Lintuzumab-Ac225 With Intensive Chemo Has Encouraging Efficacy Signal in High-risk AML

Sequential administration of lintuzumab-Ac225 (Actimab-A) after salvage chemotherapy proved to be safe and feasible, and to result in high response and minimal residual disease (MRD) negativity rates in high-risk patients with relapsed/refractory acute myeloid leukemia (AML), according to data from a phase 1 trial (NCT03441048) presented at the 2022 ASH Annual Meeting.¹

Investigators of the CLAG-M (cladribine, cytarabine, filgastrim, and mitoxantrone) chemotherapy regimen combined with lintuzumab-Ac225 met their primary objective of finding the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Additionally, favorable response and survival rates were observed, as well as high MRD negativity rates in patients with composite complete remission (CRc).

“[In] our first objective, CLAG-M salvage chemotherapy and lintuzumab-Ac225 as a combination appears to be safe. In terms of our RP2D, we will be proceeding with a dose of 0.75 uCi/kg,” Sameem M. Abedin, MD, assistant professor at the Medical College of Wisconsin, said in his ASH presentation. “In terms of outcomes, we were seeing some very promising signals of efficacy. So overall, about 65% of patients enrolled in this trial had a response amongst patients who had achieved a CRc, 75% were MRD negative, and patients then were able to bridge to allogeneic transplant.”

In this open-label, nonrandomized phase 1 trial (NCT03441048), adult patients with R/R AML received CLAG-M on days 1 to 6, then on days 7 through 9 received the humanized anti-CD33 antibody linked to actinium-225, lintuzumab-Ac225. The experimental drug was given in a dose escalation fashion to 21 patients in 4 cohorts: 0.25 uCi/kg in cohort 1 (n = 3), 0.50 uCi/kg in cohort 2 (n = 9), 0.75 uCi/kg in cohort 3 (n = 4), and 1.0 uCi/kg in cohort 4 (n = 5). A pharmacokinetic (PK) expansion cohort of an additional 5 patients received the RP2D. Efficacy evaluation was performed between days 28 and 42.

The primary end points of MTD and RP2D were assessed, as well as secondary end points of PK profile of lintuzumab-Ac225, response, transplant eligibility, and 2-year overall survival (OS). Eligible patients had an ECOG performance status of 0 to 2, adequate organ function, and more than 25% of blasts with CD33 positivity by flow cytometry.

Patients on this trial were mostly high risk and refractory. There were 74% with ELN 2019 adverse risk disease, 52% harboring TP53 mutations, 57% previously treated with venetoclax (Venclexta), and 57% treated for recurrent disease after allogeneic hematopoietic cell transplant.

Treatment-related adverse events (TEAEs), including grade 3 events, occurred in all patients. However, only 4 patients (17%) experienced dose-limiting toxicities (DLTs), although the criteria were modified to allow neutrophil recovery within 49 days. The most common grade 3/4 TEAEs occurring in 2 patients, or more were febrile neutropenia in 19 patients (83%), neutropenia in 11 (48%), and thrombocytopenia in 10 (43%). For patients in cohort 3 of 0.75 uCi/kg lintuzumab-Ac225, febrile neutropenia was the most common TEAE.

“What we saw in terms of administration of this novel, salvage regimen—we saw toxicities that we normally see with salvage chemotherapy. A particular AE of interest for us was liver toxicity, which was transiently seen at higher doses. We didn't see any signal of increased liver toxicity with this lower dose,” Abedin explained.

In cohort 1, no patients experienced DLTs. Three patients in cohort 2 had DLTs, 2 with prolonged neutropenia and 1 with tumor lysis syndrome. Of note, 3 additional patients were enrolled with FDA guidance bringing the total from 6 to 9 patients in cohort 2, but these 3 patients did not have DLTs. No patients in cohort 3 experienced DLTs, and this was chosen as the RP2D. Lastly, 2 out of 3 evaluable patients in cohort 4 had DLTs of prolonged neutropenia in 1 and mucositis in the other. Cohort 4 of was determined to be the MTD.

Of the 4 patients in the 0.75-uCi/kg cohort, 1 did not complete cycle 1. With the addition of the PK cohort, 8 patients total were evaluated for PK and response after receiving 0.75 uCi/kg of lintuzumab-Ac225. Investigators assessed the duration of radioactivity in the patient’s blood after administration. After a single 30-minute infusion of lintuzumab-Ac225, peak radioactivity was reached approximately 30 minutes later. A majority of patients no longer had radioactivity in their blood after 24 hours, showing radioactivity rapidly diminished, according to Abedin.

Lintuzumab-Ac225 showed response in 15 patients (65%) total. Twelve patients of 23 total (52%) achieved CRc, which includes CR and CR with incomplete hematologic recovery, and 5 patients (63%) who received the RP2D (n = 8) achieved CRc. The total response rate in the RP2D group was 75%. Of all patients who achieved CRc, MRD negativity was observed in 75% by multiparametric flow cytometry.

The recovery of blood counts after patients received treatment was also evaluated. The typical count recovery after administering CLAG-M is around 4 weeks for both neutrophils and platelets. For these patients, the median days to neutrophil recovery was 34 days (range, 25-61), and platelet recovery took a median of 39 days (range, 25-56).

“Of note, some patients, because this was used as a bridge to allogeneic transplant, were recovering platelets. But prior to recovery to above 50 k/uL, they proceeded to allogeneic transplant,” Adebin said. “Finally, with that, this regimen was pretty effective in terms of bridging patients to allogeneic transplant. Amongst patients who had not proceeded to transplant, about 65% of them were able to go on to transplant.”

The 1- and 2-year OS rates were 53% and 32%, respectively, in all patients. In patients with CRc and MRD negativity (n = 9), there was an 89% OS rate at 1 year and 48% OS rate at 2 years. Patients with TP53 mutations had 51% and 19% OS rates at 1 and 2 years, respectively, and patients who received prior venetoclax had 59% and 32% OS rates, respectively.

“Overall, our plans going forward is to study this combination. We plan for a large registrational study in the upcoming year where we're studying salvage CLAG-M chemotherapy with lintuzumab-Ac225 compared against CLAG-M salvage chemotherapy,” Abedin concluded.

Reference

1. Abedin S, Murthy SG, 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: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, Louisiana. Abstract 65.