Ruxolitinib for Myelofibrosis: Treatment Considerations

Pankit Vachhani, MD: In myelofibrosis, the JAK2 gene mutation occurs in about 50% to 60% of patients, the CALR gene mutation in about 25% to 30%, and MPO mutations in about 5% to 10%. In the remaining fraction of patients with myelofibrosis, about 10% to 15% have no mutation in these 3 classical driver mutation genes. What’s important to note, however, is that irrespective of the mutation status, the JAK-STAT pathway is overactive in all patients with myelofibrosis. Once again, that is irrespective of the mutation status of JAK2, CALR, or MPO.

COMFORT-I was a large, phase 3 randomized study that was performed in the United States, Australia, and Canada for patients with myelofibrosis—that could be primary myelofibrosis, or post-PV [polycythemia vera] or post-ET [essential thrombocythemia] myelofibrosis—who had intermediate-2 or high-risk disease. The study randomized patients in a 1:1 ratio to ruxolitinib or placebo. The dose of ruxolitinib was 15 mg twice daily if the patient had platelet counts of 100 to 200 x 109 per liter, and the dose was 20 mg twice daily for patients who had platelet counts greater than 200 x 109. The primary end point, which was a spleen volume reduction of 35% or more at 24 weeks, was achieved in 41.9% of patients, compared to only 0.7% of patients in the placebo group. Moreover, the crucial secondary end point, which was to decrease the symptom burden, was also in favor of ruxolitinib. For example, 45.9% of patients who received ruxolitinib achieved a 50% decrease or more in their symptom burden, compared to 5.3% of patients in the placebo group.

The COMFORT-II study was a similar, large, randomized clinical trial performed for patients with myelofibrosis. Once again, this could be primary myelofibrosis, or post-PV or post-ET myelofibrosis. The patients, however, were randomized in a 2:1 fashion to ruxolitinib or the best available therapy. As it so happened, the investigators chose hydroxyurea in about 50% of the patients as the best available therapy, while one-third of patients did not receive any medications. This was an open-label study and here too, the dosing of ruxolitinib was very comparable to how it was performed in COMFORT-I. The primary end point was a 35% spleen volume reduction at week 48. At week 48, 28% of patients in the ruxolitinib arm achieved this end point, compared to 0% of the patients in the best available therapy arm. The same numbers for week 24 were also obtained: 32% of patients in the ruxolitinib arm achieved this end point, and 0% of the patients in the best available therapy arm.

The COMFORT-I and COMFORT-II studies were performed more than a decade ago. Since then, long-term data from both these studies have become available. The secondary end point in these studies was overall survival. We have data from the pooled analysis of COMFORT-I and COMFORT-II. For example, the 5-year overall survival, using an intention-to-treat analysis, favored patients who received ruxolitinib rather than placebo or best available therapy. The median survival was 5.3 years in patients who received ruxolitinib, as opposed to 3.8 years in the comparator arm, with a hazard ratio of 0.7. If one were to use statistical tools and correct for crossover, or censor patients at crossover, the survival advantage that favors ruxolitinib would be even more pronounced.

One must remember that the package insert for ruxolitinib allows for a dosage of 5 mg twice daily of ruxolitinib, for patients with a diagnosis of myelofibrosis and platelet counts between 50 and 100 x 109. The original COMFORT-I and COMFORT-II studies didn’t include this population of patients who had platelet counts between 50 and 100 x 109. However, other studies have looked into this patient population. Phase 3b of the JUMP study, for example, included patients who had platelet counts between 50 and 100 x 109. In this study, most patients within this platelet range received ruxolitinib at a dose of 5 mg daily. They more or less stayed at that dosage and as a result, the safety and efficacy of ruxolitinib was demonstrated there too. However, I must add that since then, other studies have also been noted and reported on their outcomes in patients with myelofibrosis and thrombocytopenia. For example, the EXPAND study is a phase 1b, dose-finding study of ruxolitinib for patients who had myelofibrosis and had a platelet count between 50 and 100 x 109. In this study, the key was to obtain a maximum, safe, starting dose. The patients were divided into 2 strata. Strata 1 was patients who had platelet counts between 75 and 100 x 109. Strata 2 was patients who had platelet counts between 50 and 75 x 109. For both of these groups, the safety and efficacy data that came out from the EXPAND study suggested that 10 mg twice daily of ruxolitinib could be well tolerated in this population of patients with myelofibrosis and platelets between 50 and 100 x 109. I think this is crucial because it allows the investigators, or the clinicians, to treat their patients at a higher dose of ruxolitinib. Using this previous knowledge, it allows a higher dose of ruxolitinib to be given and in return get more benefits for patients in terms of spleen response and symptom improvement.

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