Studies presented at the 2022 ASH Annual Meeting may help inform the management of myelodysplastic syndromes (MDS).
Results from the phase 3 ASCERTAIN trial support the use of ASTX727, a fixed-dose combination of decitabine and cedazuridine, in patients with intermediate- and high-risk MDS, including those harboring biallelic TP53 mutations.1
Results from the phase 3 MEDALIST trial suggest that luspatercept may improve 3-year overall survival (OS), when compared with placebo, in patients with very low-risk MDS.2
Primary results from the ongoing phase 2 STIMULUS-MDS1 trial showed that sabatolimab plus hypomethylating agents (HMAs) did not improve progression-free survival (PFS), compared with placebo, in patients with intermediate- to very-high risk MDS.3
Final results from the phase 3 SINTRA-REV trial showed that, compared with placebo, low-dose lenalidomide prolonged time to transfusion, lowered the risk of transfusion dependency, and demonstrated no increase in progression rate or clonal evolution in patients with low-risk MDS.4
ASCERTAIN Trial: ASTX727 in TP53-Mutated MDS
A post-hoc analysis of the phase 3 ASCERTAIN trial (ClinicalTrials.gov Identifier: NCT03306264) examined the mutational profile of patients and its impact on key treatment outcomes, including OS and leukemia-free survival (LFS).1
The trial included 133 patients with MDS or chronic myelomonocytic leukemia who were randomly assigned to receive intravenous decitabine for cycle 1 and ASTX727 for cycle 2 or the opposite treatment sequence. The patients who continued treatment beyond cycle 2 received ASTX727 for all subsequent cycles. They were treated until disease progression, unacceptable toxicity, patient’s decision, or hematopoietic stem cell transplant.
In the population with TP53 mutations (n=44), the median OS was 25.5 months, and the median LFS was 22.1 months. Among patients with wild-type TP53, the median OS was 33.7 months, and the median LFS was 31.7 months.
The patients harboring a TP53 mutation were further divided by allelic status. Fourteen patients had biallelic mutations and 30 had monoallelic mutations lacking other chromosomal deletions. The median OS was 13.0 months in patients with biallelic mutations and 29.2 months in those with monoallelic mutations.
“MDS patients with mutated TP53 are of interest, given the typically poor outcomes with treatment,” said study presenter Michael R. Savona, MD, of Vanderbilt University School of Medicine in Nashville. “These results support the emerging hypothesis that a higher burden of mutant TP53 cells denotes poorer risk, and the fixed-dose combination of ASTX727 may serve as a reasonable option in these patients.”
MEDALIST Trial: Luspatercept May Improve 3-Year OS in Very Low-Risk MDS
A post-hoc analysis of the phase 3 MEDALIST Trial (ClinicalTrials.gov Identifier: NCT02631070) examined the probability of greater OS and PFS benefit from luspatercept compared with placebo in patients with Revised-International Prognostic Scoring System (IPSS-R) very low-, low-, or intermediate-risk MDS.2 Prior evidence showed that luspatercept significantly reduced transfusion burden in patients with low-risk MDS compared with placebo.
In the current analysis, the median OS was not significantly different between the luspatercept and placebo arms. However, luspatercept responders had significantly longer OS than luspatercept nonresponders at week 25 (hazard ratio [HR], 0.319; P =.0003). Additionally, the probability of 36-month OS was greater for patients with IPSS-R very-low risk MDS receiving luspatercept vs placebo (77.8% vs. 16.7%, respectively; odds ratio, 17.5; P =.0088).
The median PFS was not significantly different between the luspatercept and placebo arms (P =.3514). However, the probability of 36-month PFS in patients with a baseline serum erythropoietin level of 100 to 200 U/L was significantly higher in patients who received luspatercept than in patients who received placebo (97.3% vs 78.9%, respectively; odds ratio, 9.6; P =.0238).
“While MEDALIST was not powered to evaluate OS or PFS, these data show that achieving response with luspatercept treatment increased OS and PFS probability in certain patient subgroups,” said study presenter Valeria Santini, MD, PhD, of the University of Florence in Italy.