Abstract: To investigate the efficacy and toxicities of CPX-351 outside a clinical trial, we analyzed 188 patients (median age 65 years, range 26–80) treated for therapy-related acute myeloid leukemia (t-AML, 29%) or AML with myelodysplasia-related changes (AML-MRC, 70%). Eighty-six percent received one, 14% two induction cycles, and 10% received consolidation (representing 22% of patients with CR/CRi) with CPX-351. Following induction, CR/CRi rate was 47% including 64% of patients with available information achieving measurable residual disease (MRD) negativity ( 〈 10 −3 ) as measured by flow cytometry. After a median follow-up of 9.3 months, median overall survival (OS) was 21 months and 1-year OS rate 64%. In multivariate analysis, complex karyotype predicted lower response ( p  = 0.0001), while pretreatment with hypomethylating agents ( p  = 0.02) and adverse European LeukemiaNet 2017 genetic risk ( p   〈  0.0001) were associated with lower OS. Allogeneic hematopoietic cell transplantation (allo-HCT) was performed in 116 patients (62%) resulting in promising outcome (median survival not reached, 1-year OS 73%), especially in MRD-negative patients ( p  = 0.048). With 69% of patients developing grade III/IV non-hematologic toxicity following induction and a day 30-mortality of 8% the safety profile was consistent with previous findings. These real-world data confirm CPX-351 as efficient treatment for these high-risk AML patients facilitating allo-HCT in many patients with promising outcome after transplantation.

Abstract: Abstract 3281 Poster Board III-1 Introduction: In the two consecutive German CML studies III and IIIA (recruitment periods from 1995 to 2001 and 1997 to 2004), eligible patients were assigned to early HSCT by genetic randomization according to availability of a matched related donor. After randomization, 113 patients of study III (84% of 135) and 144 of study IIIA (87% of 166) were eventually transplanted in first chronic phase (CP) using a related donor. Despite comparable transplantation protocols and most centers participating in both studies, survival probabilities in study IIIA were significantly better, even when adjusted for the established EBMT risk score (Gratwohl et al., Lancet 1998 [1]), p + 0.0097. For further explanation, the German Registry for Stem Cell Transplantation (DRST) and the Swiss Transplant Working Group for Blood and Marrow Transplantation (STABMT) were asked for data support. Patients and Methods: The main sample characteristics of the 257 transplanted CML study patients were also applied to the registry patients: diagnosis of CML between 1994 and 2004, first HSCT with a related donor performed in first CP between 1995 and 2004 at an age between 12 and 65 years, and blood or bone marrow as stem cell sources. Thus, additional data of 582 HSCT patients were retrieved from the two registries. Age, recipient sex, donor sex, time between diagnosis and HSCT, calendar year of HSCT, stem cell source, and HLA matching were investigated as potential predictive factors for survival. Then, a sample of patients with the same risk distribution as the 113 patients of study III was randomly drawn from the registry patients. By application of repeated resampling to this new patient group, bootstrap confidence intervals for survival probabilities at various times after HSCT were extractable. This provided the basis to judge whether the survival in study III could be seen as a typical random representation of a sample with an equivalent risk structure or not. The same method was applied to the 144 patients of study IIIA. Results: The 5-year survival probability of all 839 patients resulted in 73% (229 died). Median follow-up time of living patients was 6.7 years. Due to the characteristic plateau of post-transplant survival probabilities, the predictive influence was judged by the Kaplan-Meier method and the log rank statistic. Also consideration of age and time between diagnosis and HSCT as continuous variables seemed less appropriate than working with categorizations. Furthermore, the previously published cut-points “1 year” for time from diagnosis to HSCT ([1] ) and “44 years” for age at HSCT (Maywald et al., Leukemia 2006) were independently confirmed to be the best. Cox model and logistic regression with survival status after 3 years both indicated that age at HSCT, HLA matching, time between diagnosis and HSCT, and calendar year of HSCT had independent statistically significant predictive influence on survival (p 〈 0.05). The first two factors had the strongest effects. Calendar year was only influential when distinction was made between HSCT until and after 1999. All possible combinations of the 4 factors could be summarized in 4 risk groups with significantly different survival probabilities (at 5 years: 87%, 76%, 63%, and 24%). Matched for the risk group distribution of study III [study IIIA], a maximum of 290 [428] registry patients could be drawn. For the 290 [428] patients, 5-year survival was 69% [77%] with a 95% bootstrap confidence interval from 63% to 74% [72% to 81%]. Thus, as for all yearly intervals within the first 5 years, the 5-year survival probabilities of studies III: 65% and IIIA: 79% lied within the corresponding confidence intervals. Conclusions: Along with the registry patients, the study data enabled the identification of age at HSCT, HLA matching, time between diagnosis and HSCT, and calendar year of HSCT as factors with independent predictive impact on survival which led to 4 risk groups with statistically significantly different survival probabilities. More favorable-risk patients in study IIIA stood for a better transplantation strategy. In consideration of these different risks, the survival probabilities in both studies did not significantly vary from those of registry samples with matched risk structures. Accordingly, an improved transplantation strategy along with random variation could be considered as an explanation of the significantly different survival probabilities between the two studies. Disclosures: Haferlach: MLL Munich Leukemia Laboratory: Equity Ownership. Hochhaus:Novartis, Bristol-Myers Squibb: Research Funding. Hasford:Novartis: Research Funding. Gratwohl:AMGEN, Roche, Bristol-Myers Squibb, Novartis, Pfizer: Research Funding; Novartis: Consultancy. German CML Study Group:Kompetenznetz Leukämie, European Leukemia Net, Roche, Essex, AMGEN: Research Funding.

Abstract: Background In a recent phase-III trial CPX-351 (Jazz Pharmaceuticals, Palo Alto, CA), a liposomal encapsulation of cytarabine and daunorubicin, has shown higher remission rates and longer overall survival (OS) in patients aged 60 to 75 years with AML with myelodysplasia-related changes (AML-MRC) or therapy-related AML (t-AML) in comparison to conventional 7+3 regimen. Based on this CPX-351 has been approved in the USA 2017 and in Europe 2018 for adult patients with newly-diagnosed AML-MRC or t-AML. Still, several issues such as age ( & lt;60 years), measurable residual disease (MRD), molecular subgroups and outcome after allo-HCT were not addressed in the phase-III trial. Aiming to investigate these open aspects and to provide more clinical experience with CPX-351, we performed a real-world analysis of patients with AML treated with CPX-351 as first-line therapy. Design/Methods: For this retrospective analysis, we collected data on baseline characteristics, treatment details including allo-HCT and outcome from patients with newly-diagnosed AML-MRC or t-AML, who were treated with CPX-351 according to the EMA label between 2018 and 2020 in 25 German centers participating in the Study Alliance Leukemia (SAL), German Cooperative Transplant Study Group and the AML Study Group (AMLSG). Results: A total of 188 patients (median age 65 years, range 26 to 80) with t-AML (29%) or AML-MRC (70%) including 46 patients (24%) & lt;60 years could be analyzed. Eigthy-six percent received one, 14% two induction cycles and 10% received consolidation with CPX-351. Following induction, CR/CRi rate was 47% including 64% of patients with available information achieving measurable residual disease (MRD) negativity ( & lt;10-3) as measured by flow cytometry at local laboratories. Additionally, 35 patients were categorized as MLFS at first remission control, which achieved CRi (n=16) or CR (n=10) in the further course without additional therapy. After median follow-up of 9.3 months, median overall survival (OS) was 21 months and 1-year OS rate was 64%. In multivariate analysis, complex karyotype predicted lower response (p=.0001), and pretreatment with hypomethylating agents (p=.02) and adverse European LeukemiaNet 2017 genetic risk (p & lt;.0001) were associated with lower OS. Allo-HCT was performed in 116 patients (62%) including 101 of these patients with CR prior transplant and resulted in 1-year OS of 73% (median survival not reached), especially in MRD negative patients (p=.048). With 69% of patients developing grade III/IV non-hematologic toxicity following induction and a day 30-mortality of 8% the safety profile was consistent with previous findings. Conclusion: The results from this real-world analysis confirm CPX-351 as an efficient treatment for these high-risk AML patients bridging to facilitating allo-HCT in many patients with encouraging outcome after transplantation. Disclosures Röllig: AbbVie: Honoraria, Research Funding; Amgen: Honoraria; Bristol-Meyer-Squibb: Honoraria, Research Funding; Janssen: Honoraria; Jazz: Honoraria; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Roche: Honoraria, Research Funding. Stelljes: Pfizer: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Medac: Speakers Bureau; Celgene/BMS: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; MSD: Consultancy, Speakers Bureau; Kite/Gilead: Consultancy, Speakers Bureau. Gaidzik: Janssen: Speakers Bureau; Pfizer: Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Unglaub: Novartis: Consultancy, Other: travel costs/ conference fee; JazzPharma: Consultancy, Other: travel costs/ conference fee. Thol: Abbvie: Honoraria; Astellas: Honoraria; BMS/Celgene: Honoraria, Research Funding; Jazz: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Krause: Siemens: Research Funding; Takeda: Honoraria; Pfizer: Honoraria; art-tempi: Honoraria; Kosmas: Honoraria; Gilead: Other: travel support; Abbvie: Other: travel support. Haenel: Celgene: Consultancy, Honoraria; Amgen: Consultancy; Novartis: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Bayer Vital: Honoraria; Jazz: Consultancy, Honoraria; GSK: Consultancy. Vucinic: Novartis: Honoraria; Janssen: Honoraria, Other: Travel Sponsoring; Abbvie: Honoraria, Other: Travel Sponsoring; Gilead: Honoraria, Other: Travel Sponsoring; MSD: Honoraria. Fransecky: Novartis: Honoraria; Medac: Honoraria; Abbvie: Honoraria, Research Funding; Amgen: Honoraria; Takeda: Honoraria. Holtick: Celgene: Honoraria; Sanofi: Honoraria. Kobbe: Celgene: Research Funding. Holderried: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Speakers Bureau; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; MSD: Speakers Bureau; Daiichi Sankyo: Other: travel support; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Therakos: Other: Travel support; Janssen: Other: Travel support; Abbvie: Other: Travel support; Eurocept Pharmaceuticals: Other: Travel support; Medac: Other: Travel support. Heuser: Astellas: Research Funding; Bayer AG: Honoraria, Research Funding; BMS/Celgene: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; BergenBio: Research Funding; Daichi Sankyo: Honoraria, Research Funding; Karyopharm: Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Roche: Research Funding; Tolremo: Honoraria; AbbVie: Honoraria; Janssen: Honoraria. Sauer: Pfizer: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Matterhorn Biosciences AG: Consultancy, Other: DSMB/SAB Member; Takeda: Consultancy, Other: DSMB/SAB Member. Goetze: Abbvie: Other: Advisory Board; BMS/Celgene: Other: Advisory Board, Research Funding. Döhner: Jazz Roche: Consultancy, Honoraria; Agios and Astex: Research Funding; Astellas: Research Funding; Abbvie: Consultancy, Honoraria; Janssen: Honoraria, Other: Advisory Board; Daiichi Sankyo: Honoraria, Other: Advisory Board; Novartis: Consultancy, Honoraria, Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding. Döhner: Jazz Pharmaceuticals: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Pfizer: Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Gilead: Honoraria; Janssen: Honoraria; Helsinn: Honoraria; GEMoaB: Honoraria; Amgen: Honoraria, Research Funding; Astellas: Honoraria, Research Funding; Astex Pharmaceuticals: Honoraria; AstraZeneca: Honoraria; Berlin-Chemie: Honoraria; Oxford Biomedica: Honoraria; Roche: Honoraria. Schliemann: Philogen S.p.A.: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Other: travel grants; Astellas: Consultancy; AstraZeneca: Consultancy; Boehringer-Ingelheim: Research Funding; BMS: Consultancy, Other: travel grants; Jazz Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy; Roche: Consultancy; Pfizer: Consultancy. 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 . Germing: Novartis: Honoraria, Research Funding; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria, Other: advisory activity, Research Funding; Celgene: Honoraria; Jazz Pharmaceuticals: Honoraria. Schroeder: JAZZ: Honoraria, Research Funding.

Abstract: Background Chronic myeloid leukemia (CML)-study IV was designed to explore whether treatment with imatinib (IM) at 400mg/day (n=400) could be optimized by doubling the dose (n=420), adding IFN (n=430) or cytarabine (n=158) or using IM after IFN-failure (n=128). Methods From July 2002 to March 2012, 1551 newly diagnosed patients in chronic phase were randomized into a 5-arm study. The study was powered to detect a survival difference of 5% at 5 years. The impact of patients' and disease factors on survival was prospectively analyzed. At the time of evaluation, at least 62% of patients still received imatinib, 26.2% were switched to 2nd generation tyrosine kinase inhibitors. Results After a median observation time of 9.5 years, 10-year overall survival was 82%, 10-year progression-free survival 80% and 10-year relative survival 92%. In spite of a faster response with IM800mg, the survival difference between IM400mg and IM800mg was only 3% at 5 years. In a multivariate analysis, the influence on survival of risk-group, major-route chromosomal aberrations, comorbidities, smoking and treatment center (academic vs. other) was significant in contrast to any form of initial treatment optimization. Patients that reached the response milestones 3, 6 and 12 months, had a significant survival advantage of about 6% after 10 years regardless of therapy. The progression probability to blast crisis was 5.8%. Blast crisis was proceeded by high-risk additional chromosomal aberrations. Conclusions For responders, monotherapy with IM400mg provides a close to normal life expectancy independent of the time to response. Survival is more determined by patients' and disease factors than by initial treatment selection. Although improvements are also needed for refractory disease and blast crisis, more life-time can currently be gained by carefully addressing non-CML determinants of survival. Disclosures Hehlmann: Novartis: Research Funding; BMS: Consultancy. Saussele: Pfizer: Honoraria; Incyte: Honoraria; Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Pfirrmann: BMS: Honoraria; Novartis: Honoraria. Krause: Novartis: Honoraria. Baerlocher: Novartis: Honoraria; BMS: Honoraria; Pfizer: Honoraria. Bruemmendorf: Novartis: Research Funding. Müller: Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Ariad: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Jeromin: MLL Munich Leukemia Laboratory: Employment. Hänel: Roche: Honoraria; Novartis: Honoraria. Burchert: BMS: Honoraria. Waller: Mylan: Consultancy, Honoraria. Mayer: Eisai: Research Funding; Novartis: Research Funding. Link: Novartis: Honoraria. Scheid: Novartis: Honoraria. Schafhausen: Novartis: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Ariad: Honoraria. Hochhaus: Incyte: Research Funding; MSD: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; BMS: Research Funding; ARIAD: Research Funding.

Abstract: The presence of a mutated nucleophosmin-1 gene (NPM1 mut ) in acute myeloid leukemia (AML) is associated with a favorable prognosis. To assess the predictive value with regard to allogeneic stem-cell transplantation (SCT), we compared the clinical course of patients with NPM1 mut AML eligible for allogeneic SCT in a donor versus no-donor analysis. Patients and Methods Of 1,179 patients with AML (age 18 to 60 years) treated in the Study Alliance Leukemia AML 2003 trial, we identified all NPM1 mut patients with an intermediate-risk karyotype. According to the trial protocol, patients were intended to receive an allogeneic SCT if an HLA-identical sibling donor was available. Patients with no available donor received consolidation or autologous SCT. We compared relapse-free survival (RFS) and overall survival (OS) depending on the availability of a suitable donor. Results Of 304 eligible patients, 77 patients had a sibling donor and 227 had no available matched family donor. The 3-year RFS rates in the donor and no-donor groups were 71% and 47%, respectively (P = .005); OS rates were 70% and 60%, respectively (P = .114). In patients with normal karyotype and no FLT3 internal tandem duplication (n = 148), the 3-year RFS rates in the donor and no-donor groups were 83% and 53%, respectively (P = .004); and the 3-year OS rates were 81% and 75%, respectively (P = .300). Conclusion Allogeneic SCT led to a significantly prolonged RFS in patients with NPM1 mut AML. The absence of a statistically significant difference in OS is most likely a result of the fact that NPM1 mut patients who experienced relapse responded well to salvage treatment. Allogeneic SCT in first remission has potent antileukemic efficacy and is a valuable treatment option in patients with NPM1 mut AML with a sibling donor.