Exploring Advancements in Higher-Risk MDS

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Although allogeneic transplantation remains the only curative option for patients with high-risk myelodysplastic syndrome (HR-MDS),^1,2 and despite the failure over the past 15 years to improve the current standard based on hypomethylating agents in monotherapy,³ we still have reasons to believe that we will soon see improvements for both transplant-eligible patients and those for whom transplantation is not an option due to age or comorbidities.

Currently, HR-MDS patients are defined as those with a greater risk of progression to acute myeloid leukemia and/or a short estimated survival (generally less than 3 years). This group includes patients with a revised International Prognostic Scoring System (IPSS-R) score over 3.5 or those in a moderate-high or higher-risk category, according to the molecular IPSS (IPSS-M). Additionally, we might also include patients initially considered as lower-risk MDS patients, according to IPSS-R or IPSS-M, who have a high transfusion dependence and have failed available therapies.⁴

Over the past 5 years, data have been presented from several randomized clinical trials comparing azacitidine monotherapy with combinations with several drugs (with different mechanisms of action and potentially synergistic with hypomethylating agents) such as lenalidomide (Revlimid), vorinostat (Zolinza), pevonedistat (MLN4924), sabatolimab (MBG453), durvalumab (Imfinzi), eprenetapopt (APR-246), and magrolimab. Although these combinations showed promising results in phase 1 and 2 clinical trials, they failed to demonstrate a benefit (defined as improvement in survival) over azacitidine monotherapy in phase 3 trials. While we cannot rule out the inefficacy of these combinations, other factors may explain the inability to show significant improvement in clinical trials. These factors include the inherent heterogeneity of MDS, with patients within the same high-risk group having very different genetic and molecular profiles. For example, patients with a normal karyotype but a high percentage of blasts are considered high risk, though their likelihood of responding to a specific treatment may differ significantly.^3,5 Furthermore, many clinical trials overrepresent patients with very high-risk mutations (such as TP53), making it more challenging to demonstrate improvements in the overall patient population. Another significant aspect is that the response criteria commonly used are still those from the early 2000s. However, this may change with the recent proposal of new response criteria for high-risk MDS patients.⁶

Currently, there are still 2 trials with pending final data for which we have high hopes: the combination of azacitidine with venetoclax (Venclexta), which has shown a high response rate in preliminary phases⁷ and is already approved for acute myeloid leukemia, and the combination of azacitidine with tamibarotene, specifically designed for patients with RAR-A overexpression, who account for about 30% to 50% of high-risk MDS patients.

As mentioned earlier, transplantation remains the only curative option for these patients; however, posttransplant relapse remains a problem. Therefore, continued research into posttransplant therapies is necessary to combine the antitumor effect derived from graft-vs-tumor with low-toxicity molecules that help control the disease, especially in the early months posttransplant.⁸ In conclusion, despite the negative results of the trials performed in recent years, we are in a promising time in the hematology field and in the more challenging area of MDS. The incorporation of molecular findings into routine practice will allow for the design of more specific treatments for patients. As an example of this point, we have the favorable results of ivosidenib (Tibsovo) in patients with IDH1 mutation, which has demonstrated good responses and survival, primarily when used in the first line.⁹ Although this mutation affects a small proportion of patients, this study indicates the path forward, designing studies for more homogeneous patient populations.

REFERENCES:

1. Kröger N, Sockel K, Wolschke C, et al. Comparison between 5-azacytidine treatment and allogeneic stem-cell transplantation in elderly patients with advanced MDS according to donor availability (VidazaAllo Study). J Clin Oncol. 2021;39(30):3318-3327. doi:10.1200/ JCO.20.02724

2. Nakamura R, Saber W, Martens MJ, et al. Biologic assignment trial of reduced-intensity hematopoietic cell transplantation based on donor availability in patients 50-75 years of age with advanced myelodysplastic syndrome. J Clin Oncol. 2021;39(30):3328-3339. doi:10.1200/JCO.20.03380

3. Garcia-Manero G. Current status of phase 3 clinical trials in highrisk myelodysplastic syndromes: pitfalls and recommendations. Lancet Haematol. 2023;10(1):e71-e78. doi:10.1016/S2352-3026(22)00265-4

4. Valcárcel D, Sanz G, Ortega M, et al. Use of newer prognostic indices for patients with myelodysplastic syndromes in the low and intermediate-1 risk categories: a population-based study. Lancet Haematol. 2015;2(6):e260-e266. doi:10.1016/S2352-3026(15)00067-8

5. Sekeres MA, Kim N, DeZern AE, et al. Considerations for drug development in myelodysplastic syndromes. Clin Cancer Res. 2023;29(14):2573-2579. doi:10.1158/1078-0432.CCR-22-3348

6. Zeidan AM, Platzbecker U, Bewersdorf JP, et al. Consensus proposal for revised International Working Group 2023 response criteria for higher-risk myelodysplastic syndromes. Blood. 2023;141(17):20472061. doi:10.1182/blood.2022018604

7. Garcia JS, Platzbecker U, Odenike O, et al. Efficacy and safety of venetoclax in combination with azacitidine for the treatment of patients with treatment-naive, higher-risk myelodysplastic syndromes. Blood. 2023;142 (suppl 1):319. doi:10.1182/blood-2023-189446

8. Mina A, Greenberg PL, Deeg HJ. How I reduce and treat posttransplant relapse of MDS. Blood. 2024;143(14):1344-1354. doi:10.1182/ blood.2023023005

9. DiNardo CD, Roboz GJ, Watts JM, et al. Final phase I substudy results of ivosidenib in patients with mutant IDH1 relapsed/refractory myelodysplastic syndrome. Blood Adv. Published online April 19, 2024. doi:10.1182/bloodadvances.2023012302