Is there a path forward for immunotherapy in patients with myelodysplastic syndromes?

Immunotherapy in some forms is a well established treatment in patients with myelodysplastic syndromes. Allogeneic haematopoietic stem-cell transplantation (HSCT) has long been an efficacious treatment for high-risk myelodysplastic syndromes, and it is the only option that allows durable disease control and a potential cure for some patients. 1 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: 3328-3339 Crossref PubMed Scopus (57) Google Scholar However, allogeneic HSCT is not suitable for many patients due to frailty or comorbidities. For these patients, the enduring standard of care therapy is treatment with a hypomethylating agent. In the AZA-001 trial, 2 Fenaux P Mufti GJ Hellstrom-Lindberg E et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009; 10: 223-232 Summary Full Text Full Text PDF PubMed Scopus (2201) Google Scholar patients with higher-risk myelodysplastic syndromes given the hypomethylating agent azacitidine had median overall survival of 24·5 months. However, the overall survival with azacitidine monotherapy in the AZA-001 trial might have been overestimated, because in multiple real-world analyses of azacitidine in patients with higher-risk myelodysplastic syndromes, median overall survival ranged between 12 months and 18 months. 3 Zeidan AM Stahl M Sekeres MA Steensma DP Komrokji RS Gore SD A call for action: increasing enrollment of untreated patients with higher-risk myelodysplastic syndromes in first-line clinical trials. Cancer. 2017; 123: 3662-3672 Crossref PubMed Scopus (38) Google Scholar Additionally, overall survival estimates after treatment failure of hypomethylating agents is short (5·6 months), and no therapies are approved in this setting. 4 Prebet T Gore SD Esterni B et al. Outcome of the high-risk myelodysplastic syndrome after azacitidine treatment failure. J Clin Oncol. 2011; 29: 3322-3327 Crossref PubMed Scopus (387) Google Scholar Therefore, there is an urgent unmet clinical need to develop novel therapies, hypomethylating agent-based combinations or otherwise, to improve outcomes in the front-line management of myelodysplastic syndromes. To date, no improvements in outcomes have been observed in randomised trials combining hypomethylating agents with targeted therapies, such as the histone deacetylase inhibitor vorinostat, the NEDD8 inhibitor pevonedistat, and the TP53 refolding agent APR-246, when compared with hypomethylating agents alone. 5 Frumm SM Shimony S Stone RM et al. Why do we not have more drugs approved for MDS? A critical viewpoint on novel drug development in MDS. Blood Rev. 2023; 60101056 Crossref PubMed Scopus (2) Google Scholar The remaining accruing phase 3 trials in high-risk myelodysplastic syndromes include the VERONA trial (NCT04401748) comparing venetoclax in combination with a hypomethylating agent with a hypomethylating agent alone and the SELECT-MDS-1 trial (NCT04797780) of tamibarotene, an oral selective retinoic acid receptor α agonist, with the same design. Sabatolimab plus hypomethylating agents in previously untreated patients with higher-risk myelodysplastic syndromes (STIMULUS-MDS1): a randomised, double-blind, placebo-controlled, phase 2 trialThe addition of sabatolimab to hypomethylating agents in this study did not result in a significant improvement in complete response rates or progression-free survival. Sabatolimab had a manageable safety in most patients with higher-risk myelodysplastic syndromes. A randomised phase 3 trial is ongoing to assess the potential benefit of sabatolimab plus azacitidine on overall survival in this setting. Full-Text PDF