Additon of Low-Dose Interferon-alpha (LD-IFN-a) and Lenalidomide after Failure to a Combination of Thalidomide and Prednisone in Myelofibrosis with Myeloid Metaplasia (MMM).

Primary myelofibrosis with myeloid metaplasia (MMM) is an uncommon myeloproliferative disease with limited effective treatment options. Therapy using thalidomide and prednisone (TP) or lenalidomide (L) show variable objective response of improvement of 22% in L to 62% in TP for anemia, 50% in L to 75% in TP for thrombocytopenia, and decrease in splenomegaly in 19% with TP to 33% with L and was well-tolerated. Additional clinical benefits show resolution of leukoerythroblastosis, and a decrease in medullary fibrosis and abnormal angiogenesis. Prolonged therapy with alpha-interferon (IFN-a) can improve hematopoiesis and reverse marrow fibrosis but doses used were poorly tolerated.

Methods and Patients: Here we present five patients treated with combination T at 50 mg daily, P at 0.5 mg/kg po for 2 weeks then to 20 mg daily every other day for 3 months with no response. If this was tolerated, low-dose IFN-a (LD-IFN-a) at 1.5 million units sc. three times a week was added. The clinical and hematologic criterion of the European Myelofibrosis Network (EUMNET) were used as response criteria for our study. Three males, 2 females, age ranged from 60 to 85 years who had failed previous treatments from EPO, hydrea and transfusion support. White blood cell counts ranged from 4.3 to 29.7 B/L. Hemoglobin levels ranged from 7.3 to 11.6 g/dL. Platelets ranged from 13,000 to 283,000 B/L. Three patients developed iron overload from rbc transfusions and required iron-chelation therapy.

Results: Of the five patients, one had a CR, one had a PR and two had regression that did not meet criteria for response and one unresponsive with no splenomegaly but stable disease. We noted that the addition of LD-IFN-a decreased the elevated WBC counts and Improvement in spleen size was seen about three months after the start of treatment. One patient had a CR in his WBC count approximately a month after starting therapy. The patient with CR had normal hemoglobin but had to discontinue after a year of T due to grade 2 neuropathy and was started on 10 mg/day of L while staying on IFN-a and P. She developed anemia and required transfusions for 3 months and achieved CR with shrinkage of her spleen size from 15 to 4 cm. The patient who was unresponsive to the combination of IFN-a- TP changed from T to L was stopped after the patient developed hemolytic anemia and splenomegaly.

Conclusion: Addition of LD-IFN-a to the reported TP or L to replace T show clinical activity in patients with refractory MMM and is well tolerated with minimal toxicity. The use of lenalidomide may alleviate neuropathy but may induce hemolysis as an undesirable side effect. Further studies using low doses of these agents with varying activities to MMM in combination is needed to define their clinical use in the treatment of this disease entity in a much larger number of patients.