by Zhenya Senyak
The Interferon Papers
Part III. Interferon and the treatment of polycythemia vera, essential thrombocythemia and myelofibrosis
The final word on interferon and MPN treatment comes from the three men who share the deepest clinical experience in applying a molecule derived from the cell’s own defenses to roll back the effects of myeloproliferative neoplasms. The thrust of the opening abstract is direct: Interferon works.
“(Interferon) induces complete hematologic remissions in patients with myeloproliferative neoplasms…” Stressing the importance of low dose IFN started relatively early in the course of MPNs, the promise of interferon in PV is “significant clinical, hematologic, morphologic and molecular response, this last demonstrated by reduction of the JAK2 allele burden. The changes are durable, lasting long after discontinuation of treatment. In ET platelet counts drop rapidly and in primary MF interferon “has restored normal blood counts, reduced splenomegaly and induced morphologic marrow remissions.”
The scientific paper itself, “Interferon and the treatment of polycythemia vera, essential thrombocythemia and myelofibrosis,” (Expert-Reviews – Hematology [2013) by Richard Silver (Weill-Cornell), Jean-Jacques Kiladjian( Hopital Saint-Louis, Centre d’Investigations Cliniques, Paris) and Hans Carl Hasselbalch (Roskilde Hospital, University of Copenhagen, Denmark) is a comprehensive summary of interferon treatment in MPN and includes specific dosing recommendations and detailed notes to source material for the curious and skeptical.
Opening with a description of the interferons, the authors describe the various forms of Type I interferon — recombinant IFN (Intron) the dominant IFN until the advent of pegylated IFNs which are universally used in Europe. They compare the two types of pegylated recombinant IFN — PegIntron and Pegasys and conclude Pegasys “…once weekly, compared with [Peg Intron] once daily, results in fewer side effects, higher rates of hematologic and cytogenetic response and greater overall survival in patients with CML. ” (Data is not yet available for comparisons in MPNs).
The value of this paper for the patient and the health care provider, beyond summarizing applicable MPN interferon research, is in its coverage of specific MPNs and their treatment.
Polycythemia vera
After taking issue with the World Health Organization’s classification of PV based on hemoglobin levels versus red blood cell count, the authors make a case for the importance of correct diagnosis in PV treatment. Their retrospective summary of 25 years of research covers about 400 patients in nearly 20 trials using IFN. Here’s the result: “Complete hematologic response is usually observed within one year but sometimes phlebotomies are required for up to two years depending on the dose and severity of illness. Reduction of phlebotomy rates have ranged from 47 to 100% in 12 of 17 trials.
“[Interferon] relieves pruritus, rapidly normalizes elevated leukocyte and platelet counts in the large majority of patients and is accompanied by a reduction or eliminate of the need for phlebotomies. With longer treatment splenomegaly is reduced or eliminated and in some case marrow morphology can be normalized…accompanied by fibrosis regression.”
Mostly for convenience, the authors prefer Pegasys once-a-week dosing, 45µg x 1 subcutaneously or PegIntron at 30 µg once a week. They note a significant decrease in megakaryocyte number with use of pegylated recombinant interferon. And attribute “remarkable thrombosis-free survival rates to both the cytoreductive effect of interferon and their maintenance of 40-55% patient hematocrit levels. The authors believe the optimal target hematocrit should be 45% in men and 42% in women.
They recommend sequential bone marrow biopsies, once at diagnosis and every third to fifth year thereafter…unless there are changes in developing disease.
Phlebotomy only treatment is a clinical misconception according to the authors citing misreading of study data and the dangers of chronic iron deficiency resulting from repeated phlebotomies.
The severest criticism is leveled at all alkylating agents and HU owing to their leukemogenic potential. Admitting there is no strong clinical trial data proving HU is leukemogenic they point out, reasonably, that only long-term follow-up beyond 10 years can accurately gauge the risk. There was a long-term trial of another drug (pipobroman) in which there was an HU arm. The leukemic incidents in the HU arm was16.5% after 15 years and 24.2% after 20 years. There is no evidence that IFN is leukemogenic.
While the JAK2 mutation is not the cause of PV, virtually all PV patients are positive for the mutation. “Several studies,” say the authors “have indicated the PV mutant allele burden generally correlates with extent, duration and severity of disease.”
A major finding is the decrease in JAK2 allele burden in 70% of patients treated with Pegasys. The JAK2 mutation became undetectable in 24% of patients in one series. There are reports much higher rates of sustained and maintained response in 10 of 35 patients .
Treatment of ET with IFN
There are high risk ET patients: Those over 60, those with platelet counts over 1.5 million, and those with a history of thrombosis. Those without any of those factors are low risk and there’s an intermediate group that fits between those two. The authors find Pegasys to be effective in a young group (median age: 37 years) of 59 high risk ET patients with 76% achieving complete hematologic response.
Based on the risk of conversion to MF, the authors believe an argument can be made for early treatment of ET with IFN even in low risk groups. In ET Pegasys or PegIntron can be started at 45 and 30 micrograms /week and recombinant interferon alpha 2b (rIFN-α-2b) used at a starting dose of 500,000-1,000,000µg three times weekly, adjusting dosage based on need and toxicity.
Myelofibrosis
Interferon in any form is not an effective therapy in late-stage myelofibrosis characterized by substantial collagen fibrosis and osteosclerosis.
For this reason the authors favor intervention in early stage of MF. They report on a small study of 17 patients meeting WHO diagnostic criteria for low or intermediate MF. “Of the 17 patients treated, 14 showed complete remission. Of the 15 patients with splenomegaly, nine had complete resolution. The results are promising but need to be confirmed by large-scale, long-term study.
On side effects of IFN…
Although interferon naturally occurs in the human cell and recombinant production versions are not cytotoxic, doses of therapeutic IFNare orders of magnitude higher than that naturally produced in response the presence of antigens.
Approximately 10-20% of patients suffer adverse reactions from IFN therapy. As Richard Silver has pointed out elsewhere, most ill effects appear to be dose related. (Initial MPN dosing schedules were based on treatment of CML.) In any event, certain conditions preclude treatment with interferon: depression, central nervous system disease, peripheral neuropathy, thyroid dysfunction, autoimmune disease and certain significant abnormalities of the heart, kidneys, and liver.
Concluding, the authors “believe that rIFN should be the initial treatment in patients with de novo PV, especially in PV with myelofibrosis and rIFN should be considered a first-line treatment in patients with ET.
Both because of favorable clinical, hematologic, morphologic and molecular response and the durability of effect permitting discontinuation of treatment the authors believe recombinant interferon may be the drug of choice of the MPNs.
The bottom line: Early treatment of MPNs with low-dose pegylated recombinant interferon may result in improved disease free longevity.
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© Zhenya Senyak and MPNforum.com, 2013. Unauthorized use and/or duplication of this material without express and written permission from this blog’s author and/or owner is strictly prohibited. Excerpts and links may be used, provided that full and clear credit is given to Zhenya Senyak and MPNforum.com with appropriate and specific direction to the original content.
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