The combination of Actimab-A (Lintuzumab-Ac225), an antibody radiation conjugate, and CLAG-M, a chemotherapy regimen, resulted in a high response rate and minimal residual disease (MRD) negativity among patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) with adverse features, according to a phase 1 study. 

At the 2022 ASH Annual Meeting and Exposition in New Orleans, LA, Sameem Abedin, MD, Medical College of Wisconsin, Wisconsin, presented data from the phase 1 study.

“Actimab-A (lintuzumab-Ac225) is a humanized CD33 antibody conjugated to an alpha emitting isotope, Ac225, delivering high energy radiation over a short radius to CD33 expressing AML blasts and requiring no isolation,” Abedin and coauthors wrote, “Preclinical studies also indicate that Actimab-A effectively depletes the anti-apoptotic protein MCL-1, potentially indicating another mechanism of action, which may benefit venetoclax resistant patients.”

There were 21 patients with high-risk AML with adverse features, including patients with s-AML/t-AML (n=11), adverse cytogenetics (n=14), and TP53 mutations (n=11) enrolled in this study. The median age of participants was 63 years. Patients received a median of 2 lines of therapy, and 57% (n=12) received prior venetoclax. One induction cycle was administered to all patients (300mcg/d G-CSF days 1-6; 5mg/m2 cladribine and 2g/m2g cytarabine days 2 to 6; 10 mg/m2 mitoxantrone days 2 to 4). Actimab-A was administered as a single dose to 4 separate cohorts, (range: .25uCi/kg to 1.0uCi/kg, day 8).  

The primary endpoint of this study was the MTD (maximum tolerated dose) of Actimab-A in combination with CLAG-M. The secondary endpoints were the composite complete remission (CRc) rate after one induction cycle, the MRD negative CRc rate, the median overall survival (OS), and the estimated OS at 1 and 2 year points of time. 

Results of this study determined that the MTD of Antimab-A was 1.0uCi/kg with a RP2D set to 0.75uCi/kg. 5 patients showed severe mucositis and delayed ANC recovery (>42 days) after receiving 1.0uCi/kg of Actimab-A. Grade ⅗ toxicities were observed in >10% of patients, including neutropenia, infection, rash, and hypokalemia. 52% of patients (n=11) achieved complete remission, and an additional 14% (n=3) achieved an MLFS for an overall remission rate of 67%. MRD negativity was observed in 72% of patients who achieved complete remission. The median OS of all patients was 1 year (95% CI, 0.2 to 1.8). Pharmacokinetic studies were administered in 3 patients, which revealed that Blood Ac225 radioactivity was below the limit of quantification by 48 hours in all patients. 

Dr. Abedin et al concluded that Actimab-A administered at 0.75uCi/kg in combination with CLAG-M yielded most feasible and safe results for patients with AML, demonstrating a high response rate and MRD negativity. Responses appear to last, especially if patients are able to proceed to alloHCT, as found in pharmacokinetic studies. 

“With no viable options for both R/R TP53 mutated AML and R/R AML previously treated with venetoclax, this regimen represents a potentially important option, and efforts are underway for a confirmatory study,” Dr. Abedin et al conclude. 

Source: 

Abedin S, Murthy G, Szabo A, et al. Lintuzumab-Ac225 with Combination with Intensive Chemotherapy Yields High Response Rate and MRD Negativity in R/R AML with Adverse Features. Presented at ASH Annual Meeting and Exposition; December 10-13, 2023; New Orleans, LA. Abstract 65.