Myelofibrosis
Lindsey Lyle, MS, PA-C
Practice Community
Aurora, Colorado
Hospital and Institutional Affiliations
Blood Cancers and Bone Marrow Transplant Program
University of Colorado Anschutz Medical Campus, Aurora, Colorado
Oncology Nurse Advisor (ONA): How is patient risk assessed in myelofibrosis?
Ms Lyle: In patients with myelofibrosis risk is assessed based on a variety of clinical and laboratory features. Risk is typically assigned at diagnosis using the International Prognostic Scoring System (IPSS) and throughout the course of the disease with the Dynamic International Prognostic Scoring System (DIPSS or DIPSS+). The IPSS estimates survival at the time of diagnosis and the DIPSS or DIPSS+ adjust risk depending on measurable components of a changing disease. The IPSS assigns 1 point for each of these adverse features: age older than 65, Hgb less than 10g/dL, constitutional symptoms, white blood cell count (WBC) greater than 25,000, and peripheral blasts greater than 1%. Using points, a patient is classified as low risk (0 points), intermediate-1 risk (1-2 points), intermediate-2 (3-4 points), or high risk (5-6 points). Estimated median overall survival for low risk patients is approximately 11 years compared to approximately 2 years for a high risk patient. More recently, additional clinical features have been identified as having prognostic significance and have been incorporated into the DIPSS+. These include platelets less than 100,000, PRBC transfusion requirements, and complex cytogenetics. Anemia with Hgb less than 10 infers a worse prognosis and counts for 2 points whereas all other components remain at 1 point. The presence or absence of different molecular mutations has become more important as we understand more about the disease biology, and although they are not incorporated into standard prognostic scoring system should be taken into account. While this is not a perfect system, assigning risk is important, as treatment can look very different for a low risk patient compared with a high risk patient.1,2,3
ONA: What are the goals of treatment of myelofibrosis?
Ms Lyle: Patients with myelofibrosis represent a fairly heterogeneous group and goals of treatment can vary depending on specific clinical needs. For example, if anemia is a patient’s main clinical problem, using therapies to try to increase red blood cell production and reduce transfusion requirements would be a primary goal. Additionally, having a large spleen can cause severe symptoms, which not only significantly affect quality of life but also increase risk for comorbid conditions such as portal hypertension. Therefore, focusing therapy on spleen size reduction is another common target of treatment. The only U.S. Food and Drug Administration (FDA)-approved therapy for myelofibrosis, ruxolitinib, reduces splenomegaly and spleen-related symptoms. In addition to identifying and directing therapy toward specific laboratory or clinical features, assigning risk helps direct goals of treatment. In high-risk patients who have a good performance status, allogeneic stem cell transplant may be indicated, as this is the best chance for a cure. Outside of a stem cell transplant, disease control, spleen size reduction, palliation of symptoms, and improvement of quality of life are the main goals of treatment. Certainly, we hope to prolong the life of these patients with therapy while maintaining as good of quality of life as possible.
ONA: What role does ruxolitinib play in the treatment of myelofibrosis? What other treatment options are considered for patients with myelofibrosis?4,5
Ms Lyle: Ruxolitinib was FDA approved for patients with intermediate and high risk myelofibrosis based on clinical trials that showed significant reduction in spleen size and improvement in symptoms related to the disease. As previously mentioned, if a patient has symptoms of the disease (eg, significant weight loss, itching, fatigue, getting full easily, pain under left ribs) they are already considered intermediate risk and it would be appropriate to start ruxolitinib therapy. Additionally, ruxolitinib is beneficial for controlling proliferation in patients with elevated or upward trending WBC. Ruxolitinib is a JAK1/2 inhibitor that targets the JAK-STAT pathway that is overactive in myelofibrosis, thus leading to suppressed hematopoiesis (reduction in leukocytosis) and reduction in pro-inflammatory cytokine production. Due to the suppression of the JAK-STAT pathway, therapy dose-related cytopenias are expected and CBC should be monitored closely.
While not FDA approved for myelofibrosis, other available treatment options outside of a clinical trial are aimed at specific disease features, as mentioned above. For anemia: androgens, prednisone, erythropoietin, immunomodulatory agents (thalidomide, pomalidomide). For the spleen: hydroxyurea, busulfan, cladribine. For symptoms: prednisone.4,5
ONA: Can you discuss the overall survival data available for the different treatment options? How does this data impact when you initiate treatment?
Ms Lyle: Available overall survival data exists for the phase III COMFORT trials with ruxolitinib as overall survival at 144 weeks was a secondary endpoint. The 3-year update from COMFORT-I revealed that survival probability was 70% for patients who were originally randomly assigned to receive ruxolitinib and 61% for those originally randomly assigned to receive placebo. In COMFORT-II the estimated probability of survival was 81% in the ruxolitinib arm compared with 61% in the best available therapy arm. Most recent updates with 5-year follow-up data in COMFORT-I show that survival was decreased in patients who initially received placebo and then crossed over to ruxolitinib compared with patients who initially started on the ruxolitinib arm. Another important point is that spleen response was maintained for a median of 3 years with many patients still having a durable response at the 5-year follow-up. The data showing a median overall survival benefit suggests that earlier exposure to therapy should be considered in intermediate or high-risk myelofibrosis.4,6-10
ONA: How do you assess and manage symptom burden in patients with myelofibrosis?
Ms Lyle: Patients can have a wide range of symptoms that can negatively affect their quality of life. The most common symptoms reported by patients with myeloproliferative neoplasms (MPN) include fatigue, early satiety, night sweats, itching, abdominal discomfort, weight loss, fevers, and bone pain. An MPN symptom assessment tool was developed by Ruben A. Mesa, MD, FACP, Director, UT Health San Antonio Cancer Center, and has been instrumental in the evaluation of presence and severity of symptoms at the initial visit and follow-up visits to help track response to treatment. Practically speaking, providing patients with symptom assessment forms for them to fill out at each visit is a great way to monitor symptoms. Often times, especially at diagnosis, patients do not know that the symptoms they are experiencing are due to the underlying MPN. In these cases, using this tool can help to educate patients and optimize care. Managing symptoms may involve a variety of therapeutic interventions. In my clinical practice the most difficult symptom to treat is fatigue. This often requires collaboration with my internal medicine colleagues and psychology team as we work to identify ways to “save energy” during the day and maximize nighttime sleep behaviors. Controlling the disease with medical therapies, such as ruxolitinib, should also help reduce symptoms
ONA: What does the future treatment landscape for myelofibrosis look like?
Ms Lyle: Clinical trials are a very important part of identifying best treatments for patients with myelofibrosis. Currently there are a variety of trials open with different biological agents that have different targets. For example, sotatercept is being used in trials with the goal to improve anemia. Trials with other JAK 1 and JAK2 inhibitors are also active. One specific JAK2 inhibitor, fedratinib, is on track for potential U.S. Food and Drug Administration approval later this year after the trial was put on hold due to 8 possible cases of Wernicke’s encephalopathy. This therapy may be especially useful in patients who have thrombocytopenia as it is less suppressive to the platelets. Additionally, combination therapies are being used more frequently especially in patients who have high risk disease/blast phase disease who are not eligible for high dose chemotherapy or allogeneic stem cell transplant. Combining therapies with ruxolitinib is also becoming more common as we hope to synergistically improve outcomes.
References
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(13):2895-2901.
2. Passamonti F, Cervantes F, Vannucchi AM, et al. Dynamic International Prognostic Scoring System (DIPSS) predicts progression to acute myeloid leukemia in primary myelofibrosis. Blood.2010;116(15):2857-2858.
3. Rumi E, Pietra D, Pascutto C, et al. Clinical effect of driver mutations of JAK2, CALR, or MPL in primary myelofibrosis. Blood. 2014;124(7):1062-1069. doi: 10.1182/blood-2014-05-578435
4. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799-807. doi: 10.1056/NEJMoa1110557
5. Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787-98. doi: 10.1056/NEJMoa1110556
6. Deisseroth A, Kaminskas E, Grillo J, et al. U.S. Food and Drug Administration approval: ruxolitinib for the treatment of patients with intermediate and high-risk myelofibrosis. Clin Cancer Res. 2012;18(12):3212-7. doi: 10.1158/1078-0432.CCR-12-0653
7. Verstovsek S, Mesa RA, Gotlib J, et al. Efficacy, safety, and survival with ruxolitinib in patients with myelofibrosis: results of a median 3-year follow-up of COMFORT-I. Haematologica. 2015;100(4):479-88. doi: 10.3324/haematol.2014.115840
8. Verstovsek S, Mesa AR, Gotlib J, et al. Long-term outcomes of ruxolitinib therapy in patients with myelofibrosis: 3-year update from COMFORT-I. Blood. 2013;122(21):abstract 396.
9. Cervantes F, Vannucchi AM, Kiladjian JJ, et al. Three-year efficacy, safety, and survival findings from COMFORT-II, a phase 3 study comparing ruxolitinib with best available therapy for myelofibrosis. Blood.2013;122(25):4047-53. doi: 10.1182/blood-2013-02-485888
10. Verstovsek S, Mesa RA, Gotlib J, et al. Long-term treatment with ruxolitinib for patients with myelofibrosis: 5-year update from the randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial. J Hematol Oncol. 2017;10(1):55. doi: 10.1186/s13045-017-0417-z
