Clinical and bone marrow effects of interferon alfa therapy in myelofibrosis with myeloid metaplasia

The bone marrow stromal reaction in myelofibrosis with myeloid metaplasia (MMM) may contribute to the clinical phenotype and is believed to be both reactive and cytokine mediated.1Therefore, it is reasonable to seek a treatment strategy that has the potential to curb clonal myeloproliferation and also to modulate cytokine production and activity. Interferon alpha (IFNα) has been shown to be myelosuppressive, both in vitro and in vivo, in various chronic myeloid disorders, including MMM.2,3 The drug's potential for inducing clonal suppression in myeloid disorders is an added advantage, and in vitro studies have suggested that IFNα may also inhibit fibrogenic cytokines and angiogenesis.4These observations justify the evaluation of the clinical and biologic effects of IFNα in patients with MMM.

In a phase II study, IFNα was administered to 11 chemotherapy-naı̈ve patients (median age, 50 years; 7 females) with MMM. Eight patients were classified as being at low risk according to the Dupriez score.5 Eligibility for the study included the presence of either anemia (hemoglobin level below 10 g/dL) or palpable splenomegaly, the absence of prior chemotherapy including hydroxyurea and anagrelide, and a platelet count above 100 000/μL. Treatment was initiated with subcutaneous IFNα at 3 million IU 3 times a week for the first 3 months. In the absence of unacceptable side effects, the weekly dose was increased to 15 million IU for a total treatment period of 1 year.

Overall, only 4 patients (36%) were able to complete 1 year of therapy with IFNα. Six of the remaining 7 patients experienced unacceptable drug toxicity and discontinued treatment after 10 days (1 patient) or 3 to 6 months of treatment (5 patients) (Table1). The seventh patient (patient 9) discontinued treatment because of severe cytopenia. Lesser degrees of cytopenia were frequent (Table 1). All forms of toxic reaction, constitutional and myelosuppressive, ceased after treatment was stopped. No clinically relevant improvement, including a more than 50% reduction in spleen size, was seen in any patient. Two patients had progression of their disease during treatment with IFNα.

In the 4 patients who completed 1 year of treatment with IFNα, follow-up bone marrow study at 6 and 12 months showed no appreciable change in either reticulin fibrosis or osteosclerosis. Pretreatment and posttreatment microvessel density was measured in 3 of these 4 patients. All had had grade 2 or 3 pretreatment values, which increased in 2 patients (at 6 months in one patient and at 12 months in the other). Pretreatment and posttreatment bone marrow angiogenesis data were available in 3 patients who received IFNα therapy for 3 to 6 months. The degree of angiogenesis increased in 1 patient (from grade 2 to grade 3) and remained the same in the 2 others (grade 3 in both). The extent of reticulin fibrosis and osteosclerosis was not affected by treatment in the 6 patients who received IFNα therapy for 3 to 6 months. Only 2 patients had an abnormal karyotype, which did not change with treatment.

The currently demonstrated lack of a positive effect on bone marrow fibrosis, osteosclerosis, or angiogenesis undermines the potential of IFNα in altering the natural history of MMM. The poor patient tolerance of the drug may make it clinically irrelevant to consider whether better activity might be achieved at either higher doses or a longer duration of therapy. At present, it is not clear whether the drug offers any advantage over hydroxyurea, which is better tolerated and less expensive, in the treatment of “hyperproliferative” MMM.