Session: 616. Acute Myeloid Leukemias: Investigational Drug and Cellular Therapies: Poster III
Hematology Disease Topics & Pathways:
Research, Clinical trials, Clinical Research
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.