VALIDATE-ing Treatment Strategies for High-Risk MDS

At the American Society of Hematology  Annual Meeting 2024, Ted Getz, MD, Yale University, New Haven, Connecticut, presented the findings from the International Consortium for MDS VALIDATE database, shedding new light on the prognostic impact of cytogenetic risk, particularly for patients with myelodysplastic syndromes (MDS) treated with hypomethylating agents (HMAs).¹ Among the key insights were the distinct survival outcomes associated with very complex karyotype (VCK) versus complex karyotype (CK) and the interplay between cytogenetic abnormalities and TP53 mutation status. To discuss this study and its implications, Blood Cancers Today (BCT) spoke with Dr. Getz, the presenting author.

BCT: Could you start by giving us an overview of the key findings from this study?

“Certainly. This study analyzed data from 1,940 patients with MDS. We found that the cytogenetic risk categories defined by the revised International Prognostic Scoring System (IPSS-R).² significantly correlate with overall survival (OS), even when accounting for factors like allogeneic hematopoietic stem cell transplant (alloHSCT). Notably, patients with a VCK, defined as having four or more cytogenetic abnormalities, had worse survival outcomes compared with those with a CK or noncomplex karyotype (NCK).³ Additionally, we explored how the presence of TP53 mutations further stratified survival outcomes within these groups, revealing clear links between tumor cytogenetics and molecular abnormalities.”

He added: “In patients with TP53 mutations, the distinction between VCK and CK seemed less significant. TP53 mutations may overshadow cytogenetic complexity in prognostic significance. We’ve known for a long time that complex karyotype is bad in MDS, but there’s been very little work to characterize what specific cytogenetic abnormalities within that group may lead to a worse prognosis. Among patients with three or more cytogenetic abnormalities, specific lesions such as del(17p), inv(3)/t(3q), and del(7q) were particularly detrimental.”

Furthermore, he explained: “Censoring data at the time of transplant was especially informative. For example, intermediate and poor-risk cytogenetics groups had similar outcomes when assessing the overall population. However, when censoring at transplant, these curves separated, highlighting how cytogenetics influence post-transplant decisions. Del(17p), which fits with TP53, was identified as a significant marker, while inv(3) and del(7q) also correlated with poor outcomes. These findings highlight the need for individualized therapy in MDS patients, particularly those with high cytogenetic complexity.”

Dr. Getz stressed the importance of targeted treatments: “For patients with VCK or TP53 mutations, the standard HMA therapy alone may not be sufficient. Combination therapies and early consideration of alloHSCT are critical in these high-risk populations.”

BCT: The focus on VCK in this study is particularly intriguing. How does this group differ prognostically from CK or NCK patients?

“Patients with VCK had significantly worse median overall survival (mOS) compared with those with CK or NCK. Specifically, the mOS for VCK patients was 13.6 months, while CK patients had an mOS of 19.9 months, and NCK patients had a markedly better mOS of 36.1 months. The distinction is clinically important because it highlights the unique challenges in managing patients with VCK. These patients also had a higher prevalence of concurrent TP53 mutations, which appear to drive much of the poor prognosis in this group.”

BCT: How do TP53 mutations affect outcomes, especially in the context of VCK and CK?

“TP53 mutations significantly worsen outcomes across all cytogenetic groups, but their impact is particularly notable in VCK patients. Among VCK patients with TP53 mutations, the mOS was just 12.2 months, compared with 24.2 months for TP53-mutated NCK patients. Interestingly, in TP53 wild-type patients, the difference between VCK and CK was less pronounced, suggesting that TP53 mutations may amplify the prognostic implications of cytogenetic complexity. This highlights the need for targeted therapies addressing both cytogenetic and molecular abnormalities.”

BCT: Your study also identified specific chromosomal abnormalities associated with worse outcomes. Could you elaborate on these findings?

“Yes, among patients with three or more cytogenetic abnormalities, we identified certain lesions, such as –17/del(17p), inv(3)/t(3q), and del(7q), as being particularly detrimental. For example, patients with inv(3)/t(3q) had a median overall survival of just 10.9 months, significantly lower than those without these abnormalities. These findings demonstrate that not all cytogenetic abnormalities are equal, and specific lesions may have unique impacts on disease biology and prognosis.”

BCT: How do these findings translate into clinical practice? Should hematologists approach treatment differently for VCK or TP53-mutated MDS patients?

“Absolutely. These results reinforce the need for individualized treatment strategies. For VCK or TP53-mutated patients, standard HMA therapy alone may not be sufficient. We’re seeing growing interest in combining HMAs with novel agents, such as venetoclax or TP53-directed therapies, to improve outcomes in these high-risk groups. Additionally, early consideration of alloHSCT is critical, especially for patients with VCK, as it remains the only potentially curative option for many of these patients.”

BCT: What are the next steps for research in this area?

‘’Moving forward, we need prospective studies to validate these findings and refine risk stratification tools like the IPSS-R. Additionally, we should focus on testing novel therapeutic combinations in high-risk subgroups like VCK and TP53-mutated patients. Advances in molecular profiling and targeted therapy development will be key to improving outcomes in this challenging patient population.”

References

1. Getz T, Kewan T, Bewersdorf JP, et al. Clinical outcomes and variability based on baseline cytogenetic risk of patients with MDS treated with hypomethylating agents: an analysis from the International Consortium for MDS (icMDS) Validate Database. Poster #3219. Presented at the American Society of Hematology Annual Meeting; December 7-10, 2024; San Diego, California.
2. Greenberg PL, Tuechler H, Schanz J, et al. Blood. 2012;120(12):2454-2465. doi: 1182/blood-2012-03-420489
3. Shahjahani M, Hadad E, Azizdosst S, et al. Oncol Rev. 2019;13(1):389. doi: 10.4081/oncol.2019.389