With Prolonged Treatment, Ruxolitinib Lessens JAK2 V617F Allele Burden in Patients with Myelofibrosis

A high proportion of patients with BCR-ABL1-negative myeloproliferative neoplasms (myelofibrosis, essential thrombocythemia, and polycythemia vera) have the JAK2 V617F mutation, which can lead to constitutive JAK2 activity and contribute to dysregulated JAK signaling in clonal cells. In the COMFORT-I trial, use of the oral JAK1/JAK2 inhibitor ruxolitinib led to durable reductions in splenomegaly and improvements in disease-related symptoms, which led to FDA approval of ruxolitinib for patients with intermediate-2 or high-risk myelofibrosis in November 2011.

Previous studies have suggested that ruxolitinib effects these improvements without significantly changing JAK2 V617F allele burden in JAK2 V617F-positive patients; however, these findings were based on relatively short-term follow-up. Authors of a recent Blood paper, led by Michael Deininger, MD, PhD, sought to confirm these findings with a long-term follow-up analysis of COMFORT-I data.

The phase III, placebo-controlled COMFORT-I study included patients with intermediate-2 or high-risk myelofibrosis; patients were randomized to receive ruxolitinib at 15 mg or 20 mg twice daily (n=155) or placebo (n=154). Crossover for patients receiving placebo was allowed once protocol-defined progression of splenomegaly was determined. The presence of the JAK2 V617F mutation was not required for enrollment, the authors noted, because responses to ruxolitinib can be achieved regardless of mutation status.

JAK2 V617F allele burden was measured at baseline and weeks 24, 48, 120, 144, 168, and 216. The researchers measured the allele burden percent change from baseline for all patients with the JAK2 V617F mutation at baseline (n=236) and at least one post-baseline measurement (n=214).

Patients who were randomized to receive ruxolitinib were classified in three tertiles based on the maximum reduction in allele burden:

  • Tertile 1: 100% to 24.66% reduction of allele burden (major reduction)
  • Tertile 2: 24.66% to 8% reduction (minor reduction)
  • Tertile 3: Reduction of 8% or less (no reduction or increased allele burden)

During the 24-week randomization phase, the mean percent change from baseline in allele burden decreased in the ruxolitinib group and increased in the placebo cohort. Over the course of the study, the mean and median percents of maximal change in the ruxolitinib-treated arm were 27 percent and 16 percent, compared with 19 percent and 11 percent for patients originally randomized to placebo who crossed over to ruxolitinib.

After all patients receiving placebo crossed over to ruxolitinib treatment, the mean percentage change in allele burden for those originally randomized to ruxolitinib and those originally randomized to placebo continued to decrease with ongoing ruxolitinib treatment. There was no signficant effect of ruxolitinib dose.

A total of 28 patients (12%) had a ≥50 percent decrease in JAK2 V617F allele burden. Of the 236 JAK2 V617F-positive patients, 20 achieved partial molecular response (PMR) and six achieved complete molecular response (CMR), with a median time to response of 22.2 months and 27.5 months, respectively. “Because this study was not designed to determine PMRs and CMRs,” the authors noted, “allele burden measurements were sparse, which may have led to an underestimate of confirmed PMRs and CMRs.”

“Patients with both high and low initial allele burdens had allele burden responses, indicating that changes were not dependent on starting allele burden,” Dr. Deininger and co-authors explained (TABLE 3). When baseline characteristics were compared among tertiles of best JAK2 V617F response, ruxolitinib-treated patients with the largest decreases in allele burden had the shortest mean and median times from diagnosis. Patients with greater decreases in allele burden also tended to have intermediate-risk MF, post-polycythemia vera MF, and PMF.

In terms of spleen volume reduction, patients with greater allele burden had larger mean and median percent changes at week 24 (TABLE). Patients with greater allele burden also had a greater proportion of spleen response: 63.9% for tertile 1, 55.6% for tertile 2, and 31.4% for tertile 3. However, for patients without an allele burden response or with a subsequent increase after a decrease while on therapy, there was no clear signal that allele burden either correlated with or predicted spleen response.

“These analyses demonstrate that extended duration of ruxolitinib therapy can decrease JAK2 V617F allele burden,” Dr. Deininger and co-authors wrote. “Patients originally randomized to [receive] ruxolitinib had prolonged survival and greater percentage reductions in spleen volume from the time of randomization versus patients who crossed over from placebo.”

The authors noted another limitation of the current analysis: it did not evaluate other MPN-associated mutations (MPL, CALR, etc.) or concurrent genetic factors that may affect JAK2 V617F allele responsiveness to ruxolitinib. “Given the marked allele burden changes observed in some patients over extended treatment durations, further analyses are warranted to assess treatment-related changes in other JAK-STAT pathway mutants in JAK2 V617F-negative MPNs, and to determine the role for response-modifying background mutations that may impact clonal sensitivity to treatment,” they concluded.


Reference

Deininger M, Radich J, Burn T, et al. The effect of long-term ruxolitinib treatment on JAK2V617F allele burden in patients with myelofibrosis. Blood. 2015 July 30. [Epub ahead of print]

TABLE. Maximum Percent Change in Allele Burden
  Tertile 1

(n=36)

Tertile 2

(n=36)

Tertile 3

(n=35)

Baseline allele burden
Mean 70.9% 73.5% 75.3%
Median 84.5% 81.5% 84.0%
Maximum percent change in allele burden
Mean −62.6% −15.3 −0.5%
Median −63.4% −14.8% −2.2%
Spleen volume reduction
Mean −41.2% −38.3% −23.4%
Median −45.2% −37.1% −22.7%

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