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Ruxolitinib superior to standard therapy for polycythemia vera
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Patients with polycythemia vera who were resistant to or intolerant of hydroxyurea therapy demonstrated better controlled hematocrit levels, reduced spleen volume and improved symptoms when they received ruxolitinib compared with standard therapy, according to study results.
“Polycythemia vera is a disease of the blood and bone marrow that results in too many blood cells, particularly red blood cells, that lead to an increased risk of thrombosis,” Srdan Verstovsek, MD, PhD, professor in the department of leukemia at The University of Texas MD Anderson Cancer Center and a HemOnc Today Editorial Board member, told HemOnc Today. “In addition to phlebotomy and aspirin, a majority of patients require cytoreductive therapy to control blood cell count and signs and symptoms of the disease, and hydroxyurea is the standard first medication to use. Up to 20% to 25% of patients do not do well on hydroxyurea, are resistant to or intolerant of it or lose response over time, and alternative therapeutic options are limited.”
Srdan Verstovsek
Verstovsek and colleagues sought to confirm the benefits of ruxolitinib (Jakafi, Incyte) — a JAK 1 and JAK 2 inhibitor — that were observed in a phase 2 study of patients with polycythemia vera.
The current analysis included 222 phlebotomy-dependent patients who had an inadequate response to or experienced unacceptable side effects with hydroxyurea.
Researchers assigned 110 patients to receive ruxolitinib at a starting dose of 10 mg twice daily. The other 112 patients received standard therapy selected by the investigator. Most of these patients received a lower dose of hydroxyurea to reduce side effects (58.9%), whereas 11.6% received interferon, 7.1% received anagrelide, 4.5% received immunomodulators and 1.8% received pipobroman (Vercyte, Abbott).
Hematocrit control through week 32 with at least a 35% reduction in spleen volume at week 32 served as the composite primary endpoint.
Median exposure to therapy was 81 weeks in the ruxolitinib arm and 34 weeks in the standard-therapy arm.
Significantly more patients in the ruxolitinib arm achieved the composite primary endpoint (20.9% vs. 0.9%; P˂.001).
Ruxolitinib was associated with a higher rate of hematocrit control through week 32 (60% vs. 19.6%), as well as a higher rate of patients who achieved at least a 35% reduction in spleen volume from baseline at week 32 (38.2% vs. 0.9%). Researchers also observed a significantly higher rate of complete hematologic response in the ruxolitinib arm (23.6% vs. 8.9%; P=.003).
More patients assigned ruxolitinib maintained their primary response at week 32 through week 48 (19.1% vs. 0.9%; P˂.001). Researchers calculated a 94% probability that a primary response to ruxolitinib would be maintained for 1 year.
Researchers used the Myeloproliferative Neoplasm Symptom Assessment Form to evaluate symptoms outcomes. Forty-nine percent of patients assigned ruxolitinib achieved at least a 50% reduction in their total symptom score at week 32, compared with 5% of patients on the standard-therapy arm.
More patients assigned ruxolitinib experienced grade 3 to grade 4 anemia (2% vs. 0%) and thrombocytopenia (5% vs. 4%). Grade 1 and grade 2 herpes zoster infection occurred in 6% of patients on the ruxolitinib arm vs. no patients in the standard-therapy arm.
Thromboembolic events at week 32 were more common in the standard-therapy arm (6 cases vs. 1 case).
“In this group of patients, ruxolitinib was shown to be significantly more effective than standard therapies in controlling hematocrit and eliminating a need for phlebotomy, reducing enlarged spleen, normalizing blood cell count overall and improving polycythemia vera-related symptoms,” Verstovsek said. “At the same time, ruxolitinib was well tolerated. With approval of ruxolitinib for polycythemia vera patients who were intolerant of or refractory to hydroxyurea, we have addressed the unmet need in this disease management.” – by Alexandra Todak
Srdan Verstovsek, MD, PhD, can be reached at The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030.
Disclosure: The study was funded by Incyte and Novartis. See the study for a list of the researchers’ relevant financial disclosures.
Perspective
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Jerry L. Spivak, MD
The JAK1/2 inhibitor ruxolitinib has proved to be safe and effective for the treatment of high-grade primary myelofibrosis — as well as the myelofibrosis-complicating polycythemia vera and essential thrombocytosis — with alleviation of symptoms, a reduction in spleen size, and the additional unexpected benefit of an increase in survival in a patient population for which there are few effective therapies.Vannucchi and colleagues now report on a phase 3, randomized, open-label trial that compared ruxolitinib in patients with polycythemia vera who were unresponsive to or intolerant of hydroxyurea to a control arm of patients on “standard therapy.” Crossover was allowed at 32 weeks. The randomization was excellent with respect to comparability, including prior exposure to hydroxyurea and its ineffectiveness. The study design was essentially a referendum on hydroxyurea and difficult to understand given that the FDA had already placed a black box warning on the drug, classifying it as mutagenic and clastogenic, meaning that it causes mutations while causing chromosomal breakage, amplifications, deletions and rearrangements in a blood disorder known to do this spontaneously.
I don’t know what they were thinking either but, in all fairness to the FDA, it is not clear how hydroxyurea came to be a standard of care in polycythemia vera before they became involved, since it is not an anticoagulant, does not prolong survival and — judging from the patient characteristics in this study — failed to control the hematocrit, splenomegaly or even the leukocyte count, not that the latter needs control in most patients with polycythemia vera.
Suffice to say, ruxolitinib won hands down in all categories — symptom relief, hematocrit control and spleen size reduction — with an acceptable side-effect profile except for an increased incidence of mild herpes zoster infections. It is unclear If these were de novo or recrudescent, with or without Zostavax (Zoster Vaccine Live, Merck). Skin cancer occurred in both treatment groups because hydroxyurea is a skin cancer promoter for UV radiation. The response to ruxolitinib was durable. Only 15% of patients discontinued the drug compared with 96% of those in the “standard therapy” arm.
This study demonstrates unequivocally that we now have a safe drug to control pruritus and splenomegaly in chronic-phase polycythemia vera. It is not better than phlebotomy for hematocrit control but, judging from the hematocrits of 50% in some of these patients, phlebotomy is not being employed adequately, either. Hydroxyurea should be put back on the shelf where it belongs, but we should also not attempt to control the proliferation of normal leukocytes and platelets in asymptomatic patients with polycythemia vera with a different — albeit safer — drug until it is proved that this is clinically meaningful behavior.
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