Management of polycythemia vera in the community oncology setting
Patients with the chronic myeloproliferative neoplasm polycythemia vera have shortened survival and often experience disease-related symptoms that negatively affect quality of life. Consequently, there is a demonstrable need for early diagnosis of polycythemia vera, followed by long-term, responsive, evidence-based disease management. The diagnostic and management landscape for polycythemia vera continues to improve, but gaps remain in diagnostic and treatment strategies. The diagnosis of polycythemia vera is based on World Health Organization criteria, and treatment goals for the condition include modifying the risk of cardiovascular and hemorrhagic events, reducing the risk of fibrotic and/or leukemic disease transformation, and alleviating polycythemia vera–related symptoms. The current treatment strategy for polycythemia vera is for all patients to receive aspirin and phlebotomy, with a hematocrit goal of <45%. Some patients may also benefit from cytoreductive therapy, typically with hydroxyurea. For those patients who become resistant to or intolerant of hydroxyurea, ruxolitinib is currently the only approved treatment option. This review provides community-based oncologists and other clinicians with an overview of current diagnostic and management strategies for polycythemia vera.
Accepted for publication April 28, 2017
Correspondence Michael R Grunwald, MD;
michael.grunwald@carolinashealthcare.org
Disclosures Dr Grunwald has served as a consultant, participated in advisory boards, and received research funding from Incyte Corp, the maker of ruxolitinib, a treatment option for polycythemia vera. Dr Scola has served on a speakers bureau for and is a stockholder of Incyte Corp. Dr Miller has served on advisory boards and speakers bureaus for, and received institutional research funding from, Incyte Corp and Novartis. Dr Onitilo has no conflicts to disclose. The authors received writing assistance from Complete Healthcare Communications, LLC, which was funded by Incyte Corp.
Citation JCSO 2017;15(4):e195-e203
©2017 Frontline Medical Communications
doi https://doi.org/10.12788/jcso.0349
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Allogenic transplantation. Although allogeneic transplantation is a potentially curative treatment option, it has been reserved primarily for younger patients with MPNs (age <60 years31). Furthermore, a recent systematic review concluded that overall survival was worse following allogeneic transplantation compared with a nontransplant approach (ie, phlebotomy and aspirin).48
Ruxolitinib. The oral JAK1/JAK2 inhibitor ruxolitinib has been approved by the US Food and Drug Administration (FDA) for the treatment of patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea,8 and by the European Medicines Agency (EMA) for adult patients with polycythemia vera who are resistant to or intolerant of hydroxyurea.9 Ruxolitinib is also approved by the FDA for patients with intermediate- or high-risk MF, including primary MF, post-polycythemia vera MF, and post-essential thrombocythemia MF,8 and for similar patient populations by the EMA.9
Approval of ruxolitinib for the treatment of patients with polycythemia vera was based on the phase 3 randomized, open-label, multicenter RESPONSE trial in which 222 patients with polycythemia vera who met the modified ELN criteria for hydroxyurea resistance or intolerance (Table)16,31 were randomized to ruxolitinib or best available therapy (BAT). Compared with BAT, a greater proportion of patients treated with ruxolitinib achieved the primary composite endpoint of hematocrit control without the need for phlebotomy and ≥35% reduction in spleen volume by week 32 (22.7% vs 0.9%; P < .001).16,49 When looked at individually, hematocrit control and reduction in spleen size favored ruxolitinib over BAT (hematocrit control, 60.0% vs 18.8%, ruxolitinib and BAT, respectively; ≥35% reduction in spleen volume, 40.0% vs 0.9%). Furthermore, more patients receiving ruxolitinib achieved the key secondary endpoint of complete hematologic remission than did those receiving BAT (ie, normalization of blood counts; 23.6% vs 8.0%; P = .0016).16,49 Of note is that most patients who achieved primary treatment responses maintained disease control for ≥80 weeks.49
Results from RESPONSE indicate that ruxolitinib may substantially improve polycythemia vera–related symptoms. Treatment with ruxolitinib was associated with a greater improvement in nearly all symptoms evaluated by the MPN-SAF as well as greater improvements in QoL and functional measures with the EORTC QLQ-C30 trial metric compared with BAT (Figure 1).16 In addition, a post hoc exploratory analysis of RESPONSE indicated that patients receiving ruxolitinib showed a rapid normalization of abnormal iron indices at baseline, compared with those receiving BAT.50
Treatment safety and tolerability are particularly important considerations for patients with polycythemia vera, given the long natural history of the disease. In a preplanned analysis of RESPONSE at 80 weeks, 83% of patients randomized to receive treatment with ruxolitinib remained on treatment (median exposure, 111 weeks).49 Most adverse events reported in both treatment arms were grade 1/2.16,49 The most frequent nonhematologic adverse events (per 100 patient-years of exposure) in the ruxolitinib arm were headache (10.5%), diarrhea (9.7%), pruritus (9.7%), and fatigue (8.3%). The most common grade 3/4 nonhematologic adverse events (occurring at a rate of ≥0.9 per 100 patient-years of exposure) were limited to dyspnea (1.3%), abdominal pain (0.9%), headache (0.9%), and herpes zoster (0.9%).49 Hematologic adverse event rates in the ruxolitinib and BAT arms included anemia (any grade, 27.2% vs 47.6%, respectively; grade 3/4, 0.9% vs 0%), lymphopenia (27.2% vs 78.8%; 9.7% vs 27.2%), and thrombocytopenia (14.9% vs 29.9%; 2.6% vs 5.4%).49 Herpes zoster infections occurred more frequently in the ruxolitinib arm (any grade, 5.3%; grade 3/4, 0.9%) compared with the BAT arm (no herpes zoster events).49 There was a higher rate of nonmelanoma skin cancer (NMSC) in the ruxolitinib arm (4.4%), compared with the BAT arm (2.7%),49 most of which occurred in patients with a history of NMSC or precancerous skin lesions.16 Grade 1 or 2 elevations in serum lipids and cholesterol were observed with ruxolitinib but not BAT; however, subsequent effects on patient outcomes have not been determined.8,16 The rates of MF and AML transformations were 1.3% and 0.4%, respectively, in patients randomized to receive ruxolitinib,49 similar to previously published reports for patients with polycythemia vera.44
Additional insight regarding the effect of ruxolitinib on polycythemia vera–related symptoms is available from the RELIEF trial, a randomized, multicenter, double-blind, double-dummy, phase 3b clinical trial. In RELIEF, 110 patients were randomized to receive ruxolitinib or a stable dose of hydroxyurea and were then asked to record disease-related symptoms.51 Although the study failed to meet its primary endpoint (a ≥50% improvement by week 16 in MPN-SAF total symptom score for the cytokine symptom cluster [sum of individual scores for tiredness, itching, muscle aches, night sweats, and sweats while awake]), a numerically greater proportion of patients receiving ruxolitinib achieved the primary endpoint compared with those receiving hydroxyurea (43.4% and 29.6%, respectively; P = .139; odds ratio, 1.82; 95% confidence interval, 0.82-4.04). Similarly, the proportion of patients reporting a ≥50% improvement in pruritus and fatigue favored ruxolitinib over hydroxyurea (itching, 40.0% vs 26.4%; tiredness, 54.2% vs 32.0%). The safety profile for ruxolitinib was similar to that reported in the RESPONSE trial.
