By Ruben Mesa, MD

2008-12-07

The discovery of the JAK2-V617F mutation was met in 2005 with great fanfare for its association and pathogenetic role in the Philadelphia chromosome negative myeloproliferative neoplasms (MPNs). The explosion of research that followed (discovery of related mutations signaling through JAK-STAT pathway) led to the rapid development of specific and targeted inhibitors of JAK2. The initial trials for these latter tyrosine kinase inhibitors were begun with soaring expectations, hoping to mirror some of the remitting efficacy of imatinib in chronic myeloid leukemia. These agents, and a range of pre-clinical models and clinical trial results, take center stage in multiple MPN sessions today and tomorrow.

The pipeline of JAK2 inhibitors in development is amazing for a group of disorders, the MPNs, which have long suffered from a lack of targeted or particularly efficacious therapy, especially for advancing disease (namely for myelofibrosis [MF], both primary and occurring after antecedent polycythemia vera [PV] or essential thrombocythemia [ET]). Several trials have and will be discussed in the MPN oral and poster sessions that primarily focus on MF patients (based on the greatest initial clinical need). The most mature clinical experience for a JAK2 inhibitor is for INCB018424 shared by Dr. Srdan Verstovsek, of M. D. Anderson Cancer Center, regarding the results of the largest MF trial in history (>120 patients) where the agent leads to significant reduction in splenomegaly and dramatic improvement in constitutional symptoms. (Saturday poster #I-867; abstract #1762) Although INCB018424 is well tolerated, the suppression of the JAK-STAT pathway can lead to treatment-related thrombocytopenia and anemia. Additional drugs being described at the oral session on myeloproliferative disorders at 4:30 p.m. today are mainly earlier in their clinical testing (TG101348, XL019, CEP-701, ITF2357), but preliminary results also indicate improvements in splenomegaly and symptoms in MF patients. No drug yet has reported a significant ability to improve cytopenias, fibrosis, or histologic changes associated with MF. “What separates MF from PV and ET is not yet clear, but is probably not solely the currently identified JAK2 or MPL mutations” commented Dr. Animesh Pardanani of the Mayo Clinic and lead investigator on the TG101348 trial. “This latter fact could explain why a JAK2 inhibitor could lead to only a partial response in MF patients, akin to the more limited ability of imatinib to achieve response in accelerated or blast phase CML.”

PV (with 99% of patients having a mutation somewhere in their JAK2) could well be the most straightforward target of JAK2 inhibition, and preliminary results of trials will be first unveiled tomorrow with discussion of initial efficacy of XL019, CEP-701, and ITF2347. These are significant and will be compared and contrasted with increasing discussion of pegylated interferon — 2a in PV. “We have seen long-lasting molecular remissions with this agent in PV” said French investigator Jean-Jacques Kiladjian, who will be updating ASH on the progress of the PV NORD trial during tomorrow’s oral session titled “Myeloproliferative Disorders – Clinical Trials” at 3:30 p.m. (Gateway Ballroom 104 – South, abstract #659).

Although the pipeline of JAK2 inhibitors is strong, will any of the agents discussed or in development achieve remissions or alter the course of MF? Clearly they have provided a valuable and incremental benefit over existing options, particularly for symptoms and quality of life. A study focusing on pomalidomide, a non-JAK2 inhibitor IMID, will be presented by Ayalew Tefferi, MD, of Mayo Clinic, tomorrow at 3:30 p.m. in the Gateway Ballroom 104 – South (abstract #663). Results of a large randomized international trial will demonstrate activity for anemia in MF.

Perhaps MF will require multiple forms of simultaneous therapy, given the disorder’s complex pathogenesis. Although a bullseye for the MPNs has not yet been achieved, the improved understanding, initial trial results, and breadth of potential future agents are encouraging to patients and clinicians alike.

Dr. Mesa is a co-author of Dr. Verstovsek’s abstract.

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