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Baseline factors associated with response to ruxolitinib: an independent study on 408 patients with myelofibrosis.

ABSTRACT: In patients with Myelofibrosis (MF) treated with ruxolitinib (RUX), the response is unpredictable at therapy start. We retrospectively evaluated the impact of clinical/laboratory factors on responses in 408 patients treated with RUX according to prescribing obligations in 18 Italian Hematology Centers. At 6 months, 114 out of 327 (34.9%) evaluable patients achieved a spleen response. By multivariable Cox proportional hazard regression model, pre-treatment factors negatively correlating with spleen response were: high/intermediate-2 IPSS risk (p=0.024), large splenomegaly (p=0.017), transfusion dependency (p=0.022), platelet count <200×109/l (p=0.028), and a time-interval between MF diagnosis and RUX start >2 years (p=0.048). Also, patients treated with higher (?10 mg BID) average RUX doses in the first 12 weeks achieved higher response rates (p=0.019). After adjustment for IPSS risk, patients in spleen response at 6 months showed only a trend for better survival compared to non-responders. At 6 months, symptoms response was achieved by 85.5% of 344 evaluable patients; only a higher (>20) Total Symptom Score significantly correlated with lower probability of response (p<0.001). Increased disease severity, a delay in RUX start and titrated doses <10 mg BID were associated with patients achievinglower response rates. An early treatment and higher RUX doses may achieve better therapeutic results.

SUBMITTER: Palandri F

PROVIDER: S-EPMC5668021 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Baseline factors associated with response to ruxolitinib: an independent study on 408 patients with myelofibrosis.

Palandri Francesca F Palumbo Giuseppe Alberto GA Bonifacio Massimiliano M Tiribelli Mario M Benevolo Giulia G Martino Bruno B Abruzzese Elisabetta E D'Adda Mariella M Polverelli Nicola N Bergamaschi Micaela M Tieghi Alessia A Cavazzini Francesco F Ibatici Adalberto A Crugnola Monica M Bosi Costanza C Latagliata Roberto R Di Veroli Ambra A Scaffidi Luigi L de Marchi Federico F Cerqui Elisa E Anaclerico Barbara B De Matteis Giovanna G Spinsanti Marco M Sabattini Elena E Catani Lucia L Aversa Franco F Di Raimondo Francesco F Vitolo Umberto U Lemoli Roberto Massimo RM Fanin Renato R Merli Francesco F Russo Domenico D Cuneo Antonio A Bacchi Reggiani Maria Letizia ML Cavo Michele M Vianelli Nicola N Breccia Massimo M

Oncotarget 20170627 45

In patients with Myelofibrosis (MF) treated with ruxolitinib (RUX), the response is unpredictable at therapy start. We retrospectively evaluated the impact of clinical/laboratory factors on responses in 408 patients treated with RUX according to prescribing obligations in 18 Italian Hematology Centers. At 6 months, 114 out of 327 (34.9%) evaluable patients achieved a spleen response. By multivariable Cox proportional hazard regression model, pre-treatment factors negatively correlating with sple ...[more]

PMID: 29108288

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Project description:Myelofibrosis is a BCR-ABL1-negative myeloproliferative neoplasm characterized by anemia, progressive splenomegaly, extramedullary hematopoiesis, bone marrow fibrosis, constitutional symptoms, leukemic progression, and shortened survival. Constitutive activation of the Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathway, and other cellular pathways downstream, leads to myeloproliferation, proinflammatory cytokine expression, and bone marrow remodeling. Transplant is the only curative option for myelofibrosis, but high rates of morbidity and mortality limit eligibility. Several prognostic models have been developed to facilitate treatment decisions. Until the recent approval of fedratinib, a JAK2 inhibitor, ruxolitinib was the only available JAK inhibitor for treatment of intermediate- or high-risk myelofibrosis. Ruxolitinib reduces splenomegaly to some degree in almost all treated patients; however, many patients cannot tolerate ruxolitinib due to dose-dependent drug-related cytopenias, and even patients with a good initial response often develop resistance to ruxolitinib after 2-3 years of therapy. Currently, there is no consensus definition of ruxolitinib failure. Until fedratinib approval, strategies to overcome ruxolitinib resistance or intolerance were mainly different approaches to continued ruxolitinib therapy, including dosing modifications and ruxolitinib rechallenge. Fedratinib and two other JAK2 inhibitors in later stages of clinical development, pacritinib and momelotinib, have been shown to induce clinical responses and improve symptoms in patients previously treated with ruxolitinib. Fedratinib induces robust spleen responses, and pacritinib and momelotinib may have preferential activity in patients with severe cytopenias. Reviewed here are strategies to ameliorate ruxolitinib resistance or intolerance, and outcomes of clinical trials in patients with myelofibrosis receiving second-line JAK inhibitors after ruxolitinib treatment.

Dataset Information

Baseline factors associated with response to ruxolitinib: an independent study on 408 patients with myelofibrosis.

Publications

Baseline factors associated with response to ruxolitinib: an independent study on 408 patients with myelofibrosis.

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