl. [2 x 400mg] qd according to tolerability) or placebo (2 x 1 or 2 tbl. qd) for up to 24 months. Randomization was done centrally. In case of drug related adverse events, study medication could be interrupted, stepwise reduced to a minimum of 2 x 1 tbl. qd, temporarily withheld and recommenced at a lower dose level. FLT3-ITD diagnostics was done centrally at baseline and at time of relapse. In relapsing patients, off-label compassionate use of sorafenib was possible. The primary endpoint was relapse-free survival (RFS) as defined by either hematological relapse or death from any cause. The secondary endpoint was overall survival (OS). We here report the final RFS analysis. The OS results will be unblinded only prior to the ASH meeting and will be reported there. The SORMAIN study was terminated prior to full recruitment because of slow accrual. SORMAIN was registered with the European Clinical Trials Database (EudraCT 2010-018539-16) and the German Clinical Trials Register (DRKS00000591). Results: Between October 29, 2010, and May 17, 2016, 83 patients (41 males, 42 females) were randomized and included in the primary analysis (placebo, n=40; sorafenib, n=43). Median age was 54 years (IQR 47.75 - 61.33) for the entire study population and not significantly different between sorafenib and placebo groups. With a median follow up of 41.8 months after randomization (IQR 24.1 - 42.5), median RFS was 30.9 months (lower bound of 95% CI 5.2 months) in the placebo group versus not reached in the sorafenib group, corresponding to a 2-year RFS of 53,3 % (95% CI 36.5-67.5) in the placebo versus 85.0 % (69.5-93.0) in the sorafenib group (hazard ratio [HR] 0.39, 95% CI; 0.18 -0.85; P=0.0135) (Fig. 1). Overall, sorafenib was well tolerated. The most common grade 3-4 adverse event in both groups was acute GvHD (seven [ 17.5%] in the placebo group vs. nine [20.9%] in the sorafenib group. Conclusion: Sorafenib maintenance therapy after allo-SCT is feasible and significantly reduces the risk of relapse or death in patients with FLT3-ITD positive AML. OS results will be presented at the meeting. Figure 1. Figure 1. Disclosures Burchert: Bristol Myers Squibb: Honoraria, Research Funding; Bayer: Research Funding; Pfizer: Honoraria; AOP Orphan: Honoraria, Research Funding; Novartis: Research Funding. Bug:Amgen: Honoraria; Neovii: Other: Travel Grant; Novartis Pharma: Honoraria, Research Funding; Astellas Pharma: Other: Travel Grant; Jazz Pharmaceuticals: Other: Travel Grant; Celgene: Honoraria; Janssen: Other: Travel Grant. Finke:Riemser: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Other: travel grants, Research Funding; Neovii: Consultancy, Honoraria, Other: travel grants, Research Funding; Medac: Consultancy, Honoraria, Other: travel grants, Research Funding. Stelljes:Pfizer: Consultancy, Honoraria, Research Funding; MSD: Consultancy; JAZZ: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Rollig:Bayer: Research Funding; Janssen: Research Funding. Wäsch:Pfizer: Honoraria. Lang:Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding. Ehninger:Cellex Gesellschaft fuer Zellgewinnung mbH: Employment, Equity Ownership; GEMoaB Monoclonals GmbH: Employment, Equity Ownership; Bayer: Research Funding. Serve:Bayer: Research Funding. Kroeger:Neovii: Honoraria, Research Funding; JAZZ: Honoraria; Sanofi: Honoraria; Celgene: Honoraria, Research Funding; Riemser: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Götze:JAZZ Pharmaceuticals: Honoraria; Novartis: Honoraria; Takeda: Honoraria, Other: Travel aid ASH 2017; Celgene: Honoraria, Research Funding. Schmid:Jazz Pharma: Honoraria, Other: Travel grant, Speakers Bureau. Wolf:BMS: Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Honoraria, Research Funding; AOP Orphan: Honoraria, Research Funding. Thiede:AgenDix: Other: Ownership; Novartis: Honoraria, Research Funding. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Bethge:Miltenyi Biotec GmbH: Consultancy, Honoraria, Research Funding; Neovii GmbH: Honoraria, Research Funding.