Ruxolitinib and Revlimid for Myelofibrosis – pro

Myelofibrosis is a Philadelphia chromosome-negative myeloproliferative neoplasm with a natural history characterized by progressive anemia, spleen enlargement due to extramedullary hematopoiesis, and potential for evolution to acute myeloid leukemia (AML). For patients who require treatment and are not candidates for transplantation, available therapies are palliative. Thesy 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).

The registration trials for ruxolitinib consisted of two large phase III trials: COMFORT-I was a randomized (1:1), double-blind, multicenter study comparing ruxolitinib 15 or 20 mg twice daily (dose stratified according to baseline platelet count) versus placebo, and COMFORT-II was a randomized (2:1), open-label, multicenter trial comparing ruxolitinib 15 or 20 mg bid versus best available therapy (BAT; investigator-selected including no treatment).4 Both trials met the primary endpoint of the percentage of ruxolitinib versus control patients achieving > 35 percent reduction in spleen volume at week 24 (COMFORT-I: 41.9% vs. 0.7%) and week 48 (COMFORT-II: 28.5% vs. 0%). After 24 weeks in the COMFORT-I trial, the proportion of patients with ≥50 percent improvement in total symptom score (using the myelofibrosis symptom assessment form) was 45.9 percent versus 5.3 percent (ruxolitinib vs. placebo, p<0.0001). Anemia and thrombocytopenia were common ruxolitinib-related adverse events but rarely led to drug discontinuation, and the drug was otherwise well tolerated. 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. 

Updates at the European Hematology Association ahd ASCO in 2013 suggest that Jakafi remains helpful in reducing symmptoms at the expense of some additive toxicity and prolongs PFS but does not extend survival.

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.). Patients with or without the JAK2 V617F mutation respond similarly. 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.This means that conventional therapies 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 MF patients in whom 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.

Verstovsek S, Mesa RA, Gotlib JR, et al. Results of COMFORT-I, a randomized double-blind phase III trial of JAK 1/2 inhibitor INCB18424 (424) versus placebo (PB) for patients with myelofibrosis (MF). J Clin Oncol. ASCO Meeting Abstracts. 2011;29:6500.

Harrison CN, Kiladjian J, Al-Ali HK, et al. Results of a randomized study of the JAK inhibitor ruxolitinib (INC424) versus best available therapy (BAT) in primary myelofibrosis (PMF), post-polycythemia vera-myelofibrosis (PPV-MF) or post-essential thrombocythemia-myelofibrosis (PET-MF). J Clin Oncol. ASCO Meeting Abstracts. 2011;29:LBA6501.

Verstovsek S, Mesa RA, Gotlib J, et al. Consistent benefit of ruxolitinib over placebo in spleen volume reduction and symptom improvement across subgroups and overall survival advantage: results from COMFORT-I.Blood. ASH Annual Meeting Abstracts. 2011;118: 278.

Mesa RA, Verstovsek S, Cervantes F, et al. Comparison of the efficacy of placebo and best available therapy for the treatment of myelofibrosis in the COMFORT studies. Blood. ASH Annual Meeting Abstracts. 2011;118:1753.

Pardanani A, Gotlib J, Gupta V, et al. An expanded multicenter phase I/II study of CYT387, a JAK- 1/2 inhibitor for the treatment of myelofibrosis. Blood. ASH Annual Meeting Abstracts. 2011;118:3849.

Bhagwat N, Koppikar P, Kilpivaara O, et al. Heterodimeric JAK-STAT activation as a mechanism of persistence to JAK2 inhibitor therapy. Blood. ASH Annual Meeting Abstracts. 2011;118:122.

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