Ayalew Tefferi, MD
Professor of Medicine and Hematology, Division of Hematology, Mayo Clinic College of Medicine
Next year will mark the golden anniversary of the first formal description of the classic myeloproliferative neoplasms (MPNs): polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), and chronic myelogenous leukemia (CML).1 We now recognize these MPNs as stem cell-derived clonal (or oligoclonal) disorders that display mature-appearing but abnormally increased myeloproliferation. The disease-causing mutation in CML is BCR-ABL1, and kinase inhibitors (e.g., imatinib, dasatinib) that target its corresponding oncoprotein have been shown to be therapeutically effective.2 In contrast, the genetic underpinnings of PV, ET, and PMF remain poorly understood and their treatment suboptimal.
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Beginning in 2005, novel mutations involving JAK2, MPL, TET2, ASXL1, IDH1, IDH2, CBL, IKZF1,or LNK have been described in a subset of patients with BCR-ABL1-negative MPN.3 However, none of these mutations garner the disease specificity or pathogenetic relevance otherwise displayed by BCR-ABL1. Furthermore, with the exception of JAK2V617F, which occurs in approximately 95 percent of patients with PV and 60 percent of those with ET or PMF, the mutational frequencies of these individual genes seldom exceeds 10 percent. Nonetheless, considering the fact that some of these mutations either directly (e.g., JAK2 or MPL mutations) or indirectly (e.g., LNK or CBL mutations) induce JAK-STAT hyperactivation, a number of ATP mimetic kinase inhibitors with activity against JAK2 have been developed and are currently undergoing clinical trials (see Table for summary).
Phase I/II studies of CYT3874 and AZD14805 in MPN were initiated only a few months ago, and study results are too preliminary to warrant any comments at this point. Clinical trials with XL019 are currently on hold because of concerns regarding neurologic toxicity, but the drug did show activity against splenomegaly and leukocytosis in PMF or post- PV/ET MF patients with JAK2 or MPL mutatations.6 Preliminary results with SB1518 in patients with myelofibrosis suggest activity against splenomegaly; nausea and diarrhea were the main side effects.7 CEP-701 is also associated with gastrointestinal side effects, and its therapeutic activity, so far evaluated in JAK2V617F-positive patients only, has been underwhelming; in MF, four of 22 patients experienced spleen size reduction and two became red cell transfusion-independent, whereas the drug was unexpectedly associated with thrombotic complications in PV/ET.8,9
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Fifty-nine patients with PMF or post-PV/ET MF have been treated with TG101348.10 The majority of evaluable patients achieved a > 50 percent reduction in palpable spleen size and resolution of leukocytosis, thrombocytosis, and constitutional symptoms including pruritus. In addition, a > 50 percent reduction in JAK2V617F allele burden was documented in 44 percent of evaluable cases. Side effects included gastrointestinal symptoms, anemia, thrombocytopenia, and dose-dependent and reversible increase in serum transaminase, amylase, or lipase levels. INCB018424 has been evaluated in 155 MF and 73 PV/ET patients.11,12 At the optimal dose level, 48 percent of evaluable PMF patients achieved > 50 percent reduction in spleen size, and complete hematologic remission rates in both PV and ET were < 50 percent. The drug was most effective in alleviating constitutional symptoms, including pruritus and cachexia, and this activity correlated with marked reduction in serum pro-inflammatory cytokines. Of note, serum cytokine levels did not appear to be affected by TG101348 or CEP-701.8 Side effects of INCB018424 included thrombocytopenia, anemia, and, in some patients, acute and immediate (i.e., within days) reappearance of symptoms upon drug discontinuation, which is believed to be related to a cytokine rebound effect. The drug had little effect on JAK2V617F allele burden.
Taken together, it is reasonable to make the following conclusions:
- JAK2 inhibitors currently undergoing clinical trials show substantial inter-drug differences in their toxicity and efficacy profiles. Some of these differences might be linked to their variable activity against other JAK and non-JAK kinase targets. Therefore, at this point in time, it is both premature and inappropriate to make general statements regarding the prospect of anti-JAK2 therapy in MPN. In other words, many more such drugs should be evaluated in order to appreciate the full spectrum of their benefit.
- Off-target activity of specific JAK2 inhibitors appears to matter. The accompanying figure illustrates the spectrum of cytokines that are differentially affected by inhibition of a specific JAK protein. Currently available information supports the assumption that both improvement in constitutional symptoms and “cytokine rebound phenomenon” from INCB018424 are related to its anti-JAK1 activity and mediated by druginduced alteration in proinflammatory cytokines. Similarly, off-target FLT3 inhibition displayed by TG101348, CEP-701, and SB1518 might contribute to their common side effect profile of nausea, vomiting, and diarrhea.
- On-target anti-JAK2 activity contributes to drug-induced anemia and thrombocytopenia seen with JAK2 inhibitor therapy. These drug effects are dose-dependent and might come in handy in the treatment of PV or ET. More selective anti-JAK2 drugs, such as TG101348, might be preferable in the setting of PV or ET because of their superior activity in controlling leukocytosis, thrombocytosis, and JAK2V617F allele burden as well as avoidance of extraneous and potentially harmful anti-JAK1 drug activity.
- Tefferi A. The history of myeloproliferative disorders: before and after Dameshek. Leukemia. 2008;22:3-13.
- Druker BJ. Translation of the Philadelphia chromosome into therapy for CML. Blood. 2008;112:4808-4817.
- Tefferi A. Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1. Leukemia. 2010. [Epub ahead of print]
- Pardanani A, Lasho T, Smith G, et al. CYT387, a selective JAK1/JAK2 inhibitor: in vitro assessment of kinase selectivity and preclinical studies using cell lines and primary cells from polycythemia vera patients. Leukemia. 2009;23:1441-1445.
- Hedvat M, Huszar D, Herrmann A, et al. The JAK2 inhibitor AZD1480 potently blocks Stat3 signaling and oncogenesis in solid tumors. Cancer Cell. 2009;16:487-497.
- Shah NP, Olszynski P, Sokol L, et al. A phase I study of XL019, a selective JAK2 inhibitor, in patients with primary myelofibrosis, post-polycythemia vera, or post-essential thrombocythemia myelofibrosis. Blood. (ASH Annual Meeting Abstract). 2008;112:98.
- Verstovsek S, Odenike O, Scott B, et al. Phase I dose-escalation trial of SB1518, a novel JAK2/FLT3 inhibitor, in acute and chronic myeloid diseases, including primary or postessential thrombocythemia/polycythemia vera myelofibrosis. Blood. (ASH Annual Meeting Abstract). 2009;114:3905.
- Santos FPS, Kantarjian HM, Jain N, et al. Phase 2 study of CEP-701, an orally available JAK2 inhibitor, in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis. Blood. 2010;115:1131-1136.
- Moliterno AR, Hexner E, Roboz GJ, et al. An open-label study of CEP-701 in patients with JAK2 V617F-positive PV and ET: update of 39 enrolled patients. Blood. (ASH Annual Meeting Abstract). 2009;114:753.
- Pardanani AD, Gotlib JR, Jamieson C, et al. A phase I evaluation of TG101348, a selective JAK2 inhibitor, in myelofibrosis: clinical response is accompanied by significant reduction in JAK2V617F allele burden. Blood. (ASH Annual Meeting Abstract). 2009;114:755.
- Verstovsek S, Kantarjian H, Mesa RA, et al. Long-term follow up and optimized dosing regimen of INCB018424 in patients with myelofibrosis: durable clinical, functional and symptomatic responses with improved hematological safety. Blood. (ASH Annual Meeting Abstract). 2009;114:756.
- Verstovsek S, Passamonti F, Rambaldi A, et al. A phase 2 study of INCB018424, an oral, selective JAK1/JAK2 inhibitor, in patients with advanced polycythemia vera (PV) and Essential thrombocythemia (ET) refractory to hydroxyurea. Blood. (ASH Annual Meeting Abstract). 2009;114:311.
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