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

Abstract

Background: Ruxolitinib, 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.

Methods: Ruxolitinib 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.

Results: By 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.

Conclusions: Results 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 registration: ClinicalTrials.gov NCT01348490.

Figures

Figure 1

Distribution of ruxolitinib daily dose over the 24-week study period. N values represent patients with available dose information at the time of data analysis. Data shown for each time point represent the dose (in milligrams) that patients were receiving during the previous 4 weeks. BID, twice daily; QD, once daily.

Figure 2

Efficacy results at 24 weeks. (A) Percentage change from baseline in spleen volume for individual patients at week 24. (B) Median percentage change from baseline in spleen length over time. (C) Percentage change from baseline in TSS in individual patients at week 24. (D) Median percentage change in TSS over time. Median dose is shown for patients with available dosing information. TDD, total daily dose; TSS, Total Symptom Score.

Figure 3

Mean change from baseline to week 24 in quality of life, functional domains, and symptoms assessed by the EORTC QLQ-C30.Note: n = 32 for all scales except the Role Functioning and Cognitive Functioning domain, in which n = 31. EORTC QLQ-C30, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30; QoL, quality of life; SEM, standard error of the mean.

Figure 4

Changes in hematologic parameters. (A) Mean (SEM) platelet counts over time. (B) Changes in individual platelet counts from baseline to nadir (left panel) and baseline to week 24 (right panel). (C) Mean (SEM) hemoglobin levels over time in patients who did not receive red blood cell transfusions during the study. SEM, standard error of mean; TDD, total daily dose.