HMA Combination Therapy Boosts Survival in Accelerated- or Blast-Phase MPNs

Patients with accelerated-phase or blast-phase myeloproliferative neoplasms (MPNs) appear to have better results when treated with azacitidine (Vidaza; Bristol Myers Squibb) in combination with ruxolitinib (Jakafi; Incyte) compared with azacitidine alone or with other drugs, a new study found.

The report, which was published in HemaSphere, offers insights into a hard-to-treat category of patients with a very poor prognosis.¹

The median overall survival (OS) for patients with accelerated-phase or blast-phase MPNs ranges from just 3 to 10 months, though patients who are eligible for allogeneic hematopoietic cell transplantation (allo-HCT) can experience longer survival with the procedure, noted corresponding author Jean-Christophe Ianotto, MD, PhD, of the Brest University Hospital Center, in France, and colleagues.

“This adverse outcome is due to a higher frequency of adverse cytogenetics and/or molecular abnormalities, including TP53 mutations, in comparison to other subtypes of acute myeloid leukemia (AML) that are not fully alleviated by allogeneic HCT,” Ianotto and colleagues explained.

Many of these patients are not eligible for intensive therapy on account of factors such as age and comorbidities, the authors noted, and in such cases non-curative therapies like hypomethylating agents (HMAs) can be a treatment option. Previous research has suggested that the use of the Janus kinase inhibitor ruxolitinib or the BCL2 inhibitor venetoclax (Venclexta; AbbVie and Genentech) might be effective as combination therapies with HMAs. For instance, a 2020 phase 2 study found that the combination of ruxolitinib and the HMA decitabine (Dacogen) resulted in favorable OS.²

Yet, Ianotto and colleagues said there is not yet sufficient evidence to fully understand whether HMAs, alone or in combination, will improve outcomes for this patient group.

In an effort to better understand the potential of the treatment strategy, Ianotto and colleagues conducted an analysis of a multi-center cohort of 149 patients with accelerated- or blast-phase MPNs who were ineligible for intensive therapy or allo-HCT. All of the patients received either azacitidine alone (n = 60) or in combination with other therapies (n = 89). Among those receiving combination therapies, most were given azacitidine alongside venetoclax (n = 51, though 27 patients received it in combination with ruxolitinib, 9 patients received azacitidine with both venetoclax and ruxolitinib, and 2 patients received azacitidine with dehydrogenase inhibitors.

All of the participants in the study were treated between January 2019 and October 2023; they had a median age of 75 years.

After a median follow-up of 15 months, the overall cohort had a median OS of 8.04 months and a 3-year OS rate of 13%. Those with blast-phase disease had a median OS of just 6.24 months, compared to 18.0 months among patients with accelerated-phase disease (P = .03). Patients with complex karyotype disease and TP53 mutations also had inferior survival, the investigators said. They said that the better outcome of patients with accelerated-phase disease in this study may suggest the benefits of earlier diagnosis and treatment initiation.

Ianotto and colleagues found that patients receiving azacitidine as part of combination therapy tended to live longer (10.08 months vs 6.96 months; P = .12); however, the gap in survival did not reach statistical significance, they said. They added that there was a higher proportion of patients with adverse characteristics in the HMA monotherapy group.

Among patients receiving combination therapies, though, they found significant variance. Those treated with azacitidine and ruxolitinib had a median OS of 18.0 months, compared to 9.0 months in patients receiving azacitidine plus venetoclax and 10.08 months in patients who received all 3 therapies (P = .015). The OS for patients receiving azacitidine and ruxolitinib was higher than in previous studies. However, patient heterogeneity and lack of random allocation of treatment strategies do not allow for definitive conclusions about the best treatment options.

They added, though, that their findings underscore the need for new therapeutic options, particularly for patients with high-risk characteristics.

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):e70202. Published 2025 Sep 4. doi:10.1002/hem3.70202

2. Mascarenhas JO, Rampal RK, Kosiorek HE, et al. Phase 2 study of ruxolitinib and decitabine in patients with myeloproliferative neoplasm in accelerated and blast phase. Blood Adv. 2020;4(20):5246-5256. doi:10.1182/bloodadvances.2020002119