Those of us entering hematology training in the late 1990s witnessed the transition of interferon-α (IFN-α) therapy to life-support. The approval of imatinib for CML in 2001 secured its ascendancy and quickly relegated IFN-α to a historical postscript.1 By extension, IFN-α’s reputation as a useful and tolerable drug for other chronic myeloproliferative neoplasms (MPNs) such as polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) also suffered. Several groups continued to explore its utility in MPNs, and such efforts were resuscitated by development of pegylated forms of the drug (interferon-alpha-2a [Pegasys] or -2b [PEG-Intron]) with more convenient weekly dosing and generally improved tolerability.
With the identification of the JAK2 V617F activating mutation in classic MPNs, the spotlight shifted to JAK2 inhibitors with the expectation that they would provide a successful bookend to the tyrosine kinase inhibitor legacy inaugurated by imatinib. This “second act” with JAK2 inhibitors is currently being played out in phase I-III trials of higher-risk PMF and advanced PV and ET. In PMF, the initial verdict is mixed. While noteworthy benefits include dramatic reduction of splenomegaly, decreases in leukocytosis and thrombocytosis, and improvement in constitutional symptoms/quality of life, these findings are tempered by lack of consistent improvement (and sometimes worsening) of anemia and no substantial impact on marrow fibrosis.2,3 Now with the availability of quantitative assays to measure JAK2 V617F allele burden, more sensitive methods for evaluating drug response in MPNs can be undertaken. Thus far with JAK2 inhibitors, variable reductions of mutant allele burden have been reported,3 but the clinical significance of these findings has yet to be determined.
So, where does PEG-IFN stand in this regard? The study by Quintás-Cardama and colleagues from M. D. Anderson Cancer Center reaffirms the high rates of complete hematologic remission (70% in PV, 76% in ET) previously observed. Of particular interest, the overall molecular response rate assessed by advanced DNA sequencing technology was 38 percent among 16 evaluable ET patients, including two (13%) partial remissions and one (6%) complete molecular remission. Among 35 PV patients, the overall, partial, and complete molecular remission rates were 54, 29, and 14 percent, respectively. There was a statistically significant decrease in JAK2 V617F mutant allele burden among subjects with PV, declining from a median baseline value of 64 to 12 percent after 24 months. Whereas hematologic responses were rapid, occurring within the first three months of therapy, meaningful molecular responses required at least six months to develop. With a median follow-up of 21 months, the authors reported no plateau in the molecular response and no evidence for relapse in patients in whom the JAK2 V617F mutation became undetectable. Regarding tolerability, the overall rate of drug discontinuation was 10 percent. Because of unacceptable toxicity of PEG-IFN-α-2a at the 450 mcg weekly dose, the drug was stepwise-reduced to a better tolerated dose of 90 mcg weekly, with low rates of grade 3 neutropenia, diarrhea, and liver dysfunction.
In Brief
The current work highlighting molecular responses to PEG-IFN-α suggests a preferential effect on the malignant clone and extends results of a prior French study of PV.4 Because current JAK2 inhibitors target both wild-type and mutant JAK2, inhibition of JAK2-dependent normal erythropoiesis likely contributes to the worsening anemia observed in trials of MF. The surprising finding that hydroxyurea can also generate reductions in the allelic burden of JAK2 V617F represents yet a third drug class with the potential for in-depth, higher-quality responses.5 The future role of these drugs in any of these MPNs, whether used singly or in combination, will ultimately reflect their tolerability profile and their capacity to inhibit thrombohemorrhagic complications and evolution to myelofibrosis or acute leukemia. The relationship between these prognostic endpoints and molecular response will require long-term study.
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Competing Interests
Dr. Gotlib has received research funding from Targegen, Inc., and Incyte Corporation and is a principal investigator on JAK2 inhibitor trials sponsored by these companies.
