Lintuzumab-Ac225 in Combination with CLAG-M Yields High MRD (-) Responses in R/R AML with Adverse Features: Interim Results of a Phase I Study
Authors: Abedin Sameem , Guru Murthy Guru Subramanian , Hamadani Mehdi , Michaelis Laura C. , Runaas Lyndsey , Carlson Karen , Atallah Ehab L. 
Published: November 2021

Abstract
Background:
Lintuzumab-Ac225 (Actimab-A) is a humanized CD33 antibody, lintuzumab, conjugated to an alpha emitting isotope, actinium (Ac225), with potent single agent activity against AML. We hypothesized that a low dose infusion of lintuzumab-Ac225, after salvage chemotherapy, would effectively eliminate residual leukemia and improve remission rates, and depth of remission.
Patients and Methods:
Adult patients with relapsed/refractory AML (RR-AML), and with adequate organ function and performance status were eligible for screening. On screening, we assessed CD33 expression, greater than 25% of leukemic blasts must have expressed CD33 antigen by flow cytometry for inclusion. Induction consisted of G-CSF, 300mcg/d, given D1-6, cladribine 5mg/m2, given D2-6, cytarabine 2g/m2, given D2-6, and mitoxantrone 10mg/m2, given D2-4. Lintuzumab-Ac225 was administered as a single dose on either day 7, 8, or 9. This trial enrolled to 4 cohorts, administering lintuzumab-ac225 at a dose of 0.25uCi/kg, 0.50uCi/kg, 0.75uCi/kg, and 1.0uCi/kg. Treatment consisted of one induction cycle. Disease assessment, including MRD assessment by flow, was performed between Days 29-42.
Results:
Sixteen patients with a median age of 64 yrs were evaluable for toxicity and response. Three pts were treated in cohort 1 (0.25uCi/kg), nine pts were treated in cohort 2 (0.5uCi/kg), three pts were treated in cohort 3 (0.75uCi/kg), and one pt was treated in cohort 4 (1.0uCi/kg). Patient characteristics include 63% (n=10) pts with adverse cytogenetics, mutations involving TP53 in 44% (n=7) pts, and secondary/therapy-related AML in 50% (n=8) of patients. Patients received a median 2 lines of therapy, and 50% (n=8) received a venetoclax combination regimen prior to enrollment. Table 1 summarizes patient characteristics.
No undue non-hematologic toxicities were observed in this trial. Commonest AEs were neutropenic fever and infection. Among responders, an ANC&gt;1000 was achieved in 9/10 patients, at a median of 33 days, and a platelet count &gt;50k was achieved in 6/10 patients at a median of 37 days. Of note, two patients proceeded to HCT prior to platelet recovery.
Overall, among patients enrolled in cohorts 1-3, CR/CRi was observed in 67% (n=10) pts. One patient enrolled in cohort 4 achieved an aplastic marrow by D+42, with subsequent stem cell boost and neutrophil recovery. Of responders, 70% (7/10) had no measurable disease (MRD(-)) by flow cytometry. Among patients receiving &lt;4 lines of prior therapy, 71% (n=5) pts with adverse cytogenetics, 80% (n=4) pts with TP53 mutation, and 80% (n=4) pts receiving a prior venetoclax combination achieved a remission. Estimated 6-month OS was 60%.
Conclusions:
Lintuzumab-Ac225 at a low dose appears to be safe in combination with the salvage chemotherapy regimen CLAG-M. Furthermore, this combination has demonstrated promising efficacy results among high risk RR-AML patients, namely patients with adverse molecular/cytogenetic features and patients previously receiving venetoclax. Updated Cohort 4 results will be presented at ASH.
Upon determination of MTD, we plan to explore the combination of lintuzumab-Ac225 with other salvage regimens (e.g. FLAG, FLAG-Ida, MEC) to determine whether adding this novel agent can generally improve salvage outcomes in hard to treat patients.
Figure 1 Figure 1.

Disclosures
Abedin: Helsinn: Research Funding; Agios: Honoraria; AltruBio: Research Funding; Pfizer: Research Funding; Amgen: Honoraria; Actinium: Research Funding; Astellas Pharma Inc.: Research Funding. Guru Murthy: Guidepoint: Consultancy; Cancerexpertnow: Honoraria; Techspert: Consultancy; Qessential: Consultancy; Cardinal Health Inc.: Honoraria; TG therapeutics: Other: Advisory board. Hamadani: Sanofi, Genzyme, AstraZeneca, BeiGene: Speakers Bureau; Takeda, Spectrum Pharmaceuticals and Astellas Pharma: Research Funding; Janssen, Incyte, ADC Therapeutics, Omeros, Morphosys, Kite: Consultancy. Atallah: Pfizer: Consultancy, Research Funding; BMS: Honoraria, Speakers Bureau; Takeda: Consultancy, Research Funding; Abbvie: Consultancy, Speakers Bureau; Amgen: Consultancy; Novartis: Consultancy, Honoraria, Research Funding.