To determine whether patients unresponsive to PEG-INF have mutations in genes lying outside the JAK2 pathway, investigators performed a follow-up of a phase II study of 83 patients (43 with PV and 39 with ET) treated with PEG-IFN (90 µg subcutaneously weekly).

The rate of complete hematologic response was 76% for PV and 77% for ET, and the median time to a complete response was 40 days (range, 3–1478 days). Complete and partial (≥50%) elimination of the JAK2 mutant allele occurred in 18% and 35% of PV patients and 17% and 33% of ET patients, respectively. Patients who failed to achieve complete molecular response tended to have mutant genes outside the JAK2 pathway (56% vs. 30%), but this difference was not significant. However, 9 of 14 who failed to achieve complete molecular response had evidence of clonal evolution of their disease based on the appearance of new genetic abnormalities, whereas none of the 9 patients who achieved complete molecular response acquired new abnormalities. The JAK2burden was higher in patients with a concomitant mutation in TET2 than in those without this mutation (67% vs. 39%; P=0.04), and patients with the TET2 variant did not have a significant decline in the JAK2 mutant allele with PEG-IFN treatment.

COMMENT

Symptomatic patients with polycythemia vera or essential thrombocythemia are usually treated with cytoreductive agents, but these drugs are unsuitable for younger patients, and responses are usually transient. However, if patients can tolerate pegylated interferon α-2a, remission is often sustained. Refractory patients usually have several genetic mutants, and clonal evolution frequently occurs during treatment. The development of new agents targeting mutant genes outside the JAK2pathway should increase the response rate in patients with these myeloproliferative neoplasms.