Myelofibrosis, a rare myeloproliferative neoplasm, can cause severe anemia, splenomegaly, and debilitating symptoms. It can present either as a primary condition or as a secondary condition following the transformation of essential thrombocythemia or polycythemia vera (PV), a slow-growing blood cancer in which the bone marrow produces an excess of red blood cells and often of white blood cells and platelets. Last week at the Society of Hematologic Oncology (SOHO)'s Seventh Annual Meeting, Srdan Verstovsek, MD, PhD, gave a presentation on ruxolitinib (Jakafi®, Incyte), which is approved by the FDA for the treatment of intermediate and high-risk myelofibrosis and for PV with inadequate response or intolerance to hydroxyurea. In this interview with i3 Health, Dr. Verstovsek discusses the use of ruxolitinib in the treatment of myelofibrosis and PV. He also shares information about up-and-coming therapeutic advances and gives advice for oncologists and hematologists treating patients with these conditions.
What factors should be considered in selecting patients for treatment with ruxolitinib?
Srdan Verstovsek, MD, PhD: Ruxolitinib is a good medication for patients with myelofibrosis that have symptomatic splenomegaly or general systemic myelofibrosis-related symptoms. These factors do not have a direct correlation with a risk of dying. The separation between the assessment of risk of dying and possible referral to transplant, and initiation of therapy for symptoms—either symptoms that are related to spleen or general systemic symptoms—needs to be put in place. Therefore, the National Comprehensive Cancer Network (NCCN) guidelines that are in place in the United States clearly delineate that difference. If patients are symptomatic, even if they are at low risk of dying, then they are candidates for therapy with JAK inhibitors, and the opposite is that if there is a patient who has high-risk disease and is not symptomatic, he or she should not be treated with a JAK inhibitor.
How does ruxolitinib compare with other treatments for intermediate and high-risk myelofibrosis and for PV with inadequate response or intolerance to hydroxyurea?
Dr. Verstovsek: Development of ruxolitinib for myelofibrosis was done in a way that it was compared either to placebo or to best available therapy, and it was superior in those two studies. A few weeks ago, there was a new development with the approval of another JAK inhibitor called fedratinib, which was, like ruxolitinib, compared to placebo; there was no other type of study done, just the one.
In the setting of not having a direct head-to-head comparison between fedratinib and ruxolitinib, we can with some reservation say that it appears, based on the face value of results from different studies, that the control of the spleen and symptoms appears possibly to be the same. The major difference would be in the safety of the two medications. It seems that there is a somewhat higher degree of gastrointestinal disturbance with fedratinib. Nausea, vomiting, and diarrhea occur in close to three quarters of the patients. They tend to happen at a lower grade, but they may require some supportive care medications. In addition, fedratinib has a black box warning for neurological toxicity, particularly Wernicke encephalopathy. This is possibly related to interference of uptake of thiamine, vitamin B1, from the gastrointestinal (GI) tract into the body of the patient taking fedratinib, so that needs to be measured and supplemented.
So to summarize, ruxolitinib seems to be safer and equally effective in comparison with fedratinib?
Dr. Verstovsek: Since there is no direct comparison between the two approved medications, it is difficult to say, but that appears to be the impression.
I'd also like to say that ruxolitinib is approved as a second-line therapy after hydroxyurea for PV, for which it was also compared to best available therapy, often still including hydroxyurea, but some patients did receive interferon, lenalidomide, thalidomide, or chemotherapy, and some did not receive any other treatment at all. So "best available therapy" was a concoction of different therapies, and in this second-line setting after hydroxyurea, ruxolitinib was much more active in controlling white blood cells, red blood cells, platelets, spleen, and PV-related symptoms.
What are the most common side effects of JAK2 inhibitor treatment?
Dr. Verstovsek: With some exceptions, the typical side effect of JAK inhibitors is myelosuppression. That happens with ruxolitinib. That also happens with fedratinib in the setting of myelofibrosis, apparently to the same extent, although the head-to-head comparison has not been done. About half of the patients on either ruxolitinib or fedratinib have a risk of developing significant anemia, and perhaps 15% to 20% of patients have a risk of developing significant thrombocytopenia. Other side effects with ruxolitinib are rare. The best information comes from the comparison to placebo, where it causes occasional dizziness, easy bruising, and some shortness of breath. Fedratinib causes more GI toxicity, as explained above. This is likely related to its inhibition of another protein called FLT3. Fedratinib is an FLT3 inhibitor, and it is well known that this class of drugs causes GI side effects.
What additional advancements are on the horizon for the treatment both of myelofibrosis and of PV?
Dr. Verstovsek: There are two other JAK inhibitors that are close to approval if proven valuable in phase 3 studies: momelotinib and pacritinib. Then there are a variety of other targeted agents for different abnormalities in malignant cells, ranging from epigenetic modifiers like BET/bromodomain inhibitors and PRMT5 inhibitors, to factors that would have activity on p53 expression like MDM2 inhibitors, to HSP90 inhibitors, to PRM-151, the antifibrotic agent. There is an urgent need to develop different medications other than JAK inhibitors that would, again, control symptoms and spleen, but also would improve the bone marrow function, which is a problem in all patients with myelofibrosis. There is a very active effort in place, with multiple different agents in clinical trials, to help our patients in a second-line setting after ruxolitinib or fedratinib.
Finally, what advice can you give to community hematologists and oncologists treating patients with PV or myelofibrosis?
Dr. Verstovsek: For myelofibrosis in particular, it is very important to engage patients in clinical studies. If you don't have one, look to nearby academic centers. Because of the limited treatment options, there are many, many different studies across the United States and Europe for possible accrual of patients in need of therapy for myelofibrosis. Life with myelofibrosis is hard. Bone marrow doesn't work well, and patients experience anemia, thrombocytopenia, enlarged spleen, enlarged liver, loss of weight, and poor quality of life. Let's develop new drugs together.
For PV, now we have several agents. Explore alternative options if one does not work—because we have options—and embrace the medications that have recently been approved.
About Dr. Verstovsek
Srdan Verstovsek, MD, PhD, a medical oncologist, is a Professor of Medicine in the Department of Leukemia and Director of the Clinical Research Center for Myeloproliferative Neoplasia at The University of Texas MD Anderson Cancer Center. His research is focused on understanding the biology of and developing new treatments for myeloproliferative neoplasms. The principal investigator of over 50 clinical trials of new therapies for myeloproliferative neoplasms, he has authored and co-authored over 400 peer-reviewed publications. He is the recipient of MD Anderson's Otis W. and Pearl L. Walters Faculty Achievement Award in Clinical Research, the Society of Hematologic Oncology's Distinguished Lecturer Award, and the MD Anderson Division of Cancer Medicine's Irwin H. Krakoff Award for Excellence in Clinical Research.
For More Information
Dr. Verstovsek is the Chair of i3 Health's CME-approved visiting faculty meeting series, New Clinical Perspectives in the Management of Myelofibrosis. Contact i3 Health to request a meeting if you are interested in hosting this free presentation at your institution.
Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily represent those of i3 Health.