Myelofibrosis is a Philadelphia chromosome-negative blood condition with a natural history characterized by progressive anemia, spleen enlargement due to production for ed cells there, and potential for evolution to acute myeloid leukemia (AML). For patients who require treatment and are not candidates fostem cell transplantation, available therapies have not been curative. They include: chemotherapy such as hydroxyurea; erythropoiesis-stimulating agents; immunomodulatory drugs such as thalidomide or lenalidomide, with or without corticosteroids; splenectomy; splenic irradiation; and clinical trials. In November 2011, only four years after commencing clinical trial evaluation, ruxolitinib became the first JAK inhibitor approved by the FDA for MF patients (intermediate- and high-risk). In an updated analysis of COMFORT-I, there was a significant overall survival benefit with ruxolitinib; at a median follow-up of 51 weeks, there were 13 (8.4%) deaths in the ruxolitinib group and 24 (15.7%) deaths in the placebo arm.
Ruxolitinib’s potency as a “spleen shrinker” and “symptom mitigator” is shared by other JAK inhibitors currently in clinical trials (e.g., SAR302503 [formerly TG101308], CYT387, SB518, etc.). In an ad hoc analysis of the COMFORT-I and COMFORT-II trials, worsening of spleen size as well as symptoms and quality-of-life scores were similar between the placebo and BAT control groups. his means that conventional thhapies don’t perform well long term. Although it may be premature to abandon conventional treatments such as hydroxyurea, the comparative superiority of ruxolitinib in these trials justifies its frontline use for intermediate- and high-risk Myelofibrosis(MF). The primary goal is improvement of splenomegaly and constitutional symptoms. For MF patients with anemia or RBC transfusion-dependence as the predominant clinical issue, no standard of care currently exists. Lenalidomide is anotehr new drug that elicits benefits in anemia in ~20 to 30 percent of MF patients. In regard to combining the two, there is a phase I trial: Ruxolitinib and Lenalidomide for Patients With Myelofibrosis, NCT01375140.
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