Currently available treatments for low-risk myelodysplastic syndrome (LR-MDS) have limitations, and many patients often become red blood cell transfusion dependent.1 In turn, these transfusions negatively impact progression-free survival (PFS) and OS in these patients, highlighting the urgent need for improved therapies that are transfusion-independent. Imetelstat, a first-in-class direct and competitive inhibitor of telomerase enzymatic activity, was investigated in the IMerge trial.1 This randomised, double-blind, phase II/III trial compared imetelstat vs. placebo in lenalidomide or hypomethylating agent treatment-naïve patients with heavily transfusion-dependent, erythropoiesis-stimulating agent (ESA)-relapsed, refractory, or ineligible LR-MDS. In this study, 178 patients were randomised 2:1 to receive either imetelstat (7.5 mg/kg q4w) or placebo (median age 72 and 73 years, respectively). In total, 40% of patients receiving imetelstat achieved a transfusion independence period of ≥8 weeks, and 83% of these responders had a single continuous transfusion independent period (median of 51.6 weeks vs. 13.3 weeks in the placebo-arm). Further, 18% of these patients achieved transfusion independence for ≥1 year (vs. 2% in placebo group). A concurrent haemoglobin (Hb) increase was also seen in the imetelstat group with 17% of patients experiencing ≤1 year transfusion independence with a rise of ≥1.5 g/dL in Hb vs. 0% in the placebo group. At a median follow-up of 32 months, 47% of patients were included in the imetelstat group, and 43% of patients at 28 months for placebo. Median OS was 40.4 months vs. NE, respectively (HR[95% CI]: 0.98[0.53-1.82]). This lack of a difference was also seen when the data was split responders vs. non-responders (40.4 months vs. NE; HR[95% CI]: 0.78[0.4-1.52]). The median PFS was NE in the treatment group or placebo, however, 29 PFS events were seen in the imetelstat arm vs. 14 in placebo. These results confirm that patients who received imetelstat achieved durable transfusion independence along with improvement in Hb levels. No detriment of imetelstat on OS was noted.
The efficacy of sabatolimab (SAB), an immunotherapy targeting TIM-3, in combination with AZA in the front line therapy for patients with higher-risk MDS (n= 492) or CMML-2 was assessed in the STIMULUS-MDS2 trial.2 This randomised, double-blind, placebo-controlled phase III trial enrolled 530 patients with high or very HR-MDS or CMML-2 who were not eligible for HSCT and randomised them 1:1 to receive SAB (800 mg on d8 of each cycle; q4w) + AZA (75 mg/m2/day on d1-7 or 1-5 and 8-9 of each cycle) or placebo + AZA following the same schedule. Of note, the median duration of treatment was 8.8 months for SAB + AZA vs. 6.8 months for placebo, but the median follow-up was 35.9 months and 37.7 months, respectively. This resulted in 40 patients in the SAB + AZA arm vs. 38 patients in the placebo arm for whom treatment was still ongoing. In the overall population, the OS for SAB + AZA was 22.3 months vs. 18.1 months in placebo (HR[95% CI]: 0.847[0.671-1.070], p= 0.0825). Following treatment, 9.1% of patients in the SAB + AZA arm and 11.3% in the placebo arm continued to HSCT. In patients with MDS only, the median OS was 22.5 months vs. 18.7 months. A CR was seen in 19.6% in the SAB + AZA group vs. 14.3% in the placebo arm. A numerical improvement in PFS was seen in the SAB + AZA arm (13.6 months vs. 10.1 months). In terms of safety, no new safety signals were identified. In the SAB + AZA arm, an incidence of 90.9% for grade ≥3 AE’s vs. 88.3% was seen. Further, there were fewer treatment-related deaths in the SAB + AZA arm (6.8% vs. 12.5%). Overall, STIMULUS-MDS2 is one of the largest randomised trials in higher-risk MDS, however, despite favourable trends for OS, CR rate, and PFS, this study failed to meet the primary endpoint of OS. The SAB + AZA combination was generally well-tolerated with no new safety signals identified.
The ENHANCE trial assessed the potential of magrolimab in combination with AZA vs. placebo + AZA in patients with HR-MDS. The final results from this randomised, double-blind phase III study were presented at EHA 2024.3 This trial recruited 539 patients with untreated intermediate to very HR-MDS with an ECOG PS 0-2 and randomised them 1:1 to receive either magrolimab+ AZA (median age 71) or placebo + AZA (median age 69). Of note, this study was stopped early at a prespecified interim analysis due to futility. No significant difference in CR between the arms was noted (21.3% vs. 23.6%, magrolimab vs. placebo, respectively). Fewer patients in the magrolimab arm also continued to SCT (20.9% vs. 35.4%; p= 0.0001). At the time of the final analysis, the median OS was numerically but not significantly lower in the magrolimab arm (15.9 vs. 18.6 months). In terms of safety, there was a higher incidence of grade ≥3 TEAE’s in the magrolimab arm (92.8% vs. 79.2%), which also lead to higher discontinuation and death rates in this arm (24% vs. 12.1%, and 15.2% vs. 9.8%, respectively). This study did not meet either of the primary endpoints of CR rate and OS. The addition of magrolimab to AZA led to more severe TEAE’s, higher discontinuation and death rates. These findings highlight the challenges of treatment in this population.
IDH1 mutations occur in about 3% of patients with MDS and are often associated with HR-MDS and a high rate of progression to AML.4 Ivosidenib, a first-in-class targeted inhibitor of the mIDH1 enzyme, is approved for use in the US and EU for frontline therapy of IDH1M AML, as monotherapy or in combination with AZA, and in patients with AML aged over 75 years or those unfit for intensive chemotherapy.4,5 More recently, it has received approval in the US for use in R/R MDS.4 The phase II, single-arm IDIOME study investigated ivosidenib in patients with MDS including non-proliferative AML up to 29% of bone marrow blasts with an IDH1 mutation and ECOG PS 0-2. This study comprised of 3 cohorts: cohort A; R/R HR-MDS, patients who failed to achieve any response after 6 cycles of AZA (n= 22); cohort B; first-line HR-MDS, patients with untreated HR-MDS without life-threatening cytopenia (n= 23); cohort C; R/R LR-MDS, patients with lower risk MDS with anaemia having failed erythropoietin (n= 3). Patients in cohorts A and C received ivosidenib (500 mg/d/6×28 day cycles) while those in cohort B received the same dose but only 3 cycles. Grade ≥3 TRAE’s were mainly haematological (n= 11) and 49 incidences of serious AE’s were observed. However, all AE’s were manageable and reversible. The ORR following 3 cycles in cohort A and B were 64% and 78%, including a CR rate of 14% and 48%, respectively. In cohort A, the median OS was 8.9 months with a 12-month OS rate of 15.2%. At a median follow up 25.2 months, the median OS was not reached in cohort B, but the 12-month OS was 91.3%. Of the 3 patients in cohort C, 2 achieved CR with transfusion independence. Overall, ivosidenib was well tolerated in HR-MDS patients and significant responses were seen across all cohorts. In patients with R/R HR-MDS, the OS was poor, however, ivosidenib may prove a well-tolerated and efficacious therapy for patients without available therapy and life-threatening disease. Ivosidenib was particularly effective in the treatment-naïve patients suggesting a possible indication for use in first-line therapy.
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