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Phase II Prospective Study of Intentional Pre-Treatment of Hematopoietic Cell Transplant Eligible Myelofibrosis Patients with Ruxolitinib

Year: 2025

Type: article

Abstract: Background Ruxolitinib (Rux), the first FDA approved JAK-inhibitor for the treatment of myelofibrosis (MF) was initially studied only in patients who were not considered hematopoietic cell transplantation (HCT) candidates. However, the resultant decrease in splenomegaly and improvement in total symptom score led some patients to become eligible for HCT. Whether JAK inhibitor therapy should be given routinely prior to HCT in HCT eligible MF patients is still an unanswered question. Methods We conducted a Phase II prospective single center study of Rux followed by HCT in adult patients with primary and secondary MF between 2014 - 2020. The primary endpoint was 2-year overall survival (OS). Patients had to have at least Dynamic International Prognostic Staging Score (DIPSS) Intermediate-1 disease and be considered a HCT candidate; they were not required to have symptoms or splenomegaly. The study mandated patients to take Rux for at least 8 weeks (no maximum) with a plan to taper to off by Day -4 prior to HCT conditioning. Patients received either cyclophosphamide 120mg/kg and 4-day targeted busulfan (n = 41) or fludarabine 150mg/m 2 and melphalan 140mg/m 2 (n = 20) conditioning and tacrolimus and methotrexate 10mg/m 2 x 4 for GVHD prophylaxis. Donors included peripheral blood stem cells in HLA-matched siblings (n = 24), 10/10 HLA-matched unrelated (n = 28) and 9/10 HLA- allele mismatched (n = 3) and cord blood (n = 6) grafts. Results 61 patients (59% primary MF, 70% DIPSS Intermediate 2 or High Risk) median age 57 (range 34 -71) years proceeded to HCT after a median of 7 months on Rux. Of patients who had symptoms prior to Rux, 55% had no or improved symptoms pre-HCT. Excluding those who underwent splenectomy (n = 7), 38% had > 10% decrease in splenomegaly; another 36% were stable; median spleen length was 18.7 cm at time of HCT. Patients engrafted at a median Day +20 (range 12 - 63). Non-relapse mortality (NRM) was 5% at day 100 and 13% at 1-year compared with 26% at 1-year in non-JAK inhibitor treated historical controls at our Center. At a median follow up of 5.2 years, OS was 79% (95% CI 69-90) at 2-years and 74% (95% CI 64-86) at 5-years compared to 60% at 2-years and 57% at 5-years in the historical controls. The incidence of day 100 acute grade II-IV GVHD was 71% and Grade III-IV was 19% similar to historical controls. At 3-years, chronic GVHD of any grade had been diagnosed in 52% of patients, with moderate to severe in 44%. In univariate analysis, time on pre-HCT JAK-inhibitor therapy was associated with lower risk of acute GVHD (p = 0.03) and DIPSS Intermediate-2 or higher was associated with more chronic GVHD (p =0.07). Conclusion Pre-HCT JAK inhibitors may be associated with NRM and survival benefits even for MF patients who could otherwise proceed directly to HCT. Acute and chronic GVHD incidence remains high. The relationship between GVHD and JAK-inhibitor therapy/DIPSS score is of unclear etiology and needs to be explored.

Source: Transplantation and Cellular Therapy

DOI: 10.1016/j.jtct.2025.01.170