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.
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
Table. List of JAK2 Inhibitors Currently Undergoing Clinical Trials
| Anti-JAK2 drug | Anti-JAK2 IC50 (JAK1/JAK3/TYK2 selectivity) | Non-JAK kinase targets | Clinical trials | Disease features shown to be favorably affected | Side effects |
|---|---|---|---|---|---|
| INCB01842411, 12(Phase I/II study) | 4.5 nM (x0.6/x72/x4) | MF (n=155)PV (n=34)ET (n=39) | SplenomegalyConstitutional symptomsPruritusCachexiaErythrocytosis (PV) | Thrombocytopenia (DLT)AnemiaCytokine rebound phenomenon* | |
| TG10134810 (Phase I/II study) | 3 nM (x35/x332/x135) | FLT3RET | MF (n=59) | SplenomegalyConstitutional symptomsPruritusLeukocytosisThrombocytosisJAK2V617F burden | AnemiaThrombocytopeniaNausea/vomitingDiarrheaIncreased transaminasesIncreased amylase/lipase (DLT) |
| CEP-7018, 9(Lestaurtinib)(Phase II study) | 1 nM (UNK/x3/UNK) | FLT3TrkA | MF (n=22)PV (n=27)ET (n=12) | SplenomegalyAnemia (MF)Pruritus | DiarrheaNausea/vomitingAnemia (MF)Thrombocytopenia (MF)Thrombosis (PV/ET)Leukocytosis (PV/ET)Thrombocytosis (PV/ET) |
| CYT3874 (Phase I/II study) | 18 nM (x0.6/x8.6/UNK) | JNK1CDK2 | MF | Results pending | Results pending |
| AZD14805 (Phase I/II study) | 0.26 nM (x5/x15/UNK) | TrkAAurora AFGFR1 | MF | Results pending | Results pending |
| SB15187 (Phase I/II study) | 22 nM (x58/x24/UNK) | FLT3 | MF (n=31) | Splenomegaly | DiarrheaNauseaThrombocytopenia(DLT=GI symptoms) |
| XL0196 (Phase I/II study) | 2 nM (x67/x98/x172) | MF (n=21) | SplenomegalyConstitutional symptomsLeukocytosis | Neuropathy (DLT)No myelosuppression |
| Anti-JAK2 drug | Anti-JAK2 IC50 (JAK1/JAK3/TYK2 selectivity) | Non-JAK kinase targets | Clinical trials | Disease features shown to be favorably affected | Side effects |
|---|---|---|---|---|---|
| INCB01842411, 12(Phase I/II study) | 4.5 nM (x0.6/x72/x4) | MF (n=155)PV (n=34)ET (n=39) | SplenomegalyConstitutional symptomsPruritusCachexiaErythrocytosis (PV) | Thrombocytopenia (DLT)AnemiaCytokine rebound phenomenon* | |
| TG10134810 (Phase I/II study) | 3 nM (x35/x332/x135) | FLT3RET | MF (n=59) | SplenomegalyConstitutional symptomsPruritusLeukocytosisThrombocytosisJAK2V617F burden | AnemiaThrombocytopeniaNausea/vomitingDiarrheaIncreased transaminasesIncreased amylase/lipase (DLT) |
| CEP-7018, 9(Lestaurtinib)(Phase II study) | 1 nM (UNK/x3/UNK) | FLT3TrkA | MF (n=22)PV (n=27)ET (n=12) | SplenomegalyAnemia (MF)Pruritus | DiarrheaNausea/vomitingAnemia (MF)Thrombocytopenia (MF)Thrombosis (PV/ET)Leukocytosis (PV/ET)Thrombocytosis (PV/ET) |
| CYT3874 (Phase I/II study) | 18 nM (x0.6/x8.6/UNK) | JNK1CDK2 | MF | Results pending | Results pending |
| AZD14805 (Phase I/II study) | 0.26 nM (x5/x15/UNK) | TrkAAurora AFGFR1 | MF | Results pending | Results pending |
| SB15187 (Phase I/II study) | 22 nM (x58/x24/UNK) | FLT3 | MF (n=31) | Splenomegaly | DiarrheaNauseaThrombocytopenia(DLT=GI symptoms) |
| XL0196 (Phase I/II study) | 2 nM (x67/x98/x172) | MF (n=21) | SplenomegalyConstitutional symptomsLeukocytosis | Neuropathy (DLT)No myelosuppression |
IC50 = concentration producing 50 percent inhibition; UNK = unknown; DLT = dose-limiting toxicity
*Consists of acute and immediate (i.e., within days) reappearance of symptoms and enlargement of spleen that has required hospitalization for some patients.
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.
