Proposals for revised International Working Group–European LeukemiaNet criteria for anemia response in myelofibrosis Free

Anemia in myelofibrosis (MF) is frequent, mechanistically multifactorial, and molecularly aligned with certain mutations, including U2AF1. In 1 large study,¹ ∼86% of patients with primary MF presented with anemia, ranging in severity from mild (35%) to severe (37%), with respective lower limit hemoglobin (Hb) values of ≥10 g/dl (35%) and <8 g/dL (37%).¹ Pathogenetic mechanisms include clone-intrinsic defects, splenic sequestration, and deregulated/iron-restricted erythropoiesis. Some of these abnormalities are mediated by an abnormal cytokine milieu involving inflammatory cytokines and hepcidin.² The prognostic relevance of anemia in MF is formally recognized by contemporary risk models.³ A correlation between anemia response in MF and improved quality of life (QoL) has previously been reported.⁴ 

Allogeneic cell transplantation is currently the only curative treatment in MF.⁵ Drug therapy is effective in alleviating disease-associated symptoms, including splenomegaly. JAK2 inhibitor (JAKi) therapy offers class-wide benefit in reducing spleen size and ameliorating constitutional symptoms.^6-9 However, the management strategies for MF-associated anemia have limited and short-term benefit. The first 2 Food and Drug Administration-approved JAKis, including ruxolitinib⁸ and fedratinib,⁷ are more likely to exacerbate rather than improve anemia. More recently introduced JAKis, including momelotinib⁶ and pacritinib,⁹ were less detrimental to erythropoiesis with documentation of anemia response in some patients, attributed to an off-target inhibition of activin A receptor, type 1 (ACVR1)/activin receptor-like kinase-2.¹⁰ 

The recognition that the transforming growth factor β–bone morphogenic protein (BMP)–Suppressor of Mothers against Decapentaplegic (SMAD) signaling pathway participates in the pathogenesis of ineffective and iron-restricted erythropoiesis in MF has led to a flurry of recent clinical trials with drugs directed at different components of the BMP-SMAD signaling pathway. Candidate drugs, in this regard, include transforming growth factor β ligand traps (eg, luspatercept,¹¹ sotatercept,¹² and elritercept¹³), ACVR1/activin receptor-like kinase-2 inhibitors (eg, momelotinib,⁶ pacritinib,¹⁴ and zilurgisertib¹⁵), and inhibitors of SMAD 1/5/8 signaling, including monoclonal antibody treatment targeting hemojuvelin, a coreceptor in the BMP signaling pathway.¹⁶ Another pathway of relevance involves the hypoxia-inducible factor-prolyl hydroxylase, and its inhibition with roxadustat has also been reported to have potential value in the treatment of anemia associated with myelodysplastic syndrome (MDS).¹⁷ 

The above-outlined activities signaled the need to revisit anemia response criteria in MF, previously reported by members of an International Working Group and European LeukemiaNet (IWG-ELN) committee.¹⁸ The current project was further inspired by the lack of uniformity among current clinical trial and working group definitions of transfusion status and anemia response in MF (Table 1).

Senior members of the 2013 IWG-ELN committee (T.B., G.B., A.M.V., F.P., and A.T.) were summoned with the objective to review current definitions of anemia and response criteria cited for MF and MDS (Tables 1 and 2) and prepare a set of proposals for a revised document. After securing 100% agreement among the 5 senior authors, the initial draft was circulated separately to (1) authors of the 2013 edition of the IWG-ELN response criteria in MF (overseen by A.T., who was the lead author of the project); (2) members of the ELN committee on myeloproliferative neoplasms (overseen by T.B., who is the chair of the ELN myeloproliferative neoplasm committee); and (3) a broader international panel of experts and clinical trialists in MF (overseen by A.T.). A second draft was then prepared based on discussions and feedback from each group and subsequently circulated to the entire panel for additional review before the final draft was prepared and once again circulated to secure unanimous agreement on the articles proposed (Table 3).

In principle, the authors find the commonly used Hb level of <10 g/dL as a key inclusion criterion for clinical trials targeting anemia in MF to be reasonable and in line with what has often been applied in previous studies in MF and MDS (Tables 1 and 2). However, the specific threshold overlooks physiological differences between men and women³⁰; in a Mayo Clinic study of anemia in MF,¹ the prognostic contribution of moderate or severe anemia (Hb <10 g/dL) was apparent in both men and women, whereas that of mild anemia (Hb ≥10 g/dL and less than sex-adjusted lower limit of normal) was apparent only in men. In other words, the severity of anemia in men was underestimated when using a Hb cutoff level of 10 g/dL. The specific concern has since been addressed in the context of contemporary risk models in primary MF³ and MDS,³¹ in which gender-specified Hb levels are used for risk stratification. Therefore, it is reasonable to do the same in the setting of clinical trials, and earlier intervention for Hb levels <11 g/dL might also provide protection from the risk of cardiac remodeling and QoL.³² 

The 2013 IWG-ELN definition of transfusion-dependent anemia (TDA) and response criteria were purposefully stringent, in prospect of disease-modifying targeted therapies; other definitions were either similar or more lenient and often inconsistent (Table 1). A similar pattern is apparent regarding TDA definitions in MDS (Table 2). Transfusion practices in the United States have significantly changed over the last few years, with more restrictive transfusion trigger and limitation of units transfused per episode.³³ The authors considered all of the above and agreed on ≥3 units per 12 weeks to define TDA, in line with definitions used in pivotal studies leading to recent drug approvals in MDS^27,26; the 12-week observation period would also be consistent with the required time interval for response assessment (Table 3). Patients requiring ≥6 units, within the 12-week preenrollment period constitute a high transfusion burden subcategory (Table 3). The panel voted to dispense with the requirement for Hb to be <8.5 g/dL to trigger transfusion considering the current state of restrictive transfusion practices and the requirement for a concomitant increase in Hb level from baseline to qualify as a response in TDA (Table 3).

For TDA, the 2013 IWG-ELN response criteria included a 12-week transfusion-free period, capped by a Hb level of ≥8.5 g/dL (Table 3).¹⁸ The authors agreed on preserving the 12-week transfusion-free period for “major” response (Table 1). In addition, to minimize overcalling responses stemming from variable transfusion practices, a concomitant and durable (12 weeks) increase in Hb level by an average of ≥1.5 g/dL from pretreatment baseline is required to confirm major response (Table 3). Furthermore, the panel underscores the need for transfusion policy for the individual patient to remain the same before and after study enrollment. In non-TDA, major response requires a rolling 12-week average of ≥1.5 g/dL increase in Hb from pretreatment baseline; the latter is defined as the average of the lowest 3 Hb levels in the 12 weeks before enrollment, including 1 reading collected in the 28 days before enrollment. The rationale for decreasing the required margin of Hb increase from 2 to 1.5 g/dL for major anemia response includes increasing awareness on the existence of multiple causes for MF-associated anemia, which makes it difficult for a single anemia-targeting drug by itself to produce a robust response. Furthermore, anemia response criteria used in the most recent study in MDS that led to the approval of luspatercept (Table 2) was consistent with the proposals herein set forth for MF (Table 1). Responses that do not meet the above-outlined criteria for major response are categorized as “minor” and include a ≥50% reduction in transfusion burden or, in non-TDA, an increase in Hb of ≥1 g/dL but <1.5 g/dL (Table 3).

The 2013 IWG response criteria did not include details regarding loss of anemia response.¹⁸ In MDS, loss of anemia response is considered in patients who lose transfusion-free status or experience a ≥1.5 g/dL decline in Hb level.²⁸ In the revised IWG-MDS proposal,²⁹ non-TDA patients who no longer meet response criteria for anemia (ie, ≥1.5 g/dL increase in Hb level from baseline) but nevertheless maintain a ≥1.0 g/dL increase from baseline would still count as a responder. The authors of the current project find these propositions reasonable and applicable to MF (Table 1). The current panel has also recommended definitions for “progressive” anemia, which include a ≥50% increase in transfusion requirement in TDA and, in non-TDA, either meeting criteria for TDA or a decrease in Hb by >1.5 g/dL from the baseline established at study entry, with a 12-week period of assessment required in both instances (Table 3).

Because of underlying pathogenetic heterogeneity, it is unlikely that drugs currently under investigation for the treatment of anemia in MF would result in complete correction of anemia; a more effective approach might require combination therapy using drugs with nonoverlapping mechanisms of action. Drug trials that target anemia in MF should include QoL assessment and laboratory correlative studies to identify suitable drug candidates. Our proposed changes in Hb thresholds for eligibility criteria represent a paradigm shift in our perception of treatment-requiring anemia in men. This might influence current practice in the use of erythropoiesis stimulating agents and brings attention to QoL issues in men with Hb levels between 10 and 11 g/dL, who might now be offered a chance to participate in clinical trials.

Contribution: All authors participated in the discussion and development of the study and approved the final draft of the manuscript; and A.T., G.B., F.P., and T.B. prepared the initial draft of the paper.

Conflict-of-interest disclosure: F.P. reports honoraria for lectures and advisory boards from Novartis, Bristol-Myers Squibb (BMS)/Celgene, Sierra Oncology, AbbVie, Janssen, Roche, AOP Orphan, Karyopharm, Kyowa Kirin, and MEI. J.-C.H.-B. reports fees for travel support, consultancies, and participation in meetings sponsored by BMS, AOP Health, GlaxoSmithKline (GSK), Pfizer, Novartis, and Incyte. P.B. reports research support from Incyte, BMS, CTI BioPharma Corp (CTI) (now Sobi), Kartos, Telios, Sumitomo, Karyopharm, Ionis, Disc, Blueprint, Cogent, MorphoSys, Geron, and Janssen; and honoraria/consulting fees from Incyte, GSK, CTI (now Sobi), BMS, AbbVie, MorphoSys, Pharma Essentia, Ionis, Disc, Karyopharm, Sumitomo, Geron, Keros, Novartis, Jubilant, Morphic, Blueprint, and Cogent. K.D. reports advisory role for AbbVie, AOP, Amgen, BMS/Celgene, Daiichi Sankyo, GSK, Janssen, Jazz Pharmaceuticals, Novartis, and Roche; and research funding from Agios, Astex, Astellas, BMS/Celgene, and Novartis. M.E. reports speakers bureau fees from Novartis and advisory board fees from GSK. N.G. reports advisory board fees from Disc Medicine and Agios. J.S.G. reports advisory role for AbbVie, Astellas, BMS, Genentech, Gilead, and Servier; and institutional funding from AbbVie, Genentech, Newave, Prelude, and Pfizer. H.G. reports research grants and support for attending meetings from AOP Orphan Pharmaceuticals; consulting fees from AOP Orphan Pharmaceuticals, Novartis, and BMS/Celgene; and speaker fees from AOP Orphan Pharmaceuticals, Novartis, BMS/Celgene, and GSK. J.G. reports research funding (to institution for conduct of clinical trials) from Blueprint Medicines, Cogent Biosciences, Telios, Incyte, AbbVie, Protagonist Therapeutics, Merck, and BMS and consulting fees/honoraria from Blueprint Medicines, Cogent Biosciences, and Incyte. P.G. reports speakers bureau fees from AbbVie, GSK, and Novartis and advisory board fees from GSK, Incyte, and Novartis. V.G. reports consulting fees or honorarium from Novartis, BMS Celgene, GSK, AbbVie, Pfizer, and Daiichi Sankyo and participation on a data safety or advisory board in BMS Celgene, GSK, AbbVie, Pfizer, and Daiichi Sankyo. E.O.H. reports advisory board fees from AbbVie, Blueprint Medicines, Disc Medicine, and PharmaEssentia and research funding from AbbVie, Blueprint Medicines, and Disc Medicine. C.H. reportsconsulting/advisory board fees from AOP, Celgene/BMS, Constellation Pharmaceuticals, CTI, Galecto, Geron, Gilead, Janssen, Keros, Promedior, Roche, Shire, Sierra Oncology, and Novartis; speaker honoraria from AbbVie, BMS, CTI, Geron, Sierra Oncology, and Novartis; and research funding from BMS, Constellation Pharmaceuticals, and Novartis. G.S.H. reports funding from AbbVie, BMS, GSK, Incyte, Novartis, Merck, Cogent, and PharmaEssentia. J.-J.K. reports consultant fees from Novartis, GSK, and AbbVie and advisory board fees from AOP Health, BMS, and Incyte. S.K. reports research grant/funding from Geron, Janssen, AOP Pharma, and Novartis; consulting fees from Pfizer, Incyte, Ariad, Novartis, AOP Pharma, BMS, Celgene, Geron, Janssen, CTI, Roche, Bayer, Imago Biosciences, Sierra Oncology, AbbVie, GSK, and PharmaEssentia; payment or honoraria from Novartis, BMS/Celgene, Pfizer, AbbVie, GSK, iOMEDICO, and MPN Hub; travel/accommodation support from Alexion, Novartis, BMS, Incyte, AOP Pharma, CTI, Pfizer, Celgene, Janssen, Geron, Roche, AbbVie, Sierra Oncology, GSK, iOMEDICO, and Karthos; had a patent issued for a BET inhibitor at RWTH Aachen University; and participated on advisory boards for Pfizer, Incyte, Ariad, Novartis, AOP Pharma, BMS, Celgene, Geron, Janssen, CTI, Roche, Bayer, Sierra Oncology, GSK, AbbVie, and PharmaEssentia. N.K. reports honoraria for lectures from Kite-Gilead, Jazz, MSD, Neovii Biotech, Alexion, MSD, Takeda, Novartis, Riemser, Pfizer, and BMS and has received research support from Neovii, Riemser, Novartis, and DKMS. A.T.K. reports grants from Janssen, Geron, Protagonist, and Novartis; grants and personal fees from BMS, MorphoSys, and GSK; and personal fees from AbbVie, Incyte, CTI, and Karyopharm. J.M. reports research funding from Incyte, Novartis, BMS, PharmaEssentia, CTI/Sobi, AbbVie, Geron, Kartos, Karyopharm, and Ajax and consulting fees from Incyte, Novartis, BMS, AbbVie, Roche, Merck, CTI/Sobi, Geron, Kartos, Karyopharm, MorphoSys, Galecto, GSK, Pfizer, Keros, Sumitomo, and Disc. L.M. reports advisory board fees from MorphoSys. R.M. reports consultancy fees/honoraria from Novartis, Sierra Oncology, Genentech, Sierra, Blueprint, Geron, Telios, CTI, Incyte, BMS, AbbVie, and MorphoSys; Sobi, Novartis, GSK, Incyte, Genentech, Pharmessentia, AbbVie, BMS, MorphoSys, and Geron. B.M. reports lecture fees from Novartis and advisory board fees from GSK. O.O. reports grants or contracts from AbbVie, Agios, Aprea, Astex, AstraZeneca, BMS, Calgene, CTI, Daiichi, Incyte, Janssen, Kartos, Novartis, NS Pharma, and Oncotherapy Sciences; received honoraria for participation on a data safety monitoring board for Treadwell Therapeutics; and participated on advisory boards for BMS, Calgene, Novartis, Rigel, Taiho, Kymera Therapeutics, and Blueprint Medicines. S.T.O. has consulted for AbbVie, Blueprint Medicines, Celgene/BMS, Constellation Pharmaceuticals, CTI, Disc Medicine, Geron, Incyte, Cogent, and Sierra Oncology and has received research funding from Actuate Therapeutics, Blueprint Medicines, Celgene/BMS, Constellation Pharmaceuticals, CTI, Incyte, Kartos Therapeutics, Sierra Oncology, and Takeda. A. Patel reports research funding from Kronos Bio and Pfizer and participated on the data safety monitoring board or served on an advisory board for AbbVie and BMS. N.P. reports consultancy fees/scientific advisory board fees/speaking fees from Pacylex Pharmaceuticals, Astellas Pharma US, Aplastic Anaemia and MDS International Foundation, CareDx, ImmunoGen, Inc, BMS, Cimeio Therapeutics AG, EUSA Pharma, Menarini Group, Blueprint Medicines, CTI, ClearView Healthcare Partners, Novartis Pharmaceutical, Neopharm, Celgene Corporation, AbbVie Pharmaceuticals, PharmaEssentia, Curio Science, DAVA Oncology, Imedex, Intellisphere, CancerNet, Harborside Press, Karyopharm, Aptitude Health, Medscape, Magdalen Medical Publishing, MorphoSys, OncLive, CareDx, Patient Power, Physician Education Resource, and PeerView Institute for Medical Education; research grant from United States Department of Defence and National Institutes of Health/National Cancer Institute; membership on an entity's board of directors/management in Dan's House of Hope; leadership in the American Society of Hematology Committee on Communications and the American Society of Clinical Oncology Cancer.Net Editorial Board; license fees from Karger Publishers; and was uncompensated from HemOnc Times/Oncology Times. A.R. reports fees for consultancies and participation in meetings, boards, and symposia sponsored by Amgen, Pfizer, Novartis, Kite-Gilead, Jazz, Astellas, AbbVie, Incyte, and Omeros. R.R. reports consultant fees from AbbVie, Blueprint, BMS, Constellation Pharmaceuticals/MorphoSys, CTI/Sobi, Cogent, Disc Medicine, Galecto, Incyte, Jazz Pharmaceuticals, Novartis, PharmaEssentia, Promedior, Sierra Oncology/GSK, Kartos, Karyopharm, Stemline, Zentalis, and Sumitomo Dainippon and research funding from Constellation Pharmaceuticals/MorphoSys, Incyte, Stemline, Zentalis, and Ryvu. S.S. reports for consultancy fees from and participation in advisory boards for Novartis, GSK, Disc Medicine, BMS, Incyte, Janssen, and CTI. M.T. reports advisory board fees from Sumitomo and grant support fees from BMS. P.J.V. reports consulting fees or advisory role fees from Blueprint Medicines, Incyte, AbbVie, Jazz Pharmaceuticals, CTI, Novartis, Amgen, Pfizer, and Genentech; speakers' bureau fees from Incyte; and research funding from Seattle Genetics (to the institution [Inst]) Amgen (Inst), Astex Pharmaceuticals (Inst), Incyte (Inst), Blueprint Medicines (Inst), Kartos Therapeutics (Inst), Gilead/Forty Seven (Inst), Constellation Pharmaceuticals (Inst), AbbVie (Inst), CTI (Inst), and Takeda (Inst). A.M.V. reports advisory board and speakers bureau fees from Novartis, GSK, Incyte, and Sobi. T.B. reports speaker honoraria from AOP Orphan; advisory role fees from IONIS; and institutional research funding from AOP and GSK. The remaining authors declare no competing financial interests.

Correspondence: Ayalew Tefferi, Division of Hematology, Department of Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905; email: tefferi.ayalew@mayo.edu.