Updates on Ruxolitinib from ASCO and ASH 2012, including Long-term Survival Data

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We believe that with these updates on ruxolitinib’s long-term safety and efficacy, the drug is now the standard of care therapy for appropriate patients with myelofibrosis.

Ruxolitinib (Jakafi), a novel, oral JAK1 and JAK2 inhibitor, was approved by the FDA on November 16, 2011 for patients with intermediate- or high-risk myelofibrosis. The approval was based on its efficacy in reducing spleen size and improving disease-related burdensome symptoms. In the brief In the Clinic commentary, “Ruxolitinib: Novel Drug for Myelofibrosis,” which appeared in the November 15 issue of The ASCO Post, there were important and clinically relevant discrepancies with the published literature, as well as the collective clinical experience with the JAK1/JAK2 inhibitor ruxolitinib used for the treatment of myelofibrosis.

Survival Benefit

This year, long-term follow-up data from two randomized controlled phase III trials (COMFORT-I and –II), with greater than 500 patients in over 150 study sites internationally, became available, and demonstrate a possible survival benefit. These novel data were presented at the 2012 American Society of Hematology (ASH) Annual Meeting and are summarized in the abstracts,1,2 showing that patients on ruxolitinib had significantly improved survival compared with both placebo (hazard ratio [HR] = 0.58; 95% confidence interval [CI] = 0.36–0.95) and best available therapy (HR = 0.51; 95% CI = 0.26–0.99).

In addition, results from an independent analysis of the intermediate-2 or high-risk myelofibrosis patients treated at The University of Texas MD Anderson Cancer Center (N = 107) in the earlier phase I/II study also support a survival advantage vs a matched (based on trial enrollment criteria) historical control group of 310 patients (P = .005).3 The survival benefits documented in these larger study populations were not observed in a smaller subset (n = 51) of patients from the phase I/II study treated at the Mayo Clinic, Rochester, compared to an unmatched historical control group, as reported in an earlier Letter to the Editor published in The New England Journal of Medicine.4

Furthermore, recently published analysis of the long-term outcomes of 107 patients with myelofibrosis receiving ruxolitinib at MD Anderson on the phase I/II trial provided evidence of durable safety and efficacy.3 After a median of 32 months of follow-up, 58 patients (54%) were still receiving ruxolitinib, with an overall survival of 69%. The splenomegaly and symptom reductions achieved with ruxolitinib were sustained with long-term therapy. Therapy was well tolerated; discontinuation rates were 24% at 1 year, 36% at 2 years, and 46% at 3 years. Comparison of discontinuation rates and reasons for stopping the therapy to those reported for the aforementioned 51 patients in the phase I/II trial at Mayo Clinic, Rochester (described in the November 15 article in The ASCO Post) suggested that continued therapy with ruxolitinib at optimal doses contributes to the benefits seen, including overall survival benefit.3

No Evidence of Withdrawal Syndrome

The lingering question of whether interruption of ruxolitinib is associated with a “withdrawal syndrome” has been thoroughly investigated in the COMFORT program5,6 and reviewed by the FDA and other health authorities. In the placebo-controlled COMFORT-I study, patient symptoms returned to baseline levels within approximately 1 week after treatment interruption, independently of the ruxolitinib dose from which interruption occurred.7 Grade 3 or 4 toxicity as well as serious adverse events that occurred during treatment interruption were infrequent, similar in occurrence to a placebo-treated patients, and showed no pattern of a defined “withdrawal syndrome.”

These data are consistent with COMFORT-II, as well as the report from the MD Anderson–treated cohort from the phase I/II trial. In the long-term follow-up of COMFORT-I, there continued to be no evidence of a “withdrawal syndrome”.1 Finally, the FDA-approved prescribing information for ruxolitinib specifically states that “there have been isolated cases of patients discontinuing [ruxolitinib] during acute intercurrent illnesses after which the patient’s clinical course continued to worsen; however, it has not been established whether discontinuation of therapy contributed to the clinical course in these patients.” These isolated clinical cases were the focus of a separate brief report.8

Additional long-term efficacy and safety results from COMFORT-I and –II were also presented at the 2012 ASH Annual Meeting. Our collective clinical experience with ruxolitinib when used outside the context of a research study is consistent with the above findings and conclusions. We believe that with these updates on ruxolitinib’s long-term safety and efficacy, the drug is now the standard of care therapy for appropriate patients with myelofibrosis. ■

—Srdan Verstovsek, MD, PhD
Professor of Medicine
Chief, Section for
Myeloproliferative Neoplasms (MPNs),
Department of Leukemia
Clinical Research Center for MPNs
The University of Texas
MD Anderson Cancer Center, Houston


Ruben A. Mesa, MD
Professor of Medicine
Chair, Division of Hematology & Medical Oncology
Deputy Director,
Mayo Clinic Cancer Center
Mayo Clinic, Scottsdale, Arizona


Ronald Hoffman, MD
Albert A. and Vera G. List
Professor of Medicine
Director, Myeloproliferative Disorders Research Program
Tisch Cancer Institute
Mount Sinai School of Medicine,
New York


Jason Gotlib, MD
Associate Professor of
Medicine (Hematology)
Director, Stanford MPN Center
Stanford University School of Medicine/
Stanford Cancer Institute
Stanford, California


Rami Komrokji, MD
Clinical Director
Department of Hematologic
Moffitt Cancer Center,
Tampa, Florida


Hagop M. Kantarjian, MD
Professor of Medicine
Chairman, Department of Leukemia
The University of Texas
MD Anderson Cancer Center, Houston

Disclosure: Drs. Verstovsek, Mesa, and Hoffman have received research support from Incyte for conduct of clinical trials. Dr. Gotlib has received research support from Incyte for conduct of clinical trials and is a participant in physician advisory boards. Dr. Komrokji is a member of the speaker bureau for Incyte. Dr. Kantarjian reported no potential conflicts of interest.


1. Verstovsek S, Mesa RA, Gotlib J, et al: Long-term outcome of ruxolitinib treatment in patients with myelofibrosis: Durable reductions in spleen volume, improvements in quality of life, and overall survival advantage in COMFORT-I. 54th ASH Annual Meeting. Abstract 800. Presented December 10, 2012.

2. Cervantes F, Kiladjian J-J, Niederwieser D, et al: Long-term safety, efficacy, and survival findings from COMFORT-II, a phase 3 study comparing ruxolitinib with best available therapy (BAT) for the treatment of myelofibrosis (MF). 54th ASH Annual Meeting. Abstract 801. Presented December 10, 2012.

3. Verstovsek S, Kantarjian HM, Estrov Z, et al: Long term outcomes of 107 patients with myelofibrosis receiving JAK1/JAK2 inhibitor ruxolitinib: Survival advantage in comparison to matched historical controls. Blood 120:1202-1209, 2012.

4. Tefferi A, Litzow MR, Pardanani A: Long-term outcome of treatment with ruxolitinib in myelofibrosis. N Engl J Med 365:1455-1457, 2011.

5. Verstovsek S, Mesa RA, Gotlib, J et al: A double-blind placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med 366:799-807, 2012.

6. Harrison C, Kiladjian JJ, Al-Ali HK, et al: JAK inhibition with ruxolitinib vs best available therapy in myelofibrosis. N Engl J Med 366:787-798, 2012.

7. Verstovsek S, Mesa RA, Gotlib JR, et al: Adverse events (AEs) and the return of myelofibrosis (MF)-related symptoms after interruption or discontinuation of ruxolitinib (RUX) therapy. 2012 ASCO Annual Meeting. Abstract 6624. Presented June 4, 2012.

8. Tefferi A, Pardanani A: Serious adverse events during ruxolitinib treatment discontinuation in patients with myelofibrosis. Mayo Clin Proc 86:1188-1191, 2011.