Recombinant Interferon Alpha (rIFNα) May Retard Progression of Early Primary Myelofibrosis (PM) by Reducing Splenomegaly and by Changing Marrow Morphology.

Reports of the limited effect of JAK2 inhibitors in PM, and the limited survival experienced with stem cell transplantation, led us to examine our results of treating the earlier phases of primary myelofibrosis with rIFNα. The use of rIFNα in early PM is based upon its known effects on a related myloproliferative disease, polycythemia vera, which is also characterized by myelofibrosis and its effects on megakaryopoiesis. These include decreasing megakaryocyte density and size, inhibiting thrombopoietin-induced signaling, and reducing levels of platelet derived growth factor, which play a major role in the pathogenesis of myelofibrosis. We evaluated 59 patients with PM diagnosed with the usual hematologic, clinical and bone marrow criteria for consideration for rlFNα. Of these 59 patients, 46 were excluded because of advanced marrow fibro-osteosclerosis accompanied by grade 3 or 4 reticulin and collagen deposition and no residual foci of hematopoiesis. Spleen size was measured in centimeters below the left costal margin in the mid-clavicular line (MCL). Exclusion criteria also included the usual contraindications to rIFNα therapy. We now report results of this pilot study. Thirteen patients elected treatment. There were 11 women and 2 men with a median age of 56 years. The median duration of disease prior to treatment with rIFNα was 1 year. Before rIFNα, the median values for hematocrit, hemoglobin, and platelet count were 36%, 12 g/dL, and 268,000/uL, respectively. We started treatment with low-dose rIFNα-2b at 500,000 – 1,000,000 units thrice weekly. Two of the 13 patients had no splenomegaly at onset of rIFNα and remained unchanged during treatment. The spleen became non-palpable in 3 of 4 patients initially described as having slight splenomegaly, whereas 7 patients with moderate or marked splenomegaly had a more limited, but definite response. Bone marrow follow-up studies were possible in 9 of the 13 patients, in whom the median duration of rIFNα treatment was 3.0 years. Reduction in cellularity occurred 2.5 years, on average, after the start of interferon therapy in 4 patients. Of the 8 patients with reduction of splenomegaly, change in overall marrow cellularity could be evaluated in 5 patients and reduction in cellularity occurred in 4. Significantly improved megakaryocyte morphology, marrow architecture, and striking reduction of reticulin and collagen occurred in two. The fifth patient had no change in abnormal marrow morphology or cellularity, but nevertheless, experienced a reduction in spleen size from 10 cm to 1 cm. To date, a 25% reduction in JAK2^V617F allele burden was observed in one of 4 patients. This patient had stable disease, no history of splenomegaly, and no change in bone marrow morphology. rIFNα toxicitiy occurred in 6 of the 13 patients, which included mild depression, dry skin, cough, myalgia and asthenia; these did not require dose reduction. One patient developed hyperthyroidism and rIFNα was discontinued. Six patients experienced mild cytopenias during treatment, which was dose related in general. One of the 13 had a grade 1 decrease in white blood cell count, 1 had a grade 1 decrease in platelet count, and 4 had a 10% decrease in hematocrit value. In these cases, the dose of interferon was temporarily interrupted or reduced, as required. We conclude that interferon can cause reduction in marrow cellularity, and in splenomegaly in early phase disease, but not in advanced stages of disease. Improvement in marrow cellularity and megakaryocyte morphology usually, but not always, correlated with reduction in splenomegaly. Toxicity was acceptable. We believe the effect of interferon should be systematically determined in an expanded trial in early-phase disease with regular JAK2^V617F and marrow evaluations.