An agenda to advance research in myelodysplastic syndromes: a TOP 10 priority list from the first international workshop in MDS

DNA methyltransferase inhibitor (DNMTi) monotherapy remains the standard of care therapy for higher-risk MDS.³ Despite the established role of DNMTi therapeutics in MDS, several trials and real-world registry analyses have failed to replicate the survival benefit initially described with azacitidine in the AZA-001 trial.^4,5 To improve outcomes, multiple clinical trials have tested azacitidine (or DNMTi backbone) combination therapy approaches, but to date, none have improved overall survival (OS) compared with azacitidine monotherapy.^6-8 Hence, establishing a DNMTi backbone combination therapy for the frontline treatment of MDS is the top priority that has been identified by the faculty.

Outcomes for patients with DNMTi resistance are unfortunately dismal, with a median survival of <6 months and a 2-year survival probability of only 15% for patients with higher-risk MDS.⁹ Outcomes for lower-risk patients with DNMTi resistance are also poor with a median survival of 17 months.¹⁰ There is currently no standard treatment approach approved for these patients and clinical trial options are urgently needed, especially for patients who are not candidates for allogeneic hematopoietic stem cell transplantation.

TP53 alterations (deletions and mutations) are associated with extremely poor prognosis, with lower response to all established therapies, higher rates of progression to AML, and significantly shortened OS.¹¹ Even with allogeneic stem cell transplant outcomes remain poor.¹² Hence, international efforts should be focused on dedicated trials for this patient population as a holistic platform to also include TP53-mutated AML, which shares similar features with TP53-mutated MDS.¹³ During the iwMDS, the NCI myeloMATCH program was presented which will include a multiarm phase II trial platform entirely dedicated to patients with TP53 mutated MDS. Working groups developing directed algorithms for all TP53-mutated myeloid neoplasms should be considered given the dismal outcome for these disorders irrespective of blast percentage.¹³ 

In lower-risk MDS, the goal of treatment is to improve cytopenia, most commonly anemia. The standard of care remains supportive treatment with red blood cell transfusions, erythropoiesis-stimulating agents, luspatercept, lenalidomide for certain subtypes of LR-MDS, and DNMTis. However, “lower-risk” MDS is a misconception: while temporary benefit can be derived, these approaches do not have a significant disease-modifying effect, and therefore responses are of limited durability.¹⁰ Future efforts should focus on attempting to reverse the underlying pathophysiology of MDS.^14,15 

Clinical trials should be conducted jointly in different countries to achieve rapid study completion. Trials should also promote health care equity for patients with MDS and focus on the inclusion of PROs. Collaboration among research groups worldwide will facilitate these research goals. In addition, the focus should be on optimizing the inclusivity of patients concerning eligibility criteria to encompass the older population of patients (eg, limited eligibility due to creatinine and or cardiac functions) that are currently frequently excluded, thereby hampering the investigation (and enrollment) of the population most afflicted with MDS.

Recently the World Health Organization and the International Consensus Classification for myeloid neoplasms have published separate diagnostic criteria for AML and MDS.^16,17 Several important differences between the 2 classifications exist, especially in how patients with 10% to 19% blasts are classified.¹⁸ There is a significant concern that having 2 separate classification systems could have a negative impact on clinical care and research and have the potential to create confusion among patients and providers, as well as in the design, conduct, and interpretation of clinical trials. The need to establish a unified consensus classification for MDS has been emphasized.

The current response MDS criteria suffer from significant limitations.^19,20 First, there is a clear inconsistency in how complete remission (CR) is defined for MDS based on the International Working Group 2006²⁰ compared with the definition of CR for AML in the ELN 2017²¹ and ELN 2022²² criteria. While no hemoglobin threshold is used for CR in AML, for MDS, CR requires a hemoglobin value ≥11 g/Dl, which has not been validated. These differences in CR definition can lead to different outcomes depending on which definition is used.²³ There is a need to develop and validate new response criteria for higher-risk MDS that capture meaningful clinical benefits, similar to the introduction of CR with partial hematological recovery in ELN 2022 AML criteria.^22,24,25 Conversely, the elimination of responses with doubtful clinical benefits (eg, marrow CR without meaningful count recovery) should be considered.²⁶ 

The advent and widespread availability of next generation sequencing has led to the discovery of CH, which, in some cases, is associated with higher risks of cardiovascular disease²⁷ and hematologic malignancies.^28-30 Therefore, early intervention should be monitored and considered, especially among patients with solid tumors where high-risk CH clones can dramatically expand under the selective pressure of chemotherapy, increasing the risk of subsequent therapy-related myeloid neoplasms. We need to learn more about the genotypic and phenotypic characteristics of CH evolution to accurately predict which patients with CH will develop MDS and other blood cancers. Ultimately, the goal is to develop effective secondary preventive/therapeutic strategies that reduce the risk of aggressive hematologic malignancies and/or other CH-related diseases in patients with higher-risk CH lesions. The identification of CH before exposure to intensive chemotherapy or radiation therapy is not frequently covered by insurance companies, which is a barrier to obtaining adequate informed consent and poses risks to patients when deciding to embark on potentially toxic therapies. Lastly, how best to identify and classify patients with a germ line predisposition to develop myeloid malignancies such as MDS and AML, will be a significant future focus of genetic counseling and risk prevention efforts.³¹ 

Several large MDS registries have recently been developed to better understand the natural history of MDS and to establish large biorepositories. The global MDS community should establish a common minimum data set to enable data sharing across platforms. Achieving international alignment is essential for identifying and characterizing risk factors, clinical outcomes, and particularly drug responsiveness for subgroups of this rare disease, which are likely to be increasingly subdivided into more defined molecular subtypes.

Comprehensive in vivo preclinical studies of MDS have historically suffered from the limited ability of MDS stem cells to engraft in immunodeficient murine hosts. Recently, a patient-derived xenotransplantation model in cytokine-humanized immunodeficient “MISTRG” mice has been established, allowing disease modeling across MDS subtypes.³² A broader availability of improved preclinical models and wider dissemination of these resources to laboratories around the world is critical to maximize the efficient evaluation of novel drugs and therapeutics in MDS.

We conclude that, given that MDS are rare and biologically heterogeneous blood cancers, there is an overarching dire need for international and interdisciplinary collaboration and coordination of research efforts. What became clear from this first iwMDS meeting was the necessity for the frequent continued exchange of ideas in a smaller informal setting that is more conducive to the creation of new collaborative efforts.

Acknowledgments: A.M.Z. is a Leukemia and Lymphoma Society Scholar in Clinical Research. M.E.F. is a Leukemia and Lymphoma Society Scholar. T.K.K. received the Clinician Scientist Development Award from the American Cancer Society. The authors acknowledge Kelly Norsworthy for her critical review and comments on the manuscript.

Contribution: M.S. and A.M.Z wrote the initial draft of the manuscript; M.S., A.M.Z., R.B., M.A.S., D.P.S., U.P., S.L., A.H.W., and V.S. were involved with the conception and design of the study; and all authors were involved in writing, reviewing, and editing the manuscript, and approved the final version for submission.

Conflict-of-interest disclosure: The first international workshop on MDS was planned by an independent scientific steering committee. The meeting was supported by unrestricted educational grants from Gilead, Novartis, Bristol Myers Squibb, Syros, Geron, and Karyopharm to Magdalen Medical/VJHemOnc. The participants met in Miami, FL, in June 2022, and deliberated on the content of this manuscript, which was subsequently finalized after the meeting. The meeting sponsors were not involved in the development of this manuscript. A.N., D.P.S., R.B., A.F.L., and N.K. authored this manuscript in their personal capacity, and their views do not necessarily represent/reflect that of their employers. The content is the sole responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. M.M.P., E.P., U.P., R.B., and S.L. were authors of the WHO classification. R.P.H. was a cochair of the Pathology ICC and co-leader of the ICC Premalignant Clonal Cytopenias and MDS working group. O.O., M.R.S., and A.H.W. were the authors of the ICC classification. A.M.Z. received research funding (institutional) from Celgene/Bristol Myers Squibb, AbbVie, Astex, Pfizer, Medimmune/AstraZeneca, Boehringer-Ingelheim, Cardiff Oncology, Incyte, Takeda, Novartis, Aprea, and ADC Therapeutics. A.M.Z. participated in advisory boards, and/or had a consultancy with and received honoraria from AbbVie, Otsuka, Pfizer, Celgene/Bristol Myers Squibb, Jazz, Incyte, Agios, Boehringer-Ingelheim, Novartis, Acceleron, Astellas, Daiichi Sankyo, Cardinal Health, Taiho, Seattle Genetics, BeyondSpring, Cardiff Oncology, Takeda, Ionis, Amgen, Janssen, Epizyme, Syndax, Gilead, Kura, Chiesi, ALX Oncology, BioCryst, Notable, Orum, and Tyme, and served on the clinical trial committees for Novartis, AbbVie, Gilead, BioCryst, ALX Oncology, Geron, and Celgene/Bristol Myers Squibb. D.P.S. is an employee of Novartis. U.P. received honoraria from Bristol Myers Squibb, Jazz Pharmaceuticals, AbbVie, and Geron. The National Heart, Lung, and Blood Institute received research funding for the laboratory of C.S.K. from Sellas and the Foundation of the NIH AML M.R.D. Biomarkers Consortium. F.E. had a consultancy or advisory role for Amgen, AbbVie, Janssen, and Novartis, and received research funding (institutional) from AbbVie, Amgen, and Novartis, outside the submitted work. O.O. has served on the advisory board of Bristol Myers Squibb, Celgene, Novartis, Taiho, and Kymera Therapeutics; serves on a DSMB for Threadwell Therapeutics; and received research funding (institutional) from AbbVie, Agios, Aprea, Astex, AstraZeneca, Bristol Myers Squibb, Celgene, CTI, Daiichi, Incyte, Janssen, Kartos, Novartis, NS-Pharma, and Oncotherapy Sciences. P.L.G. received research funding (institutional) from Celgene/Bristol Myers Squibb and Gilead. P.F. received research funding from Bristol Myers Squibb, AbbVie, Jazz Pharmaceuticals, Novartis, and Janssen, and had consultancy with and received honoraria from Bristol Myers Squibb, AbbVie, Jazz Pharmaceuticals, and Novartis. M.S. consulted for Curis Oncology and Boston Consulting; served on the advisory boards for Novartis and Kymera; and participated in the GME activity for Novartis, Curis Oncology, Haymarket Media, and Clinical Care Options (CCO). G.F.S. received grants/research support (institutional) from Bristol Myers Squibb, Novartis, and Gamida Cell. R.M. is on the Board of Directors of CircBio; on the advisory boards of Kodikaz Therapeutic Solutions, Syros Pharmaceuticals, and TenSixteen Bio; is an inventor on a number of patents related to CD47 cancer immunotherapy licensed to Gilead Sciences; received research support from the Gilead Sciences and CircBio; and is the cofounder and equity holder of CircBio, Pheast Therapeutics, MyeloGene, and RNAC Therapeutics. G.F.S. received honoraria, advisory board membership, or consultation fees from AbbVie, Bristol Myers Squibb, Novartis, Roche, and Takeda, and participated in the sponsored speaker’s bureau for Bristol Myers Squibb, Novartis, and Takeda. A.N. owns stock at Amazon and is an employee of Incyte Pharmaceuticals. D.T.S. is a consultant and received research funding from Kymera Therapeutics, Kurome Therapeutics, Captor Therapeutics, and Tolero Therapeutics. D.T.S. has equity in Kurome Therapeutics. D.A.S. served on the advisory boards of Aprea, AvenCell, Bluebird Bio, Bristol Myers Squibb, Intellia, Kite, Novartis, Shattuck Labs, Servier, and Syndax; served as a consultant for AbbVie, Magenta, Molecular Partners AG, and Takeda; served on the speakers’ bureau for Bristol Myers Squibb, Incyte, and Servier; and received research funding from Aprea and Jazz Pharmaceuticals. M.M.P. received research funding from Kura Oncology and StemLine Pharmaceuticals. A.M.B. received consulting or advisory board honoraria from Novartis, Acceleron, Agios, AbbVie, Takeda, Celgene/Bristol Myers Squibb, Keros Therapeutics, Taiho, and Gilead, and has research support from NIH SPORE in Myeloid Malignancies and the Edward P. Evans Foundation. E.P. receives research funding from Incyte and Bristol Myers Squibb, and honoraria from Stemline, Taiho, Blueprint, and Bristol Myers Squibb. T.K.K. received research funding from Nextcure and is a consultant for the Agenus. R.S.K. served on the speaker bureau of Jazz Pharmaceuticals, Servio, CTI, and PharmaEssentia, and served on advisory boards and received honoraria from Bristol Myers Squibb, Novartis, AbbVie, Jazz Pharmaceuticals, Servio, PharmaEssentia, Taiho, Geron, and CTI. M.S.A. has served on advisory boards for Bristol Myers Squibb, Novartis, Kurome, and Gilead. R.B. is employed by and has equity in Aptose Biosciences, and serves on independent drug monitoring committees for Gilead and Epizyme. R.P.H. has a consultancy agreement with Bluebird Bio. G.J.R. has a consultancy agreement and/or serves on the advisory board or data and safety monitoring committee for AbbVie, Amgen, Astellas, AstraZeneca, Bristol Myers Squibb, Blueprint Medicines, Bluebird Bio, Celgene, Glaxo SmithKline, Janssen, Jasper Therapeutics, Jazz Pharmaceuticals, Mesoblast, Novartis, Pfizer, Syndax, and Takeda, and received research support from Janssen. S.H. received honoraria from Forma Therapeutics. A.H.W. has served on advisory boards for Novartis, AstraZeneca, Astellas, Janssen, Amgen, Roche, Pfizer, AbbVie, Servier, Gilead, Bristol Myers Squibb, Shoreline, Macrogenics, and Agios; receives research funding (to institution) from Novartis, AbbVie, Servier, Janssen, Bristol Myers Squibb, Syndax, Astex, AstraZeneca, and Amgen; serves on speakers' bureaus for AbbVie, Novartis, Bristol Myers Squibb, Servier, and Astellas; is an employee of the Walter and Eliza Hall Institute (WEHI); and is eligible for financial benefits associated with payments that WEHI receives in relation to venetoclax. A.F.L. is employed by and has equity in Precision BioSciences, and has served as a consultant for Halia Therapeutics, CTI Biopharma, and Aileron. M.X. participated in advisory boards and/or had a consultancy agreement with and received honoraria from Seattle Genetics, Pure Marrow and Blueprint Medicines. N.G.D. has received research funding from Daiichi-Sankyo, Bristol Myers Squibb, Pfizer, Gilead, Sevier, Genentech, Astellas, Daiichi-Sankyo, AbbVie, Hanmi, Trovagene, Fate Therapeutics, Amgen, Novimmune, Glycomimetics, Trillium, and ImmunoGen, and has served in a consulting or advisory role for Daiichi-Sankyo, Bristol Myers Squibb, Arog, Pfizer, Novartis, Jazz, Celgene, AbbVie, Astellas, Genentech, ImmunoGen, Servier, Syndax, Trillium, Gilead, Amgen, Shattuck Labs, and Agios. S.L. received research support from Astellas and Amgen; owns stock from AbbVie; and has received consultancy fees/honoraria from AbbVie, Gerson Lehrman Group, QualWorld, and Guidepoint. E.A.G. received honoraria from AbbVie, Alexion Pharmaceuticals, Genentech, Novartis, CTI Biopharma, Apellis, Celgene/Bristol Myers Squibb, Takeda Oncology, Taiho Oncology, Physician Educational Resource, MediCom Worldwide, American Society of Hematology, Picnic Health, and AAMDSIF, and research support (institutional) from Astex Pharmaceuticals, Genentech, Blueprint Medicine, Alexion Pharmaceuticals, Apellis, Bristol Myers Squibb/Celgene, and Celldex Therapeutics. M.R.S. serves on a board or advisory committee for AbbVie, Bristol Myers Squibb, CTI, Forma, Geron, Karyopharm, Novartis, Ryvu, Sierra Oncology, Taiho, Takeda, and TG Therapeutics; receives research funding from ALX Oncology, Astex, Incyte, Takeda, and TG Therapeutics; and has equity ownership in Karyopharm and Ryvu. O.A.W. has served as a consultant for H3B Biomedicine, Foundation Medicine Inc., Merck, Prelude Therapeutics, and Janssen; is on the scientific advisory board of Envisagenics Inc., AIChemy, Harmonic Discovery Inc., and Pfizer Boulder; and has received prior research funding from H3B Biomedicine and LOXO Oncology, unrelated to the manuscript. The remaining authors declare no competing financial interests.

Correspondence: Amer M. Zeidan, Hematology Section, Department of Internal Medicine, Yale School of Medicine, 333 Cedar St, PO Box 208028, New Haven, CT 06520-8028; e-mail: amer.zeidan@yale.edu.