Abstract: Background Current response criteria for AML were established for and validated in younger patients (pts) fit for and treated with intensive chemotherapy (IC) in an era before hypomethylating agents (HMA) were available. According to these criteria: 1 Achievement of morphologic complete response (CR; defined as bone marrow blasts [BMB] 〈 5%, absolute neutrophil count 〉 1.0G/L, platelets ≥100G/L and red blood cell transfusion independence) is a prerequisite for cure, and is deemed the sole outcome associated with improved overall survival (OS)1 2 Pts without morphologic CR are considered non-responders1 3 Morphologic leukemia free state (MLFS; defined as 〈 5% BMB, irrespective of cytopenias) is considered inferior to CR 4 Hematologic improvement (HI) without BMB clearance is considered treatment failure1,2 However, evidence is accumulating that these definitions may not be applicable to older AML pts treated with HMA. For example, achievement of CR with HMA may not be necessary for clinical benefit and prolonged OS.3-5 We have previously shown that older AML pts achieving HI according to myelodysplastic syndrome (MDS) criteria6 have clinical benefit from extended azacitidine (AZA) treatment.3,4 In addition, treatment goals and modalities differ for HMA vs IC. Thus, the question arises whether current response criteria remain valid for older AML pts unfit for IC. Aims and methods To define new response criteria, including the 1st criteria for assessment of HI, for older AML pts unfit for IC with the intention of keeping them as simple to implement as possible. Human errors in response assessment according to these proposed criteria were excluded by the development of algorithms for automated computational calculation from data entered into the eCRF. We next assessed the supplementary value of HI in addition to BMB reduction, as well as the value of HI irrespective of BMB reduction, with regards to predicting treatment outcomes. Results In total, 193 AML pts receiving AZA 1st line were included in this analysis. Baseline and treatment characteristics were mostly comparable to those of AML pts included in a recent phase 3 clinical trial (Fig 1).7 Overall, 5 categories of HI and hematologic progression were defined, using: erythrocytes (E), platelets (P), neutrophils (N), peripheral blood blasts, and elevated white blood cells (Fig 2). We based our definitions on IWG 2006 MDS criteria and adapted these for the more aggressive disease biology and kinetics of AML, and treatment goals and modalities of HMA. Our data indicate that: 1 AML pts achieving HI (irrespective of BMB reduction) had significantly longer OS than those without HI (16.1 vs 6.0 mo, p 〈 0.001; Fig 3A) 2 OS was prolonged irrespective of the cell lineage in which HI occurred (17.1, 17.5 and 18.0 mo for pts with HI-N, HI-E or HI-P, respectively) 3 OS correlated with the number of cell lineages/types in which HI was achieved (6.0 vs 14.4 vs 19.7 mo [p 〈 0.001] for HI in 0 vs 1-2 vs 〉 2 lineages/types; Fig 3B) 4 Pts with MLFS did not have worse OS than pts with CR (Fig 3C) 5 Definition of response according to our proposed criteria resulted in clinically meaningful separation of 3 response types with significant differences in median OS: 23.0 (CR or MLFS) vs 13.5 (HI and not CR or MLFS) vs 4.4 mo (non-responders) (p 〈 0.001; Fig 3D) Conclusions While achievement of CR according to IWG 2003 criteria1 remains the primary goal for AML pts treated with IC, we guardedly introduce new response criteria for pts unfit for IC treated with non-curative treatment such as HMA. Applying these criteria to our large real world cohort, we show that pts achieving HI in the absence of BMB clearance (considered non-responders using current criteria)1, had a significant survival benefit from continued AZA treatment compared to pts with no HI. We conclude that these patients should be considered as responders and kept on treatment, and hypothesize that achievement of HI could be used as a surrogate parameter for response in pts unable or unwilling to undergo BM biopsy for response assessment. This proposal requires concerted validation efforts and we hope that our data stimulate cooperations. References 1 Cheson BD JCO 2003;21:4642 2 Lopez G Blood 2001;98:329;abs 1388 3 Pleyer L J Hematol Oncol 2013;6:32 4 Pleyer L Ann Hematol 2014;93:1825 5 Schuh AC Haematologica 2015;100:abs P575 6 Cheson BD Blood 2006;108:419 7 Dombret H Blood 2015;126:291 Disclosures Pleyer: AOP Orphan Pharmaceuticals: Honoraria; Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Off Label Use: Vidaza (azacitidine) is indicated for the treatment of adult AML patients who are not eligible for hematopoietic stem cell transplantation with 20-30% blasts and multi-lineage dysplasia, according to WHO classification. This cohort also includes AML patients with 〉 30% bone marrow blasts.. Burgstaller:Celgene: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Mundipharma: Honoraria; AOP Orphan Pharmaceuticals: Honoraria, Research Funding. Girschikofsky:Pfizer: Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria. Sill:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Thaler:AOP Orphan: Research Funding. Halter:Medical University Innsbruck: Employment. Zebisch:Celgene: Honoraria. Pichler:Celgene: Honoraria. Pfeilstöcker:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Autzinger:Wilhelminenspital: Employment. Lang:Celgene: Consultancy. Geissler:Celgene: Membership on an entity's Board of Directors or advisory committees. Geissler:Klinikum Klagenfurt: Employment. Sperr:Celgene: Consultancy; Ariad: Consultancy. Hojas:LKH Fürstenfeld: Employment. Greil:Amgen: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Boehringer-Ingelheim: Honoraria; Astra-Zeneca: Honoraria; Cephalon: Consultancy, Honoraria, Research Funding; Celgene: Consultancy; Ratiopharm: Research Funding; GSK: Research Funding; Sanofi Aventis: Honoraria; Novartis: Honoraria; Janssen-Cilag: Honoraria; Genentech: Honoraria, Research Funding; Eisai: Honoraria; Mundipharma: Honoraria, Research Funding; Merck: Honoraria; Bristol-Myers-Squibb: Consultancy, Honoraria; AOP Orphan: Research Funding; Roche, Celgene: Honoraria, Research Funding.

Abstract: Background In the Phase III trial (AML-001; NCT01074047) that assessed azacitidine (AZA) vs conventional care regimens (CCR; intensive chemotherapy, low-dose cytarabine or best supportive care as preselected by the treating physician) in older patients (≥65 years) with newly diagnosed acute myeloid leukemia (AML) and 〉 30% bone marrow (BM) blasts, AZA was associated with a clinically meaningful improvement in overall survival (OS) vs CCR.1Patient registry data, if performed with adequate quality control, can complement and be of additional value to data generated in clinical trials. The Austrian Azacitidine Registry (AAR; NCT01595295) was initiated to gain a comprehensive view of the use, safety and efficacy of AZA in patients with AML in a 'real world' clinical practice setting.2,3 No formal exclusion criteria existed, as the aim was to include all AML patients treated with AZA, irrespective of age, comorbidities, and/or previous lines of treatment.2,3 Aims and methods The aim of this analysis was to assess the efficacy and safety of 1st -line AZA in patients with AML who were included in the AAR and who fulfilled the BM blast percentage and white blood cell (WBC) count entry criteria of the AML-001 trial (BM blasts 〉 30% and WBC 〈 15G/L). Outcomes of the subgroups of patients with poor-risk cytogenetics and with AML and myelodysplasia-related changes (AML-MRC) who received 1st -line AZA were also evaluated. Results A total of 95 patients were identified that fulfilled the BM blast percentage and WBC count entry criteria of the AML-001 trial (data cut-off June 19 2015). Apart from a higher proportion of AML-MRC and a lower proportion of AML-not otherwise specified (AML-NOS) within the AAR, baseline characteristics were comparable to those observed in AML-001 (i.e. age, BM blast percentage, gender, therapy-related AML, prior myelodysplastic syndrome (MDS), Eastern Cooperative Oncology Group Performance Status (ECOG PS), cytogenetic risk, transfusion dependence, hemoglobin level, WBC count, absolute neutrophil count, and platelet (PLT) count; Figure 1). Patient status at data cut-off, reasons for AZA discontinuation and treatment characteristics were also similar: median number of AZA cycles was 5 (1-51) and 6 (1-28) for the AAR and AML-001 trial, respectively (Figure 1). Patient outcome in terms of overall response according to International Working Group criteria4 (31.5 vs 29.0%), red blood cell (42.1 vs 38.5%) and PLT transfusion independence (34.5 vs 40.6%) did not differ significantly between the AAR and the AML-001 trial. Furthermore, median OS was highly concordant between the AAR and AML-001 overall (10.8 vs 10.4 months; Figure 2A) as well as for various patient subgroups: 12.2 vs 12.7 months for patients with AML-MRC (Figure 2B); 14.6 vs 14.1 months for patients with normal cytogenetics; 13.1 vs 13.0 months for patients with intermediate-risk cytogenetics; and 7.2 vs 6.4 months for patients with high-risk cytogenetics (Figure 2C). After 1 year, 47.4% of patients were still alive in the AAR cohort compared with 46.5% in the AML-001 trial (p=0.924). Event-free survival was 5.5 (range: 0-35.3) vs 6.7 (range: 5-8.8) months in the AAR and AML-001 trial, respectively. The 30-day (8.4 vs 6.6%; p=0.642) and 60-day (15.5 vs 16.2%; p=0.903) mortality rates were comparable. The incidence of febrile neutropenia (24.2 vs 28.0%) and Grade 3-4 treatment-emergent (TE) neutropenia were similar between the AAR and AML-001; however, higher rates of TE thrombocytopenia (47.4 vs 15.7%; p=0.023) and anemia (31.6 vs 26.3%; p 〈 0.001) were observed in the AAR. Conclusion These data confirm the safety and efficacy of AZA in a patient-population for whom this drug has not yet been approved, i.e. AML with more than 30% BM blasts and without leukocytosis. These data therefore complement prospective clinical trial data and support the role of well-designed and in-depth clinical registries. References 1. Dombret H, et al. Blood 2015;126:291-9 2. Pleyer L, et al. J Hematol Oncol 2013;6:32 3. Pleyer L, et al. Ann Hematol 2014;93:1825-38 4. Cheson BD, et al. J Clin Oncol 2003;21:4642-9 Disclosures Pleyer: Celgene: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; AOP Orphan Pharmaceuticals: Honoraria. Off Label Use: Vidaza (azacitidine) is indicated for the treatment of adult AML patients who are not eligible for hematopoietic stem cell transplantation with 20-30% blasts and multi-lineage dysplasia, according to WHO classification. This cohort also includes AML patients with 〉 30% bone marrow blasts.. Burgstaller:Novartis: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; AOP Orphan Pharmaceuticals: Honoraria, Research Funding; Mundipharma: Honoraria. Girschikofsky:Mundipharma: Consultancy, Honoraria; Pfizer: Honoraria, Research Funding. Sill:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Thaler:AOP Orphan: Research Funding. Halter:Medical University Innsbruck: Employment. Zebisch:Celgene: Honoraria. Pichler:Celgene: Honoraria. Pfeilstöcker:Novartis: Consultancy, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Autzinger:Wilhelminenspital: Employment. Lang:Celgene: Consultancy. Geissler:Celgene: Membership on an entity's Board of Directors or advisory committees. Geissler:Klinikum Klagenfurt: Employment. Sperr:Ariad: Consultancy; Celgene: Consultancy. Hojas:LKH Fürstenfeld: Employment. Greil:Astra-Zeneca: Honoraria; Ratiopharm: Research Funding; GSK: Research Funding; Sanofi Aventis: Honoraria; Pfizer: Honoraria, Research Funding; Eisai: Honoraria; AOP Orphan: Research Funding; Novartis: Honoraria; Celgene: Consultancy; Merck: Honoraria; Cephalon: Consultancy, Honoraria, Research Funding; Bristol-Myers-Squibb: Consultancy, Honoraria; Genentech: Honoraria, Research Funding; Roche, Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Janssen-Cilag: Honoraria; Boehringer-Ingelheim: Honoraria.

Abstract: Background Approximately 10% of cases of acute myeloid leukemia (AML) arise following exposure to chemotherapy (treatment-related AML [tAML]). Compared to de novo AML patients, tAML patients have a poor prognosis, not least due to a higher proportion having adverse cytogenetics. Treatment options for tAML patients are limited and outcomes remain dismal. Median overall survival (OS) of 6.9 mo as of initial presentation, with 25% deaths within one month of diagnosis, was reported for a large cohort of tAML patients, with individualized treatments ranging from supportive care, to intensive chemotherapy (IC) and bone marrow (BM) transplantation.1 Few studies have assessed azacitidine (AZA) in patients with tAML, and those that have, did not report separate outcomes for this subgroup.2–4 Methods Here, we compare a subgroup of tAML patients (n=27) with patients with other World Health Organization (WHO)-AML subgroups (n=319) from the Austrian AZA Registry. The aim of the registry was to gain insight of the use, safety and efficacy of AZA in ‘real-world’ AML patients. The sole inclusion criteria were the diagnosis of WHO-AML and treatment with ≥1 dose of AZA. Results Baseline characteristics were compared between patients with tAML and WHO-AML: median age, gender, percentage with myelodysplatic syndrome (MDS)-related features, serum lactate dehydrogenase (LDH) level, and median peripheral blood and BM blasts were similar between both cohorts. However, tAML patients had poorer Eastern Cooperative Oncology Group Performance Status (ECOG PS) scores, more comorbidities, and a higher proportion of high-risk cytogenetics compared with WHO-AML patients. Of patients with tAML, 41% received AZA as 1st line therapy and 59% received AZA as ≥2nd line therapy. Baseline characteristics of these two subgroups were also comparable, except that tAML patients treated with AZA 1st line were older, had poorer ECOG PS and worse cytogenetics than ≥2nd line patients, which is in line with what would be expected from a cohort not deemed eligible for IC (Figure 1). Median number of AZA cycles was 4 (range 1–25) for tAML patients and 4 (range 1–46) for WHO-AML patients. Median time from AZA stop to death was 1.9 vs 1.8 mo for patients with tAML vs other WHO-AML subgroups. The overall response rate (ORR; International Working Group [IWG] 2003 criteria5) as well as the rate of hematologic improvement (HI; IWG 2006 criteria6) were similar for patients with tAML vs WHO-AML treated with AZA (complete response [CR] + CR with incomplete blood count recovery [CRi] + partial response [PR] : 22.2 vs 29.5%; and HI: 58.8 vs 57.7%, respectively; Figure 1). Median OS was similar for patients with tAML vs WHO-AML (8.9 vs 9.4 mo; p=0.147; Figure 1), but was longer for responders than non-responders in both groups of patients. Relapse-free survival was 7.7 vs 9.1 mo for patients with tAML vs WHO-AML. In univariate analyses, baseline factors that significantly affected OS for tAML patients were LDH 〉 225IU/L (p 〈 0.001) and white blood cell count ≥10G/L (p 〈 0.001; Figures 2a, b). Patients with tAML who received AZA 1st line achieved a significantly higher ORR than those who received AZA ≥2nd line (36.4 vs 12.5%; p 〈 0.001). Median time to AZA start as of initial diagnosis was 0.7 and 5.1 mo for tAML patients treated with AZA 1st line or ≥2nd line, respectively. Median number of AZA cycles was 6 (1–25) for AZA 1st line vs 4 (1–15) for AZA ≥2nd line. Median OS was not significantly different for tAML patients treated with AZA 1st vs ≥2nd line (9.0 vs 7.5 mo; p=0.717; Figure 1). Median relapse-free survival was 7.7 and 7.4 mo for AZA 1st line and ≥2nd line, respectively. tAML patients achieving CR/CRi/PR had a median OS of 16.1 mo with AZA 1st line and 12.8 mo for AZA ≥2nd line. Conclusions This represents the largest study reporting outcomes of tAML patients treated with AZA. Survival of tAML patients with AZA was comparable to that achieved in other WHO-AML subgroups, suggesting that AZA is a feasible treatment option for this poor prognostic subgroup. The OS data compare favorably to OS data reported for IC1 and are encouraging. Based on these ‘real-world’ data, randomized trials should assess AZA in tAML patients. 1. Smith SM, et al. Blood 2003;102:43–52 2. Bally C, et al. Leuk Res 2013;37:637–40 3. Fianchi L, et al. J Hematol Oncol 2012;5:44 4. Pleyer L, et al. Ann Hematol 2014; epub ahead of print 5. Cheson BD, et al. J Clin Oncol 2003;21:4642–9 6. Cheson BD, et al. Blood 2006;108:419–25 Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Pleyer: Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; AOP Orphan Pharmaceuticals: Honoraria; Celgene: Consultancy, Honoraria. Off Label Use: Vidaza (azacitidine) is indicated for the treatment of adult AML patients who are not eligible for haematopoietic stem cell transplantation with 20–30 % blasts and multi-lineage dysplasia, according to WHO classification. This cohort also includes AML-patients with 〉 30% bone marrow blasts.. Burgstaller:AOP Orphan Pharmaceuticals: Honoraria; Novartis: Honoraria; Mundipharma: Honoraria; Celgene: Consultancy. Stauder:Celgene: Consultancy, Honoraria, Research Funding; Ratiopharm: Honoraria, Research Funding; Novartis: Research Funding. Girschikofsky:Pfizer: Honoraria, Research Funding; Mundipharm: Consultancy, Honoraria. Pfeilstöcker:Janssen-Cilag: Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Lang:Celgene: Consultancy. Sperr:Phadia: Research Funding; Novartis: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Valent:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Greil:Sanofi Aventis: Honoraria; Roche: Honoraria; Pfizer: Honoraria, Research Funding; Boehringer-Ingelheim: Honoraria; Astra-Zeneca: Honoraria; Novartis: Honoraria; Genentech: Honoraria, Research Funding; Janssen-Cilag: Honoraria; Merck: Honoraria; Mundipharma: Honoraria, Research Funding; Eisai: Honoraria; Amgen: Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Cephalon: Consultancy, Honoraria, Research Funding; Bristol-Myers-Squibb: Consultancy, Honoraria; GSK: Research Funding; Ratiopharm: Research Funding.