Long-term effects of ruxolitinib versus best available therapy on bone marrow fibrosis in patients with myelofibrosis

Abstract

Background: Myelofibrosis (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).

Methods: The 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.

Results: Ruxolitinib 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.

Conclusions: The 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 registration: INCB18424-251, ClinicalTrials.gov identifier NCT00509899 .

Keywords: Bone marrow fibrosis; Hydroxyurea; Myelofibrosis; Ruxolitinib.

Conflict of interest statement

Ethics approval and consent to participate

This study was conducted in accordance with the International Conference on Harmonization guidelines for Good Clinical Practice. The clinical study protocol was approved by the MDACC Institutional Review Board and for the BAT group by the University of Frankfurt Ethics Committee (UCT project number SHN-07-2016). Details of the INCB18424-251 study design (Consent for publication

Not applicable.

Competing interests

H.M.K. reports receiving consulting or advisory fees from Incyte Corporation, AOP Orphan Pharmaceuticals, and Novartis; honoraria from Incyte Corporation and Novartis; research funding from AOP Orphan Pharmaceuticals and Novartis; and other remunerations from Incyte Corporation and Novartis. J.T. reports receiving consulting or advisory fees from Incyte Corporation, AOP Orphan Pharmaceuticals, Novartis, and Sanofi; honoraria from Incyte Corporation, Novartis, and Sanofi; research funding from Incyte Corporation, AOP Orphan Pharmaceuticals, Novartis, and Shire; and other remunerations from Incyte Corporation, Novartis, and Sanofi. C.E.B-R reports receiving consulting or advisory fees from Incyte Corporation and honoraria from Novartis. W.S. is an employee of and holds stock in Incyte Corporation. J.C. reports receiving consulting or advisory fees from Incyte Corporation and Sanofi and receiving research funding from Incyte Corporation and Sanofi. H.M.K. reports receiving research funding from ARIAD, Bristol-Myers Squibb, Novartis, and Pfizer. S.V. reports receiving research funding from Incyte Corporation, AstraZeneca, Lilly Oncology, Geron, NS Pharma, Bristol-Myers Squibb, Novartis, Celgene, Gilead, Seattle Genetics, Promedior, and Cell Therapeutics, Inc.

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Figures

Fig. 1

Changes in bone marrow (BM) fibrosis at 48 months following ruxolitinib (a, b) and hydroxyurea (c, d) therapy. Ruxolitinib therapy induced a significant regression of BM fibrosis from baseline grade 3 (a) to grade 0 (b). Hydroxyurea treatment had no impact on reversal of BM fibrosis; biopsy at baseline revealed a grade 1 (c), and 48 months trephine showed an increase in reticulin to grade 2 (d)

Fig. 2

Changes in bone marrow fibrosis grade during ruxolitinib (RUX) therapy and best available therapy (BAT). Individual changes were calculated as a worsening (cases with baseline BM fibrosis grade 3 were excluded from this analysis because further progression is not defined), b improvement, or c improvement or stabilization

Fig. 3

Changes in age-matched hematopoietic cellularity at different time points following ruxolitinib therapy. Values less than 1.0 indicate decreased cellularity, 1.0 reflects normal marrow cellularity, while values greater than 1.0 indicate increased cellularity

Fig. 4

Relative change in palpable spleen size reduction from baseline at different time points following ruxolitinib therapy

Fig. 5

Relative change in palpable spleen size reduction following ruxolitinib therapy at month 24 according to baseline BM characteristics