The term myelofibrosis (MF) is collectively used to denote a collection of myeloproliferative conditions including primary myelofibrosis (PMF) and myelofibrosis as part of a progression from related but different conditions polycythemia vera (PV) and essential thrombocythemia (ET); also known as post-ET MF or post-PV MF. MF, however it arises, is characterized by abnormalities of the blood counts, especially anemia; circulating immature cells (leukoerythroblastosis), progressive splenomegaly, and a variety of symptoms affecting quality-of-life (QoL)Citation1. Such symptoms include unexplained fever, drenching night sweats, and weight loss (often termed ‘constitutional symptoms’), abdominal discomfort, and pain due to massive spleen enlargement, bone, muscles or joint pain, pruritus, and profound fatigue. Prognosis is variable and death usually occurs due to progression (including but not exclusively acute leukemia), infections, thrombotic events, hemorrhage, and inanition. Abnormal activation of the JAK/STAT signaling pathway was identified as a key factor in pathogenesis in many patients due to a specific mutation, JAK2V617F, in 50–60% of patients, which was first identified in 2005; or a variety of similar mutations which were subsequently describedCitation2,Citation3.
Treatment for MF has been unsatisfactory with the inability of most agents to control systemic manifestations or influence prognosis, the only curative treatment being bone marrow transplantation which is applicable to very few, i.e. less than 10% of patients and associated with significant morbidity and mortalityCitation4,Citation5. This situation changed as we, and others, began to explore the benefits of a novel agent INCB018424 (ruxolitinib), which showed largely unanticipated efficacy against disease-associated symptoms and spleen size. These results were confirmed and expanded in the phase-3 COMFORT studies that compared ruxolitinib with placebo (COMFORT-I)Citation6 or best available therapy (COMFORT-II)Citation7 in patients with intermediate-2 and high risk MF. A greater proportion of patients in the experimental arm of COMFORT-I (45.9%) than in the placebo group (5.3%; p < 0.001) achieved a > 50% reduction in the total symptom score (TSS) from baseline. TSS is the calculated mean score for 10 items addressing fatigue, concentration, early satiety, inactivity, night sweats, itching, bone pain, abdominal discomfort, weight loss, and fever. This improvement of TSS occurred across different patient sub-groups, including type of MF, a JAK2 mutated or wild-type state. Similarly, the COMFORT-II study reported better QoL outcomes and improved role of functioning using the EORTC QLQ-C30 and FACT-Lym sub-scales. Overall survival benefit was a planned analysis but not the primary end-point of these studies and, although there was a comprehensive array of multiple scientific end-points none of these were identified a priori as surrogate markers of disease improvement. However, both studies did demonstrate a survival advantage as part of a pre-planned 15-month analysis for COMFORT-ICitation6 and at 3 years for COMFORT-IICitation8.
In 2011 ruxolitinib was approved by the FDA for the treatment of intermediate and high risk MF and in 2012 by the EMA for the treatment of splenomegaly and symptoms associated with MF; however, reimbursement of the costs of this life altering drug has been a problem in many countries. This is due to the fact that in many health economies not only does a drug or intervention have to demonstrate clinical worth, but it must also demonstrate health economic worth too. There was a gap in our understanding of the disease and a lack of endpoints which could link to both health economic worth (for example the EQ5D analysis both at baseline for the disease state and benefit of the drug); and also a lack of early demonstration of survival advantageCitation9. In a previous Journal of Medical Economics article, pharmacoeconomic modelling of the benefit of ruxolitinib as impacted by survival is presented by Vandewalle et al.Citation10; this should be contrasted with the aforementioned initial appraisal of ruxolitinib for the UK agency National Institute of Clinical Excellence which was conducted without accounting for survival benefit since it had not yet been demonstrated in COMFORT-II. While there are weaknesses in the paper by Vandewalle et al., including assumption of cost discount and some lack of clarity about health states and how a patient might move between them, the paper clearly demonstrates that ruxolitinib is increasingly likely to be reimbursed as the impact of survival advantage on drug costs becomes apparent.
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Declaration of funding
None declared.
Declaration of financial/other relationships
CH has received sponsorship/served as a speaker and on advisory boards/served as a consultant for Novartis, Shire, Sanofi, Gilead, CTI, YM Bioscience, Incyte, and Baxalta.
Department of Haematology, Guy's and St Thomas' NHS Foundation Trust, London, UK[email protected]
References
- Cervantes F. How I treat myelofibrosis. Blood 2014;124:2635-42
- Nangalia J, Massie CE, Baxter EJ, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med 2013;369:2391-405
- Klampfl T, Gisslinger H, Harutyunyan AS, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med 2013;369:2379-90
- Barbui T, Barosi G, Birgegard G, et al. Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. J Clin Oncol Off J Am Soc Clin Oncol 2011;29:761-70
- Kroger NM, Deeg JH, Olavarria E, et al. Indication and management of allogeneic stem cell transplantation in primary myelofibrosis: a consensus process by an EBMT/ELN international working group. Leukemia 2015;29:2126-33
- Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med 2012;366:799-807
- Harrison C, Kiladjian J-J, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med 2012;366:787-98
- 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;122:4047-53
- Wade R, Rose M, Neilson AR, et al. Ruxolitinib for the treatment of myelofibrosis: a NICE single technology appraisal. Pharmacoeconomics 2013;31:841-52
- Vandewalle B, Andreozzi A, Almeida J, et al. Pharmacoeconomics of ruxolitinib therapy in patients with myelofibrosis. J Med Econ 2016; Jan 8:1-8. [Epub ahead of print]