patient care perspectives

Higher-Risk MDS: Points for Patient Discussion

by Guillermo Garcia-Manero, MD

Overview

Advancements in uncovering the underlying pathogenesis of myelodysplastic syndrome (MDS) have led to the development of investigational therapies for patients with high-risk MDS. Therefore, individuals who are not eligible for intensive treatment or who have not responded to low-intensity treatment may be candidates for investigational agents and combinations, based on their age, genetic features, comorbidities, and molecular profile.

Expert Commentary

Guillermo Garcia-Manero, MD

Professor and Dr. Kenneth B. McCredie Chair in Clinical Leukemia Research
Chief, Section of Myelodysplastic Syndromes
Department of Leukemia, Division of Cancer Medicine
The University of Texas MD Anderson Cancer Center
Houston, TX

“When I discuss treatment options with my patients, I consider their age, comorbidities, cytogenetics, and molecular profile. By putting this all together, we can determine which therapies or investigational options might be best for them.”

Guillermo Garcia-Manero, MD

MDS refers to a very heterogeneous group of myeloid malignancies arising from abnormal stem cell function, immune deregulation, and multiple genomic events. Historically, MDS was categorized as higher and lower risk according to the International Prognostic Scoring System (IPSS), based mainly on the percentage of blasts but also considering the number of cytopenias and cytogenetics. Subsequently, a more robust version of this scoring system was developed, the Revised International Prognostic Scoring System (IPSS-R), which has become the standard. Both the IPSS and the IPSS-R were developed in a specific patient subset: newly diagnosed patients at the time of initial presentation. The IPSS-R categorizes patients into 1 of 5 groups, ranging from very low risk to very high risk. A newer molecular IPSS is anticipated that would include a sophisticated molecular genetic analysis and, of course, cytogenetic information.

In general, we currently identify patients with higher-risk MDS as those with either a higher percentage of blasts (eg, >10%) or poor-/high-risk cytogenetic alterations. Increasingly, we are beginning to use specific genomic lesions (eg, TP53 mutations) and to consider the number of mutations (eg, ≥3) to inform the prognosis in patients with MDS. Many of the individuals who have very high-risk disease have complex karyotype and a number of them may have high-risk mutations, such as TP53. These patients tend to have a specific prognosis; for instance, those with TP53 mutation have a very high rate of relapse post transplantation.

However, treatment decisions draw on many other factors, in addition to the IPSS-R and genomic lesions, such as patient age and comorbidities. So, to generalize, younger patients (eg, ≤65 years of age) with more benign cytogenetic/molecular alterations might be more likely to be treated with a high-intensity program as if they had acute myeloid leukemia. In contrast, older patients with higher-risk disease might be treated with a lower-intensity approach, such as either azacitidine or decitabine as a single agent or perhaps with a clinical trial protocol involving combination therapy. We often include clinical trial participation in our discussions with such patients, in hopes of improving their outcomes with the standard of care.

In summary, when I discuss treatment options with my patients, I consider their age, comorbidities, cytogenetics, and molecular profile. By putting this all together, we can determine which therapies or investigational options might be best for them.

References

Chandhok NS, Lewis R, Prebet T. Hypomethylating agent based combinations in higher risk myelodysplastic syndrome. Leuk Lymphoma. 2020;61(5):1012-1027. doi:10.1080/10428194.2019.1697812

Estey EH. Acute myeloid leukemia: 2019 update on risk-stratification and management. Am J Hematol. 2018;93(10):1267-1291. doi:10.1002/ajh.25214

Garcia-Manero G, Chien K, Montalban-Bravo G. Myelodysplastic syndromes: 2021 update on diagnosis, risk-stratification and management. Am J Hematol. 2020 Aug 3. doi:10.1002/ajh.25950

Germing U, Schroeder T, Kaivers J, Kündgen A, Kobbe G, Gattermann N. Novel therapies in low- and high-risk myelodysplastic syndrome. Expert Rev Hematol. 2019;12(10):893-908. doi:10.1080/17474086.2019.1647778

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

Lindsley RC, Saber W, Mar BG, et al. Prognostic mutations in myelodysplastic syndrome after stem-cell transplantation. N Engl J Med. 2017;376(6):536-547. doi:10.1056/NEJMoa1611604

Montalban-Bravo G, Takahashi K, Patel K, et al. Impact of the number of mutations in survival and response outcomes to hypomethylating agents in patients with myelodysplastic syndromes or myelodysplastic/myeloproliferative neoplasms. Oncotarget. 2018;9(11):9714-9727. doi:10.18632/oncotarget.23882

Nazha A, Narkhede M, Radivoyevitch T, et al. Incorporation of molecular data into the Revised International Prognostic Scoring System in treated patients with myelodysplastic syndromes. Leukemia. 2016;30(11):2214-2220. doi:10.1038/leu.2016.138

Sanz GF. In MDS, is higher risk higher reward? Hematology Am Soc Hematol Educ Program. 2019;2019(1):381-390. doi:10.1182/hematology.2019000042

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