Interim analysis of safety and efficacy of ruxolitinib in patients with myelofibrosis and low platelet counts

Abstract

BackgroundRuxolitinib, a Janus kinase 1 and 2 inhibitor, demonstrated improvements in spleen volume, symptoms, and survival over placebo and best available therapy in intermediate-2 or high-risk myelofibrosis patients with baseline platelet counts ≥100 × 109/L in phase III studies. The most common adverse events were dose-dependent anemia and thrombocytopenia, which were anticipated because thrombopoietin and erythropoietin signal through JAK2. These events were manageable, rarely leading to treatment discontinuation. Because approximately one-quarter of MF patients have platelet counts <100 × 109/L consequent to their disease, ruxolitinib was evaluated in this subset of patients using lower initial doses. Interim results of a phase II study of ruxolitinib in myelofibrosis patients with baseline platelet counts of 50-100 × 109/L are reported.MethodsRuxolitinib was initiated at a dose of 5 mg twice daily (BID), and doses could be increased by 5 mg once daily every 4 weeks to 10 mg BID if platelet counts remained adequate. Additional dosage increases required evidence of suboptimal efficacy. Assessments included measurement of spleen volume by MRI, MF symptoms by MF Symptom Assessment Form v2.0 Total Symptom Score [TSS]), Patient Global Impression of Change (PGIC); EORTC QLQ-C30, and safety/tolerability.ResultsBy week 24, 62% of patients achieved stable doses ≥10 mg BID. Median reductions in spleen volume and TSS were 24.2% and 43.8%, respectively. Thrombocytopenia necessitating dose reductions and dose interruptions occurred in 12 and 8 patients, respectively, and occurred mainly in patients with baseline platelet counts ≤75 × 109/L. Seven patients experienced platelet count increases ≥15 × 109/L. Mean hemoglobin levels remained stable over the treatment period. Two patients discontinued for adverse events: 1 for grade 4 retroperitoneal hemorrhage secondary to multiple and suspected pre-existing renal artery aneurysms and 1 for grade 4 thrombocytopenia.ConclusionsResults suggest that a low starting dose of ruxolitinib with escalation to 10 mg BID may be appropriate in myelofibrosis patients with low platelet counts.Trial registrationClinicalTrials.gov: NCT01348490.

The Impact of Jak1/Jak2 Inhibitor Ruxolitinib on the Spleen Size and Symptom Burden in Myeloproliferative Diseases.

“…28 The same logic shall be applied to thrombocytopenia. 29 We observed the positive impact of ruxolitinib on the spleen size and symptom burden in our cytopenic MPN patient group as well.…”

How I treat myelofibrosis

“…A recent study in patients with moderate thrombocytopenia (from 50 3 10 9 /L to 100 3 10 9 /L) has shown the feasibility of starting with 5 mg twice daily and then escalating to 10 mg (and occasionally to 15 mg) twice daily, without causing severe thrombocytopenia. 60 Treatment should be stopped if platelets fall below 50 3 10 9 /L. In case of renal or liver function impairment, I start with a dose of 10 mg twice daily.…”

Myelofibrosis patients in Belgium: disease characteristics

“…However, ruxolitinib is currently being tested in Phase Ib/II clinical trials in thrombocytopenic MF patients (platelet counts of 50 000-100 000/ml) with positive results (reduction in splenomegaly and constitutional symptoms). 44 In our survey, out of the total population with spleen size §5 cm under the costal margin and a platelet count above 50 000/ml, almost all patients (97%) were Intermediate to High risk (IPSS and DIPSS). Three quarters IPSS and half DIPSS patients were Int-2 and High risk, respectively.…”