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: 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: During the last years, based on its efficacy and favourable toxicity profile the hypomethylating agent (HMA) Azacitidine (Aza) has proven to be a valuable treatment option for patients with AML or MDS who relapse after allo-SCT. In contrast to Aza, reports on the use of Decitabine (DAC), the second HMA approved in Europe for the treatment of AML, as salvage therapy for relapse after allo-SCT are scarce covering a total of 9 patients so far. This prompted us to perform a retrospective survey in order to gather more experience on the use of DAC after allo-SCT. Patients and Methods: Retrieving information from the EBMT Med-A form and a study-specific questionnaire we were able to analyze data of 36 patients (median age 56 years, range 21-72 years) from 6 German transplant centers who had received at least one cycle of DAC for the treatment of relapse of AML (n=29) or MDS (n=7) after allo-SCT. Median time to haematological (n=34) or molecular (n=2) relapse was 370 days (range 43-2623 days). Results: Overall, DAC was the first treatment for relapse in 16 pts (44%), whereas 20 pts (56%) had previously received one (n=14), two (n=2) or three (n=4) lines of salvage therapy for relapse after allo-SCT. This included 16 pts treated with Aza, 3 pts with intensive chemotherapy and 2 pts with radiation. Five pts had received a second allo-SCT and 9 pts donor lymphocyte infusions (DLI) before DAC therapy. Patients received a median of 2 DAC cycles (range, 1-10) with 24 pts (67%) treated with the approved dose of 20 mg/m2 for 5 days and 12 pts (33%) treated with 20 mg/m2 for 10 days based on the local policy of the individual transplant center. In addition to DAC, DLI (median number of DLI =1, range: 1-5) were administered to 22 pts (61%). Following treatment with DAC +/- DLI the median survival was 5 months (range 1 - 40 months). Six pts achieved a complete remission (CR, 17%) and 3 pts achieved a partial remission (PR, 8%) leading to an overall response rate of 25%. Median time to documentation of CR was 157 days (range: 47-255 days) and 4 DAC cycles (range: 1-8 cycles). Of 6 patients achieving CR after DAC, 3 had received DAC as first salvage therapy and 3 had previously received Aza, including 2 pts not responding to Aza and 1 patient switched to DAC therapy due to Aza intolerability. With a median follow-up of 12 months (range: 5-40 months), 3 of 6 patients remain in ongoing remission for 4, 23, and 33 months respectively without any further antileukemic therapy, while the other 3 patients died in remission due to infectious complications after second transplant. The 2-year overall survival rate of the entire group as calculated from the start of DAC therapy was 9%. Incidence and severity of acute GvHD (overall: 19%, grade I: 3%, grade II: 8%, grade III: 5%, grade IV: 0%, missing: 3%) and chronic GvHD (overall: 6%, limited 6%, extensive 0%) were low and mild. Conclusion: Our analysis shows, that also the second HMA DAC exerts relevant clinical efficacy in patients with AML or MDS relapsing after allo-SCT and can induce durable remissions in individual pts. Given the heterogeneity of our patient group and the limitations of a retrospective analysis this asks for confirmation in a prospective trial. Disclosures Platzbecker: Onconova, Teva, Celgene, Janssen, Novartis, Amgen: Honoraria, Research Funding. Kobbe:Jansen: Honoraria, Other: travel support; Celgene: Honoraria, Other: travel support, Research Funding.

Abstract: 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.

Abstract: Azacitidine combined with donor lymphocyte infusions (DLI) is an established treatment for relapse of myeloid malignancies after allogeneic transplantation. Based on its immunomodulatory and anti-leukemic properties we considered Lenalidomide to act synergistically with Azacitidine/DLI to improve outcome. We therefore prospectively investigated tolerability and efficacy of this combination as first salvage therapy for adults with post-transplant relapse of AML, MDS and CMML. Patients were scheduled for 8 cycles Azacitidine (75 mg/m2 day 1-7), Lenalidomide (2.5 or 5mg, day 1-21) and up to 3 DLI with increasing T cell dosages (0.5×106-1.5×107 cells/kg). Primary endpoint was safety, while secondary endpoints included response, graft-versus-host disease (GvHD) and overall survival (OS). Fifty patients with molecular (52%) or hematological (48%) relapse of MDS (n=24), AML (n=23) or CMML (n=3) received a median of 7 (range, 1 to 8) cycles including 14 patients with 2.5mg and 36 with 5mg Lenalidomide daily dosage. Concomitantly, 34 patients (68%) received at least one DLI. Overall response rate was 56% and 25 patients (50%) achieved complete remission being durable in 80%. Median OS was 21 months and 1-year OS rate 65% with no impact of type of or time to relapse and Lenalidomide dosages. Treatment was well tolerated indicated by febrile neutropenia being the only grade ≥3 non-hematologic adverse event in 〉 10% of patients and modest acute (grade II-IV 24%) and chronic (moderate/severe 28%) GvHD incidences. In summary, Lenalidomide can be safely added to Azacitidine/DLI without excess of GvHD and toxicity. Its significant anti-leukemic activity suggests that this combination is a novel salvage option for post-transplant relapse. (NCT02472691)