Overcoming treatment challenges in myelofibrosis and polycythemia vera: the role of ruxolitinib.

Jeffrey C Bryan,Srdan Verstovsek

doi:10.1007/s00280-016-3012-z

Jeffrey C Bryan, Srdan Verstovsek

Open Access

https://doi.org/10.1007/s00280-016-3012-z

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Abstract

Myelofibrosis (MF) and polycythemia vera (PV) are BCR-ABL1-negative myeloproliferative neoplasms associated with somatic hematopoietic stem cell mutations leading to over activation of JAK–STAT signaling. MF and PV are pathogenically related and share specific clinical features such as splenomegaly and constitutional symptoms. The MF phenotype is dominated by the effects of progressive bone marrow fibrosis resulting in shortened survival. In contrast, elevated thrombosis risk due to erythrocytosis is the primary clinical concern in PV. Ruxolitinib, an oral JAK1/JAK2 inhibitor, is approved in the USA for the treatment of patients with intermediate- or high-risk MF and patients with PV who have had an inadequate response to or are intolerant of hydroxyurea. For MF, results of two phase III studies demonstrated that ruxolitinib therapy reduced spleen volume and MF-related symptom burden, improved quality-of-life measures, and was associated with prolonged overall survival. Treatment benefits were generally sustained with continued therapy. Dose-dependent cytopenias were common but generally manageable with transfusions (for anemia), dose reduction, or treatment interruption. Optimal dosing management is critical to maintain long-term treatment benefit, because cessation of therapy resulted in rapid return of symptoms to baseline levels. Results of the phase III PV trial showed that ruxolitinib was significantly more effective than standard therapy in controlling hematocrit levels and improving splenomegaly and PV-related symptoms. Only 1 of 110 patients in the ruxolitinib arm compared with 6 of 112 patients in the control arm experienced a thromboembolic event through week 32. Grade ≥3 cytopenias were uncommon.

Highlights

Philadelphia chromosome–negative myeloproliferative neoplasms (MPNs), including myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET), are genetically related, but heterogeneous chronic diseases characterized by overactive signaling through the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway as the central pathogenic mechanism [1,2,3,4,5]
Deletion of STAT3 in mutant clones has been shown to be insufficient to suppress inflammatory signaling [17]. This finding supports the importance of inhibiting JAK–STAT signaling in nonmalignant cells to mitigate inflammation-related symptoms and would explain the effectiveness of ruxolitinib in providing rapid symptom mitigation without clinically significant reduction in mutant allele burden
An ad hoc comparison of COMFORT-II data with those from a historical control group determined that patients with primary myelofibrosis (PMF) receiving ruxolitinib had longer overall survival from the time of diagnosis than patients receiving conventional therapy [median survival 5 vs 3.5 years; hazard ratio 0.61 (0.41–0.91), P = 0.0148], suggesting that ruxolitinib may modify the natural history of PMF [76]

Summary

Introduction

Philadelphia chromosome–negative myeloproliferative neoplasms (MPNs), including myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET), are genetically related, but heterogeneous chronic diseases characterized by overactive signaling through the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway as the central pathogenic mechanism [1,2,3,4,5]. The general prolongation of survival observed with ruxolitinib versus placebo or BAT in the COMFORT trials may be the result of overall improvement in patients’ health status, including the reduction of cachexia (unwanted weight loss) and other constitutional symptoms, which are known prognostic factors in MF [32].

Results

Conclusion