Azacitidine, Ruxolitinib Pairing Highlighted in Advanced MPN

Findings from an observational retrospective study¹ evaluating the outcome of patients with accelerated‐phase or blast‐phase myeloproliferative neoplasms (AP/BP-MPNs) who received azacitidine monotherapy or in combination revealed a median overall survival (OS) of 8.04 months after a median follow-up of 15 months, particularly for those without high-risk genetic features. Overall, OS was lower in patients with BP vs AP (6.24 vs 18.0 months; P = .03), complex karyotype (6.0 vs 13.08 months; P =.005), and TP53 mutation (8.0 vs 11.0 months; P =.009), respectively.

When reviewing monotherapy vs combination therapy, OS was nonsignificantly higher in patients receiving combination therapy (10.1 vs 7.0 months; P =.012). When analyzing azacitidine combinations separately, patients who were treated with azacytidine/ruxolitinib (Jakafi) vs azacitidine/venetoclax (Venclexta) vs azacitidine/venetoclax/ruxolitinib had higher OS (18.0 vs 9.0 vs 10.1 months; P =.015).

This survival benefit was especially pronounced in patients without complex karyotype or TP53 mutations. 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.

A total of 149 patients with AP/BP-MPN who were unfit for allogeneic hematopoietic cell transplantation (allo-HCT) received either azacitidine alone (n = 60) or a combination (n = 89).

AP/BP‐MPN was defined as the occurrence of 10% or more blasts in the peripheral blood (PB) or bone marrow (BM) in patients with an underlying MPN, such as essential thrombosis (ET), polycythemia vera (PV), and myelofibrosis (MF), with 10% to 19% blasts defining AP‐MPN and 20% or more blasts defining BP‐MPN.

The median age for the overall cohort was 75 years, reflecting a typical cohort of patients excluded from intensive treatment. Forty percent of the patients were female, and 39% had ET, 33% had PV, and 28% had MF. Regarding the combination therapy, 35% received venetoclax, 18% received ruxolitinib, and 6% received both agents.

The prognosis for patients with AP/BP‐MPN remains dismal, with median OS often measured in months. The clinical significance of these findings is substantial. Community oncologists often manage older, comorbid patients with advanced MPN who have limited options. This study suggests that for a subset of these patients—particularly those with prior myelofibrosis, splenomegaly, or JAK2 mutations—a combination of azacitidine and ruxolitinib may provide meaningful survival extension. Importantly, the treatment was manageable in the outpatient setting for many, with similar hospitalization rates across treatment groups.

Safety profiles were comparable across groups, with infection and progressive disease being the most common causes of death. The rate of intensive care unit admission was low and did not differ significantly between treatment strategies, according to the investigators.

The study has 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. Nevertheless, the improved outcomes with azacitidine and ruxolitinib—especially in patients continuing ruxolitinib from the chronic phase—suggest a potential role for JAK inhibition throughout the disease course.

Previous studies have demonstrated better OS in patients who received treatment while in the AP, which suggests the benefit of early treatment initiation.² The investigators acknowledged that this might not be feasible in a significant proportion of patients with MPNs that directly transform into acute myeloid leukemia.

Next steps should include prospective trials comparing azacitidine-ruxolitinib to other combinations in molecularly defined subgroups.

“New therapeutic options are urgently needed, especially in patients with complex karyotype and/or TP53 mutations,” the investigators concluded.

REFERENCES:

1. Orvain C, Tavitian S, Mediavilla C, et al. Outcome of patients with accelerated and blast‐phase myeloproliferative neoplasms not eligible for intensive chemotherapy or allogeneic hematopoietic cell transplantation treated by azacitidine alone or in combination—A FIM study. HemaSphere. 2025;9(9):e702702

2. Davidson MB, Kennedy JA, Capo-Chichi JM, et al. Outcomes of intensive and nonintensive blast-reduction strategies in accelerated and blast-phase MPN. Blood Adv. 2024;8(5):1281-1294. doi:10.1182/bloodadvances.2023011735