Anemia response in myelofibrosis revisited

In this issue of Blood, Tefferi et al, on behalf of the International Working Group–European LeukemiaNet (IWG-ELN), propose revised criteria for assessing anemia response in myelofibrosis to harmonize evaluation and facilitate interstudy consistency.¹ Anemia in myelofibrosis is common, debilitating, and confers a negative prognostic impact on survival and quality of life.

Anemia continues to pose a significant challenge in treating myelofibrosis, and effective treatments to target anemia remains an area of need and ongoing research. The IWG-Myeloproliferative Neoplasms Research and Treatment (MRT) and ELN 2013 criteria clearly define efficacy endpoints related to splenomegaly and symptom burden, but there are inherent limitations and a lack of clarity with regard to assessing anemia response.² The 2013 anemia response assessment criteria cannot be applied broadly in trials and the incorporated hemoglobin thresholds for transfusion dependence create ambiguity.³ Improved understanding of physiological differences in hemoglobin levels in males and females, the need for consistency in assessing emerging drugs that target anemia in myelofibrosis, and current general transfusion guidelines recommending a restrictive transfusion practice have triggered the requirement for updated criteria for assessing anemia response in myelofibrosis.

A recent global harmonization study has identified higher hemoglobin thresholds for identifying anemia in males compared with females.⁴ Sex- and severity-adjusted hemoglobin thresholds were found to be more discriminative for prognosis and have been incorporated into updated risk-stratification myelofibrosis models in MIPPS 70+ version 2.⁵ These physiological and prognostic implications question the rationale of applying the same anemia threshold for treatment initiation in males and females. Tefferi et al propose applying a different hemoglobin threshold (males <11 g/dL and females <10 g/dL) for entry into clinical trials to avoid underestimation of the anemia burden in males and allow earlier interventions.

The treatment landscape of myelofibrosis is poised for change with a flurry of drugs targeting anemia. Novel JAK and ACVR1/ALK2 inhibitors (pracritinib and momelotinib) have demonstrated an ability to improve anemia-related outcomes in the PERSIST-2 and MOMENTUM studies, respectively.^6,7 Other candidate drugs, such as transforming growth factor β ligand traps like luspatercept, which target the pathogenetic bone morphogenetic protein-SMAD signaling pathway, have been shown to improve hemoglobin and transfusion dependence in myelofibrosis.⁸ A major limitation in understanding the efficacy of these drugs is the different definitions of transfusion dependence and anemia response that have been applied in those studies. The overlap of drugs between myelofibrosis and myelodysplastic syndrome to treat anemia also require a consistent and transparent approach in assessing anemia response to support ongoing drug development.

Response assessment criteria, in addition to being sensitive to meaningful change and broadly applicable, should also be consistent with current practice. Pivotal studies leading to drug approvals in myelodysplastic syndrome have used a less stringent definition of transfusion dependence. The proposed definition of transfusion-dependent anemia (TDA) is consistent with recommended restrictive transfusion practice and a limited number of transfused units per episode.⁹ Accordingly, the newly proposed definition allows ≥3 units over a 12-week period to establish TDA. A separate high-transfusion-burden subcategory is defined as ≥6 units within the 12-week period.

The revised criteria provide clear guidance on establishing the baseline hemoglobin concentration for both TDA and non-TDA for response assessment. Introduction of minor response criteria in addition to the definition of major response allows grading of response in both TDA and non-TDA in myelofibrosis. The updated criteria also define entities not previously included, namely duration of anemia response, progressive and stable anemia promoting standardized terminology in assessment, and drug development.

The criteria proposed by Tefferi et al provide a uniform framework for measuring anemia response, enabling reliable comparisons in clinical research and ultimately enhancing patient care in myelofibrosis. Application of harmonized criteria will lead to informed decision-making in the identification of effective drug treatments for improving anemia and outcomes in patients with myelofibrosis.

Conflict-of-interest disclosure: A.B. serves on the advisory committee for AbbVie; serves on advisory committee and speaker bureau and as a consultant to Amgen; serves on the advisory committee and as a consultant for Astellas; serves on advisory committee for Glaxo-Smith-Kline; and is a consultant for Novartis, Pfizer, and Takeda.