Ruxolitinib for Myelofibrosis: From ‘Palliation’ to Prolongation of Survival
Ruxolitinib for Myelofibrosis: From ‘Palliation’ to Prolongation of Survival
Myelofibrosis is the most aggressive of the classic myeloproliferative neoplasms. It is characterized by progressive bone marrow fibrosis and osteosclerosis; worsening blood cell count with development of significant anemia; extramedullary hematopoiesis with splenomegaly and hepatomegaly; and significant constitutional symptoms, including bone pain, night sweating, low-grade fevers, and weight loss. Patients experience progressive deterioration of their quality of life and die prematurely after an average of 5 years. In 2005, the discovery of the Janus kinase (JAK) gene mutation at residue V617 (JAK2V617F) in most patients with myeloproliferative neoplasm led to the development of JAK inhibitors as therapy for these patients, particularly for patients with myelofibrosis. Ruxolitinib (Jakafi) is an oral JAK1 and JAK2 inhibitor that was approved in the United States by the Food and Drug Administration in 2011 and in 2012 by the European Medicines Agency for treatment of patients with myelofibrosis. Ruxolitinib inhibits the hyperactive JAK-STAT (Janus kinase/signal transducers and activators of transcription) pathway, which is a pathophysiological abnormality in all patients with myeloproliferative neoplasms. In patients with myelofibrosis, inhibition of the JAK-STAT pathway results in antiproliferative and anti-inflammatory effects that translate into significant clinical benefits for patients: significant reduction in organomegaly (splenomegaly and hepatomegaly) and significant improvement in debilitating myelofibrosis-related constitutional symptoms. Ruxolitinib is effective therapy for patients with and without the JAK2V617F mutation. Testing for the presence of JAK2V617F mutation is useful as a part of the diagnostic process for myeloproliferative neoplasms, but the absence of this mutation should not have an influence on therapeutic decision making. Patients without the JAK2V617F mutation have the same chance of responding to ruxolitinib as those with the mutation. In this issue of ONCOLOGY, Dr. Kremyanskaya and colleagues clarify the use of ruxolitinib in patients with myelofibrosis. In this commentary on the article, I will provide additional information about the pros and cons of ruxolitinib therapy and highlight salient points that may lead to improved management of patients receiving ruxolitinib in everyday practice.
Ruxolitinib reduces splenomegaly in a great majority of patients with myelofibrosis. It has been shown that as little as a 10% reduction in splenic volume is clinically beneficial for these patients. Naturally, therefore, patients with symptomatic splenomegaly are good candidates for therapy with ruxolitinib. Ruxolitinib also improves hepatomegaly in patients, although at a slower rate. Some patients with advanced myelofibrosis may have debilitating myelofibrosis-related constitutional symptoms, without the presence of organomegaly. Since the effectiveness of ruxolitinib in alleviating patients’ systemic symptoms does not depend on the presence of organomegaly, patients in this setting are also good candidates for therapy with ruxolitinib, as it enables patients to improve their performance status and gain weight, while eliminating constitutional symptoms. Long-term follow-up of patients on ruxolitinib reveals that patients who were maintained on the 10-mg twice-a-day dose of ruxolitinib, or higher doses, had a very good, durable control of splenomegaly and improvement in their quality of life.
Thrombocythemia and anemia are the main side effects of ruxolitinib therapy, and usually develop during the first few months following initiation of therapy. Close monitoring of patients during this period and proactive dose adjustments are highly recommended. Maintaining the patient on therapy without interruptions is important because interruptions lead to a loss of response in symptom control within 7 to 10 days. Therefore, adjustments to a dose as low as 5 mg twice a day in cases of myelosuppression are prudent to maintain the patient under therapy; the dose can then be increased to 10 mg twice a day or higher as soon as it is safely possible, to achieve long-term benefit. By following this approach for almost all patients, one can arrive at an effective and safe dose regimen, with only rare patients discontinuing therapy due to myelosuppression. Once-daily dosing of ruxolitinib should not be used, due to the short half-life of the medication and a lack of significant clinical activity with this schedule. If interruption of ruxolitinib therapy is necessary, tapering off ruxolitinib or using corticosteroids upon discontinuation has been suggested.
After splenomegaly/hepatomegaly and a very poor quality of life, anemia is the third main clinical problem in patients with myelofibrosis. Its presence traditionally has been managed by anti-anemia medications, including danazol (Danocrine), prednisone, or erythropoietin. While ruxolitinib can cause worsening of anemia in some patients, the presence of anemia is not a contraindication to its use. To avoid worsening anemia, one may consider starting ruxolitinib therapy at a lower dose, ie, 10 mg twice a day, and increasing it in monthly increments to a safe and effective dosing regimen. While this particular approach has not been formally evaluated yet in a clinical study, a similar approach has been tested in patients with low platelet counts. In patients with low platelet counts, starting with ruxolitinib at 5 mg twice a day, and increasing the dosage in monthly increments to 10 mg twice a day or higher, has been reported to be relatively safe. Another approach that can help patients with anemia who are receiving ruxolitinib is to use a combination of medications, combining ruxolitinib with danazol, for example. Although not yet formally tested in clinical studies, there are good clinical grounds for following this strategy. With each of these approaches, it is important to remember that finding the best dose for a patient during the first few months of therapy is imperative, because dose increases at later time points have been reported to be less effective.
Patients with advanced myelofibrosis, those with intermediate-2 and high-risk disease, have been the primary patient population in clinical studies with ruxolitinib so far. Most recent updates of the two phase III COMFORT (COntrolled MyeloFibrosis study with ORal JAK inhibitor Treatment) trials, which led to FDA approval of ruxolitinib, reveal a survival advantage for patients randomized to ruxolitinib therapy. In the COMFORT-I study, patients were randomly assigned to either ruxolitinib or placebo in a blinded fashion. Three quarters of patients in the placebo arm crossed over to ruxolitinib therapy after an average of 41 weeks. Despite the large number of patients on the placebo arm now receiving ruxolitinib, there has been a statistically significant difference in overall survival reported between the two arms in the intent-to-treat analysis; patients who were randomly assigned to ruxolitinib in the beginning of the trial had a survival advantage. A recent update of the COMFORT-II study, in which patients were randomly assigned to either ruxolitinib or best available therapy (BAT), showed similar results. Despite the fact that approximately half the patients initially randomized to BAT crossed over to ruxolitinib, there was a statistically significant difference in overall survival: the mortality rate has been reduced by half in patients initially randomized to ruxolitinib. How do we explain the extension of life in patients on ruxolitinib? Ruxolitinib provides good control of the disease’s signs and symptoms, in large part via an inhibition of inflammatory cytokines, levels of which are known to be extremely high in patients with myelofibrosis. Certain cytokine levels have been associated with outcome in this setting. By inhibiting inflammatory cytokines and controlling the signs and symptoms of myelofibrosis, the patient’s body condition improves as the disease is kept under good control. Ultimately, prolonged exposure of a patient with myelofibrosis to ruxolitinib at a clinically effective dose results in prolongation of the his or her life.
Financial Disclosure: Dr. Verstovsek has received research support from Incyte.
1. Mascarenhas J, Mughal TI, Verstovsek S. Biology and clinical management of myeloproliferative neoplasms and development of the JAK inhibitor ruxolitinib. Curr Med Chem. 2012;19:4399-4413.
2. Verstovsek S. Ruxolitinib: an oral Janus kinase 1 and Janus kinase 2 inhibitor in the management of myelofibrosis. Postgrad Med. 2013;125:128-135.
3. Kremyanskaya M, Atallah E, Hoffman R, Mascarenhas J. Clarifying the use of ruxolitinib in patients with myelofibrosis. Oncology (Williston Park). 2013;26:706-714.
4. Mesa RA, Gotlib J, Gupta V, et al. Effect of ruxolitinib therapy on myelofibrosis-related symptoms and other patient-reported outcomes in COMFORT-I: a randomized, double-blind, placebo-controlled trial. J Clin Oncol. 2013;31:1285-92.
5. Benjamini O, Jain P, Estrov Z, Kantarjian HM, et al. Therapeutic effects of ruxolitinib in patients with myelofibrosis without clinically significant splenomegaly. Blood. 2012;120:2768-9.
6. 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 Abstracts. 2012;120:Abstr 800.
7. Talpaz M, Paquette R, Afrin L, et al. Efficacy, hematologic effects, and dose of ruxolitinib in myelofibrosis patients with low starting platelet counts (50-100 × 109/L): a comparison to patients with normal or high starting platelet counts. 54th ASH Annual Meeting Abstracts. 2012;120:Abstr 176.
8. Geyer H, Cannon K, Knight E, et al. Ruxolitinib in clinical practice for therapy of myelofibrosis: single USA center experience following FDA approval. Leuk Lymphoma. 2013. In press.
9. Vannucchi A, Kiladjian JJ, Cervantes F. Long-term outcomes from a phase 3 study comparing ruxolitinib with best available therapy (BAT) for the treatment of myelofibrosis (MF): a 3-year update of COMFORT-II. Presented at the 18th Congress of the European Hematology Association. June 13-16, 2013. Stockholm, Sweden. Available from: http://www.ehaweb.org.
10. Mascarenhas J, Hoffman R. A comprehensive review and analysis of the effect of ruxolitinib therapy on the survival of patients with myelofibrosis. Blood. 2013. In press.