Cleveland Clinic’s Hemato-Oncology Team Spearheads the Development of Guidelines for Genomic Profiling of MDS to Inform Allo-HCT

Allogeneic hematopoietic cell transplantation (allo-HCT) is the only potentially curative treatment for patients with myelodysplastic syndrome (MDS). However, allo-HCT is not widely available and patient outcomes after transplant are highly variable and dependent on multiple factors. To better inform the suitability for, and the timing of, allo-HCT in patients with MDS, Cleveland Clinic investigators and their collaborators published two studies outlining the recommendations for genomic profiling in MDS.

"The field progressed so that the time was ripe for the new guidelines to incorporate the current innovations, mostly in the field of genomics," says Jaroslaw Maciejewski, MD, PhD, Chair of Cleveland Clinic's Department of Translational Hematology and Oncology Research and co-author on both studies. "These types of papers are important to the field and practicing hematologists. The fact that physicians from Cleveland Clinic hematology program and, in particular, those in the bone marrow transplant program, are at the forefront of a decision-making process like this indicates the prestige and academic excellence of our center and its research program."

Integrating genomic data into transplant decision-making

The first study, led by Department of Translational Hematology and Oncology project staff member Carmelo Gurnari, MD, PhD, and published in Blood, provides an updated set of recommendations for allo-HCT in MDS. The guidelines were drafted by an international panel of experts and based on the molecular International Prognostic Scoring System (IPSS-M). IPSS-M was originally developed and published in 2022 in NEJM Evidence by the International Working Group for Prognosis in MDS to improve risk stratification of patients with MDS. Unlike the International Prognostic Scoring System-Revised (IPSS-R), which only considers hematologic parameters and cytogenetic abnormalities, IPSS-M also includes genes with prognostic value in MDS.

The new Blood guidelines for allo-HCT represent an update of the 2017 European Society for Blood and Marrow Transplantation original recommendations, which were largely based on clinical parameters. These updates reflect a more personalized approach to allo-HCT in MDS, integrating genomic profiling and patient-specific risk factors into the decision-making process.

“We now have updated molecular diagnostic and prognostic classifiers [in MDS], and we had to fill a gap on how to use these classifiers in deciding on when, how and who to transplant,” says Dr. Gurnari.

The emphasis on IPSS-M scoring, TP53 allelic state and measurable residual disease assessment underscores the growing role of precision medicine in transplantation. Additionally, the updated guidelines provide recommendations on cytoreductive therapy and post-transplant strategies in select groups of patients.

IPSS-M improves transplant timing

The second study, led by Cristina Astrid Tentori, MD, of the Humanitas Clinical and Research Center-IRCCS in Milan, Italy, was published in JCO and co-authored by Drs. Maciejewski and Gurnari. It deals with the newly developed clinical and genomic-based scoring system (IPSS-M) to define the optimal timing of allo-HCT in MDS. In a large retrospective cohort of 7,118 patients, the authors compared the outcomes of transplantation policies based on IPSS-M versus the original IPSS-R and assessed whether the integration of genomic information would change the optimal timing of HSCT.

“We have shown that IPSS-M can improve, in about one out of six patients (15% to 19%), the timing of the transplantation,” Dr. Gurnari says. “Therefore, the genomic features can really help in further defining the timing of this procedure.”

Improving personalized medicine in patients with chronic myelomonocytic leukemia

In line with their efforts to improve personalized care of patients with myeloid neoplasms, Drs. Maciejewski and Gurnari presented a newly developed molecular-based international CMML Prognostic Scoring System (iCPSS) at the 66^th American Society of Hematology Annual Meeting held in San Diego in December of 2024. In this study, the authors used MOSAIC, an AI-based framework for multimodal analysis in rare cancers, to develop a molecular-based tool for classification and prognostication of chronic myelomonocytic leukemia (CMML) in a large cohort of 3,182 CMML patients. The goal of iCPSS is to improve personalized medicine in patients with CMML.

“The idea here is to do for CMML the same that we have done for MDS: implement molecular genetics into CMML prognostication and develop an ecosystem that we can use for transplantation candidacy purposes,” Dr. Gurnari says. “The training set included 3,182 retrospective CMML patients, and validation was done on 516 prospectively collected patients.”

While this study is currently still underway and has not been peer reviewed yet, Drs. Maciejewski and Gurnari are optimistic that the new genomic-based tools will improve the outcomes of patients with CMML moving forward.