Introduction

Patients with accelerated phase or blast phase myeloproliferative neoplasms (AP/BP-MPN) experience poor clinical outcomes and lack standardized treatment. For transplant-eligible patients, guidelines recommend bridging therapy followed by an allogeneic hematopoietic cell transplant (alloHCT). For transplant-ineligible patients, the optimal lower intensity treatment is unclear. Patients with AP/BP-MPN are underrepresented in AML clinical trials; thus, real-world evidence is critical for identifying the optimal treatment approaches.

Methods

We performed a multicenter, retrospective cohort study among nine US centers participating in the Hematology Research & Outcomes (HERO) Consortium. Adults (>18 years) with a diagnosis of AP/BP-MPN per WHO criteria who received lower intensity therapy as initial treatment were screened for inclusion. Patients with MDS/MPN overlap and those with incomplete records were excluded. Patients were divided into two main cohorts for analysis: hypomethylating agents (HMA) +/- JAK inhibitor (HMA group), or HMA + venetoclax (ven) +/- JAK inhibitor (HMA+ven group). The primary endpoint was overall survival (OS). Secondary efficacy endpoints included rates of complete response plus complete response with incomplete count recovery (CR/CRi), morphologic-leukemia-free state (MLFS), and partial response (PR). Other secondary endpoints included rates of alloHCT, ven dose and duration, safety outcomes, and other survival endpoints. Chi-square or Fisher's exact tests were used to evaluate dichotomous variables. Continuous variables were analyzed via the Mann-Whitney U test. Overall survival was estimated using the Kaplan-Meier method and compared between treatment groups using the log-rank test. A multivariable Cox proportional hazards regression model was used to assess the association between treatment and OS, adjusting for age, white blood cell count, hemoglobin (hgb), platelet count, alloHCT, and cytogenetic risk. Hazard ratios (HR) with corresponding 95% confidence intervals (CI) and p-values were reported. Statistical significance was defined as a two-sided p value <0.05.

Results

One hundred eighty-nine patients with AP/BP-MPN were included in this analysis. The median age was 71 years (range, 32-87), 37% were female, and 20% were non-White/Caucasian. The median number of cycles of therapy was 2 (range, 1-45). Ninety-four patients received HMA +/- JAK inhibitor therapy (50%) and 56 received HMA+ven +/- JAK inhibitor (30%); the remaining 39 patients (20%) received alternative low intensity therapies and were not included in this analysis. The initial ven duration was 28 days for 59% of patients and 21 days for 37% of patients. For patients who received >1 ven-containing cycle, 61% had ven durations reduced during subsequent cycles.

Baseline characteristics were well-balanced between the HMA and HMA+ven groups, with the exception of median hgb at diagnosis (8.6 g/dL vs. 9.4 g/dL, p=0.009), the choice of HMA (azacitidine 22% vs. decitabine 63%, p<0.0001), the addition of JAK inhibitors to therapy (62% vs. 16%, p<0.0001) and the presence of SRSF2 mutations (12% vs. 31%, p=0.0347).

Median OS was 9.2 months in the HMA group and 9.2 months in the HMA+ven group (log-rank p=0.569). The receipt of JAK inhibitors was not associated with improved OS. The rate of alloHCT was not different between the groups (HMA vs. HMA+ven, 14% vs. 18%, p=0.51). On multivariable Cox regression, age (HR 1.04; 95% CI, 1.009-1.065; p=0.008), hgb (HR 0.87; 95% CI, 0.764-0.996; p=0.044), and alloHCT (HR 0.37; 95% CI, 0.192-0.730; p=0.004) were significant predictors of OS; treatment with HMA+ven was not significantly associated with improved OS compared to HMA alone (HR 0.83; 95% CI, 0.55–1.24; p=0.364). The rate of CR/CRi and CR/CRi/MLFS were both higher in the HMA+ven group (36% vs. 11%, p=0.0002 and 52% vs. 16%, p<0.0001).

There were no differences in the rate of febrile neutropenia, documented infections, bleeding events, or rate of ICU admission between the two groups. The rate of colitis was numerically higher with HMA+ven but was not statistically significant (11% vs. 2%, p=0.0526).

Conclusions

This large, multicenter, real-world analysis demonstrated the addition of ven to HMA therapy in patients with AP/BP-MPN was safe and improved response rates but did not translate into an improvement in OS. Younger age, higher hgb at baseline, and alloHCT were significant predictors of improved OS in this population.

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2025
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