Abstract: High CD33 expression in acute myeloid leukemia (AML) with mutated NPM1 provides a rationale for the evaluation of gemtuzumab ozogamicin (GO) in this AML entity. We conducted a randomized trial to evaluate GO in combination with intensive induction and consolidation therapy in NPM1-mutated AML. PATIENTS AND METHODS Between May 2010 and September 2017, patients ≥ 18 years old and considered eligible for intensive therapy were randomly assigned up front for induction therapy with idarubicin, cytarabine, etoposide, and all- trans-retinoic acid with or without GO. The early ( P = .02) primary end point of event-free survival (EFS) was evaluated 6 months after completion of patient recruitment. RESULTS Five hundred eighty-eight patients were randomly assigned (standard arm, n = 296; GO arm, n = 292). EFS in the GO arm was not significantly different compared with that in the standard arm (hazard ratio, 0.83; 95% CI, 0.65 to 1.04; P = .10). The early death rate during induction therapy was 10.3% in the GO arm and 5.7% in the standard arm ( P = .05). Causes of death in both arms were mainly infections. The cumulative incidence of relapse (CIR) in patients achieving a complete remission (CR) or CR with incomplete hematologic recovery (CRi) was significantly reduced in the GO arm compared with the standard arm ( P = .005), with no difference in the cumulative incidence of death ( P = .80). Subgroup analysis revealed a significant beneficial effect of GO in female, younger (≤ 70 years), and FLT3 internal tandem duplication–negative patients with respect to EFS and CIR. CONCLUSION The trial did not meet its early primary end point of EFS, mainly as a result of a higher early death rate in the GO arm. However, in patients achieving CR/CRi after induction therapy, significantly fewer relapses occurred in the GO compared with the standard arm.

Abstract: Background: Chemotherapy-free treatment with arsenic trioxide and all-trans retinoic acid (ATO/ATRA) of patients with acute promyelocytic leukemia (APL) with presenting white blood counts (WBC) 〈 10 G/l has been shown to be at least equivalent or even better with regard to survival and quality of life compared to standard treatment according to the AIDA scheme which includes idarubicin, mitoxantrone in combination with ATRA followed by a two-year maintenance therapy with 6-mercaptopurin, methotrexate and ATRA (Lo Coco F et al., N. Engl. J. Med. 2013;369(2):111-21; Efficace F et al J Clin Oncol. 2014 accepted). Aims: To evaluate costs in relation to benefits in a cost-effectiveness analysis comparing ATO/ATRA to standard treatment with AIDA in newly diagnosed APL with WBC 〈 10G/l from a third party payers perspective Methods: The study included 55 patients with newly diagnosed APL treated in Germany within the APL0406 study (NCT00482833), n=29 in the experimental arm (ATO) and n=26 in the standard arm (AIDA). Costs were calculated based on data of treated patients to determine average estimates as of 2014. Costs were calculated based on the background of the German Diagnosis-Related Groups system including additional reimbursement for platelet transfusions and ATO as well as payment for out-patient treatment and care. Costs for 1 mg arsenic trioxide were 46.17€ both for in-patient and out-patient treatment. Results: For induction therapy all patients were hospitalized. The median hospital stay, the proportion of patients with severe complications comprising coagulopathy, differentiation syndrome, and fever triggering a higher DRG grouping, as well as median amount of platelet transfusion were 30 days (range, 16-47 days) and 33 days (range, 21-80 days) (p=0.13), 67% (20/29) and 81% (21/26) (p=0.37), 5 (range, 0-32) and 10 (range, 0-30) (p=0.13) for the ATO-arm and the AIDA-arm, respectively. The median amount of administered ATO was 290mg (range, 100-780mg) in the ATO-arm. Total costs for induction therapy were calculated with 27,211€ and 15,472€ for the ATO-arm and the AIDA-arm, respectively. During the 4 consolidation cycles in the ATO-arm, 21 of 94 cycles were administered on an in-patient basis (median duration of hospital stay, 20 days; range, 1-30 days). In 8 patients initially treated on an out-patient basis hospitalization due to fever/infection was necessary with a median duration of 19 days (range, 3-51days). One patient received a single platelet transfusion during 94 consolidation cycles. Total costs for all 4 consolidation cycles including in- and out-patient treatment were calculated with 56,305€. During the 3 consolidation cycles in the AIDA-arm, 36 of 67 cycles were administered on an in-patient basis (median duration of hospital stay, 9 days; range, 1-30 days). In 12 patients initially treated on an out-patient basis a total of 14 hospitalizations due to fever/infection were necessary (median duration, 13 days; range, 6-31days). In 10 patients, 11 platelet transfusions were given during 67 consolidation cycles. Combining the in-patient and out-patient treatment cost of all 3 consolidation cycles including rare complications of fever and platelet transfusion, total costs were calculated with 17,159€. In addition, a maintenance therapy of 2 years with 24 cycles was intended; n=15 patients received a median of 10 cycles (range 7-14 cycles). The preterm cessation of maintenance therapy in all patients was due to cytopenias and drug intolerance. Therefore, costs for 10 cycles were estimated as average costs of maintenance therapy with a total amount of 4,264€. The higher total costs in the ATO/ATRA-arm of 85,516€ (49,402€ attributed to ATO) per patient as compared to the AIDA-arm of 36,895€ per patient were accompanied by a significantly better event-free and overall survival reported in the original report (Lo Coco F et al. N Engl J Med. 2013;369(2):111-21) at 2 years of 97% and 99% compared to 86% and 91%, respectively. Based on the published overall survival data with ATO/ATRA we calculated numbers-needed-to-treat to save one life based on follow-up data of 2 years. By using the average risk difference approach a number of 14 patients has been calculated (95%-confidence interval, 12-17). Conclusions: Treatment with ATO/ATRA in newly diagnosed APL with WBC 〈 10G/l was associated with 2.3-time higher costs. At least 14 patients have to be treated with ATO to save one additional life. Disclosures Schlenk: TEVA Pharma GmbH: Research Funding, Speakers Bureau. Fiedler:TEVA: Travel reimbursement for meeting attendance Other. Ehninger:Celgene: Research Funding; GEMoaB Monoclonals GmbH: Equity Ownership, Honoraria. Döhner:TEVA: Research Funding. Lo Coco:TEVA: Consultancy, Speakers Bureau; Lundbeck: Consultancy, Speakers Bureau. Platzbecker:TEVA: Research Funding, Speakers Bureau.

Abstract: Abstract 1381 Background: Acute myeloid leukemia (AML) is a heterogenous disease. In addition to cytogenetic aberrations, somatic mutations in several genes (e.g. NPM1, FLT3, DNMT3A, WT1) have been identified which are involved in the pathogenesis of AML and affect the prognosis of these patients. Recently, it was shown that also germline mutations in the gene encoding the reverse transcriptase component of the human telomerase complex (TERT) are associated with AML and occur with a frequency of approximately 3–5% (Calado et al. Proc Natl Acad Sci USA 2009; 106:1187–92). These mutations lead to a reduced enzymatic activity of the telomerase complex. The most frequent of these mutations is an G 〉 A conversion in codon 1062 in exon 15 of TERT which leads to an alanine 〉 threonine substitution (A1062T). Telomerase complex mutations had previously been described in patients with bone marrow failure or other organ dysfunction such as liver cirrhosis or pulmonary fibrosis. The impact of such mutations on the clinical course and prognosis of AML patients, however, is unknown. Aims: We wanted to analyze the clinical and prognostic impact of the most common TERT mutation A1062T in younger AML patients treated within two prospective multicenter trials. Methods: The mutational hotspot in exon 15 of the TERT gene was analyzed by direct sequencing in 420 patients (age 16–60 years) with AML treated with intensive double induction and consolidation therapy within the AMLSG 295 and 0199 trials (NCT00209833). The patients were also analyzed for mutations/aberrations in the genes NPM1, FLT3, WT1 and DNMT3A. Median follow up was 79 months. Results: Fifteen of the 420 analyzed patients (3.3%) carried a TERT A1062T mutation. In the four patients of whom remission bone marrow or blood samples were available, the mutation was also detected in complete remission suggesting a germline origin of the mutation. Patients with TERT mutations had a trend (p = 0.06) towards less favorable (13% vs. 42%) and more intermediate-2/adverse karyotypes/genotypes (60% vs. 31%) according to the ELN classification. Other clinical and molecular parameters did not differ from wildtype patients. In univariate analysis, patients with TERT mutations had a significantly inferior overall survival (OS) compared to wildtype patients (HR 2.31; 95% CI 1.29 – 4.13, p = 0.005; 3year OS 20% vs. 46%). Also, in multivariate analysis TERT mutations were an independent negative factor for OS when analyzed together with age, leukocytes/peripheral blasts, platelets, extramedullary disease, de novo vs. secondary AML, ELN risk classification, WT1 SNP rs16754 and mutations in NPM1, FLT3 and DNMT3A. In addition to a high relapse rate, TERT mutated patients also showed a high rate of treatment related mortality: 5/15 (33%) of the mutated patients died during induction therapy or in CR as compared to 62/405 (15%) of the wildtype patients (p = 0.07). Of note, three of four TERT mutated patients who received an allogeneic stem cell transplantation in first CR died in CR. Therefore, we also analyzed treatment related toxicity during induction therapy. In the TERT mutated patients, 14/15 (93%) suffered from non-hematological/non-infectious grade 3 or 4 adverse events (mostly hepatic and/or mucosal) as compared to 216/405 (53%) wildtype patients (p = 0.006). In multivariate analysis, TERT mutations were an independent risk factor predicting for adverse events during induction (OR 9.6; 95% CI 1.24 – 75.23, p = 0.031) when analyzed together with age, ELN risk classification, other gene mutations, blood counts, extramedullary disease, ECOG performance status, response to first induction therapy, and de novo vs. secondary AML. Conclusions: TERT A1062T mutations are an independent negative prognostic factor in younger patients with AML. These mutations seem to predispose AML patients to treatment-related toxicity and mortality. Disclosures: No relevant conflicts of interest to declare.

Abstract: Abstract 6 Background Simultaneous ATRA and chemotherapy (CHT) is the current gold standard for newly diagnosed APL resulting in ∼80% cure rates, while arsenic trioxide (ATO) is the treatment of choice for relapsed patients. ATO in variable combinations including ± ATRA ± CHT has also been tested as front-line therapy yielding encouraging results in several pilot studies as well as in two phase III studies conducted in China and the US. So far, no randomised studies have compared front-line CHT-free ATO+ATRA combination against the standard ATRA+CHT approach. Patients and Methods The phase III, randomised, prospective APL0406 trial was started in October 2007 by the Italian GIMEMA group and joined in November 2008 by the German SAL and AMLSG multicenter groups. Eligible patients were adults aged 18- 〈 71 years with newly diagnosed, genetically confirmed, non-high-risk (WBC≤10×109/L) APL. Patients were randomized to receive the ATO+ATRA combination originally reported by the MD Anderson group (Estey et al. Blood 2006, arm A), or the Italian AIDA2000 risk-adapted protocol for non high-risk disease (arm B). Patients in arm A received ATO 0.15/kg plus ATRA 45 mg/m2 daily until CR, then ATO 5 days/week, 4 weeks on 4 weeks off, for a total of 4 courses and ATRA 2 weeks on and 2 weeks off for a total of 7 courses. Patients in arm B received the standard AIDA (ATRA+Idarubicin) induction followed by 3 cycles of anthracycline-based plus ATRA consolidation and low dose CHT and ATRA for maintenance as reported (Lo-Coco et al., Blood 2011). The primary study objective was EFS at 2 years. The study was designed to show that the rate of patients alive event-free at two years in the experimental treatment arm is at least 80%. Secondary objectives included OS, DFS, CIR rates, molecular response and toxicity profile. Results From October 2007 to September 2010, the required sample size of 162 enrolled patients was completed. Median age was 45.3 years (18.7–70.2 years) and median WBC 1.50 × 109/L. As to the Sanz's risk score, 61.8% and 38.2% of patients were in the intermediate- and low-risk categories, respectively. The two treatment arms were well balanced for main baseline characteristics including age, sex, median WBC and Sanz's score. Eight patients were not evaluable for induction due to ineligibility or protocol violation. Of 154 patients evaluable for response to induction, CR was achieved in 150 (97.4%): 75/75 (100%) in arm A vs 75/79 (95%) in arm B (P=0.12). After a median follow-up of 31 months (range 0.07–50.4) the 2 year EFS (primary objective) was 97% (C.I.95%: 93.1–100) and 86.7% (C.I.95%: 80.3–93.6) in arms A and B respectively (P=0.03). There were 1 death in CR and 2 relapses in arm A, and 7 deaths (4 in induction, 3 in CR) and 4 relapses in arm B. As to secondary objectives, OS, DFS, and CIR rates were 98.7% vs. 91.1% (P=0.03), 97% vs. 91.6% (P=0.19) and 1.6% vs. 4.3% (P=0.41) in arm A and B, respectively. Fever episodes, prolonged ( 〉 15 d) grade ≥ 3 neutropenia and thrombocytopenia were significantly more frequent in patients in arm B as compared to those in arm A (P 〈 .001 for all comparisons). Other side effects including differentiation syndrome and increase of liver enzymes were recorded with similar frequency in the two study arms. Two patients in arm A had QTc prolongation requiring ATO discontinuation with final withdrawal in one case. PCR analysis of PML/RARA (sensitivity 10−4) was centrally performed in Rome (F. Lo-Coco) and Dresden (C. Thiede) and showed molecular CR in 141/142 (99%) of evaluable patients after completion of 3rd consolidation. One patient in arm B who tested PCR-positive at this time point was considered resistant and taken off protocol as per study design. Conclusions For patients with newly diagnosed non-high-risk APL, as compared to the standard AIDA regimen, the front-line CHT-free ATO+ATRA combination is at least not inferior for 2 year EFS. Disclosures: Lo-Coco: Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Cephalon: Speakers Bureau. Off Label Use: Arsenic Trioxide (ATO) is currently approved for therapy of relapsed APL in the US and Europe. In this study the role of ATO in front-line therapy of APL is explored. Fiedler:Pfizer Inc.: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Breccia:Celgene: Honoraria; Novartis: Honoraria; BMS: Honoraria. Platzbecker:GlaxoSmithKline: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Amgen: Consultancy.

Abstract: Introduction:The role of autologous stem cell transplantation (ASCT) in patients with marginal zone lymphomas (MZL) is not fully elucidated. The aim of the present study was to determine the outcome of patients undergoing ASCT for relapsed/refractory MZL, and define prognostic factors affecting that outcome. Methods: Eligible for this study were patients with nodal, extra-nodal (MALT) or splenic MZL , aged ≥18 ears, who underwent a first ASCT between July 1994 and February 2013, and reported to the European Society for Blood and Marrow Transplantation (EBMT) registry, and/or the Fondazione Italiana Linfomi (FIL) and the Gruppo Italiano Trapianto di Midollo Osseo (GITMO) networks. Patients with a history of MZL transformation were excluded. Review of written diagnostic reports was mandatory for inclusion. Log rank tests were used to assess the impact of baseline characteristics on overall survival (OS) and event-free survival (EFS). In multivariate analysis, the effect of prognostic factors was evaluated using Cox regression models. Cumulative incidence of relapse (IR) and cumulative incidence of non-relapse mortality (NRM) were estimated with a competing-risk approach. Risk factors for IR and NRM were estimated by Pepe & Mori test or by Fine & Gray model. Results: The study included 199 patients, 111 patients (56%) with MALT lymphoma, 55 patients with nodal MZL (28%) and 33 patients (16%) with splenic MZL.. Median age at transplantation was 56 years (range, 25-71 years). Median time from diagnosis to ASCT was 2 years (0.1-28.0). Median number of prior therapies was 1 , (range 1-8) , including rituximab in 74%. 96% were transplanted with chemosensitive disease; 70 (37%) in CR1/PR1 ,113(59%) in CR/PR 〉 1 and 7 in SD (4%) Median calendar year of ASCT was 2006, with 17,1% of transplants being performed before 2001. Total body irradiation-based high-dose regimen was used in 16 patients (8%), whilst 92% of the patients received high-dose chemotherapy only. Median follow-up was 4.1 years (0.1-19.1). Five-year cumulative incidence of relapse/progression (IR) and non-relapse mortality (NRM) were 38% (95%CI 30-45%) and 9 %( 95%CI 6-14%) respectively. Five-year event-free survival (EFS) and overall survival (OS) were 53% (95%CI 45-61%) and 73% (95%CI 65-79%), respectively. Multivariate analysis revealed age 〉 65 years to be associated with shorter EFS and a shorter OS (HR=8.6, 95%CI 2.8-26.2, p 〈 0.001 and HR=5.2,95%CI 1.9-14, p=0.001 respectively). Additionally, MZL predicted a shorter OS than MALT (HR=3.2, 95%CI 1.2-8.7, p=0.023). Notably, rituximab had no statistically significant effect on transplant outcome.Risk of secondary malignancies approached 6.8%. Conclusions: ASCT is a feasible and effective procedure when offered to MZL patients younger than 65 years, even in those previously exposed to rituximab. Disclosures Zaja: MedImmune: Research Funding.

Abstract: Background:Despite recent advances in identifying novel molecular targets in AML patients, intensive chemotherapy followed by allogeneic hematopoietic stem cell transplantation (HSCT) still remains a cornerstone of AML therapy. However, outcome of HSCT depends on the availability of a donor and the donor type. Prior studies comparing HSCT from HLA-matched related donors (MRD) with matched unrelated donors (MUD), demonstrated conflicting results with regards to outcome. These conflicting results might be attributed to the genetic heterogeneity of AML. Aims:To analyze outcome with respect to donor type of 952 AML patients who received HSCT in first complete remission (CR) and were treated within prospective AMLSG trials. Methods:Within the AMLSG trials conducted between 1993 and 2013, of a total of 4991 patients (excluding acute promyelocytic leukemia), 3408 (2744 younger ( 〈 61 years old), 664 older (≥61 years old)) patients achieved a first CR after intensive double induction therapy. Of these, 867 (31%) younger and 85 (13%) older patients received HSCT in first CR. Distributions of donor types were 511 matched related donors (MRD), 435 matched unrelated donors (MUD) and 6 haplo-identical donors. The latter were grouped together with MUD. Results:Distributions of donor type over time are illustrated in table 1 indicating two clear trends with increasing numbers of MUD transplants and increasing median age in MUD- and MRD-transplants in recent years. There was no significant difference in overall survival, cumulative incidence of relapse (CIR) and death (CID) all estimated at 4 years according to the three time periods for MRD (p=0.56, p=0.15, p=0.10, respectively) and MUD (p=0.27, p=0.20, p=0.88, respectively). Table 1 Time period 1993-2002 2003-2007 2008-2013 Total no. 1036 1102 1270 MRD  No. 186 (18%) 182 (17%) 143 (11%)  Median age 42.7yrs 46.0yrs 51yrs  4-yr-OS (95%-CI) 59% (53-67) 66% (59-73) 61% (53-72)  4-yr-CIR (SE) 21% (3%) 25% (3%) 29% (4%)  4-yr-CID (SE) 25% (3%) 15% (3%) 18% (3%) MUD  No. 42 (4%) 131 (12%) 268 (21%)  Median age 41.1yrs 47.9yrs 50.6yrs  4-yr-OS (95%-CI) 52% (39-70) 46% (38-58) 54% (47-61)  4-yr-CIR (SE) 21% (3%) 25% (3%) 29% (4%)  4-yr-CID (SE) 25% (3%) 15% (3%) 18% (3%) Table 2 ELN risk category low inter-1 inter-2 high Total no. 867 711 433 318 MRD  No. 78 (9%) 122 (17%) 66 (15%) 57 (18%)  4-yr-OS (95%-CI) 84% (76-93) 50% (51-69) 53% (41-67) 57% (44-72)  4-yr-CIR (SE) 7% (3%) 24% (4%) 35% (6%) 49% (7%)  4-yr-CID (SE) 13% (4%) 23% (4%) 23% (6%) 12% (4%) MUD  No. 21 (2%) 139 (20%) 76 (18%) 109 (36%) 4-yr-OS (95%-CI) 69% (52-93) 58 (49-68) 52% (41 67) 35% (26-46)  4-yr-CIR (SE) 0% 28% (4%) 32% (6%) 44% (5%)  4-yr-CID (SE) 31% (11%) 20% (4%) 17% (5%) 28% (4%) There were no differences in stratified survival analyses for time period between MRD and MUD-transplants in the low, intermediate-1 and intermediate-2 risk groups with respect to OS (p=0.12, p=0.86, p=0.98), CIR (p=0.28, p=0.54, p=0.94) and CID (p=0.09, p=0.57, p=0.39). In the high risk group, OS was significantly superior after MRD-transplant compared to MUD-transplant (p=0.02), but without significant differences in CIR (p=0.74) and CID (p=0.08). Equivalent efficacy could also be shown in a subgroup analyses focusing on all FLT3-ITD positive patients (MRD, n=103, MRD, n=147) for OS (p=0.71), CIR (p=0.53) and CID (p=0.69). Conclusions: Our results based on prospective interventional studies support the perception that MUD-transplants are equal to MRD-transplants in patients with AML in first CR. Only within the ELN high risk group, patients with MRD-transplants showed superior OS but without differences in CIR and CID as compared to MUD-transplants. Disclosures Kobbe: Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Medac: Other; Astellas: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Neovii: Other. Götze:Celgene Corp, Novartis Pharma: Honoraria. Fiedler:TEVA: Travel reimbursement for meeting attendance Other. Petzer:Celgene: Honoraria, unrestricted grant Other. Lübbert:Cephalon / TEVA: Travel support Other. Greil:Bristol-Myers-Squibb: Consultancy, Honoraria; Cephalon: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Amgen: Honoraria, Research Funding; Eisai: Honoraria; Mundipharma: Honoraria, Research Funding; Merck: Honoraria; Janssen-Cilag: Honoraria; Genentech: Honoraria, Research Funding; Novartis: Honoraria; Astra-Zeneca: Honoraria; Boehringer-Ingelheim: Honoraria; Pfizer: Honoraria, Research Funding; Roche: Honoraria; Sanofi Aventis: Honoraria; GSK: Research Funding; Ratiopharm: Research Funding. Döhner:Novartis: Research Funding. Döhner:TEVA: Research Funding.

Abstract: The role of autologous stem cell transplantation ( ASCT ) in patients with marginal zone lymphoma ( MZL ) is debatable. This study investigated the outcome and prognostic factors affecting the outcome of patients undergoing ASCT for MZL . Eligible patients had non‐transformed nodal, extra‐nodal ( MALT ) or splenic MZL ( SMZL ), aged ≥18 years, who underwent a first ASCT between1994 and 2013 and were reported to the European Society for Blood and Marrow Transplantation, Fondazione Italiana Linfomi or Gruppo Italiano Trapianto Di Midollo Osseo registries. The study included 199 patients, [111 MALT lymphoma, 55 nodal MZL ( NMZL ) and 33 SMZL ]. Median age at transplantation was 56 years. The median number of prior therapies was 2 (range 1–8), including rituximab in 71%. 95% had chemosensitive disease. 89% received a chemotherapy‐based high‐dose regimen. There were no significant differences in patient and transplant characteristics between the 3 histological subtypes except for a lower percentage of patients previously treated with rituximab in the MALT sub‐group and more transplants performed in recent years in the other sub‐groups. After a median follow‐up of 5 years, 5‐year cumulative incidence of relapse/progression and non‐relapse mortality were 38% and 9%, respectively. Five‐year event‐free survival ( EFS ) and overall survival ( OS ) were 53% and 73%, respectively. Five‐year cumulative incidence of second malignancies was 6%. Multivariate analysis revealed age ≥65 years was associated with a shorter EFS and OS . In addition, patients with SMZL had a shorter OS than those with MALT . ASCT may provide clinical benefit in MZL patients who have failed multiple lines of chemoimmunotherapy.

Abstract: Background: Mutations of the NPM1 gene are one of the most frequent genetic aberrations in adult AML. AML with mutated NPM1 is categorized as a disease entity according the WHO-2016 classification and clinically associated with female sex, high white blood cells at diagnosis, normal karyotype and high CD33 antigen expression. We recently showed that patients with NPM1-mutated AML benefit from all-trans retinoic acid (ATRA) as adjunct to intensive induction therapy (Ann Hematol. 2016; 95:1931-1942; Haematologica. 2009;94:54-60). Based on the regular high CD33 expression in AML with mutated NPM1 we hypothesized that gemtuzumab ozogamicin (GO) added to intensive therapy with ATRA may further improve clinical outcome in AML with mutated NPM1. Aim: To evaluate GO in combination with intensive induction and consolidation therapy and ATRA in NPM1 mutated AML within the randomized AMLSG 09-09 trial (NCT00893399) Methods: Between May 2010 and September 2017, patients ≥18 years of age and considered eligible for intensive therapy were randomized up-front for open-label treatment with GO. Induction therapy consisted of two cycles of A-ICE (idarubicin 12mg/m² iv, day 1,3,5 [in induction II and for patients 〉 60 years reduced to d 1, 3]; cytarabine 100mg/m² continuous iv, day 1 to 7; etoposide 100mg/m² iv, day 1-3 [in induction II and for patients 〉 60 years reduced to d 1, 3]; ATRA 45 mg/m²/day po on days 6-8 and 15mg/m² days 9-21, +/- GO 3mg/m² iv day 1). Consolidation therapy consisted of 3 cycles of high-dose cytarabine (HiDAC; 3g/m² [reduced to 1g/m² in patients 〉 60 years] bid, days 1-3; Pegfilgrastim 6mg sc, day 10; ATRA 15 mg/m²/day po, days 4-21; +/- GO 3mg/m² on day 1 [first consolidation only] ). The primary endpoints of the study were event-free survival (EFS) as early endpoint tested 6 months and overall survival (OS) tested 4 years after study completion with sequential testing according the fallback procedure described by Wiens (Statistics 2003;2:211-215). This report focusses on the early EFS endpoint. Further secondary endpoints were response to induction therapy, cumulative incidence of relapse (CIR) and cumulative incidence of death (CID). Results: In total 588 patients were evaluable for analysis (n=296, standard-arm; n=292 GO-arm). Median age was 58.7 years (range, 18.4-82.3 years), ECOG performance status was 0 in 34.1% and 1 in 55.1%, and FLT3-ITD was present in 16.8% of the patients, with baseline characteristics well balanced between the two arms. After first induction therapy death rates were significantly higher in the GO-arm (7.5%) (p=0.02) compared to the standard-arm (3.4%); in both study-arms causes of death were mainly infections. Following induction therapy complete remission (CR) and CR with incomplete count recovery (CRi) were 88.5% and 85.3% (p=0.28), refractory disease (RD) 6.1% and 5.1% (p=0.72), death 5.4% and 9.6% (p=0.06) in the standard- and GO-arm, respectively. Due to prolonged thrombocytopenia after second induction therapy in the GO-arm, the protocol was amended in that GO was omitted in second induction and first consolidation cycles, if prolonged cytopenias were observed during first induction therapy. The study treatment was completed in 197 and 171 patients (p=0.11), allogeneic hematopoietic cell transplantation in first CR was performed in 18 and 21 patients (p=0.51) in the standard- and GO-arm, respectively. Median follow-up was 2.6 years (95%-CI, 2.4-3.1 years). Two- and 4-year EFS were 53% (95%-CI, 48-60%) and 58% (95%-CI, 52%-64%), and 44% (95%-CI, 38-52%) and 52% (95%-CI, 46%-59%) in the standard- and GO-arm, respectively. According to the pre-specified significance level of 0.025, EFS in the GO-arm was not different to that in the standard-arm (p=0.21). In patients achieving CR/CRi after induction therapy, CIR was significantly reduced in the GO-arm compared to the standard-arm (p=0.018), whereas no difference in CID was noted between both arms (p=0.89). Conclusion: The addition of GO to intensive induction therapy with ICE plus ATRA was associated with a higher death rate. In patients achieving a CR/CRi after induction therapy significantly less relapses occurred in the GO- compared to the standard-arm. Disclosures Schlenk: Pfizer: Research Funding, Speakers Bureau. Paschka:Astex: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees, Travel support; Otsuka: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Sunesis: Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Other: Travel support, Speakers Bureau; Jazz: Speakers Bureau; Amgen: Other: Travel support; Janssen: Other: Travel support; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Travel support. Fiedler:Amgen: Other: support for meetíng attendance; Gilead: Other: support for meeting attendance; Pfizer: Research Funding; Amgen: Research Funding; Amgen: Patents & Royalties; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; ARIAD/Incyte: Membership on an entity's Board of Directors or advisory committees, support for meeting attendance; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSO: Other: support for meeting attendance; Teva: Other: support for meeting attendance; JAZZ Pharmaceuticals: Other: support for meeting attendance; Daiichi Sankyo: Other: support for meeting attendance. Lübbert:Cheplapharm: Other: Study drug; Celgene: Other: Travel Support; Janssen: Honoraria, Research Funding; TEVA: Other: Study drug. Götze:Novartis: Honoraria; Takeda: Honoraria, Other: Travel aid ASH 2017; JAZZ Pharmaceuticals: Honoraria; Celgene: Honoraria, Research Funding. Schleicher:Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Investigator; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Ipsen: Membership on an entity's Board of Directors or advisory committees; Eissai: Other: Investigator; Astra Zeneca: Other: Investigator; Pfizer: Speakers Bureau; Janssen: Speakers Bureau; Celgene: Speakers Bureau. Greil:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Honoraria, Research Funding; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Honoraria, Research Funding; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sandoz: Honoraria, Research Funding; Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Heuser:Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Astellas: Research Funding; BergenBio: Research Funding; Karyopharm: Research Funding; Daiichi Sankyo: Research Funding; Sunesis: Research Funding; Tetralogic: Research Funding; Bayer Pharma AG: Consultancy, Research Funding; StemLine Therapeutics: Consultancy; Janssen: Consultancy. Ganser:Novartis: Membership on an entity's Board of Directors or advisory committees. Döhner:Agios: Consultancy, Honoraria; Pfizer: Research Funding; Sunesis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Agios: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Celator: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Jazz: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Pfizer: Research Funding; Sunesis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Research Funding; Seattle Genetics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Celator: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding.

Abstract: Background Cyto- and molecular-genetic abnormalities evaluated at initial diagnosis are the most powerful prognostic and in part also predictive markers in acute myeloid leukemia (AML) with regard to achievement of complete remission (CR) and survival. Nonetheless, after relapse the prognostic impact of clinical characteristics and genetic abnormalities assessed at initial diagnosis with respect to achievement of subsequent CR and survival are less clear. Aims To evaluate the probability of CR achievement and survival in relapsed AML patients in correlation to clinical characteristics and genetic abnormalities assessed at initial diagnosis as well as treatment strategy. Methods The study includes intensively treated adults with newly diagnosed AML enrolled in 5 prospective AMLSG treatment trials between 1993 and 2009. Patients with acute promyelocytic leukemia were excluded. All patients received intensive therapy, including allogeneic (allo) and autologous (auto) hematopoietic stem cell transplantation (HSCT) during first line therapy. Results A total of 3218 patients (median age, 54 years; range, 16-85 years) were enrolled in 5 AMLSG treatment trials. Of these, 1307 (41%) patients (16-60 years, n=958; ≥61 years, n=349) experienced relapse, n=194 after alloHSCT, n=75 after autoHSCT and 1038 after chemotherapy. Salvage strategies were as follows: (i) n=907, intensive chemotherapy (INT) followed in n=450 by HSCT (matched related donor [MRD], n=114; matched unrelated donor [MUD] , n=303; cord blood graft [CB], n=3; haplo-identical family donor [HID] , n=18; autoHSCT, n=12); (ii) n=100, direct alloHSCT (MRD, n=31; MUD, n=63; HID, n=4) or n=2 autoHSCT (TPL); (iii) n=29, donor lymphocyte infusions (DLI) in patients after alloHSCT in CR1; (iv) n=60, demethylating agents/low-dose cytarabine (NON-INT); (v) n=24, experimental treatment within phase I/II studies (EXP); (vi) all other patients (n=187) received best supportive care (BSC). After salvage therapy CR rate was 38% and after the different treatment approaches as follows: INT, 37%; TPL, 73%; DLI, 38%; NON-INT, 8%; EXP, 29%. After failure to respond to INT, n=159 additional patients achieved a CR2 after HSCT resulting in an overall CR2 rate of 50%. A logistic regression model revealed CEBPA double-mutant (dm) (OR, 6.42; p=0.0001), core-binding factor (CBF) AML (OR, 2.87; p=0.0002), a direct HSCT strategy (OR, 3.32; p=0.0002), and mutated NPM1 (OR, 1.59; p=0.02) as favorable (only if response after HSCT was included) and FLT3-ITD (OR, 0.66; p=0.04), age (difference of 10 years; OR, 0.82; p=0.003), NON-INT (OR, 0.08; p=0.0001) and in trend a previous alloHSCT in CR1 (OR, 0.65; p=0.08) as unfavorable independent parameters for achievement of CR2. Median follow-up for survival after relapse was 4.3 years and survival after 4 years was 22% (95%-CI, 19-25%). Patients proceeding to alloHSCT after first relapse (n=536; MRD, n=145; MUD, n=366; HID, n=22; CB, n=3) had a 4-year survival of 36% (95%-CI, 32-41%) and those not proceeding to alloHSCT of 8% (95%-CI, 6-11%). In univariable analyses the combined genotype mutated NPM1 in the absence of FLT3-ITD (p=0.66) was not associated with a favorable outcome. A multivariable regression model including alloHSCT as a time-dependent co-variable revealed alloHSCT performed after relapse (HR, 0.34; p 〈 0.0001), CEBPAdm (HR, 0.48; p=0.002), CBF- AML (HR, 0.50; p 〈 0.0003) and DLI in relapsed patients with a previous alloHSCT performed in CR1 (HR, 0.40; p=0.002) as significant favorable factors, whereas FLT3-ITD (HR, 1.35; p=0.005) and in trend NON-INT (OR, 1.40; p=0.06) were unfavorable factors. Due to collinearity of FLT3-ITD with duration of first remission (cut point at 1 yr), the latter was not included into the multivariable models. Of 561 patients achieving CR2, 252 experienced 2nd relapse (REL2) and 114 died in CR2. Most REL2 patients (n=117) received INT whereas n=54 received BSC only. Allo- and autoHSCT were performed in 55 and 3 REL2 patients, respectively. CR3 rate in patients who received treatment was overall 40% including response to HSCT of 58%. Conclusions Patients with relapsed AML have an overall probability of less than 50% to achieve a CR2 and CR3 after intensive salvage chemotherapy; the only exceptions are AML with CEBPAdm and CBF-AML. AlloHSCT either as direct treatment of relapse or as salvage therapy after failure of intensive chemotherapy may overcome chemo-resistance. Disclosures: Schlenk: Celgene: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Chugai: Research Funding; Amgen: Research Funding; Novartis: Research Funding; Ambit: Honoraria. Off Label Use: Pomalidomide in Myelofibrosis. Kindler:Novartis: Membership on an entity’s Board of Directors or advisory committees.

Abstract: T-cells with specificity for antigens derived from Wilms-Tumor-gene (WT1), Proteinase3(Pr3), and mucin1(MUC1) have been demonstrated to lyse AML blasts and MM cells and strategies to enhance or induce such tumor-specific T-cells by vaccination are currently explored in multiple clinical trials. To test the safety and immunogenicity of a vaccine composed of WT1-, Pr3-, and MUC1-derived Class I-restricted peptides in combination with CpG 7909 and Montanide ISA51 adjuvants and the PADRE helper epitope, 9 patients with AML or MM were repetitively vaccinated. No clinical responses were observed. Comprehensive immunologic analyses revealed that 5 out of 9 patients harboured non-functional and 2 out of 9 functional MUC1- or WT1-specific CD8+ T-cells prior vaccination. However, neither the pre-existing nor naive de novo WT1-/Pr3-/MUC1-specific CD8+ cells were expanded in vivo by vaccination. Moreover, the pre-existing WT1-/MUC1-specific T-cells became no longer detected following vaccination, whereas the frequency and function of CMV-specific CD8+ T-cells was unchanged. A more than 2-fold increase in PADRE-specific CD4+ T-helper-cells was observed but these did not produce IL2, and CD4+ T-cells with a regulatory phenotype increased more than 2-fold. These results are in stark contrast to previous vaccination studies, and should be carefully taken into consideration in the context of multiple ongoing as well as future clinical vaccination trials.