JAK2 Inhibitor Therapy and Mechanisms of Response

Abstract SCI-36

Myeloproliferative neoplasms (MPN) are stem cell-derived clonal (or oligoclonal) hemopathies and are phenotypically characterized by abnormally increased left-shifted myeloproliferation. “BCR-ABL1-negative MPN” is an operational sub-category of MPN that includes polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). Beginning in 2005, novel mutations involving JAK2, MPL, TET2, ASXL1, IDH1, IDH2, CBL, IKZF1, or LNK have been described in a variable proportion of patients with BCR-ABL1-negative MPN. The evidence so far suggests that none of these mutations garner the disease specificity or pathogenetic relevance otherwise displayed by BCR-ABL1. Nevertheless, considering the fact that some of these mutations exhibit high mutational frequency (e.g. JAK2 mutations) and either directly (e.g. JAK2 or MPL mutations) or indirectly (e.g. LNK or CBL mutations) induce JAK-STAT hyperactivation, it is reasonable to evaluate the therapeutic value of anti-JAK drugs in these disorders. In this regard, the ATP-mimetic small molecule kinase inhibitors have so far been the focus and those that have made it into clinical trials include TG101348, INCB018424, CEP-701, CYT387, AZD1480, SB1518, XL019 and LY2784544 (clinicaltrials.gov). Preliminary results from clinical studies suggest notable differences among these drugs in their toxicity and efficacy profiles, some of which might be linked to their variable in vitro activity against other JAK and non-JAK kinase targets and the resultant effect on JAK-STAT-dependent cytokines. For example, off-target FLT3 inhibition displayed by TG101348, CEP-701 and SB1518 might contribute to their common side effect profile of nausea, vomiting and diarrhea. Similarly, the impressive activity of INCB018424 in alleviating constitutional symptoms has been correlated with marked reduction in serum pro-inflammatory cytokines and therefore possibly related to its primarily anti-JAK1 activity whereas serum cytokine levels did not appear to be affected by either TG101348 or CEP-701. 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. Regardless, because most MPN-associated mutations do not necessarily represent the primary clonogenic event, we should curb our expectations from anti-JAK2 treatment trials and continue to pursue other treatment strategies. Furthermore, in considering the prospect of anti-JAK therapy in MPN, one should recognize the fact that life expectancy in the majority of patients with PV or ET is near-normal and disease complications are effectively managed by treatment with low-dose aspirin, phlebotomy or hydroxyurea. Therefore, controlled studies are needed to show added value and justify the risk of unknown long-term health effects associated with new drugs, including JAK inhibitors, in PV and ET. The unmet need for new treatment is in PMF where survival and quality of life are significantly worse and current therapy is inadequate. This session will i) summarize results of current anti-JAK clinical trials in MPN, ii) discuss putative mechanisms of action in terms of both therapeutic benefit and toxicity and iii) define the potential role of JAK inhibitors in the context of current therapeutic approaches for MPN.