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4258 Outcome of Patients with TP53 Mutated Relapsed/Refractory AML with Lintuzumab-Ac225 in Combination with CLAG-M Following Venetoclax Plus Hypomethylating Agent Therapy

Program: Oral and Poster Abstracts
Session: 616. Acute Myeloid Leukemias: Investigational Drug and Cellular Therapies: Poster III
Hematology Disease Topics & Pathways:
Research, Clinical trials, Clinical Research
Monday, December 9, 2024, 6:00 PM-8:00 PM

Sameem Abedin, MD1, Guru Subramanian Guru Murthy, MBBS2, Mehdi Hamadani, MD3, Laura C. Michaelis, MD2, Karen-Sue Carlson, MD, PhD4, Lyndsey Runaas, MD5*, Katelyn Gauger6*, Avinash Desai7*, Mary Chen7, Patrik Brodin7*, Kate L Li, PhD7*, Mojisola Rotibi7*, Umar Sayeed, MS8*, Alexandra M. Harrington, MD, MT(ASCP)9 and Ehab L. Atallah, MD2

1Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI
2Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI
3Department of Medicine, Medical College of Wisconsin, Milwaukee, WI
4Department of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI
5Medical College of Wisconsin, Division of Hematology/Oncology, Milwaukee, WI
6Medical College of Wisconsin, MILWAUKEE, WI
7Actinium Pharmaceuticals, New York, NY
8Actinium Pharmaceuticals, New York
9Medical College of Wisconsin, Milwaukee, WI

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.

Disclosures: Abedin: AbbVie, Daichii Sankyo, Servier: Consultancy, Honoraria; Actinium Pharmaceutical, AltruBio, Incyte: Research Funding. Guru Murthy: Gilead Sciences/Kite: Other: Advisory board, Research Funding; Pfizer: Other: Advisory board; BMS: Other: Advisory Board; Rigel: Speakers Bureau; Syndax: Other: Advisory Board; Autolus: Other: Advisory board; BeiGene: Other: Advisory board, Research Funding; LOXO/Lilly: Research Funding; Amgen: Consultancy, Speakers Bureau; Stemline: Speakers Bureau; Zentalis: Research Funding; Merck: Research Funding; Schrodinger: Research Funding. Hamadani: Autolus: Consultancy; Allovir: Consultancy; Caribou: Consultancy; CRISPR: Speakers Bureau; DMC, Inc: Speakers Bureau; Genentech: Speakers Bureau; Myeloid Therapeutics: Speakers Bureau; Takeda: Research Funding; AbbVie: Consultancy; Kite Pharma: Consultancy, Speakers Bureau; Spectrum Pharmaceuticals: Research Funding; ADC Therapeutics: Consultancy, Research Funding, Speakers Bureau; Byondis: Consultancy; BeiGene: Speakers Bureau; AstraZeneca: Speakers Bureau; Sanofi Genzyme: Speakers Bureau; CRISPR: Consultancy; Genmab: Consultancy; Astellas Pharma: Research Funding; Omeros: Consultancy; Forte Biosciences: Consultancy; BMS: Consultancy. Michaelis: Disc Medicine: Consultancy; Kura Oncology: Consultancy; Merck Pharmaceuticals: Consultancy, Honoraria; Nkarta: Consultancy. Desai: Actinium Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Chen: Actinium Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Brodin: Actinium Pharmaceuticals: Current Employment. Li: Actinium Pharmaceuticals: Current Employment. Rotibi: Actinium Pharmaceuticals: Current Employment. Sayeed: Actinium Pharmaceuticals: Current Employment. Atallah: Novartis Pharmaceuticals Corporation: Honoraria.

*signifies non-member of ASH