Myelofibrosis Drug Shrinks Symptoms

A partial response in spleen volume reduction, the primary endpoint in both trials, was a more clear-cut benefit.

In COMFORT-II, a reduction of at least 35% in spleen volume as seen on imaging was seen in 32% of patients at week 24 and in 28% at week 48 in the ruxolitinib group; none of the patients on best available therapy showed a reduction in spleen volume of 35% (both P<0.001).

That response persisted for the median 12-month follow-up in 80% of responders.

In COMFORT-I, the similar benefit at week 24 was maintained by 67% of ruxolitinib responders through at least week 48.

That trial showed an improvement of 50% or more in total symptom scores at 24 weeks in 45.9% of ruxolitinib-treated patients but in just 5.3% of placebo patients (P<0.001).

The other trial also indicated substantial improvements in myelofibrosis symptoms overall and in individual symptoms like fatigue and and insomnia with the drug compared with a worsening with best available treatment.

Nonhematologic adverse events were seldom serious in COMFORT-II and occurred at a similar rate between groups in COMFORT-I. The most common events were diarrhea and, in the latter trial, fatigue.

Grade 3 or worse hematologic abnormalities were mostly thrombocytopenia (13% and 8% in COMFORT-I and -II, respectively) and anemia (45% and 42%, respectively).

Transformation to acute myeloid leukemia wasn’t consistently more common with ruxolitinib, as the COMFORT-I study had two cases with the drug only but COMFORT-II had two cases only in the non-ruxolitinib group.

Longer-term follow-up will be needed to better define this risk, Verstovsek’s group noted.

Stopping ruxolitinib led to gradual return of myelofibrosis symptoms to baseline levels without a clear pattern of a specific withdrawal effect in COMFORT-I.

In COMFORT-II, 19 of the 32 patients who stopped the drug had adverse events in the subsequent two weeks, three with grade 3 events.

Primary source: New England Journal of Medicine
Source reference: Verstovsek S, et al “A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis” N Engl J Med 2012; 366: 799-807.

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Additional source: New England Journal of Medicine
Source reference: Harrison C, et al “JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis” N Engl J Med 2012; 366: 787-98.