American Society of Hematology

Ask the Hematologist: March-April 2012

Jason Gotlib, MD, MS
Stanford University School of Medicine, Stanford, CA

Published on: March 01, 2012

Associate Professor of Medicine (Hematology) and Director, Hematology Fellowship Program, Stanford University School of Medicine and Stanford Cancer Institute

Dr. Gotlib receives research funding from Incyte (manufacturer of ruxolitinib), Sanofi-Aventis (manufacturer of SAR302503), YMBiosciences (manufacturer of CYT387), andCelgene (manufacturer of lenalidomide).

ASH does not recommend or endorse any specific tests, physicians, products, procedures, or opinions, and disclaims any representation, warranty, or guaranty as to the same. Reliance on any information provided in this article is solely at your own risk.

The Question

How does the recent FDA approval of the JAK inhibitor ruxolitinib influence your management of patients with myelofibrosis?

My Response

Myelofibrosis (primary and post-PV/ET MF) is a Philadelphia chromosome-negative myeloproliferative neoplasm with a natural history characterized by progressive anemia, spleen enlargement due to extramedullary hematopoiesis, and potential for evolution to acute myeloid leukemia (AML). Impairment of quality of life is due to both massive splenomegaly (e.g., early satiety and abdominal discomfort) and inflammatory cytokines, which mediate debilitating symptoms such as night sweats, fevers, muscle/bone pain, and cachexia. The activating JAK2 V617F mutation is present in 50 to 60 percent of patients, and the MPL mutation (W515L/K), resulting in ligand-independent activation of the thrombopoietin receptor, is identified in an additional 5 to 10 percent of individuals. It has become abundantly clear, however, that MPNs such as MF are more genetically complex. Molecular alterations in additional genes and dysregulation of the epigenetic machinery also contribute to disease pathogenesis.

Prognostic scoring systems based on clinical and laboratory factors obtained either at the time of diagnosis (IPSS)1 or during the disease course (dynamic IPSS, or DIPSS)2 have been developed in order to estimate both overall survival and risk of progression to AML. The IPSS uses five adverse prognostic factors: age >65, hemoglobin <10 g/dL, white blood cell count >25,000/mm3, constitutional symptoms, and peripheral blood blasts >1 percent. The DIPSS-Plus refines prognosis assessment by incorporating three additional adverse risk factors: platelet count <100,000/mm3, the need for red blood cell transfusions, and poor-risk cytogenetics. Using the IPSS as an example, patients can be stratified into one of four risk groups: low (score 0), intermediate-1 (score 1), intermediate-2 (score 2), or high (score >3), with a median overall survival among the groups ranging from approximately 11 years to just over two years.1

Age, performance status, and prognostic risk group drive decision making about treatment options. The Table (below) illustrates this point using three patients. Patient 1 is a lowrisk patient with excellent performance status, minimally abnormal blood counts and splenomegaly, and no constitutional symptoms. Such patients do not warrant immediate treatment and a watch-and-wait approach may be undertaken. At the other end of the spectrum, Patient 3 is a younger, high-risk patient characterized by abnormal blood counts, marked splenomegaly, and poor-risk cytogenetics. The DIPSS-Plus estimate of overall survival is 16 months, and the five- and 10-year leukemia rates are 18 and 31 percent, respectively.2 Given this patient’s younger age and relatively poor prognosis, evaluation for a potentially curative myeloablative hematopoietic stem cell transplant would be encouraged.

For patients who require treatment and are not candidates for transplantation, available therapies for MF-related cytopenias, splenomegaly, and symptoms are considered palliative. These options have included chemotherapy such as hydroxyurea; erythropoiesis-stimulating agents; immunomodulatory drugs such as thalidomide or lenalidomide, with or without corticosteroids; splenectomy; splenic irradiation; and clinical trials. In November 2011, only four years after commencing clinical trial evaluation, ruxolitinib became the first JAK inhibitor approved by the FDA for MF patients (intermediate- and high-risk).

The registration trials for ruxolitinib consisted of two large phase III trials: COMFORT-I was a randomized (1:1), double-blind, multicenter study comparing ruxolitinib 15 or 20 mg twice daily (dose stratified according to baseline platelet count) versus placebo,3 and COMFORT-II was a randomized (2:1), open-label, multicenter trial comparing ruxolitinib 15 or 20 mg bid versus best available therapy (BAT; investigator-selected including no treatment).4 Both trials met the primary endpoint of the percentage of ruxolitinib versus control patients achieving > 35 percent reduction in spleen volume at week 24 (COMFORT-I: 41.9% vs. 0.7%) and week 48 (COMFORT-II: 28.5% vs. 0%). After 24 weeks in the COMFORT-I trial, the proportion of patients with ≥50 percent improvement in total symptom score (using the myelofibrosis symptom assessment form) was 45.9 percent versus 5.3 percent (ruxolitinib vs. placebo, p<0.0001). Anemia and thrombocytopenia were common ruxolitinib-related adverse events but rarely led to drug discontinuation, and the drug was otherwise well tolerated. In an updated analysis of COMFORT-I, there was a significant overall survival benefit with ruxolitinib; at a median follow-up of 51 weeks, there were 13 (8.4%) deaths in the ruxolitinib group and 24 (15.7%) deaths in the placebo arm.5 The implications of these short-term data are unclear since JAK inhibitors exert modest or no impact on fundamental disease-related features such as JAK2 mutant allele burden or marrow fibrosis.

Ruxolitinib’s potency as a “spleen shrinker” and “symptom mitigator” is shared by other JAK inhibitors currently in clinical trials (e.g., SAR302503 [formerly TG101308], CYT387, SB518, etc.). Patients with or without the JAK2 V617F mutation respond similarly. Therefore, firstline treatment with a JAK inhibitor would be an ideal choice for Patient 2 described in the table and could be considered a bridging option for Patient 3 until a transplant is performed.

In an ad hoc analysis of the COMFORT-I and COMFORT-II trials, worsening of spleen size as well as symptoms and quality-of-life scores were similar between the placebo and BAT control groups.6 Although it may be premature to abandon conventional treatments such as hydroxyurea, the comparative superiority of ruxolitinib in these trials justifies its frontline use for intermediate- and high-risk MF patients in whom the primary goal is improvement of splenomegaly and constitutional symptoms. For MF patients with anemia or RBC transfusion-dependence as the predominant clinical issue, no standard of care currently exists. In this regard, differences among JAK inhibitors may prove informative in tailoring particular agents to specific patient presentations. For example, the JAK 1/2 inhibitor CYT387 has demonstrated improvements in hemoglobin/transfusion-dependence in an ongoing phase II trial.7 Lenalidomide (or pomalidomide, on a trial basis) may also elicit benefits in anemia in ~20 to 30 percent of MF patients.

Given the rapid “on/off” action of JAK inhibitors, caution must be undertaken when stopping these agents because of the potential for return of symptoms in a short period of time. During therapy, disease “persistence” (incomplete regression or return of splenomegaly and symptoms) can occur and may be partly explained biologically by reactivation (phosphorylation) of JAK2 through heterodimerization with JAK family members JAK1 and TYK2.8 Future directions will therefore be focused on combination trials of JAK inhibitors with other targeted targets (e.g., histone deacetylase inhibitors, anti-fibrotics, PI3 kinase/ AKT inhibitors) to improve the quality and duration of responses.

Table: MF Patient Profiles


 Patient 1Patient 2Patient 3
ECOG Performance Status011
WBC (/mm3)9,20018,70031,000
Hb (g/dL), Transfusion-dependent
Platelet Count (/mm3)155,000218,00085,000
PB Blasts (%)025
Constitutional SymptomsNoYesYes
Splenomegaly*4 cm15 cm21 cm
CytogeneticsNormalNormalMonosomy 5
JAK2 V617F MutationYesNoYes
IPSS Score/Risk Group0/Low2/Intermediate-24/High


PB=peripheral blood

*below left costal margin by palpation

  1. Cervantes F, Dupriez B, Pereira A, et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood. 2009;113:2895-2901.
  2. Gangat N, Caramazza D, Vaidya R, et al. DIPSS plus: a refined dynamic International Prognostic Scoring System for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status. J Clin Oncol. 2011; 29:392-397.
  3. Verstovsek S, Mesa RA, Gotlib JR, et al. Results of COMFORT-I, a randomized double-blind phase III trial of JAK 1/2 inhibitor INCB18424 (424) versus placebo (PB) for patients with myelofibrosis (MF). J Clin Oncol. ASCO Meeting Abstracts. 2011;29:6500.
  4. Harrison CN, Kiladjian J, Al-Ali HK, et al. Results of a randomized study of the JAK inhibitor ruxolitinib (INC424) versus best available therapy (BAT) in primary myelofibrosis (PMF), post-polycythemia vera-myelofibrosis (PPV-MF) or post-essential thrombocythemia-myelofibrosis (PET-MF). J Clin Oncol. ASCO Meeting Abstracts. 2011;29:LBA6501.
  5. Verstovsek S, Mesa RA, Gotlib J, et al. Consistent benefit of ruxolitinib over placebo in spleen volume reduction and symptom improvement across subgroups and overall survival advantage: results from COMFORT-I.Blood. ASH Annual Meeting Abstracts. 2011;118: 278.
  6. Mesa RA, Verstovsek S, Cervantes F, et al. Comparison of the efficacy of placebo and best available therapy for the treatment of myelofibrosis in the COMFORT studies. Blood. ASH Annual Meeting Abstracts. 2011;118:1753.
  7. Pardanani A, Gotlib J, Gupta V, et al. An expanded multicenter phase I/II study of CYT387, a JAK- 1/2 inhibitor for the treatment of myelofibrosis. Blood. ASH Annual Meeting Abstracts. 2011;118:3849.
  8. Bhagwat N, Koppikar P, Kilpivaara O, et al. Heterodimeric JAK-STAT activation as a mechanism of persistence to JAK2 inhibitor therapy. Blood. ASH Annual Meeting Abstracts. 2011;118:122.
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