Myelodysplastic Syndrome

Educational Objectives

The goal of this program is to improve management of myelodysplastic syndrome (MDS). After hearing and assimilating this program, the clinician will be better able to:

1. Cite differences in the World Health Organization classification and the International Consensus Classification of MDS.
2. Summarize the benefits of using genomic information to stratify risk in patients with MDS.
3. Identify current and emerging therapies used for management of low- and high-risk MDS.

Summary

Myelodysplastic syndromes (MDS): comprised of a group of heterogeneous clonal hematopoietic cell neoplasms with a variable risk for progression to acute myeloid leukemia (AML); the incidence of MDS increases with age; MDS is characterized by wide genetic heterogeneity with multiple gene mutations; cytogenetic alterations have been identified in ≥40% of patients diagnosed with MDS; the presence of most mutations portends a poor prognosis in MDS, with the exception of the SF3B1 mutation (which occurs in ≈30% of patients with MDS); most patients have ≥3 mutations identified at diagnosis; greater number of mutations is associated with worse prognosis

Classification of MDS: updated World Health Organization (WHO) classification and the International Consensus Classification (ICC) of Myeloid Neoplasms and Acute Leukemias were published in 2022

Differences between classifications: can be challenging for clinicians and patients because the diagnosis may be different depending on the classification system used; in the ICC system, a patient with a blast percentage >10% is classified as MDS-AML, whereas this patient is classified as MDS with increased blasts (MDS-EB2) in the WHO classification; differences in genetic annotations for mutations (eg, deletion [del](5q), SF3B1 and TP53 mutations) between the WHO and ICC classifications may be important for prognosis and outcome; SF3B1 mutation has been described differently (excludes del[5q], monosomy 7, or complex karyotype) in the most recent WHO classifications compared with the 2016 version

Validation of WHO and ICC classifications (Ball et al [2022]): patients with MDS (median follow-up of 60 mo) were reclassified using WHO 2022 and ICC 2022 criteria; patients with SF3B1 mutations had a better prognosis compared those with biallelic TP53 mutations (median overall survival [OS] was ≈13 mo for the latter group); in the ICC 2022 categories, patients with SF3B1 mutations had median OS of 111 mo, and those with TP53 mutations had median OS of ≈14 mo; blast percentage — in the WHO 2022 categories, a difference in median leukemia-free survival (LFS), but not OS, was observed between patients with blast percentage <10% vs≥10%; among patients with multi-hit TP53 mutations, differences in median LFS and OS were observed between blast percentage <10% and ≥10%

Conclusion: molecularly defined entities are unique; TP53 mutation predicted dismal LFS and OS in both classification systems and is an independent predictor of survival; blast percentage cutoff of >5% correlated better with OS compared with a cutoff of >10%, and the precise cutoff used in classification needs to be reexamined; grade 2 to 3 fibrosis was associated with worse OS in the high-blast group and was an independent predictor of OS; work is ongoing to unify the classifications, which is important to help patients understand risks and prognosis

Prognostic scoring systems: the International Prognostic Scoring System (IPSS) was revised in 2012 (IPSS-R; Greenberg et al [2012]); other scoring systems include WHO Classification-based Prognostic Scoring System (WPSS), MD Anderson Lower-Risk MDS PSS, and other scoring systems for chronic myelomonocytic leukemia

IPSS-Molecular (IPSS-M): the incorporation of genetic information can improve the ability to prognosticate survival, and Bernard et al (2022) proposed the IPSS-Molecular (IPSS-M); the IPSS stratifies patients into risk categories based on blast percentage, chromosome changes, and blood cell counts; the IPSS-M includes data on mutations, clonal hematopoiesis, and patient age; the likelihood that inflammation influences the pathogenesis of clonal evolution increases in the aging population, specifically in those with genetic predisposition states; IPSS-M has helped with identification of VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic), which is characterized by a mutation of UBA1 gene and involves a triad of rheumatologic disorders, cardiac disease, and myeloid neoplasms (eg, MDS); patients with VEXAS syndrome have a poor prognosis

Features: IPSS-M includes 15 genetic variables and other residual variables related to genetic mutation; use of the model does not require mutational statuses for all the genes; uses a 6-category risk schema; incorporation of genomic information restratified ≥50% of patients; of those, 75% were restratified into a higher risk category than they would have without the use of genomic information

Validation: Sauta et al (2022) evaluated the clinical applicability of the IPSS-M using patient data from the GenoMed4All cohort; validation was also performed in patients without detectable mutations, indicating that the scoring system was effective in a large population; the IPSS-M model is valid in patients who are receiving disease-modifying therapies; the model identified patients at high risk for relapse in the post-transplantation setting

Low-risk MDS

Lenalidomide: has been shown to benefit patients with del(5q) mutations; improvement in transfusion independence (TI) of ≈25% was observed in patients without the del(5q) mutation

Imetelstat: in the IMerge phase 2 study, Platzbecker et al (2022) randomized patients with transfusion-dependent, low-risk MDS to receive imetelstat (a telomerase inhibitor) or placebo; meaningful TI was observed in 42% of patients receiving imetelstat, with a median duration of TI (mdTI) of 88 wk; in patients with TI that lasted >1 yr, the mdTI was >90 wk; imetelstat was well tolerated, even with long term use

ASTX727: a fixed-dose combination of oral decitabine (a hypomethylating agent [HMA]) and cedazuridine; ASTX727 is approved for patients with high-risk MDS; in a phase 1 study, Garcia-Manero et al (2022) evaluated low-dose ASTX727 in patients with low-risk MDS; the dose given for the cohort B1 was identified as the recommended phase 2 dose; adverse events (AEs) included neutropenia and gastrointestinal toxicities; TI and hematologic responses were observed; phase 2 study is ongoing

Luspatercept: recently approved in 2022; the phase 3 COMMANDS trial (NCT03682536) compares luspatercept with epoetin alfa in patients with MDS without ring sideroblasts; the MEDALIST trial (Fenaux et al [2020]) found that patients with MDS who received luspatercept had improvement in TI compared with those who received placebo

High-risk MDS: median OS for patients who receive azacitidine (AZA) or decitabine is between 11 and 12 mo; median OS in patients who do not respond to AZA is 5.6 mo; a phase 3 study evaluating AZA plus venetoclax (Bcl-2 inhibitor) in patients with newly diagnosed high-risk MDS is ongoing; magrolimab (a CD47-targeted monoclonal antibody) with an HMA is being studied; SY-1425 is being studied in combination with AZA in patients with newly diagnosed RARA — positive high-risk MDS

Sabatolimab: TIM-3 is expressed in leukemia stem cells and blasts but not on the normal hematopoietic stem cells and plays a key role in regulating the innate and adaptive immune responses; in the STIMULUS-MDS1 trial (Zeidan et al [2022]), patients were randomized to receive sabatolimab (TIM-3 inhibitor) or placebo plus HMA; no differences in complete response or progression-free survival were observed between the arms; patients who received sabatolimab had a longer duration of remission compared with those who received placebo; sabatolimab plus HMA had a tolerable safety profile; a phase 3 study (STIMULUS-MDS2) is ongoing

Venetoclax plus AZA: yielded an overall response of >80% in the frontline setting; AEs include pancytopenia and increased risk for infections

Novel agents: next-generation sequencing (NGS) is essential; in frontline setting, response rates of 50% are observed with oral IDH inhibitors; an unmet need exists for TP53-mutated AML; menin inhibition is under evaluation for KMT2A rearrangements or NPM1 mutations; SX-682 is being studied in MDS

Questions and Answers

Approach for a patient with MDS: obtaining a pathology report to understand the classification is the first step; a prognostic scoring system (eg, IPSS-M) that incorporates NGS information helps to predict the prognosis in patients who harbor mutations

Readings

Aguirre LE, Al Ali N, Ball S, et al. Validation of the Molecular International Prognostic Scoring System (IPSS-M) risk stratification model for myelodysplastic syndromes. Blood. 2022;140(Supplement 1):1125-1127. doi:10.1182/blood-2022-170878; Arber DA, Orazi A, Hasserjian RP, et al. International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data. Blood. 2022;140(11):1200-1228. doi:10.1182/blood.2022015850; Baer C, Huber S, Hutter S, et al. Risk prediction in MDS: A validation of the IPSS-M and comparison to IPSS-R and to two other personalized prediction tools. Blood. 2022;140(Supplement 1):1128-1129. doi:10.1182/blood-2022-159939; Ball S, Singh AM, Ali NA, et al. A product of “clash of titans” or true reflection of disease biology? Validation of 2022 WHO and ICC classifications in a large dataset of patients with myelodysplastic syndrome. Blood. 2022;140(Supplement 1):1118-1120. doi:10.1182/blood-2022-170158; Bernard E, Tuechler H, Greenberg PL, et al. Molecular International Prognostic Scoring System for myelodysplastic syndromes. NEJM Evidence. 2022;1(7):EVIDoa2200008. doi:10.1056/EVIDoa2200008; Fenaux P, Platzbecker U, Mufti GJ, et al. Luspatercept in patients with lower-risk myelodysplastic syndromes. New England Journal of Medicine. 2020;382(2):140-151. doi:10.1056/NEJMoa1908892; Garcia-Manero G, Bachiashvili K, Amin H, et al. ASTX727-03: phase 1 study evaluating oral decitabine/cedazuridine (ASTX727) low-dose (LD) in lower-risk myelodysplastic syndromes (LR-MDS) patients. Blood. 2022;140(Supplement 1):1112-1114. doi:10.1182/blood-2022-156512; Greenberg PL, Tuechler H, Schanz J, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012;120(12):2454-2465. doi:10.1182/blood-2012-03-420489; Khoury JD, Solary E, Abla O, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia. 2022;36(7):1703-1719. doi:10.1038/s41375-022-01613-1; Platzbecker U, Komrokji RS, Fenaux P, et al. Imetelstat achieved prolonged, continuous transfusion independence (TI) in patients with heavily transfused non-del(5q) lower-risk myelodysplastic syndrome (LR-MDS) relapsed/refractory (R/R) to erythropoiesis stimulating agents (ESAs) within the IMerge phase 2 study. Blood. 2022;140(Supplement 1):1106-1108. doi:10.1182/blood-2022-169050; Sauta E, Robin M, Bersanelli M, et al. Real-world validation of Molecular International Prognostic Scoring System (IPSS-M) for myelodysplastic syndromes. Blood. 2022;140(Supplement 1):1121-1124. doi:10.1182/blood-2022-163634; Zeidan AM, Ando K, Rauzy O, et al. Primary results of STIMULUS-MDS1: a randomized, double-blind, placebo-controlled phase II study of TIM-3 inhibition with sabatolimab added to hypomethylating agents (HMAs) in adult patients with higher-risk myelodysplastic syndromes (MDS). Blood. 2022;140(Supplement 1):2063-2065. doi:10.1182/blood-2022-158612.

Disclosures

For this program, the following relevant financial relationships were disclosed and mitigated to ensure that no commercial bias has been inserted into this content: Dr. Carraway is on the advisory board for AbbVie, Bristol-Myers Squibb, Daiichi Sankyo, and Jazz Pharmaceuticals; is on the data and safety monitoring panel for Syndax; receives grant support from Celgene Bristol-Myers Squibb; and is a speaker for Agios Pharmaceuticals and Jazz Pharmaceuticals. Members of the planning committee reported nothing relevant to disclose. Dr. Carraway's lecture includes information related to the off-label or investigational use of a product, therapy, or device.

Acknowledgements

Dr. Carraway was recorded at the 22nd Annual ASH Review, held on January 25, 2023, in Cleveland, OH, and presented by Taussig Cancer Institute, Cleveland Clinic. For more information about upcoming CME activities from this presenter, please visit clevelandclinicmeded.com. Audio Digest thanks the speakers and Taussig Cancer Institute, Cleveland Clinic for their cooperation in the production of this program.

CME/CE INFO

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