Evaluation of an alternative ruxolitinib dosing regimen in patients with myelofibrosis: an open-label phase 2 study

Abstract

BackgroundRuxolitinib improves splenomegaly and symptoms in patients with intermediate-2 or high-risk myelofibrosis; however, nearly half develop grade 3/4 anemia and/or thrombocytopenia, necessitating dose reductions and/or transfusions. We report findings from an open-label phase 2 study exploring a dose-escalation strategy aimed at preserving clinical benefit while reducing hematological adverse events early in ruxolitinib treatment.MethodsPatients with myelofibrosis received ruxolitinib 10 mg twice daily (BID), with incremental increases of 5 mg BID at weeks 12 and 18 for lack of efficacy (maximum, 20 mg BID). Symptom severity was measured using the Myelofibrosis Symptom Assessment Form Total Symptom Score (MFSAF TSS).ResultsForty-five patients were enrolled, 68.9% of whom had a Dynamic International Prognostic Scoring System score of 1 to 2 (i.e., intermediate-1 disease risk). Median percentage change in spleen volume from baseline to week 24 was − 17.3% (≥ 10% reduction achieved by 26 patients [57.8%]), with a clear dose response. Median percentage change in MFSAF TSS from baseline at week 24 was − 45.6%, also with a dose response. The most frequent treatment-emergent adverse events were anemia (26.7%), fatigue (22.2%), and arthralgias (20.0%). Grade 3/4 anemia (20.0%) and dose decreases due to anemia (11.1%) or thrombocytopenia (6.7%) were infrequent.ConclusionsA dose-escalation approach may mitigate worsening anemia during early ruxolitinib therapy in some patients with myelofibrosis.Trial registrationClinicalTrials.gov identifier, NCT01445769. Registered September 23, 2011.

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“…Ruxolitinib, a JAKitinib that inhibits the active kinase domain of JAK2 (and other JAKs), was approved for the treatment of myeloproliferative disorders in 2011. However, many patients treated with ruxolitinib lose or have a suboptimal response to this drug, or develop cytopenia during treatment, resulting in ruxolitinib being discontinued within months 170 , 171 . Indeed, in a couple of phase III trials, discontinuation rates for ruxolitinib at 3 and 5 years were 50% and 70%, respectively.…”

Fedratinib, a newly approved treatment for patients with myeloproliferative neoplasm-associated myelofibrosis

“…Evidence suggests there may be a survival benefit with ruxolitinib compared with conventional therapies [ 30 , 31 ]. However, many patients treated with ruxolitinib lose response, have a suboptimal response, or develop cytopenias during treatment, resulting in ruxolitinib discontinuation within a few months and subsequent risk of disease rebound [ 32 , 33 ]. In the phase III COMFORT-I and COMFORT-II trials, pooled ruxolitinib discontinuation rates at 3 and 5 years were ~50% and ~70%, respectively [ 30 , 31 ].…”

“…In the phase III COMFORT-I and COMFORT-II trials, pooled ruxolitinib discontinuation rates at 3 and 5 years were ~50% and ~70%, respectively [ 30 , 31 ]. Suboptimal ruxolitinib dosing to avoid treatment-related adverse events (AEs), at least initially [ 33 ], appears to be relatively common [ 32 ].…”

Targeted therapies for myeloproliferative neoplasms

“…In particular, treatment for patients with MF and extensive splenomegaly and symptomatic burden has been significantly improved following the introduction of the ruxolitinib. However, ruxolitinib for MPNs is still largely inadequate to cope with significant challenges including reduction of mutated allele burden, reversion of fibrosis, normalization of life span and prevention of hematological progression [56]. Recently, some clinical trials of novel type I JAK inhibitors showed equal, even better effect of reduction in splenomegaly and transfusion and improvement in symptomatic burden and these results really shed light on treatment options for ruxolitinib-resistant or ruxolitinib-intolerant MPN patients.…”