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• The combination of hypomethylating agents with the selective Bcl-2 inhibitor venetoclax (VEN-HMA) as a bridge to allogeneic hematopoietic cell transplantation (alloHCT) is associated with favorable HCT outcomes. • VEN-HMA could allow more patients of older age to proceed to potentially curative alloHCT. • AlloHCT outcomes are particularly good in patients who undergo HCT in complete remission after VEN-HMA therapy. The combination of hypomethylating agents with the selective Bcl-2 inhibitor venetoclax (HMA-VEN) has emerged as a highly active regimen in patients with acute myelogenous leukemia (AML) in both the upfront and relapsed/refractory (r/r) settings. We report our early experience with a cohort of patients who were able to proceed to allogeneic hematopoietic cell transplantation (alloHCT) after HMA-VEN therapy. Thirty-two patients with AML (19 r/r and 13 de novo) with a median age of 62 years underwent alloHCT after HMA-VEN therapy. Twenty-two (68.8%) were in complete remission (CR)/CR with incomplete count recovery at time of HCT. With a median follow up of 14.4 months, the 1-year overall survival (OS) was 62.5%, and disease-free survival was 43.8%. The 1-year nonrelapse mortality rate was 18.8%, and the cumulative incidence of relapse was 37.5%. Among patients who underwent alloHCT in CR, the 1-year OS was 77.3%, and the cumulative incidence of nonrelapse mortality was 9.1%. The cumulative incidence of grade II-IV acute graft-versus-host disease was 43.8%. We conclude that alloHCT after HMA-VEN is therapy associated with favorable allogeneic HCT outcomes in newly diagnosed older patients with AML, as well as those with r/r AML. [ABSTRACT FROM AUTHOR]

We previously demonstrated poor outcomes of patients with acute myeloid leukemia (AML) with antecedent myeloproliferative neoplasms (MPN) undergoing allogeneic hematopoietic stem cell transplantation (HCT) (Gupta et al, BBMT, 2019; abstract 140). In particular, we did not find any difference in outcomes of patients who received transplant "in remission" defined as blood and bone marrow blasts < 5% compared to those with "active leukemia" defined as blood and or bone marrow blasts ≥ 5%. We hypothesized that genetic mutations may help in predicting the efficacy of HCT in molecularly defined sub-groups of post MPN AML. In addition, we hypothesized that patients considered "in remission" at the time of HCT may have a molecular profile similar to those who have "active leukemia" at the time of HCT. Of the 177 patients with post MPN AML identified in the Center for International Blood and Marrow Transplant Research (CIBMTR) database, 95 (54%) had sufficient DNA to perform molecular analysis that consisted of targeted Next-Generation sequencing on 49 genes clinically relevant in hematologic malignancies. Of the 95 patients analyzed, 54 were "in remission", and 41 had "active leukemia". Adverse risk cytogenetics was seen in 39 patients. The most frequently mutated genes (≥10% patients) in study cohort were: JAK2 (55%); TP53 (23%); ASXL1 (22%); TET2 (19%), SRSF2 (16%); DNMT3A (14%), RUNX1 (14%); CALR (13%); SF3B1 (10%). Cumulative incidence of non-relapse mortality (NRM), relapse, progression-free survival (PFS), and survival in the study cohort at 5-years were 23% (95% CI 15-32), 66% (95% CI 56-75), 11% (95% CI 6-19) and 16% (95% CI 9-25). In a multivariate model, TP53 mutation status was the only factor associated with outcomes of HCT; patients with mutated TP53 mutations had inferior overall survival [RR 1.99 (95% CI 1.14-3.49)] and increased relapse [RR 2.59 (95% CI 1.41-4.74)], and inferior PFS (RR 2.18 (95% CI 1.25-3.82)]. Disease status at HCT was not associated with outcomes. Moreover, there were no differences in the mutational landscape, number of mutations and variant allele frequency (VAF) between patients who underwent HCT "in remission" (n=54) versus those with "active leukemia" (n=41). We conclude that there is minimal benefit of HCT in patients with post MPN AML with mutated TP53, and novel strategies are required for these patients. We did not observe any difference in clinical outcomes or mutational profile of patients undergoing transplant "in remission" compared to those with "active leukemia" questioning the clinical benefit of blast reduction strategies in post MPN AML. [ABSTRACT FROM AUTHOR]