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A phase 2 study of ruxolitinib in combination with azacitidine in patients with myelofibrosis.

ABSTRACT: Ruxolitinib (RUX)-based combinations may provide benefit for patients with myelofibrosis (MF). In this open-label, nonrandomized, prospective phase 2 study, patients with MF initially received RUX twice per day continuously in 28-day cycles for the first 3 cycles. Azacitidine (AZA) 25 mg/m2 (days 1-5) was added starting with cycle 4 and could be subsequently increased to 75 mg/m2 (days 1-5). Forty-six patients were enrolled with a median follow-up of 28 months (range, 4-50+ months). An International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) response was achieved in 33 patients (72%), with a median time to response of 1.8 months (range, 0.7-19.0 months). One-fourth (7 of 33) of the IWG-MRT responses occurred after the addition of AZA. A reduction of >50% in palpable spleen length at 24 weeks and at any time on the study was achieved in 62% and 71% of the evaluable patients, respectively. Among patients who achieved a >50% reduction in spleen length at 24 weeks, 95% had maintained it at 48 weeks. Notably, improvements in bone marrow reticulin fibrosis grade occurred in 57% of the patients at 24 months. Treatment discontinuations as a result of drug-related toxicities occurred in 4 patients (9%), all as a result of cytopenias. New onset grade 3 to 4 anemia and thrombocytopenia occurred in 35% and 26% of patients, respectively. RUX and AZA were safe, with encouraging spleen response rates and improvement in bone marrow fibrosis in patients with MF. This trial was registered at www.clinicaltrials.gov as #NCT01787487.

SUBMITTER: Masarova L

PROVIDER: S-EPMC6265645 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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A phase 2 study of ruxolitinib in combination with azacitidine in patients with myelofibrosis.

Masarova Lucia L Verstovsek Srdan S Hidalgo-Lopez Juliana E JE Pemmaraju Naveen N Bose Prithviraj P Estrov Zeev Z Jabbour Elias J EJ Ravandi-Kashani Farhad F Takahashi Koichi K Cortes Jorge E JE Ning Jing J Ohanian Maro M Alvarado Yesid Y Zhou Lingsha L Pierce Sherry S Gergis Romany R Patel Keyur P KP Luthra Rajyalakshmi R Kadia Tapan M TM DiNardo Courtney D CD Borthakur Gautam G Bhalla Kapil K Garcia-Manero Guillermo G Bueso-Ramos Carlos E CE Kantarjian Hagop M HM Daver Naval N

Blood 20180905 16

Ruxolitinib (RUX)-based combinations may provide benefit for patients with myelofibrosis (MF). In this open-label, nonrandomized, prospective phase 2 study, patients with MF initially received RUX twice per day continuously in 28-day cycles for the first 3 cycles. Azacitidine (AZA) 25 mg/m<sup>2</sup> (days 1-5) was added starting with cycle 4 and could be subsequently increased to 75 mg/m<sup>2</sup> (days 1-5). Forty-six patients were enrolled with a median follow-up of 28 months (range, 4-50+ ...[more]

PMID: 30185431

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Project description:BACKGROUND:The JAK inhibitor (JAKi) ruxolitinib is standard treatment for myelofibrosis (MF), but some patients are unresponsive. Pre-clinical and clinical data suggest that addition of a Hedgehog pathway inhibitor (HPI) to ruxolitinib might improve response. Vismodegib is an HPI approved for treatment of locally advanced and metastatic basal cell carcinoma. The MYLIE study assessed the safety and efficacy of combining ruxolitinib with vismodegib in ruxolitinib-naive patients with MF and characterized the pharmacokinetics (PK) of vismodegib in this setting. METHODS:In this phase Ib study, ten patients with intermediate- or high-risk primary or secondary MF received open-label vismodegib (150 mg/day orally) and ruxolitinib (15 or 20 mg orally twice daily, depending on baseline platelet count) for up to 48 weeks, or until withdrawal or discontinuation. PK samples were collected throughout the study for comparison with other patient populations. Efficacy outcomes at week 24 included spleen response (??35% reduction in volume by imaging) and improvement in bone marrow fibrosis by central and investigator assessment, symptom response (??50% reduction in Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom score), and anemia response (per International Working Group for Myeloproliferative Neoplasms Research and Treatment revised response criteria). RESULTS:As of November 17, 2017, eight patients had completed 48 weeks of treatment with vismodegib and ruxolitinib; two discontinued treatment early. At week 24 (±?1 week), three patients experienced a spleen response by central review and no patients showed a 1-grade improvement in bone marrow fibrosis by central review. Five patients experienced symptom response at week 24, and no patients experienced an anemia response. The most common adverse events were muscle spasm (100% of patients), alopecia (70%), dysgeusia (50%), thrombocytopenia (50%), and nausea (40%); these events were predominantly grade 1/2. Three patients experienced a total of six serious adverse events. CONCLUSIONS:The combination of vismodegib and ruxolitinib was tolerable and no new safety signals were seen, but there was no evidence that the addition of vismodegib to ruxolitinib improved any of the efficacy outcome measures assessed. Further evaluation of this combination will not be pursued. TRIAL REGISTRATION:ClinicalTrials.gov, NCT02593760 . Registered November 2, 2015.

Dataset Information

A phase 2 study of ruxolitinib in combination with azacitidine in patients with myelofibrosis.

Publications

A phase 2 study of ruxolitinib in combination with azacitidine in patients with myelofibrosis.

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