An experimental JAK2 inhibitor has been shown to be well tolerated and to produce a significant reduction in disease burden and durable clinical benefit in patients with myelofibrosis reports a study in the Journal of Clinical Oncology.

Currently there are no FDA approved treatments for myelofibrosis, a debilitating chronic myeloproliferative disorder where bone marrow is replaced by fibrous tissue. Common treatments of the malignancy, which is associated with anaemia and splenomegaly, are palliative and do not alter the natural course of the disease. Median survival ranges from less than two years to greater than 15 years.

Patients with myelofibrosis frequently harbour JAK-STAT activating mutations that are sensitive to TG101348, a selective small-molecule Janus kinase 2 (JAK2) inhibitor. It is estimated that JAK-2 mutations occur in approximately 50 % of patients. Last September researchers reported positive results from a trial testing the experimental agent INCBO18424, (which inhibits JAK1 as well as JAK2) in patients with advanced myelofibrosis.

In the current phase 1 study, Ayalew Tefferi and colleagues from the Mayo Clinic (Rochester, MN) enrolled 59 patient, including 28 who took part in the dose-escalating phase. A substantial portion of patients experienced improvements in primary symptoms including splenomegaly, leukocytosis, thrombocytosis, and constitutional symptoms. There was also evidence for significant reductions in genomic disease burden, indicating the potential for disease-modifying activity. Although the drug was generally well tolerated, it caused anaemia in some patients, especially at higher doses. A follow-up study is planned to see whether adjusting the dose will allow patients to achieve the benefits without the anaemia.

"The current study provides a proof-of-concept for selective JAK2 inhibition with TG101348 as a therapeutic strategy in myelofibrosis," wrote the authors, adding that the number of patients in the study was too small to correlate clinical responses with mutant allele reduction. A message to the scientific community, Tefferi added, is that the anti-JAK 2 drugs tested to date differ from each other in terms of therapeutic activity and side effects. Patients at risk of anaemia should consider drugs that do not have this side effect.

In an accompanying editorial Srdan Verstovsek from the University of Texas MD Anderson Cancer Center wrote, "The development of JAK2 inhibitors has ushered in a new era of targeted therapies for Philadelphia-negative MPNs. These drugs do not eradicate the malignant clone, but they provide significant clinical benefit. Given that the current clinical management of patients with MF is largely palliative and minimally effective, significant improvements in two of the three most important clinical manifestations of MF (splenomegaly and systemic symptoms) seen with JAK2 inhibitors is significant therapeutic progress."

Long term results, he added, are required to determine the full potential of JAK2 inhibitors in myelofibrosis and to determine whether they will have an impact on survival.

Reference

A Pardanani, J Gotlib, C Jamieson, et al Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis Journal of Clinical Oncology (2011) Doi 10.1200/JCO.2010.32.8021.

S Verstovsek Janus-activated kinase 2 inhibitors: a new era of targeted therapies providing significant clinical benefit for Philadelphia chromosome-negative myeloproliferative neoplasms Journal of Clinical Oncology (2011) Doi 10.1200/JCO.2010.33.4508