Srdan Verstovsek on the Use of a JAK Inhibitor in Myelofibrosis

New Hot Paper Commentary, January 2012

Srdan Verstovsek

Article: Safety and Efficacy of INCB018424, a JAK1 and JAK2 Inhibitor, in Myelofibrosis


Authors: Verstovsek, S;Kantarjian, H;Mesa, RA;Pardanani, AD;Cortes-Franco, J;Thomas, DA;Estrov, Z;Fridman, JS;Bradley, EC;Erickson-Viitanen, S;Vaddi, K;Levy, R;Tefferi, A
Journal: N ENGL J MED, 363 (12): 1117-1127 SEP 16 2010
* Univ Texas MD Anderson Canc Ctr, Leukemia Dept, Unit 428,1515 Holcombe Blvd, Houston, TX 77030 USA.
* Univ Texas MD Anderson Canc Ctr, Leukemia Dept, Houston, TX 77030 USA.
(Addresses have been truncated)

Srdan Verstovsek talks with ScienceWatch.com and answers a few questions about this month's New Hot Paper in the field of Clinical Medicine.


SW: Why do you think your paper is highly cited?

Myelofibrosis is the most serious of the myeloproliferative neoplasms, which are clonal proliferative diseases. This devastating condition is associated with shortened life span and debilitating symptoms that impair quality of life (such as night sweats, itching, fatigue, abdominal pain, and cachexia). Historically, patients with myelofibrosis have had few treatment options. Most traditional therapies are palliative and have little clinical benefit.

Discovery of mutations in the JAK pathway in 2005 provided the first molecular clues for the pathogenesis of these diseases. It is remarkable that within a very short duration of time, ruxolitinib was advanced into clinical trials. This article describes the first clinical study evaluating the efficacy and safety of a JAK inhibitor in patients with myelofibrosis. In addition, these findings supported the design of the phase III studies that led to the recent FDA approval of ruxolitinib in intermediate or high risk myelofibrosis.

SW: Does it describe a new discovery, methodology, or synthesis of knowledge?

Ruxolitinib represents a new class of drugs and a new approach to the treatment of myelofibrosis. Ruxolitinib inhibits Janus kinases (JAK)1 and JAK2.

"Dysregulated JAK activity may play an important role in other hematologic malignancies and solid tumors, and consequently, ruxolitinib continues to be evaluated in other indications."

Under normal conditions, Janus kinases (JAK1, JAK2, JAK3, and tyrosine kinase 2) play important roles in hematopoiesis (development of blood cells) and regulation of the immune system. Unchecked activation of the JAK pathway, either through activating mutations in JAK2 or through exaggerated expression of cytokines that activate JAK1 and JAK2, can lead to pathological states such as myelofibrosis.

The findings described in this publication demonstrated that ruxolitinib treatment—by inhibiting JAK1 and JAK2—resulted in significant clinical benefits including reductions in spleen size and improvements in myelofibrosis symptoms. Remarkably, ruxolitinib significantly down-modulated the high levels of proinflammatory cytokines present in the circulation in myelofibrosis patients. Furthermore, this study demonstrated an association between reductions in cytokines and improvements in symptoms.

SW: Would you summarize the significance of your paper in layman terms?

Prior to this study, it was unknown what effect a JAK inhibitor would have in patients with myelofibrosis and how well such a therapy would be tolerated. The results of this phase I-II study provided the first evidence that ruxolitinib is an effective therapy for myelofibrosis by reducing spleen size and improving myelofibrosis-associated symptoms. Side effects were predictable based on the known mechanism of action, and reversible. Importantly, these data validated JAK1 and JAK2 as molecular targets for the treatment of myelofibrosis.

SW: How did you become involved in this research and how would you describe the particular challenges, setbacks, and successes?

Ruxolitinib (INCB018424) was identified as a selective inhibitor of JAK1 and JAK2 by the scientists at Incyte. After preclinical characterization and phase I trials in healthy volunteers, my colleagues and I collaborated with Incyte to develop the phase I-II clinical trial with ruxolitinib in patients with myelofibrosis.

Excitement in the area of JAK inhibitors actually began six to seven years ago with the discovery of the JAK2V617F mutation followed by other JAK-activating mutations. This led to further investigation of the role of JAK2 in the pathogenesis of myeloproliferative neoplasms. However, only about half of patients with myelofibrosis were found to have the JAK2 mutation. In this study, we observed that patients with and without the mutation responded to ruxolitinib, which led us to hypothesize that the JAK pathway is dysregulated even in patients without any mutations. We also discovered that regardless of mutational status, high levels of inflammatory cytokines are present in these patients.

One of the major successes of the study is that we were able to identify starting doses based on baseline platelet count and preserve the benefits of ruxolitinib while minimizing the hematologic adverse events. Patients were experiencing noticeable and meaningful reductions in spleen size and improvements in symptoms early on in the treatment period, and these benefits tended to be maintained with continued therapy.

The results from this trial provided the basis for design of the pivotal phase III trials (COMFORT-I and COMFORT-II).

SW: Where do you see your research leading in the future?

The COMFORT-I and COMFORT-II phase III trials have been completed. These randomized studies demonstrated the efficacy of ruxolitinib in decreasing spleen volume compared with placebo or best available therapy. Moreover, significant improvements in myelofibrosis-related symptoms and quality of life were reported. Another important observation in these studies was the continued worsening of spleen size and symptoms in groups receiving placebo or best available therapy. The efficacy and safety data from these large studies (>500 patients) provided support for the FDA approval of ruxolitinib in patients with intermediate- or high-risk myelofibrosis.

Dysregulated JAK activity may play an important role in other hematologic malignancies and solid tumors, and consequently, ruxolitinib continues to be evaluated in other indications. A phase I-II study in patients with polycythemia vera and essential thrombocythemia has been completed, and a phase III study in patients with polycythemia vera has been initiated. Additional clinical trials are ongoing in adults with pancreatic cancer, adults with advanced hematologic malignancies (acute myeloid leukemia, acute lymphocytic leukemia, myelodysplastic syndrome and chronic myelogenous leukemia) and relapsed or refractory acute leukemia, and in children with hematologic malignancies and solid tumors.End

Srdan Verstovsek, M.D., Ph.D.
Associate Professor
Leukemia Department
MD Anderson Cancer Center
Houston, TX, USA

KEYWORDS: MYEOLOFIBROSIS, INCB018424, JNK1, JNK2, SAFETY, EFFICACY, INTERNATIONAL WORKING GROUP, QUALITY OF LIFE, MYELOID METAPLASIA, MYELOPROLIFERATIVE DISORDERS, PROGNOSTIC FACTORS, POLYCYTHEMIA VERA, SCORING SYSTEM, SURVIVAL, BURDEN, EXPECTANCY.

 
 

   |   BACK TO TOP