Azacitidine-Ruxolitinib Combination Shows Promise for Advanced Myeloproliferative Neoplasms
Key Insights
A retrospective study of 149 patients with advanced myeloproliferative neoplasms (search) found median overall survival of 8.04 months, with combination therapy showing nonsignificantly higher survival than monotherapy.
Patients treated with azacitidine-ruxolitinib demonstrated superior overall survival of 18.0 months compared to azacitidine-venetoclax (9.0 months) or triple combination therapy (10.1 months).
The survival benefit was particularly pronounced in patients without complex karyotype or TP53 (search) mutations, suggesting molecular profiling may guide treatment selection.
A multinational retrospective study has revealed encouraging survival outcomes for patients with advanced myeloproliferative neoplasms (search) (MPNs) treated with azacitidine-based combination therapy, particularly when paired with ruxolitinib (Jakafi). The findings, published in HemaSphere, offer new insights for managing one of hematology's most challenging patient populations.
Study Design and Patient Population
The observational study evaluated 149 patients with accelerated-phase or blast-phase myeloproliferative neoplasms (search) (AP/BP-MPNs) who were unfit for allogeneic hematopoietic cell transplantation. Patients received either azacitidine monotherapy (n = 60) or combination therapy (n = 89) between 2019 and 2023.
The median age was 75 years, reflecting a typical cohort of patients excluded from intensive treatment due to age and comorbidities. The patient population included 40% females, with underlying diagnoses of essential thrombosis (search) (39%), polycythemia vera (search) (33%), and myelofibrosis (search) (28%). AP/BP-MPN was defined as 10% or more blasts in peripheral blood or bone marrow, with 10-19% blasts defining accelerated phase and 20% or more defining blast phase.
Survival Outcomes and Treatment Efficacy
The overall cohort achieved a median overall survival of 8.04 months after a median follow-up of 15 months. As expected, survival varied significantly based on disease phase and molecular characteristics. Patients with blast phase disease had markedly shorter survival compared to those with accelerated phase (6.24 vs 18.0 months; P = .03).
Molecular features strongly influenced outcomes. Patients with complex karyotype demonstrated inferior survival compared to those without (6.0 vs 13.08 months; P = .005). Similarly, TP53 (search) mutations were associated with reduced survival (8.0 vs 11.0 months; P = .009).
Combination Therapy Benefits
When comparing treatment approaches, combination therapy showed a trend toward improved survival over monotherapy (10.1 vs 7.0 months; P = .012), though this difference was not statistically significant. However, when analyzing specific combinations separately, clear differences emerged.
Patients treated with azacitidine-ruxolitinib achieved the longest median overall survival at 18.0 months, compared to 9.0 months for azacitidine-venetoclax (Venclexta) and 10.1 months for the triple combination of azacitidine-venetoclax-ruxolitinib (P = .015). This survival benefit was especially pronounced in patients without complex karyotype or TP53 (search) mutations.
Among combination therapies, 35% of patients received venetoclax, 18% received ruxolitinib, and 6% received both agents alongside azacitidine.
Safety and Tolerability
Safety profiles were comparable across treatment groups, with infection and progressive disease being the most common causes of death. The treatment was manageable in the outpatient setting for many patients, with similar hospitalization rates across treatment strategies. The rate of intensive care unit admission was low and did not differ significantly between treatment approaches.
Clinical Implications
Lead investigator Corentin Orvain and colleagues noted that although the combination was not statistically superior in all subgroups, the signal was strong enough to warrant prospective validation. The clinical significance of these findings is substantial for community oncologists who often manage older, comorbid patients with advanced MPN who have limited therapeutic options.
The study suggests that for a subset of patients—particularly those with prior myelofibrosis (search), splenomegaly, or JAK2 (search) mutations—the combination of azacitidine and ruxolitinib may provide meaningful survival extension. The improved outcomes with azacitidine-ruxolitinib, especially in patients continuing ruxolitinib from the chronic phase, suggest a potential role for JAK inhibition throughout the disease course.
Study Limitations and Future Directions
The investigators acknowledged several limitations, including the non-randomized design, missing molecular data for some patients, and lack of dosing information. These factors preclude definitive conclusions about superiority of any regimen.
Previous studies have demonstrated better overall survival in patients who received treatment while in the accelerated phase, suggesting the benefit of early treatment initiation. However, this approach might not be feasible in a significant proportion of patients with MPNs that directly transform into acute myeloid leukemia (search).
The research team emphasized that new therapeutic options are urgently needed, especially in patients with complex karyotype and/or TP53 (search) mutations. They recommended that next steps should include prospective trials comparing azacitidine-ruxolitinib to other combinations in molecularly defined subgroups.
The prognosis for patients with AP/BP-MPN remains challenging, with median overall survival often measured in months. Only about one in eight patients in this cohort were alive at three years, underscoring the urgent need for more effective therapeutic approaches in this vulnerable population.