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

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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.

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Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis.

Srdan Verstovsek, Hagop Kantarjian, Ruben Mesa … (2010)

Myelofibrosis is a Philadelphia chromosome–negative myeloproliferative neoplasm associated with cytopenias, splenomegaly, poor quality of life, and shortened survival. About half of patients with myelofibrosis carry a gain-of-function mutation in the Janus kinase 2 gene (JAK2 V617F) that contributes to the pathophysiology of the disease. INCB018424 is a potent and selective Janus kinase 1 (JAK1) and JAK2 inhibitor. We conducted a phase 1−2 trial of INCB018424 in patients with JAK2 V617F−positive or JAK2 V617F−negative primary myelofibrosis, post–essential thrombocythemia myelofibrosis, or post–polycythemia vera myelofibrosis. A total of 153 patients received INCB018424 for a median duration of more than 14.7 months. The initial dose-escalation phase established 25 mg twice daily or 100 mg once daily as maximum tolerated doses, on the basis of reversible thrombocytopenia. A dose-dependent suppression of phosphorylated signal transducer and activator of transcription 3 (STAT3), a marker of JAK signaling, was demonstrated in patients with wild-type JAK2 and in patients with the JAK2 V617F mutation. We studied additional doses and established that a 15-mg twice-daily starting dose, followed by individualized dose titration, was the most effective and safest dosing regimen. At this dose, 17 of 33 patients (52%) had a rapid objective response (≥50% reduction of splenomegaly) lasting for 12 months or more, and this therapy was associated with grade 3 or grade 4 adverse events (mainly myelosuppression) in less than 10% of patients. Patients with debilitating symptoms, including weight loss, fatigue, night sweats, and pruritus, had rapid improvement. Clinical benefits were associated with a marked diminution of levels of circulating inflammatory cytokines that are commonly elevated in myelofibrosis. INCB018424 was associated with marked and durable clinical benefits in patients with myelofibrosis for whom no approved therapies existed. (Funded by Incyte; ClinicalTrials.gov number, NCT00509899.)

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Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia.

Pierre Fenaux, Ghulam J Mufti, Eva Hellstrom-Lindberg … (2010)

In a phase III randomized trial, azacitidine significantly prolonged overall survival (OS) compared with conventional care regimens (CCRs) in patients with intermediate-2- and high-risk myelodysplastic syndromes. Approximately one third of these patients were classified as having acute myeloid leukemia (AML) under current WHO criteria. This analysis compared the effects of azacitidine versus CCR on OS in this subgroup. Patients were randomly assigned to receive subcutaneous azacitidine 75 mg/m(2)/d or CCR (best supportive care [BSC] only, low-dose cytarabine (LDAC), or intensive chemotherapy [IC]). Of the 113 elderly patients (median age, 70 years) randomly assigned to receive azacitidine (n = 55) or CCR (n = 58; 47% BSC, 34% LDAC, 19% IC), 86% were considered unfit for IC. At a median follow-up of 20.1 months, median OS for azacitidine-treated patients was 24.5 months compared with 16.0 months for CCR-treated patients (hazard ratio = 0.47; 95% CI, 0.28 to 0.79; P = .005), and 2-year OS rates were 50% and 16%, respectively (P = .001). Two-year OS rates were higher with azacitidine versus CCR in patients considered unfit for IC (P = .0003). Azacitidine was associated with fewer total days in hospital (P < .0001) than CCR. In older adult patients with low marrow blast count (20% to 30%) WHO-defined AML, azacitidine significantly prolongs OS and significantly improves several patient morbidity measures compared with CCR.