Myelofibrosis management in routine clinical practice with a focus on patients with cytopenias: recommendations from a global consensus group

Myelofibrosis (MF) is a Philadelphia chromosome ( BCR::ABL1 )-negative myeloproliferative neoplasm, a hallmark of which is progressive deposition of fibrotic tissue in bone marrow [ 1 ]. Clinical manifestations of MF often include splenomegaly, cytopenias (such as severe anemia), and extramedullary hematopoiesis [ 1 ]. The Janus kinase inhibitor (JAKi) therapies ruxolitinib (RUX) and fedratinib (FED) have demonstrated significant clinical efficacy in splenic volume reduction and symptom improvement, but they may induce treatment-related anemia and thrombocytopenia [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 ]. Other JAKi options include pacritinib (PAC), which received FDA approval in 2022 for patients with MF and severe thrombocytopenia (platelet count <50 × 10 9 /l), and momelotinib (MMB), which received FDA and EMA approval in 2023/2024, respectively, for patients with MF and anemia [ 10 , 11 , 12 ]. Clinical trials with JAKis in MF are summarized in reference [ 1 ]. National and international guidelines exist for the management of MF; however, a need remains for practical guidance applicable in everyday clinical practice, especially for patients experiencing cytopenias or potential failure of current therapy. The landscape is further complicated by the availability of multiple prognostic tools for MF; as such, clinicians may find disease prognostication challenging and confusing. Additionally, to maximize clinical applicability of trial data, inclusivity of eligibility criteria in the context of the real-world MF patient population should be considered. Recognizing these significant challenges, an international expert consensus group was established to provide best practice recommendations for healthcare professionals, intending to supplement, but not replace, existing guidelines. The consensus program was conducted between March and September 2023, led by a Steering Committee (SC) of nine international hematology experts. The program utilized a modified Delphi methodology; the SC performed several rounds of consensus statement review before submission to the Extended Faculty (EF) of hematologists and patients—nominated by the SC—for a decisive vote. Funding was provided by GlaxoSmithKline (GSK), Brentford, UK. Importantly, GSK had no involvement in formulating questions or recommendations, and no representative participated in the voting process. The SC identified 25 key clinical questions across five consensus themes: 1. Defining the thresholds for anemia, and when to initiate/modify treatment 2. Defining the threshold for thrombocytopenia and when to initiate/modify treatment 3. Defining JAKi failure and what would warrant switching treatment 4. How and when to determine prognosis in patients with MF 5. Unmet needs in MF clinical trials The EF assessed the importance of the questions, resulting in the selection of the 15 highest scoring questions for the consensus program. To address each, a systematic literature review was conducted following the PICO (Population, Intervention, Comparison, Outcome) framework, providing a comprehensive evaluation of relevant evidence (see Supplementary Table S1 ). From this, the SC developed a clinical recommendation (CR) to address each question. An online voting platform was used to obtain agreement scores for each recommendation from the SC (nine hematologists) and EF (20 hematologists and nine patients). 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). The strength of each recommendation was identified by obtaining the median and mean values from the votes (see Table 1 ). The level of consensus was determined by the percentage of votes falling within the range of 7–9 among all obtained votes. Table 1 Consensus recommendations. Full size table Following the first voting round, consensus was achieved among voters (hematologists [ n = 29] and patients [ n = 9] from Europe, the United States, Canada, Australia, Israel, and India) for all 15 recommendations. Upon reviewing the feedback from voters who scored recommendations ≤6, and in the interest of producing the best outcome, the SC amended nine of the 15 recommendations for a second round of voting, after which consensus was achieved among voters (hematologists [ n = 21] and patients [ n = 5]) for eight of the nine recommendations that were submitted for revote. Following amendment of the remaining recommendation for a third voting round, consensus was achieved among voters (hematologists [ n = 20] and patients [ n = 4])—13 recommendations achieved consensus in the range of 90–100% and two in the range of 80–90%. The CRs are provided in Table 1 , with a full description of feedback from each voting round in Supplementary Tables S2 – S9 . The recommendations are not intended to replace or modify/update existing guidelines. Theme 1 (CR1–CR4) focused on optimizing anemia management in MF. Diagnosing and addressing anemia in patients with MF is complex, as it is frequently multifactorial and may be disease and/or treatment related [ 13 ]. A comprehensive workup, accurate diagnosis, and appropriate treatment are of critical importance. All current and emerging treatment options for MF- and treatment-related anemia should be considered and are outlined in Table 2 . Importantly, only MMB is approved specifically for MF-related anemia [ 11 , 12 ]. In addition to JAKi monotherapy, existing data support the efficacy of RUX-based combination therapies in managing MF with anemia; clinical trials featuring RUX-based combination therapies are summarized in reference [ 14 ]. Table 2 Current and emerging treatments for anemia in myelofibrosis. Full size table Theme 2 (CR5–CR7) considered the management of patients with MF and thrombocytopenia. Recommendations from the German Society of Hematology and Medical Oncology and the Society of Thrombosis and Hemostasis Research [ 15 ] can be used as a foundation for treatment decisions for patients with thrombocytopenia. MMB and PAC are the only JAKis specifically approved for use in patients with severe thrombocytopenia (at platelet counts ≥25 × 10 9 /l and <50 × 10 9 /l, respectively) [ 10 , 11 , 12 ]. For patients with platelet counts of 50–100 × 10 9 /l, the options are less clear. Consideration should be given to JAKi dose optimization/intensity, severity of anemia, tolerance of worsening thrombocytopenia, and concomitant medications, and be balanced against the reason for treatment. Theme 3 (CR8–CR11) discussions included defining JAKi failure; while the stringent criteria for RUX failure (Supplementary Table S10 ) serve as a useful starting point, collaborative efforts should focus on their refinement to accurately differentiate intolerance and resistance, reflecting real-world clinical scenarios and a patient’s overall condition, and be applicable to JAKis other than RUX. Defining suboptimal response was challenging due to variable disease presentation and treatment goals, but was conceptualized as JAKi therapy benefiting the patient in certain aspects, but not meeting specified therapeutic targets. Parameters for assessing treatment response were then explored, as well as strategies for treatment switching. Importantly, physicians should not feel bound by definitions of relapsed, refractory, and suboptimal response; they are a guide to help inform the timing of potential treatment switches. Theme 4 (CR12 and CR13) examined the utility of prognostic scoring tools (Supplementary Table S11 ) and clinical variables in predicting survival benefits, to guide clinical decision-making. Theme 5 (CR14 and CR15) emphasized the need for broader inclusion criteria in clinical trials, while advocating for improved trial endpoints to enhance their relevance and applicability in real-world clinical settings. Patient insights should be central to shaping the MF diagnosis and treatment landscape, and patients in the EF involved in this program understood the importance of recommendations that help to ensure consistent and comprehensive care. Including patients in the EF ensured appropriate consideration was given to aspects outside a strictly medical viewpoint, such as burden of illness/therapy and quality of life. Patients highlighted the importance of effective communication and the development of trust between patients and healthcare professionals; this, in turn, facilitates patients’ active involvement in their own care, and effective shared decision-making based on mutual understanding. Patients want to know their condition is frequently and consistently monitored, and that their best interests remain the focal point of care. The recommendations presented herein provide an up-to-date overview of contemporary MF treatment, offering a valuable supplement to existing treatment guidelines without aiming to replace them. A strength of this program lies in its recruitment of a diverse, international group, comprising an SC of nine expert hematologists and an EF of 20 hematologists and nine patients, thus ensuring robustness of the process and the incorporation of the patient perspective. The rigorous development process, involving multiple rounds of enhancements and revoting, highlighted the prevailing ambiguity and variability in current clinical practices, and underscored the importance of recommendations to guide and standardize care. A limitation of these recommendations pertains to the relatively small number of experts and patients who actively participated in the voting process. Furthermore, an inherent weakness of the consensus-building process emerged, marked by a drop-off in participation during the voting rounds. However, this challenge is expected when accommodating diverse perspectives and expertise. Additionally, at present, there is a lack of available data for certain agents discussed herein in the context of MF. This gap indicates the need for continued research and data collection to inform comprehensive clinical decision-making. Finally, since completion of the voting rounds, MMB was approved by the FDA and EMA as the first treatment for adults with intermediate- or high-risk MF and anemia. While clinical recommendations were initially crafted prior to its approval, our work was revised in acknowledgment of this approval, with all co-authors contributing to these revisions. In this collaboration between an international panel of physicians with expertise in MF and a diverse EF, a high level of consensus was achieved on recommendations addressing a wide range of critical gaps in MF management. These recommendations provide a valuable framework to support clinicians in optimizing care for patients with MF. Additional information The third party material in this article (Table 2 and Supplementary Table S10 ) is licensed under the Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/ .

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