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Interferon- 2b: A New Treatment for Polycythemia Vera
- From the New York Hospital-Cornell Medical Center, New York, New York. Requests for Reprints: Richard T. Silver, MD, Section of Clinical Oncology Chemotherapy Research, New York Hospital-Cornell Medical Center, 525 East 68 Street, Box 581, New York, NY 10021. Acknowledgments: The author thanks Helen Zurawinsky, BS, for administrative assistance, Audrey Gutfriend, BS, RN, for patient care responsibilities, and Arthur Sawitsky, MD, and Ted P. Szatrowski, MD, PhD, for review of the manuscript. Grant Support: In part by grants from the United Leukemia Fund and Cancer Research and Treatment Fund, Inc. No funds for this study were requested or provided by Schering Corporation, the manufacturer of recombinant interferon- 2b (Intron-A). However, three patients have been supplied with Intron-A on a compassionate basis at my request.
Polycythemia vera is characterized by an increased red cell mass and thrombohemorrhagic complications. In general, treatment has consisted of phlebotomy to reduce the red cell mass. However, because treatment with phlebotomy only is associated with early, frequently fatal thrombosis or hemorrhage [1], myelosuppressive therapy is also used. Unfortunately, the agents used, chlorambucil and radioactive phosphorus, are leukemogenic [1].
Although hydroxyurea is used as an alternative drug, a potential for leukemia still exists [2], especially in patients who develop postpolycythemic myeloid metaplasia [3]. Despite conventional treatment, many patients experience night sweats and pruritus [4] and develop iron deficiency. The inexorable course of polycythemia vera includes progressive splenomegaly and myelofibrosis. For all these reasons, other treatments are required [1].
Recombinant interferon- has myelosuppressive activity [5, 6]. Platelet-derived growth factor, a product of megakaryocytes, initiates proliferation of fibroblasts that may be involved in the myelofibrosis of advanced polycythemia vera. Interferon- antagonizes the action of platelet-derived growth factor by inhibiting the activation of Go cells for G1 traverse- and S-phase entry [7]. Additionally, platelet-derived growth factor stimulates the proliferation of early and late erythroid progenitor cells [8]; interferon- inhibits erythroid progenitor growth in vitro [9]. Thus, a physiologic basis now exists for treating polycythemia vera with agents other than nonspecific marrow suppressive drugs and without the risk for leukemia. My previous report [10] documented preliminary beneficial results in five patients with polycythemia vera treated with recombinant interferon- 2b, but the maximum follow-up was only 34 months. This extends the follow-up period to 72 months and discusses six more patients.
Methods
During a 6-year study, 11 sequential patients with polycythemia vera who had initially been treated with phlebotomy only joined this recombinant interferon- 2b trial. The criteria used for diagnosis and clinical remission were those of the Polycythemia Vera Study Group [1]. Although the duration of disease differed, all patients had active disease as indicated by the need for therapeutic phlebotomy. For the 11 patients, the median number of phlebotomies per year was 4.5 (range, 2 to 18 phlebotomies).
The starting dose of recombinant interferon- 2b was 3.0 106 U/m2 body surface area administered subcutaneously three times a week. In four patients, one to five supplemental phlebotomies were necessary during the first 6 months to maintain the hematocrit at or below 0.45. In six patients the dose was escalated approximately 30% by gradually increasing the initial dose or its frequency in order to maintain the hematocrit at or below 0.45. Thereafter, patients received a maintenance dose that was determined by decreasing the maximum dose by 25% every 2 months until the smallest dose of recombinant interferon- 2b was found that maintained the hematocrit at or below 0.45.
Results
Laboratory variables at the start of recombinant interferon- 2b treatment and at the latest response are shown in Table 1. Nine patients had a palpable spleen at the start of treatment; it became nonpalpable in seven patients 1 year after beginning recombinant interferon- 2b therapy. The spleen size was only slightly reduced in patient 8, who had a previous portal vein thrombosis. The spleen in patient 9 was reduced in size by approximately 50% at the time of this analysis. In all patients, red blood cell microcytosis associated with iron deficiency disappeared as hemoglobin values and red blood cell mass came into balance. Slight leukopenia (leukocyte count 5.0 109/L) was noted in eight patients. The mean decrease in platelet counts was 411 109/L. The maintenance dose has been approximately 3.0 106 U/m2 three to five times weekly.
Annual bone marrow aspirations and biopsies have been done. Patients 1 and 2 (under treatment the longest) developed slightly hypocellular marrows. The other patients remain hypercellular with no clinically significant change compared with pretreatment marrow variables, even in those with complete regression of splenomegaly. No clinically significant change in marrow reticulin or serum erythropoietin levels has occurred in any patient. With the longest follow-up of 72 months and the median follow-up being more than 36 months, no thrombohemorrhagic events have occurred.
Nonhematologic effects of recombinant interferon- 2b, including asthenia, myalgia, and fever, occurred in all but one patient. These side effects gradually decreased and, after the first year of treatment, quality of life and performance status were excellent. No patient withdrew from treatment.
Discussion
These results indicate that red cell values can be controlled with recombinant interferon- 2b within 6 to 12 months, eliminating the need for phlebotomy. No thrombohemorrhagic events have occurred, in contrast to the 40% incidence of significant thrombotic complications in the phlebotomy group during the first 3 years of therapy reported by the Polycythemia Vera Study Group. Thrombocytosis and splenomegaly can be reversed. Thus, the degree of disease control in these patients is far better than that reported by the Polycythemia Vera Study Group with phlebotomy or chemotherapy or both [1]. The expected side effects of recombinant interferon- 2b were tolerable and could be alleviated during the first year of therapy. Thus, recombinant interferon- 2b may be an important new treatment. Because polycythemia vera is a disease of long duration, additional follow-up is required.
- Copyright 2004 by the American College of Physicians
