Managing Patients With Myelofibrosis Following Ruxolitinib Failure

Srdan Verstovsek, MD, PhD

Professor
Division of Cancer Medicine
Department of Leukemia
The University of Texas MD Anderson Cancer Center
Houston, Texas


Srdan Verstovsek, MD, PhD, has disclosed that he has received funds for research support from Blueprint Medicines, Celgene, CTI BioPharma, Genentech, Gilead Sciences, Incyte, Novartis, NS Pharma, Promedior, and Roche and consulting fees from Celgene, Constellation, Incyte, Novartis, Pragmatist, and Sierra.


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Released: October 7, 2019

The JAK1/2 inhibitor ruxolitinib is now a standard first-line therapy for patients with symptomatic and/or higher-risk myelofibrosis based on findings from the randomized phase III COMFORT-I and -II studies, which showed significant improvements in spleen responses, symptom reduction, and survival with ruxolitinib vs placebo and/or best available therapy. Despite this, for many patients, the response to ruxolitinib is finite, with the median duration of spleen response being approximately 3 years. Many patients who lose response or experience intolerance to ruxolitinib proceed to second-line treatment with immunomodulatory drugs, chemotherapy, or hypomethylation agents, with which outcomes are poor; quality of life suffers due to spleen and liver enlargement, anemia, and thrombocytopenia, and median survival is limited to approximately 14-23 months after ruxolitinib discontinuation. Given the poor outcomes with current modalities, what are the best options for patients in this challenging setting?

Clinical Trials
Participation in clinical trials is recommended, where available, for patients with intolerance or resistance to ruxolitinib. Numerous agents are now in various stages of clinical development. For example, the JAK2/IRAK1 inhibitor pacritinib showed promise in treating patients with previous ruxolitinib experience in the phase III PERSIST-2 trial and is currently undergoing further evaluation in patients with intolerance or resistance to ruxolitinib in the phase II PAC203 trial, with the phase III PACIFICA trial planned for later this year.  In addition, momelotinib, a JAK1/2 inhibitor, was found to be active in patients previously treated with ruxolitinib in the phase III SIMPLIFY 2 trial, with benefits seen in spleen response and anemia improvement. This agent will continue to undergo evaluation in the phase III MOMENTUM trial in the second-line setting for patients with symptomatic myelofibrosis who are anemic.

Various additional agents are also in clinical development, including the telomerase inhibitor imetelstat—with which promising survival was observed in the phase II MYF2001 trial in patients who were relapsed/refractory after ruxolitinib treatment—as well as antifibrotics such as PRM‑151. Another area of active research involves evaluating combinations with ruxolitinib for patients who have had suboptimal spleen and symptom responses or have significant anemia despite treatment with this agent. Combinations currently under investigation include ruxolitinib plus azacytidine, decitabine, interferon, lenalidomide, thalidomide, or the PI3K inhibitor INCB050465.

An analysis presented at the 2019 European Hematology Association Congress reported that treatment with novel agents was associated with a significant survival benefit vs conventional therapies for patients previously treated with ruxolitinib. Although these findings were limited by the retrospective, nonrandomized nature of the analysis, they suggest that receiving novel agents through clinical trials may offer benefit for patients with intolerance or resistance to ruxolitinib.

Fedratinib
In August 2019, the FDA approved fedratinib—a JAK2-specific inhibitor that also targets FLT3—as a treatment option for patients with intermediate 2–risk and high-risk myelofibrosis. This approval was based on the randomized phase III JAKARTA trial, which demonstrated a significantly higher rate of spleen volume reduction with fedratinib vs placebo for patients with myelofibrosis who were naive to JAK2 inhibitors.

The single-arm phase II JAKARTA-2 trial assessed fedratinib treatment specifically in patients with myelofibrosis who were intolerant or resistant to ruxolitinib. Data presented at ASCO 2019 indicated that fedratinib is active in this setting, with a spleen volume response rate of 31% and a symptom response rate of 27%. These rates are much higher than those observed with other available options in this setting. Based on our experience with ruxolitinib, I anticipate that we will see improved survival with fedratinib, given its control of symptoms. Although the JAKARTA-2 data were noncomparative, the ongoing randomized FREEDOM2 trial is comparing fedratinib vs best available therapy for patients with myelofibrosis who were previously treated with ruxolitinib. At this time, I believe it is reasonable to consider fedratinib for our patients in the second‑line setting after ruxolitinib.

Your Thoughts?
What treatment options do you currently recommend to your patients with myelofibrosis who are intolerant or resistant to ruxolitinib? Please answer the polling question on your screen and share your thoughts in the comments box.

Attending the ASH annual meeting in Orlando this year? Sign up here to attend CCO’s satellite symposium, “Approaches to the Individualized Management of MPNs: Best Practices and Guidance to Optimize Care,” on the evening of Friday, December 6, during which I will discuss patient case studies and recent advances in the treatment of myeloproliferative neoplasms with our esteemed panel, including Jean Jacques Kiladjian, MD, PhD; Raajit Rampal, MD; and Alessandro M. Vannucchi, MD. Not attending ASH but still want to view this exciting educational event? Sign up here to watch the live simulcast from your computer.

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