Myelofibrosis (MF) is a type of cancer characterized by the buildup of fibrous tissue in the bone marrow, which prevents normal blood cell formation and can lead to a low red blood cell count (anemia) and a low platelet count (thrombocytopenia) [1]. As a result, patients often experience symptoms such as fatigue, bone pain, and fever [2]. The treatment of MF is challenging. Janus kinase (JAK) inhibitors, such as ruxolitinib and fedratinib, are effective in blocking the JAK-STAT pathway (a critical signaling pathway in MF) and have demonstrated improvements in symptoms [3–7]. However, these medications may cause treatment-related anemia and/or thrombocytopenia [3–6].
The symptom profiles and responses to treatment vary among patients, which increases the complexity of patient care. Further complexity arises due to the variety of assessment tools available to determine prognosis, and deciding which is the most appropriate can be challenging. While guidelines exist for the treatment of MF, there was an unmet need for guidance to help clinicians in everyday clinical practice, particularly for treating patients with cytopenias or experiencing therapy failure. In response, an international group of expert hematologists led a consensus program to develop best practice recommendations for healthcare professionals (HCPs) to use alongside current guidelines when treating patients with MF.
Figure 1. A plain language summary of the consensus process
Achieving consensus
An overview of the consensus process is provided in Figure 1. Briefly, clinical questions were developed across five key themes, and supporting evidence was obtained from a systematic literature review (SLR). The SLR results and clinical expertise of the Steering Committee (SC) were combined to develop recommendations in response to these clinical questions. The SC and an Extended Faculty of hematologists and patients with MF then voted on the extent to which they agreed with these recommendations, providing feedback if necessary. Consensus was achieved when ≥75% of respondents agreed within the range of 7–9 on a 9-point scale (1=strongly disagree, 9=strongly agree). After three rounds of voting, consensus was achieved for all recommendations. Importantly, these recommendations do not intend to replace nor modify current guidelines, but instead act as a practical supplement for HCPs to use alongside existing guidelines when treating patients with MF.
Key highlights across the five consensus themes
Themes 1 and 2 focused on managing patients with MF and anemia or thrombocytopenia, respectively. Clinical recommendations under Theme 1 included HCPs conducting comprehensive anemia testing and using the results to select a treatment approach to manage anemia alongside treating MF. Theme 2 considered which therapies are best suited to patients with MF and thrombocytopenia, and how doses can be adjusted depending on platelet counts.
Theme 3 explored definitions of JAK inhibitor failure and suboptimal response, which reflect real-world clinical scenarios and are applicable to all JAK inhibitors, not only ruxolitinib. The clinical recommendations developed emphasized that physicians should not feel bound by the definitions for treatment failure, but rather use these as a guide for switching between therapies. Other recommendations included key parameters that can be used to monitor MF progression, and subsequently how these can guide treatment switching decisions.
Theme 4 described currently available tools for assessing patient prognosis, and their appropriate use to aid clinical decision-making. Theme 5 highlighted the importance of broadening inclusion criteria for clinical trials, with recommendations on how this may be achieved. Improving trial endpoints to be more representative of real-world clinical settings would ensure trial results are both relevant and applicable.
The patient perspective in shaping optimal care in MF
Patients living with MF have unique insights that are invaluable for improving diagnosis and treatment approaches. The patients involved in this consensus program contributed a perspective of MF outside of a purely medical standpoint, such as the burden disease has on quality of life. Effective communication between HCPs and patients, through frequent disease monitoring and collaborative decision-making, was highlighted as a key factor to optimize patient care in MF.
Implementing the results of this consensus program in the real world
Despite therapeutic advancements and increased understanding, MF remains a complex disease with heterogeneous symptom profiles and responses to treatment among patients, making it difficult for HCPs to confidently assess and implement an appropriate treatment strategy. The value of these recommendations lies in bridging existing gaps in MF treatment guidance and providing a practical framework for HCPs to use in clinical practice. These recommendations aim to optimize patient care by tailoring treatment approaches to each individual patient’s specific needs.
References
Passamonti F, Mora B. Myelofibrosis. Blood. 2023;141(16):1954–70.
Tefferi A. Myelofibrosis with myeloid metaplasia. N Engl J Med. 2000;342(17):1255–65.
Harrison C, Kiladjian JJ, Al-Ali HK, Gisslinger H, Waltzman R, Stalbovskaya V, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787–98.
Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799–807.
Pardanani A, Harrison C, Cortes JE, Cervantes F, Mesa RA, Milligan D, et al. Safety and efficacy of fedratinib in patients with primary or secondary myelofibrosis: a randomized clinical trial. JAMA Oncol. 2015;1(5):643.
Harrison CN, Schaap N, Vannucchi AM, Kiladjian J, Jourdan E, Silver RT, et al. Fedratinib in patients with myelofibrosis previously treated with ruxolitinib: an updated analysis of the JAKARTA2 study using stringent criteria for ruxolitinib failure. Am J Hematol. 2020;95(6):594–603.
Sureau L, Orvain C, Ianotto JC, Ugo V, Kiladjian JJ, Luque Paz D, et al. Efficacy and tolerability of Janus kinase inhibitors in myelofibrosis: a systematic review and network meta-analysis. Blood Cancer J. 2021;11(7):135.