KEY TAKEAWAYS
- The SIERRA phase 3 trial aimed to report characteristics and outcomes of patients with TP53 mutations.
- The primary endpoint was dCR.
- The results showed that 131I-apamistamab led HCT improves outcomes in patients with R/R AML, including TP53-mutation, overcoming their poor prognosis.
Allogeneic hematopoietic cell transplant (HCT) emerges as the sole potential cure for patients with relapsed or refractory acute myeloid leukemia (R/R AML). Patients harboring TP53 mutations face dismal prognoses characterized by poor therapy response and high relapse rates, with only a minority qualifying for HCT.
Iomab-B (131I-apamistamab), an anti-CD45 radioimmunoconjugate, administers targeted radiation to hematopoietic cells, achieving myeloablation and leukemia eradication while mitigating off-target toxicity. Its innovative mechanism of action promises enhanced disease management and safer HCT accessibility, offering potential outcomes improvement for TP53 mutation-positive patients.
Dr. Hannah Choe and the team aimed to detail the characteristics and outcomes of patients with TP53 mutations participating in the SIERRA trial.
SIERRA (NCT02665065) conducted a multi-center, randomized, controlled phase 3 study comparing Iomab-B-based conditioning with physician-selected Conventional Care (CC) in patients aged ≥55 years with active, R/R AML. Patients (N=153) were randomly assigned in a 1:1 ratio to receive either CC or Iomab-B combined with fludarabine and total body irradiation (2 Gy), followed by HCT (CC, n=77; Iomab-B, n=76).
The primary endpoint was durable complete remission (dCR), defined as complete remission (CR)/complete remission with incomplete platelet recovery (CRp) lasting ≥6 months. Patients were evaluated for CR/CRp at 28-56 days post-HCT in the Iomab-B arm or at 28-42 days post-start of CC. Patients who did not achieve CR/CRp had the option to crossover to Iomab-B.
Among the 153 randomized patients, all individuals who received a therapeutic dose of Iomab-B (n=66) underwent HCT, compared to only 14 (18.2%) in the CC group. In evaluable patients, the rates of dCR at 6 months were 22% in the Iomab-B group versus 0% in the CC group (95% CI [12.29, 34.73]; P<0.0001).
About 37 patients with TP53 mutations (TP53mut) were enrolled (CC=20; Iomab-B=17), accounting for a prevalence of 24.2%. Baseline characteristics of patients with or without TP53 mutations were well-balanced regarding median age, disease risk/status, number of prior lines of therapy, HCT co-morbidity index, and Kanofsky performance status.
The safety profile of Iomab-B in this population resembled that of the overall SIERRA trial patient population, with a low rate of serious adverse events. Rates of CR and dCR were similar in Iomab-B-treated patients regardless of mutational status. In TP53mut patients treated with Iomab-B, CR and dCR were achieved in 55.6% and 14.8%, respectively, compared to 58.1% and 16.1% in patients with TP53 wild-type (TP53wt).
Among non-crossover (CO) CC patients who were TP53wt, 17.4% achieved CR, but none achieved dCR. No TP53mut patients in the non-CO CC cohort achieved CR or dCR. The median overall survival (OS) for patients with TP53wt in the Iomab-B group was 6.37 months versus 5.72 months for patients with TP53mut (HR=0.66; 95% CI [0.37, 1.18]; P=0.16).
In the CC group (including CO patients), the median OS for patients with TP53mut was 2.96 months. In a post hoc analysis of the CC group excluding CO patients, the median OS was 6.51 months versus 1.66 months for the TP53wt and TP53mut groups, respectively (HR=0.28; 95% CI [0.12, 0.67]; P=0.0022).
The median OS was 5.49 months in patients who received Iomab-B (Iomab-B + CO) versus 1.66 months in patients who did not receive Iomab-B (CC excluding CO) (HR=0.23; 95% CI [0.10, 0.52]; P=0.0002).
The study concluded that 131I-apamistamab led HCT markedly enhances outcomes in patients with R/R AML harboring TP53 mutations. These results aligned with outcomes observed in individuals with wild-type TP53, highlighting the therapy’s ability to mitigate the adverse effects associated with this mutation and improve survival rates.
Consequently, these findings endorse the utilization of 131I-apamistamab led induction/conditioning and HCT in the management of R/R AML, particularly among patients with TP53 mutations.
The trial was sponsored by the Actinium Pharmaceuticals.
Clinical Trial: https://clinicaltrials.gov/study/NCT02665065
Choe H, Tomlinson B, Gyurkocza B, et al. (2024). “131I-APAMISTAMAB-LED ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANT RESULTS IN IMPROVED SURVIVAL OUTCOMES IN R/R AML PATIENTS WITH HIGH-RISK TP53 MUTATIONS IN THE RANDOMIZED PHASE III SIERRA TRIAL.’ Presented at EHA 2024 (S267)
