Interferon Alfa for Polycythemia Vera
DATE: 29 Jan 1997 TO: MPD-SUPPORT-L FROM: R. Freeburg SUBJECT: review of Silver's new article
INTERFERON ALFA: EFFECTS OF LONG-TERM TREATMENT FOR POLYCYTHEMIA VERA by Richard Silver, published in Seminars in Hematology, Vol.34, No. 1, 1997.
NEED: Silver begins with the problems of the "standard," existing treatments for PV - phlebotomy-only and hydroxyurea (HU). Here, and again later in the article, he emphasizes that PV, treated only by phlebotomy, progresses sooner to myelofibrosis. He uses the Najean data (which we have listed before) and states that "some form of myelosuppression, especially for younger patients, is mandatory." (This is consistent with the other current literature by Najean, Rain, Boivin, and - with respect to platelets- Messinezy.) The problems with HU (also introduced here and mentioned through out the article) include the potential for leukemia - chromosome abnormalities have been found in HU cell cultures and in 36% of patients treated with HU (one study). Other problems - failure to control the disease (platelets, hematocrit, splenomegaly), constitutional problems (pruritus, night sweats), and toxicity (thrombocytopenia/leukopenia, gastric symptoms, rash). Macrocytosis is also caused by HU (the BIG red blood cells). Silver notes later that previous PVSG "control of the disease" allowed for a hematocrit of up to 50% and permitted more than 6 phlebotomies per year. He states that this is no longer considered satisfactory (controlled).
DATA: The article includes the data on 28 patients treated with interferon (IFN) making it the largest and longest follow-up of PV patients treated with IFN. Sixteen of the patients have been followed for more than 6 years (as of the cut-off date of December, 1995). Prior treatment was phlebotomy-only (18 patients) or hydroxyurea (10 patients). It is noted with interest that 23% were under 40 years old. (I can't read all the graphs clearly on my faxed copy, but I guess that must mean 9 patients.) IFN dose was targeted to reach 3 mu/3 x's per wk (or sometimes 5 mu) and adjusted accordingly to keep hematocrit below 45% - an increase or decrease of 25% every 2 months. Although originally, 3 mu was the starting dose, later (to minimize side-effects), all patients were started with 1 mu/3 x's per wk and increased every 2 to 4 weeks by .5 mu until the target dose was reached. Median dose at the end of one year was 10.5 mu/week and at the end of the 2nd year was 7.5 mu/week. So by the end of the second year, most patients were taking LESS than 3 mu/3 x's per week.
CLINICAL RESULTS: Phlebotomy requirement before IFN was a median of 10/yr in the phleb-only group and 7/yr in the HU group. Although phlebotomies were still required in 16 patients during the first year (to keep hematocrit below 45%), only 2 patients required phlebotomies the second year. (!!!!) Platelet counts are also charted and again showed a significant response. Only one patient from phleb-only had a platelet count of 625,000 after two years, and the HU group also significantly decreased. Spleen size had also diminished by the end of the second year in all 13 patients who started with splenomegaly. (Even those patients with HUGE spleens - three had over 15 cm below left costal margin when starting.) Iron stores were replenished; hypochromic/microcytic anemia (that's the little red blood cells with little hemoglobin - meaning poor oxygen-carrying capacity - caused by phlebotomies) was corrected. Macrocytosis from HU also corrected. There were no thrombotic events.
SIDE EFFECTS: These were generally dose-related and, mainly, of the influenza variety. Thirteen patients reported nothing significant after six months; 15 continued to have some for another six months. Only two patients discontinued the IFN. One lady on IFN for six years was apparently persuaded by another hematologist to switch to HU (this is my drift, not the way Silver stated it) and another went off after developing a bilateral lower extremity neuritis. This did clear up and the 62 yr old woman went on HU plus phlebotomy. One thyroid problem was cleared up; any liver problems returned to normal with temporary cessation of the IFN. (.....Silver does not mention any problems with drug-induced autoimmune disease - unless the thyroid problem could be considered here. IFN-induced autoimmune disease is found in the literature and mentioned to us by Dr. Krieg - a lupus specialist - but, it is seldom severe and, apparently, reversible when it does occur. And, although called "maintenance dose" levels in at least one of the reports on CML, I'm not sure what that dose was.........) Silver notes, interestingly, that tolerance/toxicity are somewhat variable terms that can depend on the physician and patient's conviction about the merits of a treatment.
BONE MARROW: Although consistent chromosome abnormalities have not been noted in PV, IFN has given improvement in some instances. However, Silver's patients (other than 2 who remained in clinical remission after a year) needed continued IFN treatment, while bone marrow hypercellularity and reticulum (fiber) remained. Silver emphasizes that IFN in PV is "suppressive," not "curative."
UNIQUENESS OF IFN: Megakaryocytes (platelets) are believed to play a special role in the development of myelofibrosis in MPD. (......Remember the strong statements about this in the Messinezy article. We've also noted an interesting article about MPD developing in frequent blood donors and, in another article, it is noted that frequent blood donors have higher concentrations of megakaryocyte colony-forming progenitors. These are strictly my comments, not Silver's!!!.....) Silver notes that platelet-derived growth factor (PDGF) is involved in this fibrosis, along with other growth factors ((including transforming growth factor beta (TGF-beta)).
- IFN is known to antagonize (suppress) PDGF.
- IFN causes TGF-beta to return to normal levels.
- IFN is ANTIangiogenic. (Angiogenesis is the first step in the formation of new blood vessels. This is very important in the growth of malignancies. ) In addition, TGF-beta is a strong promoter of angiogenesis.
-IFN inhibits erythroid progenitors in vitro (test tube) and affects platelet maturation, etc. In some reports IFN had corrected biochemical abnormalities of platelets.
So IFN is the first drug offered as treatment for PV that actually may be able to alter the course of the disease. Silver calls it the "therapeutic evolution of the PVSG" in its search for PV treatment. (Since phlebotomy-only and hydroxyurea as PV treatments came FROM the PVSG in 1986 -this is VERY interesting as coming in the "last official publication of the PVSG.") Silver summarizes the reasons for using IFN in PV including abatement of constitutional symptoms (like pruritus), maintenance of hematocrit & platelets, avoidence of iron-deficient anemia (from phlebotomies) and macrocytosis (from HU). He also states the LACK OF MUTAGENICITY and PREVENTION OR DELAY OF POST-POLYCYTHEMIA MF if used EARLY in PV (emphasis is mine).
RECOMMENDATIONS: Silver concludes with his recommendations for the treatment of PV. It includes phlebotomy to keep hematocrit between 40 and 45% with strict attention to platelets. Interferon (IFN) gradually increasing from 1 mu/3 x's per wk to a target dose of 3 or 5 mu/3 x's per week which then may be modified to keep hematocrit below 45%. He says only occasional phlebotomies should be required after the second year on IFN. He does include aspirin - enteric-coated, 80 mg daily. For YOUNG patients who can not accept IFN, he considers anagrelide (for platelet control) with phlebotomies. For ELDERLY (over 70 years), he considers radioactive phosphorus (P32) or HU.