Myelofibrosis Drug Shrinks Symptoms

The kinase inhibitor ruxolitinib (Jakafi) alleviates spleen enlargement and other symptoms of the bone marrow disease myelofibrosis, but with a questionable impact on survival, two randomized trials showed.

Spleen volume dropped by more than a third over 24 weeks in 42% of patients on the JAK 1 and 2 inhibitor compared with less than 1% on placebo (P<0.001), Srdan Verstovsek, MD, PhD, of the MD Anderson Cancer Center in Houston, and colleagues reported in the COMFORT-I trial.

Those rates were similar against best available therapy - hydroxyurea, chemotherapy agents, or corticosteroids. None of those shrank spleens by at least 35% in any patient in the COMFORT-II trial, Claire Harrison, DM, of Guy’s Hospital in London, and colleagues found.

Ruxolitinib also significantly improved quality-of-life and reduced myelofibrosis symptoms in both trials, which were published in the March 1 issue of the New England Journal of Medicine.

The results led to ruxolitinib’s approval by the FDA late last year as the first-in-class JAK inhibitor and the first treatment specifically for myelofibrosis.

But it’s not all good news with the drug, Ayalew Tefferi, MD, of the Mayo Clinic in Rochester, Minn., cautioned in an accompanying editorial.

Although discovery of JAK mutations in myeloproliferative neoplasms led to hopes of a targeted therapy similar to imatinib (Gleevec) for chronic myeloid leukemia, it now looks unlikely that JAK inhibitors will offer more than transient palliation, he explained.

Neither study showed histopathologic, cytogenetic, or molecular remissions, and the drug was more likely to cause than to correct anemia and thrombocytopenia, noted Tefferi, whose group previously reported on severe withdrawal from the drug.

“Approximately 30% of patients with myelofibrosis present with ruxolitinib-sensitive symptoms, and the drug might be useful in a fraction of these patients who are not candidates for allogeneic stem-cell therapy or for clinical trials of potentially better drugs, including newer and more selective JAK inhibitors,” he concluded.

COMFORT-1, which randomized 309 patients with intermediate-2 or high-risk myelofibrosis to double-blind treatment, showed 50% fewer deaths with twice daily oral ruxolitinib than with placebo (13 versus 24, P=0.04).

However, “its apparent superiority over placebo was confounded by the lack of risk stratification during randomization and the possibility that withholding the best available therapy enabled occult or overt progression of disease and negatively influenced coexisting conditions,” Tefferi warned in the editorial.

COMFORT-2, which included 219 patients with the same conditions or post–polycythemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis, was underpowered for survival outcomes but showed no differences in mortality:

- By 48 weeks, six patients randomized to ruxolitinib had died compared with four deaths in patients on best available therapy (4% versus 5%, hazard ratio 0.70, 95% CI 0.20 to 2.49).
- With an additional two months of follow-up for a planned safety update, the difference reversed direction but remained statistically nonsignificant with 11 deaths versus four (8% versus 5%, HR 1.01, 95% CI 0.32 to 3.24).

Long-term outcomes from an earlier phase study with ruxolitinib also suggested no survival benefit.