Primary Results of Stimulus-MDS1: A Randomized, Double-Blind, Placebo-Controlled Phase II Study of TIM-3 Inhibition with Sabatolimab Added to Hypomethylating Agents (HMAs) in Adult Patients with Higher-Risk Myelodysplastic Syndromes (MDS)

Zeidan, Amer M.; Ando, Kiyoshi; Rauzy, Odile Beyne; Turğut, Mehmet; Wang, Ming-Chung; Cairoli, Roberto; Hou, Hsin‐An; Kwong, Yok-Lam; Sangerman, Montserrat Arnán; Meers, Stef; Pullarkat, Vinod; Malek, Kamel; Kiertsman, Flavia; Lyu, Jiaying; Ramos, Pedro Marques; Fenaux, Pierre; Miyazaki, Yasushi; Platzbecker, Uwe

doi:10.1182/blood-2022-158612

Cited by 18 publications

(8 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…50 Results from a randomized phase II study STIMULUS-MDS1 (NCT03946670) were reported recently. 51 Although response rates and survival were similar between the 2 groups (sabatolimab plus HMA vs. placebo plus HMA), median duration of CR was considerably longer in the sabatolimab group, suggesting possible delayed benefit with sabatolimab. Phase III STIMULUS-MDS2 (NCT04266301) with a primary endpoint of OS has completed accrual, and results are awaited, which will definitively inform sabatolimab's role in higher-risk MDSs.…”

Section: Investigational Combinatorial Approachesmentioning

confidence: 83%

“…Currently, several phases I–III trails are ongoing with sabatolimab 50 . Results from a randomized phase II study STIMULUS-MDS1 (NCT03946670) were reported recently 51 . Although response rates and survival were similar between the 2 groups (sabatolimab plus HMA vs. placebo plus HMA), median duration of CR was considerably longer in the sabatolimab group, suggesting possible delayed benefit with sabatolimab.…”

Section: Higher-risk Mdsmentioning

confidence: 97%

See 1 more Smart Citation

Overview of the Management of Higher-Risk Myelodysplastic Syndromes

Singh

Carraway

2023

Cancer J

View full text Add to dashboard Cite

Myelodysplastic syndromes or myelodysplastic neoplasms (both abbreviated MDSs) (Leukemia 2022;36:1703–1719) have historically been challenging diseases to treat owing to their complex biology, molecular diversity, and a patient population that is elderly with comorbidities. As the patients are living longer, incidence of MDSs is rising, and challenges in selecting MDS treatments or lack thereof have been becoming more apparent. Fortunately, with better understanding of molecular underpinnings of this heterogeneous syndrome, numerous clinical trials reflecting the biology of disease and catering to the advanced age of MDS patients are in development to maximize the likelihood of identifying active drugs. Addressing this diverse nature of genetic abnormalities, novel agents, and combinations are in development to formulate personalized treatment approaches for MDS patients. Myelodysplastic syndrome is categorized into subtypes that are associated with lower or higher risk for leukemic evolution, and that knowledge helps with therapy selection. Currently, as it stands, for those with higher-risk MDSs, hypomethylating agents are the first-line therapy. Allogenic stem cell transplantation represents the only potential cure for our patients with MDSs and should be considered for all eligible patients with higher-risk MDSs at the time of diagnosis. This review discusses current MDS treatment landscape, as well as new approaches in development.

show abstract

Section: Investigational Combinatorial Approachesmentioning

confidence: 83%

Section: Higher-risk Mdsmentioning

confidence: 97%

Overview of the Management of Higher-Risk Myelodysplastic Syndromes

Singh

Carraway

2023

Cancer J

View full text Add to dashboard Cite

show abstract

“…Progression-free survival between the two groups was 11.3 months versus 8.3 months, respectively. In the TP53 mutant cohorts (n = 39 and 38), the OS was no different at 15 months [65].…”

Section: Allogenic Hematopoietic Stem-cell Transplantation In Tp53-mu...mentioning

confidence: 90%

“…With newly diagnosed TP53 mutated AML, the CR was 40% with a median duration of response of 6.4 months. However, in the recently presented double blind placebo controlled trial of azacitidine + sabatolimab versus sabatolimab alone, there was no improvement in response or OS in patients with TP53 mutant MDS [64]. The adverse events of sabatolimab + HMA were similar to HMA alone, with the two most common being neutropenia and thrombocytopenia [48].…”

Section: Novel Therapies To Improve Outcomes In Tp53 Mutant Mds/aml P...mentioning

confidence: 99%

TP53-Mutated Myelodysplastic Syndrome and Acute Myeloid Leukemia: Current Guidelines, Therapies, and Future Considerations

DiGennaro,

Sallman

2023

Acta Haematol

View full text Add to dashboard Cite

Background Acute Myeloid Leukemia (AML) is a heterogeneous hematological malignancy characterized by uncontrolled proliferation and impaired differentiation of myeloid cells in the bone marrow. The tumor suppressor gene TP53 plays a crucial role in maintaining genomic integrity and preventing the development of cancer. TP53 mutations are frequently observed in AML (~10% of patients) and are associated with aggressive disease behavior, resistance to therapy, and poor prognosis. Summary Recent changes in classification of TP53-mutated myelodysplastic syndrome (MDS) have occurred related to the allelic status of TP53 and more importantly to harmonize MDS/AML patients as a homogeneous hematological malignancy. Current treatment regimens involve hypomethylating agents +/- venetoclax or intensive chemotherapy although unfortunately independent of treatment regimen the overall survival (OS) of this patient cohort is around 6 months with poor long-term outcomes after allogeneic stem cell transplantation. Recent developments geared towards the treatment of TP53-mutated MDS/AML have focused on immunotherapies. Key Messages Notably, there is optimism surrounding these new therapies that could provide breakthroughs with improving outcomes either as monotherapy or combined with established nonimmune therapies. This paper aims to provide an overview of TP53-mutated MDS/AML, including the underlying mechanisms, clinical implications, and emerging therapeutic strategies targeting this hematologic malignancy.

show abstract

“…In the subsequent STIMULUS-MDS1 study (NCT03946670), CR and PFS were not statistically different between patients with intermediate-risk (IR)/HR/vHR-MDS given sabatolimab + HMA versus HMA alone. Considering the potential of a delayedonset benefit and that OS is more indicative of the effect of an immunomodulatory therapy compared with short-term CR, the study is still ongoing to collect long-term safety and survival data, 32 and the STIMULUS-MDS-2 study (NCT04266301), which has a primary OS endpoint, has completed enrollment.…”

Section: Discussionmentioning

confidence: 99%

Phase Ib study of sabatolimab (MBG453), a novel immunotherapy targeting TIM‐3 antibody, in combination with decitabine or azacitidine in high‐ or very high‐risk myelodysplastic syndromes

Brunner,

Esteve,

Porkka

et al. 2023

American J Hematol

View full text Add to dashboard Cite

Patients with higher-risk myelodysplastic syndromes/neoplasms (MDS) and chronic myelomonocytic leukemia (CMML) have poor prognoses and need novel therapies that produce durable responses with sustained clinical benefit. [1][2][3][4] Initial therapy for higher-risk MDS usually includes a hypomethylating agent (HMA), either azacitidine or decitabine, 5 but benefits are modest, with <20% of patients achieving complete remission (CR) and a median duration of any response <15 months. 6,7 Patients with CMML treated with HMAs 8 also have poor outcomes. 9 T-cell immunoglobulin domain and mucin domain-3 (TIM-3) 10 are expressed on immune cells and myeloid leukemic cells, and function as an inhibitory surface receptor regulating innate and adaptive immune responses, as well as promoting leukemic stem cell (LSC) self-renewal through interaction with galectin-9. [11][12][13][14][15] Increased TIM-3 expression on leukemic progenitors has been described at the time of leukemic progression, suggesting the TIM-3 pathway may be involved in disease transformation to acute myeloid leukemia (AML). 16,17 Conditional knockout of TIM-3 on dendritic cells (DCs) promotes strong antitumor immunity. 18 Sabatolimab, a novel monoclonal antibody targeting TIM-3, may interact with the dysregulated immune microenvironment in MDS, and directly with TIM-3-expressing leukemic progenitors. 11,19,20 Early studies indicate the pharmacokinetic and safety profile of sabatolimab monotherapy is favorable for combination with standard of care therapies in the management of patients with myeloid malignancies. [21][22][23] This Phase Ib trial of sabatolimab + HMA was conducted to evaluate safety, response rate by revised International Working Group (IWG) criteria, and durability of response in patients with high-or very high-risk MDS (HR/vHR-MDS) or CMML. 24

show abstract

Primary Results of Stimulus-MDS1: A Randomized, Double-Blind, Placebo-Controlled Phase II Study of TIM-3 Inhibition with Sabatolimab Added to Hypomethylating Agents (HMAs) in Adult Patients with Higher-Risk Myelodysplastic Syndromes (MDS)

Cited by 18 publications

References 0 publications

Overview of the Management of Higher-Risk Myelodysplastic Syndromes

Overview of the Management of Higher-Risk Myelodysplastic Syndromes

TP53-Mutated Myelodysplastic Syndrome and Acute Myeloid Leukemia: Current Guidelines, Therapies, and Future Considerations

Phase Ib study of sabatolimab (MBG453), a novel immunotherapy targeting TIM‐3 antibody, in combination with decitabine or azacitidine in high‐ or very high‐risk myelodysplastic syndromes

Contact Info

Product

Resources

About