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

Abstract

Background: Ruxolitinib 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.

Methods: Patients 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).

Results: Forty-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.

Conclusions: A dose-escalation approach may mitigate worsening anemia during early ruxolitinib therapy in some patients with myelofibrosis.

Trial registration: ClinicalTrials.gov identifier, NCT01445769 . Registered September 23, 2011.

Keywords: Anemia; Janus kinase; Myelofibrosis; Ruxolitinib; Thrombocytopenia; Transfusion.

Conflict of interest statement

Ethics approval and consent to participate

This study was conducted in accordance with the study protocol, Good Clinical Practice (GCP), as defined in Title 21 of the US Code of Federal Regulations Parts 50, 54, 56, 312, and Part 11, and the International Conference on Harmonisation GCP consolidated guidelines (E6: Guideline for Good Clinical Practice) and applicable regulatory requirements. All aspects of the ethics review were conducted in accordance with the Declaration of Helsinki or local laws, whichever provided the greater level of protection for patients. The protocol and all amendments were reviewed and approved by qualified independent review boards (IRBs), including Quorum Review IRB, Avera IRB, University of Michigan IRB, Georgia Health Sciences University Human Assurance Committee, Human Research Protection Office at the University of Maryland School of Medicine, Western IRB, Emory University IRB, and Cleveland Clinic IRB, before enrollment of patients in the study at each site. Informed consent was obtained from each patient in writing before any protocol-specific screening tests were performed.

Consent for publication

Not applicable

Competing interests

MT has participated as an investigator in clinical trials funded by Incyte Corporation, NS Pharma, CTI BioPharma, and Gilead. SE-V and KH are employees and stockholders of Incyte Corporation. SH is a member of the speaker’s bureau for Incyte Corporation. MRB has participated as an investigator in clinical trials funded by Incyte Corporation.

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Figures

Fig. 1

Mean percentage change in spleen volume from baseline to week 24. Includes patients from the intent-to-treat population with data at week 24. *The average daily dose during the 28 days before the spleen volume assessment (inclusive) at week 24

Fig. 2

Maximum change in a spleen volume and b palpable spleen length from baseline to week 24. Includes patients from the intent-to-treat population (n = 40). Each bar represents an individual patient

Fig. 3

Median percentage change in MFSAF TSS from baseline to week 24. Includes patients from the intent-to-treat population with data at week 24. MFSAF TSS, Myelofibrosis Symptom Assessment Form Total Symptom Score. *The average daily dose during the 28 days before the spleen volume assessment (inclusive) at week 24

Fig. 4

Hematologic parameters: a median hemoglobin levels, b platelet counts, and c ANCs over time. Includes patients from the safety-evaluable population. Error bars represent 25th and 75th percentiles. Dotted lines represent the median value at baseline. ANC, absolute neutrophil count; BL, baseline