Background. Ruxolitinib (RUX), the first JAK1/2 inhibitor approved for the treatment of myelofibrosis (MF), has significantly improved spleen and symptom control, demonstrating a survival benefit in responding patients (pts). However, on-target RUX-associated anemia represents a major therapeutic limitation, negatively affecting quality of life, prognosis, and treatment duration.

Novel JAK1/2 inhibitors, such as momelotinib and pacritinib, also target ACVR1 and may ameliorate anemia both in RUX-naïve and -exposed pts. However, there is a number of standard anemia-directed therapies (ADT), including erythropoietin (EPO), danazol, steroids and immunomodulatory agents (e.g. thalidomide), that have been used for a long time to manage anemia in MF. Information about the concurrent use of standard ADT with RUX is still scarce.

Aims.

To evaluate the impact of anemia on RUX drug survival, to assess the efficacy of various standard ADT in combination with RUX, to explore predictive factors of erythroid response and, finally, to analyze whether optimal anemia management with RUX-combined therapies can extend RUX drug survival.

Methods.

Retrospective registry study of pts with primary or secondary MF treated with RUX at 3 reference Hematology centers in Triveneto (Northern East region of Italy). Detailed clinical and laboratory data were collected at diagnosis and every 3 to 6 months during treatment for all pts. The definition of transfusion-dependent anemia (TDA) and response criteria for anemia were according to IWG-ELN 2024. Anemia response was evaluated after 3, 6, 9 and 12 months of RUX and ADT combination: pts already exposed to ADT before or at RUX start were not included in this analysis. Statistical analyses were performed using “R” software.

Results. The overall study population included 238 pts (57.1% males) who started RUX from 2011 to 2024. Primary and secondary MF were 39.5% and 60.5%, respectively. Driver mutations were JAK2/CALR/MPL/triple negative in 191 (80.2%)/26 (10.9%)/12 (5%)/4 (1.7%) pts, respectively (information not available in 5). Median RUX survival for the overall study population was 48.9 months (95% CI: 37.8-63.0).

At or after RUX start 164/238 pts (68.9%) developed moderate to severe anemia (Hb <10 g/dL), with a median time of 3 months (range 0-96) from RUX start. The presence of moderate to severe anemia at any time during RUX was associated to a significantly shorter RUX drug survival (median 42 vs 92 months, p=0.001).

Anemia was treated with ADT in 77/164 pts (46.9%), while 68 pts received RBC transfusions only (41.5%) and the remaining cases did not receive specific treatments.

EPO was the most frequently used ADT (46 pts, 59.7%), followed by steroids (25 pts, 32.5%), danazol (13 pts, 16.8%) and thalidomide (4 pts, 5.2%). Twelve pts received two or more different ADT, either concurrently or sequentially.

Median time from RUX to EPO start was 6.8 months (range 1-138); median time from RUX to other ADT start ranged from 15.5 to 20 months.

Rates of anemia major response to the combination of EPO and RUX ranged from 27.8% to 33.3% at 3-12 months, and 42.5% of pts received EPO for more than 12 months. Rates of anemia major response to the other ADT were considerably lower at all the timepoints (9-10% for steroids, 16-25% for danazol, 0% for thalidomide).

The combination of EPO and RUX was associated with significantly superior RUX survival compared to other ADT (76.8 vs 33.3 months, p=0.0368). Pts non-TDA pre-EPO showed better RUX survival (78.4 vs 21.9 months, p=0.0016).

Cumulative incidence of accelerated/blast phase (A/BP) at 60 months was 6.7% in pts treated with EPO alone vs 29.5% with other ADT +/- EPO (p=0.0108), suggesting a favorable safety profile for the use of EPO as unique supportive treatment for RUX-associated anemia.

A “Response to Ruxolitinib after 6 Month” (RR6) low/intermediate score was predictive of major response to EPO (64.5% vs 0% for pts with high score, p=0.0123). Notably, the achievement of major response was associated with a trend toward lesser progression to A/BP both in pts treated with EPO alone (p=0.0607) or other ADT (p=0.059).

Conclusions. Proactive anemia management with EPO, initiated early before the establishment of TDA, is associated with better RUX survival and favorable safety profile. These results support a personalized approach integrating early prognostic assessment with optimized anemia management strategies, in order to maximize treatment benefits.

This content is only available as a PDF.
2025
Sign in via your Institution