Morsia, Erika

Introduction: Mutations in the gene isocitrate dehydrogenase 2 (IDH2) occur in ~12-15% of patients with acute myeloid leukemia (AML). Enasidenib, an oral small molecule selective targeted inhibitor of IDH2 enzymes, was approved forIDH2mutated relapsed/refractory AML (RR-AML) in 2017 (Stein et. al., 2017). There is limited data regarding its efficacy and toxicity outside the context of clinical trials. Using Mayo Clinic's cohort of AML patients, we provide a real-world look at outcomes forIDH2mutated RR-AML patients treated with enasidenib. Methods: A total of 13 patients treated with enasidenib for RR-AML were identified, all of which experienced at least one relapse following induction chemotherapy. Response assessment was based on European Leukemia Net (ELN) 2017 response criteria.Complete blood counts including blast percentage and transfusion dependency were obtained at AML diagnosis, initiation of enasidenib, 2 months and 6 months following initiation of therapy. Transfusion dependency was defined by the need for either a red cell or platelet transfusion within 4 weeks of the designated time frame. We compared the clinical characteristics of patients who achieved complete response (CR) (n=4) to those not achieving CR (n=9), using the Mann-Whitney U test for numerical variables and the Fischer's Exact test for quantitative data. Results: The median age at diagnosis of our 13 patients was 68 years (range 60-82), with a male predilection (n=11) (Table 1). Cytogenetic and molecular genetic findings are provided in Table 2. Complete response (CR) was achieved in 4 (30.7%) patients by cycle 2 and 2 of those patients (50%) proceeded to an allogeneic hematopoietic stem cell transplant (AHSCT). The median time from diagnosis to initiation of treatment for patients in CR was 3.5 months (range 1-7), and for patients not achieving CR was 13 months (range 6-53; p=0.048), with median time of follow up after treatment initiation of 23.5 months (range, 5-36) and 7 months (range, 1-14), respectively. Among 8 patients who were transfusion dependent at baseline, all the CR patients (2/2) achieved red blood cell and platelet transfusion independence 6 months after treatment, instead only (3/6) 50% of those not in CR achieved transfusion independence (p=0.028). An initial trajectory of improvement in counts is noted from the time of diagnosis to the 2 month mark post treatment with 75% of the responder cohort showing improvement in counts which was durable through the 6 month mark, whereas 55% of those that did not respond had worsening counts at month 2 and died prior to 6 month follow up. At the time of data cut-off, the median duration of CR was 14 months (range, 2-33), with 3 of 4 (75%) of responders maintaining CR. Figure 1 details overall responses and outcomes in all 13 patients. None of the patients in our study experienced differentiation syndrome. Five patients were hospitalized in the course of treatment for infectious complications. Two patients were noted to have hyperbilirubinemia however there was no clear indication that this was secondary to enasidenib Median overall survival for all 13 patients was 21 months (range, 6-53 months) with leukemia free survival of 7 months (range, 5-19 months). Furthermore, median overall survival for patients in CR was 27 months (range, 6-42), and those not in CR was 16 months (range, 6-53) (p=0.20). In addition, we observed that 75% of patients who attained CR are alive compared to 11.1% of those not in CR (p = 0.052). Conclusion: We demonstrate a superior CR rate of 30.7% with enasidenib amongstIDH2mutated RR-AML patients compared with clinical trial data showing CR rate of 19.6% (Stein et. al., 2019) despite our patients being heavily pre-treated with median number of two prior therapies (range; 1-5) including prior AHSCT in 2 patients. Moreover, a subset of patients (2 of 4 in CR) were able to undergo ASCHT. Finally, the achievement of CR at 2 months after initiation of therapy serves as an appropriate time point for response assessment. Disclosures No relevant conflicts of interest to declare.

Introduction: Myeloproliferative neoplasms (MPN), including primary myelofibrosis (PMF), essential thrombocythemia (ET) and polycythemia vera (PV), have a propensity to evolve into blast phase myeloproliferative neoplasm (BP-MPN) with a 20-year incidence rate of 9.3 %, 3.9% and 2.6%, respectively. (Szuber et al., 2019)Treatment options for BP-MPN are limited and the prognosis of these patients is dismal with a median survival of only 3.6 months and 5-year survival rate of <5%.(Tefferi et al., 2018) Considering the recent reported data on the efficacy of venetoclax when combined with hypomethylating agents (HMA) in acute myeloid leukemia (AML) in both relapsed/refractory and newly diagnosed unfit patients, we have extended such combination therapy for patients with BP-MPN. Methods: We retrospectively analyzed 14 consecutive BP-MPN patients who received venetoclax plus HMA therapy between August 2018 and June 2020. We collected data regarding clinical characteristics of chronic phase MPN and BP-MPN, cytogenetic and leukemia mutation profile, efficacy and outcome. Oral venetoclax was administered in combination with azacitidine 75 mg/m2 days 1-7 (5 patients) or decitabine 20 mg/m2 days 1-5 (9 patients). Venetoclax dose was adjusted based on drug interactions particularly with azole antifungal prophylaxis. Diagnostic, risk and response assignments were according to the 2017 European LeukemiaNet (ELN) criteria.(Döhner et al., 2017) Minimal residual disease (MRD) assessment by flow cytometry, karyotype or next-generation sequencing (NGS) was performed in a subset of patients. Results: Patient characteristics at time of leukemic transformation, treatment details, response rates and overall outcome are shown in Table 1. Median age of patients was 67 years (range 48-81) with poor-risk cytogenetics in 69% of patients. JAK2 was mutated in 10 patients (71%) and CALR in 2 (14%); other mutations included TP53 in 5 patients (36%), TET2 in 4 (29%), KRAS in 3 (21%), IDH1/2 in 3 (21%), ASXL1 in 2 (14%) and U2AF1 in 2 (14%). Eight patients (57%) received venetoclax and HMA combination therapy upfront for their BP-MPN, 2 patients (14%) had failed HMA therapy previously and one patient had prior allogeneic hematopoietic stem cell transplant (AHSCT). Two patients (14%) presented with myeloid sarcoma; one of these two patients documented partial resolution of the extramedullary tumor by imaging studies, after treatment with venetoclax plus HMA. Among the remaining 12 patients, overall response rate (ORR) was 42% (n=5) and included complete remission (CR) in 3 patients (25%) and partial remission (PR) in another 2 (17%). The best response to therapy was seen after a median of 1 month (range, 1-2). Among 3 CR responders, 2 (66.6%) had minimal residual disease negative by NGS and not evidence of preceding MPN, then they successfully transitioned to AHSCT, while the third CR patient at the time of best response showed persistence of the TP53 mutation. Additionally, one PR patient subsequently relapsed and received salvage chemotherapy followed by AHSCT. (Table 2) Although data is limited by the small cohort and short follow up when the outcome of patients treated with venetoclax in combination with HMA were compared to Mayo Clinic's historical control of patients with BP-MPN treated with HMA alone (n=26) or intensive chemotherapy (n=69), there was higher CR rate in patients treated with venetoclax and HMA (25%) compared to those receiving HMA alone (4%; p=0.048) but not to those receiving intensive chemotherapy (35%; p<0.0001). Moreover, the intensive chemotherapy cohort showed 24% of CR with incomplete hematologic recovery (CRi) not seen in patients receiving HMA alone or HMA with venetoclax (Figure1). Conclusions: The relatively high rate of complete response observed in our patients with BP-MPN were similar to those reported in a pivotal study of elderly unfit AML patients treated upfront with venetoclax + HMA with overall response rates of 68%.(DiNardo et al., 2019) Furthermore, responders included patients with adverse molecular risk factors who usually respond poorly to conventional chemotherapy (i.e. TP53 mutated patients). Our observations provide preliminary evidence for the potential efficacy of venetoclax and HMA combination therapy in BP-MPN with the goal of achieving CR/CRi followed by consolidative AHSCT wherever possible to provide durable remission and meaningful survival benefit. Disclosures Foran: Agios: Honoraria, Research Funding; Trillium: Research Funding; Takeda: Research Funding; Kura Oncology: Research Funding; Aptose: Research Funding; Aprea: Research Funding; Actinium: Research Funding; Boehringer Ingelheim: Research Funding; Abbvie: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Revolution Medicine: Consultancy; Xencor: Research Funding; H3Biosciences: Research Funding.

AbstractVenetoclax and hypomethylating agent (HMA) combination therapy is FDA‐approved for elderly or unfit acute myeloid leukemia (AML) patients unable to withstand intensive chemotherapy. The primary objective of the current study was to impart our institutional experience with the above regimen, outlining response, survival outcomes, and its determinants amongst 86 treatment‐ naïve and relapsed/refractory AML patients. A total of 44 treatment‐naïve AML patients, median age 73.5 years, enriched with secondary, therapy related and ELN adverse risk disease (n = 27) were studied. The CR/CRi rates of 50% (22 of 44 patients) were superior to 23% in a matched AML cohort treated with HMA alone (P = .005). Response rates were similar with TP53, FLT3, NPM1 and IDH mutations (P = .31). Moreover, CEPBA mutations (P = .03) and neutropenia (P = .05) emerged as predictors of complete response. Survivalwas prolonged in patients achieving CR/CRi (17 vs 3 months without CR/CRi, P < .001; conversely adverse ELN risk portended inferior survival. Amongst 42 relapsed/refractory AML patients, half received ≥2 prior therapies excluding transplant, and 15 (35.7%) had received HMA. A group of 14 patients (33.3%) attained CR/CRi; age > 65 years, AML with myelodysplasia, JAK2, DNMT3A, and BCOR mutations predicted complete response. Survival distinctions were based on CR/CRi (median survival 15 vs 3 months with/without CR/CRi; P < .001), and TP53 mutation status (P = .04). In summary, we corroborate existing reports demonstrating superior response and prolonged survival with venetoclax and HMA in treatment ‐naïve and relapsed/refractory AML patients regardless of genotype. Additionally, we identify unique predictors of response to therapy which require validation.