Chhetri, Rakchha

Abstract Introduction: Therapy related myeloid neoplasm (t-MN) is a rare but devastating complication of cytotoxic therapy used for management of unrelated malignancy or autoimmune diseases. Therapeutic options for t-MN are limited and although hypomethylating agents (HMA) are frequently used, the benefit of it in t-MN is unclear. There are no prospective trials of HMA in t-MN and published experience is based on retrospective analysis of small number of cases (n=42 to 54). The aim of this study was to assess the efficacy of HMA therapy in t-MN patients and evaluate predictors for it. Methods: t-MN patients managed with first line HMA therapy were analyzed. This study was approved by the participating institutional review board. Criteria for inclusion were a pathologically confirmed diagnosis of t-MN based on WHO 2016 criteria, age >18 years, and ≥1 cycle of decitabine or azacitidine. Patient characteristics were summarized by frequency (percentage). Overall survival was calculated from the time of starting azacitidine to last follow up or death date using Kaplan-Meier analysis. Multivariable analysis was performed using Cox proportional hazard model. Statistical analysis was performed using R program and significance was defined as P<0.05. Results: Of the 554 t-MN patients analyzed, 184 (33%) patients were treated with HMA as the first line therapy and were included in the study. Median age at t-MN diagnosis was 70 (IQR 64-75) years and 112 (60%) patients were male. At the time of diagnosis, 84% (n=154) and 16% (n=30) patients were classified as t-MDS and t-AML and 47% (87/184) and 46% (49/107) of the evaluable patients had complex karyotype and TP53 somatic mutations (TP53 Mut) respectively. Azacitidine (n=145, 79%) was most frequently used HMA followed by decitabine (n=39, 21%). Median survival of the whole cohort since t-MN diagnosis was 13.2 months. At the time of analysis further treatment details were available for 78 patients and outcome of these patients were compared with primary MDS (p-MDS) and oligoblastic AML managed at the same institute. Completion of six-cycles of HMA (50% vs. 62%; P=0.07) and overall response rate (47 vs. 50%, P=0.22) was not significantly different between t-MN and p-MDS. However, median OS of t-MN was significantly poor compared to p-MDS (10 vs. 20 months, P=0.0004; Figure 1A). In t-MN patients treated with HMA as the first-line agent, median OS was significantly shorter in t-AML compared to t-MDS (7 vs.10 months, P=0.04; Figure 1B). Median OS was significantly shorter in patients with TP53 Mut and complex karyotype (Figure 1C-D). In Cox proportional hazard analysis, t-AML and complex karyotype were independently associated with poor outcome. Conclusion: This study demonstrates significantly poor outcome of t-MN patients treated with HMA therapy as first line. The outcome is particularly poor in t-AML and patients with complex karyotype and TP53 Mut. Hence there is urgent need for clinical trials of novel therapies for t-MN. Figure 1 Figure 1. Disclosures Sharplin: Kite Gilead: Honoraria; Novartis: Other: Travel Support. Ross: Keros Therapeutics: Consultancy, Honoraria; Bristol Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hiwase: Novartis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees.

Abstract Introduction: Therapy-related myeloid neoplasm (t-MN) is defined as the development of a myeloid neoplasm in the context of prior DNA damaging therapies. t-MN is an aggressive disease with no effective therapies. BCL2-inhibitor venetoclax (VEN) represents a novel treatment for acute myeloid leukemia (AML) patients including those with high-risk features. Available VEN studies included only a small portion of t-AML patients, and its efficacy in t-MDS is not known. Our aim was to study the efficacy and outcomes of VEN in t-MN. Methods: Patients diagnosed with t-MN based on the WHO criteria who received VEN were identified. Minimal residual disease (MRD) assessment was performed in a subset of patients by multiparametric flow cytometry or molecular marker as available. Best response to VEN was divided into 3 categories: 1) MRD(-) complete remission (CR); 2) other CR [including complete morphological remission, MRD(+) CR, and CR with incomplete count recovery]; and 3) partial response/progressive disease/stable disease (PR/PD/SD). Progression-free (PFS) and overall survival (OS) were calculated from the time of initiation of VEN therapy using Kaplan-Meier analysis using Wilcoxon test. Logistic regression analysis was performed using Cox Proportional Hazard method. Statistical analysis was performed using JMP (v14.1, SAS Institute) and significance was defined as P<0.05. Results: Of 332 t-MN patients identified (248 at Mayo Clinic, 84 at the Central Adelaide Health Network), 65 (19.6%) received VEN. Clinical and pathological characteristics of patients that received VEN and did not receive VEN (non-VEN) were matched except: a higher proportion of VEN patients had t-AML (49.2% vs. 32.6%, P=0.004), higher peripheral (2% vs. 0%, P=0.02), and bone marrow blasts (18% vs. 8%, P=0.02). VEN patients had a higher proportion of abnormality of chromosome 17, complex karyotype, and monosomal karyotype compared to non-VEN patients. The proportion of patients with pathogenic/likely pathogenic variant (PV) in TP53 or RAS genes was not different. The proportion of patients receiving stem cell transplant for t-MN was not different (Table 1). The indication for VEN was treatment naïve t-MN, relapsed/refractory (R/R) disease, and maintenance in 31 (47.7%), 32 (49.2%), and 2 (3.1%) patients respectively. Prior to VEN, patients received a median of 1 (range 0-4) lines of therapy. The median duration of VEN exposure was 3 cycles (IQR 1-4). VEN was administered with azacitidine, decitabine, low dose cytarabine, intensive chemotherapy, single agent, and >1 agents in 37.9%, 40.9%, 12.1%, 4.5%, 4.5%, and 2.9% respectively. The best and the final responses to VEN are shown in Table 2. Median PFS and OS from initiation of VEN was 5 months (IQR 2-9.5, Fig. A) and 6.5 months (2-14.5, Fig. B) respectively. Female sex (vs. male, χ 2 9.6, P=0.03), VEN as the 1 st line of therapy (vs. other line of therapy, χ 2 8.3, P=0.02), and hypomethylating agent (HMA)-backbone (vs. other, χ 2 12.1, P=0.02) were associated with a significantly higher likelihood of achieving CR. Abnormality of chromosome 7 was associated with a shorter PFS (3.5 vs. 6 months, P=0.03) and OS (4.7 vs. 10.5 months, P=0.02). Using VEN as the 1 st line therapy was associated with an improved PFS (5.5 vs. 2.7 months, P<0.01) and a trend towards improved OS (9.3 vs. 5.1 months, P=0.06). Using HMA (n=51), Ara-C based (n=8), and single agent VEN (n=3) was associated with median PFS of 5.5, 4.2, and 1.5 months (P<0.01) and OS of 9.1, 4, and 1.5 months (P<0.01, Fig. C) respectively. Achieving MRD(-) CR (n=7), other CR (n=17), and PR/PD/SD (n=36) was associated with a median PFS of 7.7, 9.5, and 2 months (P<0.001) and median OS not reached, 12.9, and 2.9 months respectively (P<0.01, Fig. D). Finally, best response rate, PFS, and OS did not differ based on morphological diagnosis [t-MDS vs. t-AML] at diagnosis or bone marrow blast percent [<20% vs. ≥20%] at the start of VEN therapy. On multivariate analysis, only the best response remained an independent predictor of PFS and OS. Conclusion: VEN induced remission, including MRD(-) remission, in a subset of patients. However, progression was noted in 83% patients with continued use, and PFS and OS were overall short. The morphological diagnosis of t-MDS/t-AML or blast percentage at the start of VEN therapy did not impact outcome. Earlier use of VEN, using HMA-based therapies, and achieving deeper responses were associated with improved outcomes. Figure 1 Figure 1. Disclosures Al-Kali: Novartis: Research Funding; Astex: Other: Research support to institution. Patnaik: StemLine: Research Funding; Kura Oncology: Research Funding. Wei: Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Macrogenics: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: 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, Research Funding, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Tiong: Pfizer: Consultancy; Amgen: Speakers Bureau; Servier: Consultancy, Speakers Bureau. Hiwase: Novartis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: venetoclax is not approved in the treatment of myelodysplastic syndrome.