Janus-activated kinase 2 inhibitors: a new era of targeted therapies providing significant clinical benefit for Philadelphia chromosome-negative myeloproliferative neoplasms.

Myelofibrosis (MF; either primary or postpolycythemia vera/ essential thrombocythemia) is a chronic and debilitating myeloproliferative neoplasm (MPN) for which there is no well-accepted therapeutic standard of care. Clinical signs of this disease, cytopenias (primarily anemia), splenomegaly, and constitutional symptoms (eg, hypercatabolic state, fatigue, night sweats, fever, bone pain) create significant treatment challenges. Common treatments are palliative, are frequently ineffective, and do not alter the natural course of MF. No agent has yet been approved by the US Food and Drug Administration for therapy of MF. Starting in 2005, mutations that directly or indirectly led to deregulated activation of nonreceptor tyrosine kinase (TK) Janusactivated kinase 2 (JAK2) have been implicated in the pathogenesis of MPN, including JAK2V617F and JAK2 exon 12 mutations, thrombopoietin receptor mutations, and mutations in the adapter protein LNK. These mutations activate the JAK2–signal transducer and activator of transcription (STAT) intracellular signaling pathways, which lead to increased cellular proliferation and resistance to apoptosis. These discoveries spurred the development of molecularly targeted agents (JAK2 inhibitors) as therapy for MPNs. The results of several studies of JAK2 inhibitors in MF (INCB018424, TG101348, and CEP701) have been reported in peer-reviewed journals. JAK2 inhibitors in clinical development exhibit differential inhibitory activity against the JAK family members, and some exhibit effects on other receptor kinases and therefore are not selective for JAK2 TK. For example, INCB018424 inhibits JAK1, whereas CEP701 and TG101348 inhibit FLT3. JAK2 inhibitors are small molecules that act by competing with adenosine triphosphate for the adenosine triphosphate–binding catalytic site in the TK domain. The V617F mutation locates outside the TK domain of JAK2. Therefore, the current JAK2 inhibitors target both wild-type and mutated JAK2 indiscriminately. This could explain why these drugs are active in patients with both wild-type and mutated JAK2. However, targeting the wild-type JAK2 is expected to lead to myelosuppression as a result of the exquisite signaling through JAK2 of thrombopoietin and erythropoietin receptors in normal hematopoiesis. This probably explains the reported therapy-related anemia and thrombocytopenia observed with JAK2 inhibitors in clinical trials. Some common features have emerged from current clinical studies. The primary therapeutic benefit with JAK2 inhibitors appears to be a reduction in splenomegaly (and hepatomegaly in those with enlarged livers) with significant improvement in the quality of life. In an intent-to-treat analysis, responses are seen in patients with and without JAK2V617F mutation; at 6 months, a 50% or greater reduction in splenomegaly (“Clinical Improvement” by the International Working Group for Myelofibrosis Research and Treatment response criteria) was seen in 52% of patients treated with optimal dose/schedule of INCB018424 and in 45% of patients treated with the maximumtolerated dose of TG101348. This benefit is usually seen within the first 2 months of therapy and is durable beyond 1 year of therapy. No significant improvement in bone marrow fibrosis has been reported so far, and the effect on the JAK2V617F allelic burden varied among studies. CEP-701 caused no significant change in the allelic burden in patients with clinical response. In 34 evaluable patients, INCB018424 suppressed allelic burden by 13% after 12 cycles of therapy. Similarly, TG101348 suppressed allelic burden in the study cohort (median 20% at baseline decreased to 19% after 12 cycles; P .01) but more so in the patients with baseline allelic burden of more than 20% (median 60% at baseline decreased to 32% after 12 cycles; P .002). Assessment of the clinical significance of these findings is confounded by at least two issues. First, there are no standardized, reference tests to measure JAK2V617F allelic burden in patient samples; different studies use different tests with different sensitivity and specificity, different controls, and different cells (mononuclear cells v granulocytes) as a source material. Second, the clinical relevance of JAK2V617F allelic burden in MF is not clear, and the significance of its modification during therapy is therefore unknown. One study reported that patients with MF and high allelic burden had higher hemoglobin and WBC counts, developed massive splenomegaly, and had higher risk of leukemic transformation. Two other studies reported that patients with MF and low JAK2V617F allelic burden had lower hemoglobin levels, a low incidence of splenomegaly, and worse survival either resulting JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L S VOLUME 29 NUMBER 7 MARCH 1 2011