Abstract
BackgroundMyelofibrosis (MF) is a life-shortening complication of myeloproliferative neoplasms associated with ineffective hematopoiesis, splenomegaly, and progressive bone marrow (BM) fibrosis. The oral Janus kinase (JAK) 1/JAK2 inhibitor ruxolitinib has been shown to improve splenomegaly, symptom burden, and overall survival in patients with intermediate-2 or high-risk MF compared with placebo or best available therapy (BAT).MethodsThe effects of ruxolitinib therapy for up to 66 months on BM morphology in 68 patients with advanced MF with variable BM fibrosis grade were compared with those in 192 matching patients treated with BAT. Available trephine biopsies underwent independent, blinded review by three hematopathologists for consensus-based adjudication of grades for reticulin fibrosis, collagen deposition, and osteosclerosis.ResultsRuxolitinib treatment versus BAT was associated with greater odds of BM fibrosis improvement or stabilization and decreased odds of BM fibrosis worsening based on changes from baseline in reticulin fibrosis grade. Generally, these changes were accompanied by a sustained higher level of individual spleen size reduction and regression of leukoerythroblastosis. Patients with more advanced baseline fibrosis showed lower spleen size response.ConclusionsThe finding that long-term ruxolitinib therapy may reverse or markedly delay BM fibrosis progression in advanced MF suggests that sustained JAK inhibition may be disease-modifying.Trial registrationINCB18424-251, ClinicalTrials.gov identifier NCT00509899.
Highlights
Myelofibrosis (MF) is a life-shortening complication of myeloproliferative neoplasms associated with ineffective hematopoiesis, splenomegaly, and progressive bone marrow (BM) fibrosis
Despite the rapid clinical improvements observed in the vast majority of patients treated with Janus kinase (JAK)-inhibitors like ruxolitinib, short-term local assessments (e.g., ≤ 6 months of therapy) did not reveal any substantial treatment impact on BM histomorphology [33, 42,43,44,45]. These findings raise the possibility that long-term therapy with ruxolitinib may influence the evolution of disease progression [46]. To further explore this possibility, we evaluated the effects of long-term ruxolitinib therapy on BM fibrosis in patients enrolled in the aforementioned phase 1/2 study at the MD Anderson Cancer Center (MDACC) and compared them with changes in BM fibrosis observed in a control cohort of patients with primary MF (PMF) and matching degrees of BM fibrosis at baseline who received conventional therapy
Patients in the best available therapy (BAT) group, who were matched to the ruxolitinib cohort, had lower International Prognostic Scoring System (IPSS) scores, which was reflected by less severe splenomegaly and higher hemoglobin values and platelet counts at baseline (Table 1)
Summary
Myelofibrosis (MF) is a life-shortening complication of myeloproliferative neoplasms associated with ineffective hematopoiesis, splenomegaly, and progressive bone marrow (BM) fibrosis. Generalization of the disease process in the course of BCR-ABL1-negative myeloproliferative neoplasms (MPNs) is usually associated with the development of BM fibrosis and ineffective hematopoiesis [2]. Along these lines, the prognostic value of BM fibrosis remains to be defined; several studies have provided. The initial emergence and time-dependent progression of BM fibrosis in patients with MPN-associated MF is believed to be a concomitant effect of neoplastic (clonal) myeloproliferation [18, 19]. Consensus guidelines establishing a simplified scoring system for reticulin fibrosis in MPN have been developed [27] and were adopted by the World Health Organization (WHO) [13], comparable guidelines for the evaluation of the important processes of collagen deposition and osteosclerosis have been developed only recently [25]
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