Minimal Residual Disease and Normalization of the Bone Marrow after Long-Term Treatment with Alpha-Interferon2b in Polycythemia Vera. A Report on Seven Patients in Sustained Complete Hematological Remission with Major Molecular Responses.

Background : Polycythemia vera (PV) is a clonal myeloproliferative disorder characterized by the presence of the JAK2V617 mutation in virtually all patients. Recently several studies have shown that the JAK2V617F mutational load decreases during treatment with alpha-interferon2 (1–6).

Aim: To report on molecular and histomorphological bone marrow responses in seven PV patients with complete molecular remissions during and after long-term treatment with alpha-interferon 2b.

Patients: Seven patients treated with alpha-interferon2b for a median of 84 months (range 31–120) are reported. In four of the patients alpha-interferon2b was started at the time of diagnosis and in three patients 9, 36 and 42 months from the time of diagnosis, respectively.

Methods: The mutation was determined by allele specific PCR (n=2 only) (7) and quantitative PCR (qPCR) (n=5) (8). In three out of these patients qPCR JAK2V617F was performed on archived bone marrow from diagnosis (2 patients) and on peripheral blood (one patient) prior to treatment with alpha-interferon2b. A complete molecular remission (CMoR) was defined by less than 2 % JAK2 V617F mutated alleles (7).

Results: Molecular Responses. All patients obtained a CMoR after a median of 84 months (29–120 months) of treatment with alpha-interferon2b. Subsequently all patients have discontinued alpha-interferon with a follow-up period of median 10 months (range 4–30 months) and sustained complete hematological remission. Furthermore, in three patients molecular responses have recently been updated – April and May 2008 - showing CMoRs in all (1,2 %, 0,9 % 0,1 % mutated alleles, respectively).

Bone Marrow Responses. Follow-up bone marrow biopsies were available in five patients. Complete normalization of the bone marrow was seen in three patients after treatment with alpha-interferon2b for 84, 132 and 132 months, respectively. In the bone marrow from the patient being treated with alpha-interferon for 132 months a qPCR JAK2V617 analysis was performed detecting the mutation at a very low level (0,5 % mutated alleles). In two other patients, being treated with alpha-interferon2b for 24 and 120 months, respectively, and having obtained a CmoR in peripheral blood the bone marrow histomorphology showed marked regression of PV-features but in both patients still with focal areas displaying an increased number of morphologically abnormal megakaryocytes. Updated histomorphological and molecular response patterns will be presented.

Discussion and Conclusion : Previous studies on the molecular response during alpha-interferon2a treatment have shown that a substantial proportion of patients achieve a significant molecular response after 12 months with a continuous decrease in the JAK2V617F mutation load at 24 and 36 months (1,5,6). This report confirms and extends preliminary data, showing that long-term treatment with alpha-interferon 2b in a subgroup of PV-patients is able to induce complete molecular remissions with normalization of the bone marrow morphology, which may even be sustained after discontinuation of alpha-interferon2b for up to 20 months (5). Prolonged treatment for several years seems necessary to induce such sustained responses, since treatment for only a few months has been reported to be followed by rapid recurrence of clonal hematopoiesis (9). In conclusion, a state of “minimal residual disease” may be achieved in PV by long-term immune therapy using alpha-interferon 2. Our observations call for large prospective clinical studies in which treatment with alpha-interferon is initiated up-front in patients with JAK2-positive PV and allied diseases. These studies should also aim at exploring the minimal dose of alpha-interferon needed to elicit complete molecular responses in order to minimize side effects of the drug and accordingly diminish the high drop-out rates reported in most previous studies.