Outcome of Patients with TP53 Mutated Relapsed/Refractory AML with Lintuzumab-Ac225 in Combination with CLAG-M Following Venetoclax Plus Hypomethylating Agent Therapy
Authors: Abedin Sameem , Guru Murthy Guru Subramanian , Hamadani Mehdi , Michaelis Laura C. , Carlson Karen-Sue , Runaas Lyndsey , Gauger Katelyn , Desai Avinash , Chen Mary , Brodin Patrik , Li Kate L , Rotibi Mojisola , Sayeed Umar , Harrington Alexandra M. , Atallah Ehab L. 
Published: December 2024

Background

In acute myeloid leukemia (AML), guidelines support use of BCL2-inhibitor venetoclax (ven) and hypomethylating agents (HMAs) as frontline or salvage therapy, regardless of fitness, in patients with poor risk AML, such as TP53-mutated AML. Despite availability of this novel regimen in poor risk disease, outcomes have not significantly improved. This is partly due to a lack of effective options after ven+HMA failure. Recent publications, indicate dismal survival in poor risk AML after ven+HMA failure, in the range of 2 months (Maiti et al Haematologica 2021, Gangat et al Haematologica 2023).

Lintuzumab-Ac225 is a humanized CD33 antibody conjugated to the alpha emitting isotope, Actinium225 (Ac225). Clinical studies have shown that the high-energy alpha-particle emissions from lintuzumab-Ac225 elicit single and double-stranded DNA breaks in targeted tumor cells, bypassing chemoresistance pathways. Further, pre-clinical evidence also demonstrates that Lintuzumab-Ac225 depletes MCL-1 protein levels, which is an anti-apoptotic protein implicated in ven resistance. We completed a Phase I study where lintuzumab-Ac225 was administered after CLAG-M, a salvage chemotherapy, in relapsed/refractory (R/R) AML. Here, we report the outcomes in patients enrolled to study after ven+HMA treatment, particularly poor risk (TP53 mut) AML patients.

Methods

Patients enrolled in the phase I study of CLAG-M + Lintuzumab-Ac225, who received ven+HMA as a prior treatment (n=13) were included in this analysis. All patients were followed for up to 2 years after enrollment. Endpoints evaluated include response based on ELN 2017 criteria, measurable residual disease (MRD) determined by flow cytometry, and overall survival (OS).

Results

Baseline features of prior ven+HMA treated patients include median age of 63 years, 3 (range: 1-5) prior lines of therapy, 10 patients with poor risk disease, including 9 patients with a TP53 mutation. Among the high-risk patients, the common Grade 3/4 toxicities included febrile neutropenia and cytopenias which were manageable and expected in this population. The complete remission CR/CRi (CRc) rate was 38.5% in this population, and including patients achieving a morphologic leukemia free state (MLFS), the overall response rate (ORR) was 53.8%. Notably all patients achieving CRc were MRD negative by flow. Overall, the median OS was 7.26 months.

Two patients received frontline ven+HMA followed by enrollment onto this study; 100% achieved CR, and median OS was 21.4 months. Another 3 patients received ven+HMA as second line therapy prior to enrollment, 67% achieved CR/CRi, and median OS was 22.5 months. Among the 9 patients with TP53 mutated disease, 3 patients achieved CRc (33%), another 2 patients achieved a MLFS (22%) for an ORR of 55% (5/9) and MRD negative of 60% (3/5). Median OS was 6.9 months in these patients.

Conclusions

There is a critical need for more effective therapies in poor risk AML patients with disease progression after ven+HMA. Among these patients who were fit for intensive therapy, our data indicated that CLAG-M followed by Lintuzumab-Ac225 had a tolerable safety profile and yielded high responses with high MRD negativity translating to improved overall survival including in patients with TP53 mutated AML. Given these promising results in a historically challenging patient population, these results support a larger clinical study investigating CLAG-M followed by Lintuzumab-Ac225.