Exploring Advancements in Higher-Risk MDS
Despite recent setbacks in clinical trials, there is still hope for improving treatments for high-risk myelodysplastic syndromes.
Blood cells : © Dr_Microbe - stock.adobe.com
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.
