Searching for polycythemia vera's Holy Grail

Comment on Kiladjian et al, page 2037

In this issue, Kiladjian and colleagues report that pegylated interferon therapy results in not only clinical but also molecular responses in patients with polycythemia vera.

The search for an effective therapy for patients with polycythemia vera (PV) has been the goal of clinicians for more than half a century. Recently, investigators' attention has been focused on the discovery of an acquired mutation affecting JAK2 (JAK2V617F) that occurs in 90% to 95% of patients with PV.¹  This acquired somatic mutation could potentially be used as a target for the development of new chemotherapeutic drugs, as well as being a molecular marker for quantitating the response to therapy. Although phlebotomy and low-dose aspirin therapy remain the core treatment options for patients with PV, alkylating agents, P³², pipobroman, hydroxyurea, interferon, imatinib, and anagrilide have all been used. Kiladjian and colleagues report that therapy with a pegylated form of interferon-α-2a results in not only hematologic remissions in patients with PV but also a reduction in the percentage of JAK2V617F by a mean of 49%. The use of interferons to treat patients with PV actually began in the late 1980s, in the hope that such therapy would be effective, nontoxic, and nonleukemogenic.²  These studies suggested that interferon might preferentially suppress the malignant PV clone, based on the observations that interferon therapy reversed chromosomal abnormalities and restored polyclonal hematopoiesis. Jones et al³  have recently reported that patients receiving either imatinib or interferon therapy experienced a significant reduction in the median percentage of mutant JAK2 alleles, although these responses were considered modest.

In an attempt to improve patient compliance, attachment of a polyethylene glycol moiety to interferon has been pursued to prolong the half-life and achieve a smaller volume of distribution. These structural modifications permit weekly administration of this form of the drug, rather than the daily administration required with unpegylated forms. At present, 2 pegylated forms of interferon are commercially available: PEG-Intron (Schering-Plough, Kenilworth, NJ), a chemically altered form of interferon-α-2b; and Pegasys (Roche Laboratories, Milan, Italy), a pegylated form of interferon-α-2a. Whether these pharmacologic properties translate into differences in clinical activity or toxicity is unknown. Recently, however, Samuelsson and colleagues⁴  reported that pegylated interferon-α-2b therapy, while effective at achieving hematologic responses, was associated with significant toxicity, indicating that its long-term use might not be practical in many patients.

The report of Kiladjian and colleagues raises many important new questions. Although we can apparently reduce the PV tumor load with interferon therapy, is such therapy tolerable? What degree of reduction in the JAK2V617F burden will translate into a greater long-term survival and fewer disease-related complications in patients with PV? Which interferon preparation is optimal? Will JAK2V617F inhibitors currently under development be more effective and less toxic then the pegylated interferons? Answering these questions requires appropriately powered randomized clinical trials with significant periods of follow-up. The completion of such trials might be expedited by the use of well-validated biomarkers, including JAK2V617F. Validating the utility of such biomarkers, as well as performing these clinical trials, is ambitious but necessary if improvement in the treatment of patients with PV is to be realized. ▪