Impact of new or worsening anemia and thrombocytopenia on clinical outcomes in JAK inhibitor–naive myelofibrosis patients treated with ruxolitinib

Abstract Introduction Myelofibrosis (MF) is characterized by splenomegaly, constitutional symptoms, and cytopenias such as anemia and thrombocytopenia. Management of splenomegaly is often prioritized when treating MF. Ruxolitinib, a JAK inhibitor (JAKi), provides spleen and symptom benefits but is often associated with cytopenias. A SIMPLIFY-1 subgroup analysis in patients with hemoglobin (Hb) <10 g/dL showed that lower starting doses of ruxolitinib in those with baseline platelet counts <200×10⁹/L resulted in lower spleen volume reduction ≥35% (SVR35) response rates at week 24. SVR35 response rates were 49% for patients with platelet counts >200×10⁹/L, 24% for those with platelet counts 100 to 200×10⁹/L, and 0% for those with platelet counts 50 to <100×10⁹/L. This highlights the importance of full-dose JAKi therapy for optimal spleen response (Palandri F, et al. EHA 2025. Poster PS1829). This post hoc analysis of SIMPLIFY-1 (NCT01969838) evaluates the impacts of new or worsening (n/w) anemia and thrombocytopenia on spleen and symptom response and ruxolitinib dose reductions in JAKi-naive MF patients treated with ruxolitinib. Methods In the first analysis, patients treated with ruxolitinib were stratified by presence vs absence of baseline anemia (Hb <10 g/dL or transfusion dependent) and n/w anemia within 12 weeks of starting ruxolitinib (Hb decrease ≥1.5 g/dL and Hb <10 g/dL or new transfusion requirement of ≥2 units within 8 weeks at weeks 4, 8, or 12 after starting ruxolitinib). In a second analysis, patients treated with ruxolitinib were stratified by both baseline thrombocytopenia (platelet counts <200×10⁹/L) and n/w thrombocytopenia within 12 weeks of starting ruxolitinib (platelet count decrease >50×10⁹/L and platelet counts <200×10⁹/L). A third analysis evaluated outcomes in baseline anemic patients with baseline or n/w thrombocytopenia. Key outcomes included SVR35 at week 24, Total Symptom Score reduction ≥50% (TSS50) at week 24, and ruxolitinib dose modifications captured by week 12. Results A total of 216 patients (55% male) were included in the analysis. At baseline, 103 patients were anemic, with 84 (81.5%) developing n/w anemia within 12 weeks of starting ruxolitinib. Among the 113 nonanemic patients, 23 (20.4%) developed n/w anemia. Patients with n/w anemia had lower SVR35 response rates vs those without n/w anemia; the relative reduction in SVR35 response rate with n/w anemia was 21.4% for baseline nonanemic patients and 13.5% for baseline anemic patients. Similarly, TSS50 response rates were lower with n/w anemia vs without n/w anemia; the relative reduction in TSS50 response rate was 10.2% for baseline nonanemic patients and 20.4% for baseline anemic patients. Mean starting ruxolitinib daily doses were similar between groups: 32.1 mg for patients who later developed n/w anemia and 34.6 mg for those who did not. By week 12, patients with n/w anemia had greater mean reductions in ruxolitinib daily dose (3.7-mg reduction in baseline anemic patients; 5.2-mg reduction in baseline nonanemic patients) vs patients without n/w anemia (1.7-mg reduction in baseline anemic patients; 3.9-mg reduction in baseline nonanemic patients). Of the 216 patients, 86 (39.8%) had baseline thrombocytopenia. Patients with baseline thrombocytopenia had a 69% relative reduction in SVR35 response rates and a 24.4% relative reduction in TSS50 response rates. Of the 216 patients, 167 (77.3%) had n/w thrombocytopenia, with most platelet counts decreasing to <200×10⁹/L after 12 weeks of ruxolitinib treatment. Patients with baseline thrombocytopenia started on lower ruxolitinib doses vs those without baseline thrombocytopenia. Patients who developed n/w thrombocytopenia experienced additional dose reductions, averaging a 7-mg reduction over 12 weeks. Similar results were observed in patients with both thrombocytopenia and baseline anemia. Conclusions Reduced spleen and symptom response rates observed in patients with anemia or thrombocytopenia may be attributable to dose-limiting toxicities necessitating ruxolitinib dose reductions. These findings have implications for real-world practice, as managing ruxolitinib dose to balance spleen and symptom benefits vs worsening cytopenias is challenging. This underscores the need for careful, individualized management strategies, including exploring alternative therapies early in the course of treatment for patients with cytopenias and compromised therapeutic efficacy due to low ruxolitinib dose.

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