Venetoclax with azacitidine or decitabine in blast‐phase myeloproliferative neoplasm: A multicenter series of 32 consecutive cases

Abstract

Venetoclax (Ven) combined with a hypomethylating agent (HMA) has now emerged as an effective treatment regimen for acute myeloid leukemia, in both de novo and relapsed/refractory setting. The current multicenter study retrospectively examined Ven + HMA treatment outcome among 32 patients (median age 69 years; 59% males) with blast‐phase myeloproliferative neoplasm (MPN‐BP). Pre‐leukemic phenotype included essential thrombocythemia (ET)/post‐ET myelofibrosis (34%), polycythemia vera (PV)/post‐PV myelofibrosis (38%) and primary myelofibrosis (28%). Twenty‐nine study patients were fully annotated cytogenetically and molecularly (NGS): 69% harbored complex karyotype and/or mutations, including TP53 (41%), IDH1/2 (21%), ASXL1 (21%), N/KRAS (14%), SRSF2 (10%), EZH2 (10%) and U2AF1 (7%). All patients received Ven combined with either azacitidine (n = 12) or decitabine (n = 20); either up front (n = 23) or after failing another induction therapy (n = 9). Complete remission with (CR) or without (CRi) count recovery was achieved in 14 (44%) patients and was more likely to occur in the absence of pre‐leukemic PV/post‐PV myelofibrosis phenotype (p < .01), complex karyotype (p < .01) or K/NRAS (p = .03) mutations; seven of eight patients (88%) without vs four of 21 (19%) with complex karyotype or K/NRAS mutation achieved CR/CRi (p < .01); all 11 informative patients with pre‐leukemic PV/post‐PV myelofibrosis phenotype displayed complex karyotype (p < .01). In contrast, neither TP53 (p = .45) nor IDH1/2 (p = .63) mutations affected response. Compared to historical controls treated with HMA alone (n = 26), the CR/CRi rate (44% vs 4%) and median survival (8 vs 5.5 months) were more favorable with Ven + HMA, but without significant difference in overall survival. Importantly, six patients with CR/CRi subsequently received allogeneic hematopoietic stem cell transplant (AHSCT). Note, Ven + HMA produces robust CR/CRi rates in MPN‐BP, especially in the absence of RAS mutations and complex karyotype, thus enabling AHSCT, in some patients.

Reduced intensity hematopoietic stem cell transplantation for accelerated-phase myelofibrosis

“… 30 A recent retrospective multicenter study investigated combination therapy with venetoclax and hypomethylating agents (azacytidine or decitabine) in 32 patients with blast-phase myelofibrosis, either up front or after failing another induction. 31 Complete remission was achieved in 44% of patients, especially in the absence of RAS mutations. In comparison with historical controls only treated with hypomethylating agents, complete remission rate and median survival appeared to be higher for combination therapy (8 vs 5.5 months).…”

Myeloproliferative Neoplasms, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology

“…The role of venetoclax combinations has not yet been established in MPN-BP/AML. 243 Allogeneic HCT remains the only curative option resulting in long-term disease control in selected transplant-eligible patients who achieve a CR to induction chemotherapy. [244][245][246][247] Early referral to transplant is recommended for planning purposes.…”

Outcomes of venetoclax‐based therapy in chronic phase and blast transformed chronic myelomonocytic leukemia

“…The ORR in CMML-BT (42.9% in the BT subgroup and 42.9% in patients previously treated wih HMA) was also similar to those seen in blast phase MPN (42.0%), where OS was similar with HMA monotherapy versus the combination of HMA and venetoclax. 13,14 The limitations of our study include its retrospective design, small sample size, lack of longitudinal genomic data, and lack of measurable residual disease data. The smaller patient numbers could potentially explain why RAS mutations were not predictive of response/resistance.…”