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Background: In vitro and clinical data suggest a therapeutic role for alpha2 interferon (IFN) in the treatment of the chronic myeloproliferative disorders. Accordingly, a multiinstitutional, Phase II trial of IFN in patients with agnogenic myeloid metaplasia (AMM), essential thrombocythemia (ET), and polycythemia rubra vera (PRV) in the spent phase was initiated. The objectives of this study were 1) to investigate the response rates that may be achieved with IFN in the treatment of patients with these disorders, 2) to estimate the durability of the responses, and 3) to assess the toxicities of IFN in these populations., Methods: Enrollment was limited to patients with AMM, ET, or PRV who already had developed 1) anemia or transfusion dependency, 2) thrombocytosis uncontrolled by standard therapy, 3) hemostatic complications, or 4) symptomatic splenomegaly. Initially, patients were started on IFN at a dose of 5 MU/m(2) per day as a subcutaneous injection. After the first 16 patients had been treated, the starting dose of IFN was reduced to 2 MU/m(2) per day because of unexpected toxicities., Results: IFN demonstrated different levels of efficacy and toxicity in each of the three diseases studied. The overall response rates achieved among the evaluable patients in each category were as follows: ET, 88.2% (n = 17 patients; 1 complete response and 14 partial responses); PRV, 41.7% (n = 12 patients; 1 complete response and 4 partial responses); and AMM, 3.2% (n = 31 patients; 0 complete responses and 1 partial response). Thrombocytosis and leukocytosis were controlled in nearly all patients, with reversal of splenomegaly and resorption of myelofibrosis achieved in fewer patients. The toxicities attributed to IFN differed notably among the three disease groups: patients who had AMM suffered systemic and neurologic toxicities more frequently than patients who had PRV or ET; whereas patients who had ET experienced a greater than expected incidence of hepatic abnormalities, most typically transient elevations of serum amino acid transaminase levels., Conclusions: The current study demonstrated the safety and efficacy of IFN in patients with ET, PRV, and AMM. Objective responses and/or disease stabilization were obtained in patients with all three disease entities, including the reversal of splenomegaly and resorption of myelofibrosis in some patients., (Copyright 2003 American Cancer Society.DOI 10.1002/cncr.11486)