Clinical outcomes in patients with accelerated or blast-Phase MPN treated with triplet regimen of hypomethylating agent, JAK inhibitor, and venetoclax (HMA/JAKi/Ven): A multicenter case series Free

Background: Myeloproliferative neoplasm in accelerated or blast phase (MPN-AP/BP) carries a dismal prognosis of 3-5 months with allogeneic hematopoietic stem cell transplantation (HSCT) as the only definitive treatment. Combining hypomethylating agents (HMAs) with the JAK2 inhibitor (JAKi) ruxolitinib may improve response rates and survival in this setting, compared to HMA alone (Orvain et.al). More recently, the standard acute myeloid leukemia (AML) regimen of HMA plus venetoclax (Ven) had modest efficacy for patients with MPN-AP/BP (Orvain et.al). Because each agent in the HMA/JAKi/Ven triplet regimen is potentially active, with preclinical data suggesting that ruxolitinib may enhance leukemic cell sensitivity to Ven, the triplet regimen of HMA/JAK2i/Ven has been explored at our centers. Here, we describe our multicenter experience and report clinical outcomes using HMA/JAK2i/Ven in patients with MPN-AP/BP.

Methodology: This retrospective case series included MPN-AP/BP patients treated at Weill Cornell Medical Center (WCM) and Memorial Sloan Kettering Cancer Center (MSKCC) between 2020-2024. Patients were included if they received any HMA, JAKi, and Ven concurrently. The study was conducted under the institutional review board approval of each center. Diagnosis and response were determined from review of electronic medical records and classified according to European LeukemiaNet (ELN) criteria. Here, we report frequency of responses overall (ORR), complete (CR), partial (PR), clinical improvement (CI), as well as relapse and HSCT. Overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan–Meier method, defined as time from initiation of triple therapy to death (OS) or to progression (PFS).

Key outcomes: The cohort included 4 patients from WCM (median age 60; range 40-74) and 7 from MSKCC (median age 75; range 68-80). Diagnoses at triplet therapy initiation were MPN-BP in 55% and MPN-AP in 45%. The most common antecedent MPN diagnosis was secondary myelofibrosis (from essential thrombocythemia (27.3%) or polycythemia vera (18.2%)), followed by primary myelofibrosis (36.4%) and essential thrombocytosis (18.2%). The median duration of MPN-AP/BP before triple therapy initiation was 7.3 months (range 0.6-45.6). The HMA was azacytidine or decitabine, the JAKi was ruxolitnib or momelotinib. MPN driver mutations were JAK2/CALR/MPL in 64%/27.3%/18.2% of patients. Co-occurrent mutations involved ASXL1/TP53/U2AF1/SRSF2/EZH2, 63.6%/36%/27.3%/9.1%/9.1%. Unfavorable and very-high-risk karyotypes were present in 18% and 36% of patients, respectively. The ORR was 55%, with a CR in 18.2%, and PR in 9.1%. One patient who achieved CR and OS of 1 year and 10 months before disease progression and death had a TP53 mutation. Two patients (18%) achieved CI underwent HSCT, but only one survived and is the only survivor as of last follow-up (9%). Causes of death included infections (40%), disease progression (30%), and other causes (30%). Median OS was 3.5 months (95% CI, 2.8-NA) and median PFS 14.13 months (95% CI, 2.9-NA). Notably, a favorable median OS of 15.8 months (95% CI, 2.8-NA) was observed in overall responders, compared to 3.07 months (95% CI, 1.96-NA; p = 0.074) in non-responders. Median PFS also favored responders at 14.8 months (95% CI, 1.3-18) versus 3.06 months (95% CI, 1.90-5.03; p = 0.49). When comparing baseline characteristics, responders exhibited higher median WBC and ANC (32.6 vs. 4.4 ×10³/µL and 14.2 vs. 1.4 ×10³/µL), lower median hemoglobin and platelet (7.0 vs. 9.1 g/dL and 75.5 vs. 140 ×10³/µL), normal cytogenetics (50% vs 0%) and lower unfavorable/very high risk cytogenetics (33% vs. 80%), less frequent CALR mutation and lower JAK2 V617F allele frequency. U2AF1 mutations occurred exclusively in responders. ASXL1 and TP53 mutations were common in both groups, whereas MPL and TET2 mutations occurred exclusively in non-responders.

Conclusion: In this two-center case series, triplet therapy HMA/JAK2i/Ven for MPN-AP/BP offers an ORR of 55% but the PFS/OS remain poor and do not signal an advantage over historic expectations for HMA/Ven and HMA/JAK2i. However, a subset of patients may respond favorably to this regimen. These were patients who presented with high WBC, more favorable cytogenetics and lower JAK2 V617F burden and a unique mutational landscape. These patterns, if evaluated in larger cohorts, might help predict who, if any, may benefit from HMA/JAK2i/Ven.