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JAK1/2 Inhibitor Ruxolitinib Improves Survival in High-Risk Myelofibrosis

February 2014 Vol 7, No 1, Special Issue ASH 2013 Payers' Perspectives in Oncology - Conference Highlights ASH

New Orleans, LA—Long-term analyses of patients with high-risk myelofibrosis show continued efficacy of ruxolitinib in reducing mortality risk compared with conventional therapy. The efficacy of ruxolitinib on outcomes was not affected by the presence of detrimental genetic mutations.

Ruxolitinib is an oral inhibitor of the Janus kinase (JAK) 1 and JAK2 tyrosine kinases designed to target overactivation of the JAK/STAT signaling pathway.

The data presented at ASH 2013 were updates from 2 studies known as COMFORT (Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment)-I and COMFORT-II, in which patients with intermediate-2 or high-risk primary myelofibrosis, post–polycythemia vera myelofibrosis, or postessential thrombocythemia myelofibrosis were randomized to ruxolitinib or to control (best available treatment or placebo). In both studies, the patients were allowed to cross over from the con­trol arms to ruxolitinib upon protocol-­defined progression events, primarily progressive splenomegaly.

A 3-year update from COMFORT-I was provided by Srdan Verstovsek, MD, PhD, Professor, Department of Leukemia, M.D. Anderson Cancer Center, Houston, TX. Some 309 patients were randomized to ruxolitinib or to placebo; doses of ruxolitinib could be titrated for lack of efficacy or excess toxicity. The patients originally randomized to ruxolitinib had a 31% reduction in mortality risk compared with those receiving placebo (P = .067).

Of the 154 patients randomized to placebo, 111 crossed over to ruxolitinib at a median of 41 weeks. “The hazard of death for patients originally randomized to placebo decreased as patients crossed over to ruxolitinib,” said Dr Verstovsek. The suggested risk of death for patients who crossed over had decreased to approach that for patients originally randomized to ruxolitinib.

In COMFORT-II, 219 patients with primary or post–polycythemia vera/essential thrombocythemia myelofibrosis were randomized in a 2:1 ratio to receive ruxolitinib or best available therapy. Mutations in 12 genes were genotyped at baseline in 166 of the patients (120 randomized to ruxolitinib, 46 randomized to best available therapy).

The impact of gene mutations characterizing high molecular risk on the reduction in spleen, development of anemia, and overall survival was assessed. Forty-six (38.3%) patients in the ruxolitinib group and 20 (43.5%) patients in the best available therapy group were classified as high molecular risk. Next-generation sequencing was used for the analysis.

Ruxolitinib had a similar survival benefit in patients with and without high-risk mutations.

“The negative impact of high molecular risk status on survival is halved by treatment with ruxolitinib compared with best available therapy, and the effect of ruxolitinib is similar in both the high molecular risk and low molecular risk groups,” said Paola Guglielmelli, MD, PhD, of the Department of Experimental and Clinical Medicine, University of Florence, Italy.

In addition, high molecular risk status did not affect the likelihood of obtaining a ≥35% spleen volume reduction nor the risk of developing anemia on treatment.

A pooled overall survival analysis of the COMFORT studies showed that the risk of death at 3 years was reduced by 35% in patients initially randomized to ruxolitinib compared with controls (P = .01).

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Last modified: August 30, 2021