clinical topic updates
High-Risk MDS: Investigating Novel Combination Therapies
An improved understanding of high-risk myelodysplastic syndrome (MDS) has led to clinical trials exploring novel combination treatment strategies. Our featured expert discusses this research and assesses the potential for newer therapies to emerge.
“I think that we are definitely going to move toward combination approaches. There are a few novel combinations that are already in phase 3 clinical trials. If the results are positive, that will translate into new treatment options for patients with high-risk MDS.”
The combination of a hypomethylating agent (HMA) plus venetoclax is well established in acute myeloid leukemia, whereas it is still investigational in high-risk MDS. The combination of venetoclax plus azacitidine has shown benefit in patients with treatment-naive, higher-risk MDS. The updated safety and efficacy data from a phase 1b study examining this combination were reported at the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition, with researchers revealing an overall response rate of 77%. Real-world data that we presented at the 63rd ASH Annual Meeting and Exposition did not show an overall survival increase for the whole group with MDS, but we did see promising activity with HMA therapy plus venetoclax as a bridge to allogeneic stem cell transplantation. The overall survival benefit for an HMA plus venetoclax can only be addressed in randomized clinical trials, and we will be interested to see data from the phase 3 VERONA study, which is evaluating venetoclax plus azacitidine in treatment-naive, higher-risk MDS.
In addition, a couple of immune-based approaches look promising in higher-risk MDS. Most of these combinations begin with HMA therapy as a backbone because that is the standard of care that has shown a survival advantage. Magrolimab, an anti-CD47 monoclonal antibody, blocks a “don't-eat-me signal” that prevents macrophages from phagocytizing the leukemia cells, and CD47 is overexpressed in MDS and acute myeloid leukemia. The combination has looked promising in early phase studies. For instance, a phase 1b study reported that magrolimab plus azacitidine led to high response rates (objective response rate, 91%; complete response rate, 42%) and an acceptable safety profile without significant immune-related adverse events.
And then there is sabatolimab, which is a TIM-3 inhibitor. TIM-3 is expressed on leukemic progenitors and on T cells. What has been really appealing with sabatolimab is that the responses seem to be very durable in MDS/acute myeloid leukemia. Another phase 1b study presented at the 63rd ASH Annual Meeting and Exposition showed a median duration of response in patients with complete response of 21.5 months. Responses were also durable in those with adverse-risk mutations, including TP53 mutations. The toxicity profile for this immune therapy is very reasonable compared with other immune therapies that are used in patients with solid tumors.
It is an exciting time in that we have probably learned more about the biology and heterogeneity of this disease in the last 5 to 10 years than we have in the last 100 years. That knowledge is now translating into additional research and clinical trials that are evaluating novel approaches. I think that we are definitely going to move toward combination approaches. There are a few novel combinations that are already in phase 3 clinical trials. If the results are positive, that will translate into new treatment options for patients with high-risk MDS.
Bewersdorf JP, Carraway H, Prebet T. Emerging treatment options for patients with high-risk myelodysplastic syndrome. Ther Adv Hematol. 2020;11:2040620720955006. doi:10.1177/2040620720955006
Brunner AM, Esteve J, Porkka K, et al. Efficacy and safety of sabatolimab (MBG453) in combination with hypomethylating agents (HMAs) in patients (pts) with very high/high-risk myelodysplastic syndrome (vHR/HR-MDS) and acute myeloid leukemia (AML): final analysis from a phase Ib study [abstract 244]. Abstract presented at: 63rd American Society of Hematology Annual Meeting and Exposition; December 11-14, 2021.
Garcia JS, Wei AH, Borate U, et al. Safety, efficacy, and patient-reported outcomes of venetoclax in combination with azacitidine for the treatment of patients with higher-risk myelodysplastic syndrome: a phase 1b study [abstract 656]. Abstract presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020.
Garcia-Manero G, Guastad Daver N, Xu J, et al. Magrolimab + azacitidine versus azacitidine + placebo in untreated higher risk (HR) myelodysplastic syndrome (MDS): the phase 3, randomized, ENHANCE study. J Clin Oncol. 2021;39(suppl 15):TPS7055. doi:10.1200/JCO.2021.39.15_suppl.TPS7055
Komrokji RS, Ali NA, Chan O, et al. Assessing the role of venetoclax in combination with hypomethylating agents in higher risk myelodysplastic syndromes [abstract 536]. Abstract presented at: 63rd American Society of Hematology Annual Meeting and Exposition; December 11-14, 2021.
Marofi F, Rahman HS, Al-Obaidi ZMJ, et al. Novel CAR T therapy is a ray of hope in the treatment of seriously ill AML patients. Stem Cell Res Ther. 2021;12(1):465. doi:10.1186/s13287-021-02420-8
Sallman DA, Al Malki M, Asch AS, et al. Magrolimab in combination with azacitidine for untreated higher-risk myelodysplastic syndromes (HR-MDS): 5F9005 phase 1b study results [abstract 7017]. Abstract presented at: 2020 American Society of Clinical Oncology Virtual Scientific Program; May 29-31, 2020.
Sallman DA, Al Malki M, Asch AS, et al. Tolerability and efficacy of the first-in-class anti-CD47 antibody magrolimab combined with azacitidine in MDS and AML patients: phase 1b results [abstract 7507]. Abstract presented at: 2020 American Society of Clinical Oncology Virtual Scientific Program; May 29-31, 2020.
Wei AH, Garcia JS, Borate U, et al. A phase 1b study evaluating the safety and efficacy of venetoclax in combination with azacitidine in treatment-naïve patients with higher-risk myelodysplastic syndrome. Blood. 2019;134(suppl 1):568. doi:10.1182/blood-2019-124437
Zeidan AM, Garcia JS, Fenaux P, et al. Phase 3 VERONA study of venetoclax with azacitidine to assess change in complete remission and overall survival in treatment-naïve higher-risk myelodysplastic syndromes. J Clin Oncol. 2021;39(suppl 15):TPS7054. doi:10.1200/JCO.2021.39.15_suppl.TPS7054