Azacitidine Plus Ruxolitinib Shows Durable Responses in Myelofibrosis

The combination of azacitidine (Vidaza) and ruxolitinib (Jakafi) produced robust and durable responses with no new safety signals in patients with myelofibrosis, according to final results of a phase 2 study (NCT01787487) published in Haematologica.¹

Among the 54 patients with chronic phase disease, a cohort enriched for adverse-risk features, objective responses per the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria occurred in 42 patients (78%). Clinical improvement in spleen response occurred in 27 of 41 evaluable patients (66%; 54% by week 24), and clinical improvement in total symptom score (a reduction of at least 50%) occurred in 30 of 44 evaluable patients (68%; 52% by week 24); among 34 patients evaluable for both, 17 (50%) attained dual responses. Additional responses included anemia response in 3 of 21 patients (14%), a partial molecular response in 4 of 25 patients (16%), and a cytogenetic complete response in 2 of 23 patients (9%). Responses were durable, with a median duration of response of 33.1 months (95% CI, 19.1-46.7) for any response, 47.4 months (95% CI, 19.1-not reached [NR]) for symptom response, and 46.7 months (95% CI, 29.3-NR) for spleen response.

After a median follow-up of 95.3 months (95% CI, 75.7-130.2), the median overall survival (OS) in the chronic phase cohort was 56 months (95% CI, 38.2-99.3), corresponding to a 5-year OS rate of 47%; upon censoring at allogeneic stem cell transplantation (ASCT), the median OS was 71.6 months (95% CI, 44.1-100.2). By baseline Dynamic International Prognostic Scoring System (DIPSS) risk, the median OS was 100.2 months for intermediate-1, 56 months for intermediate-2, and 29 months for high-risk patients (log-rank for trend, P = .003). Leukemic transformation occurred in 4 patients (7%) on study, and 13 patients (24%) were bridged directly to ASCT. Among the 7 patients with accelerated phase disease, responses occurred in 3 (43%), and the median OS was 30.8 months (95% CI, 9.2-34.1).

In the full cohort (n = 61), all patients experienced at least 1 adverse event (AE), with grade 3 or higher AEs in 52 patients (85%). The most common grade 3 to 5 hematologic AEs were anemia (54%), thrombocytopenia (39%), and leukopenia/neutropenia (23%), while the most common grade 3 to 5 non-hematologic AEs were pneumonia (15%), fatigue (15%), and hypertension (13%).

No grade 5 treatment-related AEs were observed; 3 patients (5%) died on study due to AEs (pneumonia, intracranial hemorrhage, and sepsis), all considered unrelated to the regimen. AEs led to dose reductions in 27 patients (44%) and permanent discontinuation in 4 patients (7%).

“Similar to the data from the interim analysis, we report robust and durable responses with the [azacitidine/ruxolitinib] combination, especially in patients with chronic phase [myelofibrosis], with no new safety signals identified,” wrote corresponding author Naval Daver, MD, professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center, with study coinvestigators.¹ “Our findings support continued investigation of [azacitidine/ruxolitinib] and other novel [hypomethylating agent and JAK inhibitor] combinatorial strategies.”

The phase 2, open-label, single-institution study enrolled adults with primary or secondary myelofibrosis in need of therapy and DIPSS intermediate-1, intermediate-2, or high-risk disease, with bone marrow or peripheral blasts up to 19%; patients with prior ruxolitinib or azacitidine exposure were excluded. To mitigate overlapping myelosuppression, patients received single-agent ruxolitinib per label for the first 3 cycles, with azacitidine at a starting dose of 25 mg/m² on days 1 to 5 of each 28-day cycle, up-titratable to 75 mg/m², initiated at cycle 4. A total of 61 patients were treated between March 2013 and October 2021 (median age, 66 years), including 54 with chronic phase and 7 with accelerated phase disease.

The primary end point of the study was objective response rate per the 2013 IWG-MRT criteria. The key secondary end point was safety. Exploratory end points included bone marrow morphologic and cytogenetic responses, molecular responses, transfusion independence, duration of response, and survival.

Reductions in the underlying disease clone were observed; a reduction in bone marrow fibrosis by at least 1 grade occurred in 18 of 51 evaluable patients (35%), and a reduction in JAK2 variant allele frequency of at least 20% occurred in 11 of 23 evaluable patients (48%), findings the investigators said indicate the regimen may exert effects on disease biology with potential for disease modification. Neither marker was associated with a statistically significant OS benefit, which the authors attributed to likely underpowering given small numbers.

The authors noted that major limitations included the single-institution cohort, the lack of a control arm, and the lower starting dose of azacitidine (25 mg/m²) relative to standard dosing in myeloid neoplasms (75 mg/m²), with the full dose used in only 13% of patients with chronic phase disease. This strategy was intended to limit early cytopenias that may have constrained the therapeutic effect of azacitidine.

The response rates compared favorably with prior single-agent ruxolitinib data (spleen/symptom responses of 30% to 50% at week 24) and were similar to other ruxolitinib-based combinations. The 96-week leukemic transformation rate of 3.7% was comparable with the placebo/ruxolitinib and pelabresib/ruxolitinib arms of the phase 3 MANIFEST-2 study (NCT04603495) despite a higher proportion of adverse-risk features in the present cohort, and the findings extend those of the previously reported interim analysis of this trial.²

References

1. Arora S, Senapati J, Chu V, et al. Final results of a phase II study of the combination of azacitidine and ruxolitinib in patients with myelofibrosis. Haematologica. Published online August 27, 2026. doi:10.3324/haematol.2026.301178
2. Rampal R, Mascarenhas J, Grosicki S, et al. Durable efficacy and long-term safety with pelabresib plus ruxolitinib in JAK inhibitor-naive myelofibrosis: 96-week results from the phase III MANIFEST-2 study. Blood. 2025;146(suppl 1):910. doi:10.1182/blood-2025-910