The treatment journey for Myelodysplastic Syndromes (MDS) is fraught with challenges due to its heterogeneity, hematopoietic failure, complications, and transformation risks, all of which significantly complicate therapy. Notably, the 29th Annual Meeting of the European Hematology Association (EHA 2024), held from June 13 to 16, 2024, showcased significant progress in the field of MDS treatment. In this issue of "Oncology Frontier - Hematology Frontier," we have invited Professor Zonghong Shao from Tianjin Medical University General Hospital to provide an in-depth introduction and commentary on key research in the MDS treatment domain. We hope Professor Shao's insightful sharing will reveal the latest developments in the MDS field, aiding our colleagues in grasping the forefront of treatment and jointly seeking better therapeutic options for MDS patients.1. Sabatolimab Does Not Significantly Extend Survival in High-Risk MDS Patients
At the EHA 2024 meeting, Professor Amer M. Zeidan presented preliminary results from the Phase III STIMULUS-MDS2 study (S180): the combination of sabatolimab and azacitidine as first-line treatment for higher-risk MDS or CMML-2 patients did not meet the primary endpoint of overall survival (OS), despite showing positive trends in OS, CR rate, PFS, and LFS.
Sabatolimab (MBG453, SABA) is an immunotherapy targeting TIM-3, an immune-myelodysregulation factor expressed on immune and leukemia stem cells. In the Phase II randomized, placebo-controlled STIMULUS-MDS1 study, sabatolimab combined with hypomethylating agents (HMA) extended the duration of complete remission (CR) and suggested an improvement trend in progression-free survival (PFS), although the primary endpoints (CR rate + PFS) were not met.
STIMULUS-MDS2 is a Phase III randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of sabatolimab combined with azacitidine (AZA) as a first-line treatment for high-risk MDS (I-, H-, or vH) or CMML-2 patients.
Inclusion Criteria: Patients aged ≥18 years with IPSS-R scores indicating intermediate, high, or very high-risk MDS or non-proliferative CMML-2, who are not eligible for allogeneic transplantation at enrollment. Patients were stratified by MDS IPSS-R and CMML-2, and randomized 1:1 to receive sabatolimab 800 mg or placebo intravenously on Day 8 of each 28-day cycle, along with AZA 75 mg/m2/day (IV or SC) on Days 1-7 (or Days 1-5, 8, 9). The primary endpoint was overall survival (OS). Key secondary endpoints included time to fatigue worsening (without subsequent improvement), red blood cell transfusion independence duration, fatigue improvement, and physical and emotional functioning. Secondary endpoints included PFS, leukemia-free survival (LFS), and response rates. An initial OS analysis was planned after 282 OS events.
A total of 530 patients were randomized into two groups (265 per group). The median age was 71.0 years; the number of intermediate, high, very high-risk MDS, and CMML-2 patients were 144 (27.2%), 177 (33.4%), 171 (32.3%), and 38 (7.2%), respectively. Baseline characteristics were well balanced between the two groups. Among MDS patients (N=492), the proportions of patients with <5%, 5-<10%, and 10-<20% bone marrow blasts were 117 (23.8%), 169 (34.3%), and 206 (41.9%), respectively. One patient in each group did not receive treatment after randomization.
As of the data cutoff date of September 15, 2023, 40 patients (15.1%) in the SABA+AZA group and 38 patients (14.3%) in the PBO+AZA group were still on treatment, with median exposure times of 8.8 months and 6.8 months, respectively. Post-treatment, 9.1% of patients in the SABA group and 11.3% in the PBO group underwent transplantation. Median OS for the SABA+AZA and PBO+AZA groups was 22.31 and 18.83 months [HR 0.85 (95% CI: 0.67-1.07); one-sided P-value 0.0825].
The subgroup that benefited most from SABA+AZA in terms of OS included patients with very high-risk MDS (IPSS-R), very high-risk MDS (IPSS-M), poor/very poor cytogenetic risk, and ≥10% bone marrow blasts (Figure 2). Median PFS and LFS were 13.6 and 10.1 months [HR 0.70 (0.56-0.86)], and 19.4 and 13.7 months [HR 0.78 (0.61-1.00)] in the SABA and PBO groups, respectively; CR rates were 19.6% and 14.3%, bone marrow CR rates were 29.1% and 26.0%, PR rates were 1.5% and 0.4%, and CR+PR+hematologic improvement rates were 42.6% and 34.7%.
The incidence of any and the most common ≥3 grade adverse events (AEs) were: 90.9% and 88.3% (SABA+AZA [N=263] and PBO+AZA [N=265]); anemia, 36.9% and 29.1%; neutropenia, 35.4% and 27.9%; decreased neutrophil count, 24.0% and 20.4%; febrile neutropenia, 22.8% and 16.2%; thrombocytopenia, 22.4% and 17.4%.
Expert Commentary
Professor Zonghong Shao: Despite showing promising trends in OS, CR rate, PFS, and LFS, the combination of sabatolimab and azacitidine as a first-line treatment for high-risk MDS or CMML-2 patients did not achieve the primary endpoint of OS in the overall study population. Preliminary data suggest that the combination therapy may benefit patients with poorer prognosis in high-risk MDS, such as those with very high-risk scores, poor cytogenetics, and higher blast counts. Further analysis is needed to identify the specific patient subgroups that might benefit. Additionally, the relationship between TIM-3 expression levels on MDS stem cells and CD8+ T cells and treatment efficacy warrants further investigation.
2. Magrolimab Does Not Significantly Improve Survival in High-Risk MDS Patients
At the EHA 2024 meeting, Professor David Sallman presented results from the Phase III ENHANCE study (S181): the combination of magrolimab (Magro) and azacitidine (AZA) for the initial treatment of high-risk MDS patients did not meet the primary endpoints of overall survival (OS) and complete response rate (CRR) and showed more severe treatment-related adverse events (TEAEs).
High-risk MDS patients have low long-term survival rates and are prone to progress to acute myeloid leukemia (AML). AZA is the standard treatment for high-risk MDS, but it has a low complete response rate (CRR, <20%) and short overall survival (OS; <2 years). Magrolimab is a first-in-class monoclonal antibody that blocks CD47, an anti-phagocytic signal overexpressed on cancer cells. A large Phase 1b study (n=95) showed good efficacy and acceptable safety for Magro+AZA in frontline high-risk MDS, with targeted anemia mitigation through dose preconditioning. A subsequent Phase III study was conducted to confirm these results, highlighting the urgent need for more effective and safe treatments for high-risk MDS patients.
The randomized, double-blind, multicenter Phase III ENHANCE study evaluated the efficacy and safety of Magro+AZA versus PBO+AZA in frontline high-risk MDS patients.
Based on the revised International Prognostic Scoring System, treatment-naive patients with intermediate, high, or very high-risk MDS were randomized to receive Magro (D1 and D4: 1 mg/kg, D8: 15 mg/kg, D11 and D15: 30 mg/kg, then weekly for 5 weeks, followed by maintenance dosing every 2 weeks) + AZA (75 mg/m2 daily for D1-7 or D1-5, 8-9 in 28-day cycles) or placebo + AZA. Stratification was done based on geographic region, cytogenetic risk, and percentage of bone marrow blasts. Dual primary endpoints were CRR and OS.
Results: From September 2020 to October 2022, 539 patients were randomized to the Magro+AZA group (n=268) and the PBO+AZA group (n=271). Baseline characteristics were generally well-balanced between the two groups (Magro+AZA and PBO+AZA); however, there were differences in the proportion of patients aged <65 years (23.9% vs. 29.9%), those with known TP53 mutations (29.5% vs. 23.6%; wild-type, 32.8% vs. 42.1%; unknown/missing, 37.7% vs. 34.3%), and those not requiring red blood cell transfusions (47.8% vs. 53.9%). The median duration of treatment was 19.1 weeks for Magro and 19.3 weeks for PBO. More patients in the Magro+AZA group discontinued treatment due to adverse events (AEs) compared to the PBO+AZA group.
More patients in the PBO+AZA group (35.4%) underwent transplantation than in the Magro+AZA group (20.9%). The study did not meet the primary endpoints of OS (median time, 15.9 vs. 18.6 months; hazard ratio = 1.203; 95% CI: 0.947-1.528; P=0.13) or CRR (21.3% vs. 23.6%; odds ratio = 0.876; 95% CI: 0.585-1.312; P=0.52). Secondary endpoint results are shown in the table.
The frequency of ≥3 grade TEAEs and any grade TEAEs were higher in the Magro+AZA group compared to the PBO+AZA group (see table). The most common ≥3 grade TEAEs occurring in ≥20% of patients in either group (Magro+AZA and PBO+AZA) included neutropenia (44.5% vs. 40.9%), anemia (42.6% vs. 21.2%), thrombocytopenia (40.3% vs. 33.3%), and febrile neutropenia (22.8% vs. 18.9%). In April 2022, an urgent safety measure (USM) was implemented to ensure hemoglobin levels were ≥9 g/dL within 24 hours prior to the first two doses of Magro/PBO. The USM numerically improved the safety/tolerability of Magro. The study was terminated due to pre-specified futility based on interim analysis results. Efficacy subgroup analysis will follow.
Expert Commentary
Professor Zonghong Shao: In the ENHANCE study, the combination of magrolimab and AZA as frontline treatment for high-risk MDS did not improve OS or increase the complete response rate and showed more severe treatment-related adverse events. The results highlight the significant challenges in developing anti-CD47 therapies for high-risk MDS.
