A Phase 2 Study of Actinium-225 (²²⁵Ac)-Lintuzumab in Older Patients with Previously Untreated Acute Myeloid Leukemia (AML) Unfit for Intensive Chemotherapy

Background: Older patients (pts) unfit for induction chemotherapy have high early death rates and limited overall survival (OS), both of which depend on age, prior MDS, comorbidities, and performance status (PS) (Heaematologica 2012;97:1916). ²²⁵Ac-lintuzumab (Actimab-A) is a radioimmunoconjugate composed of ²²⁵Ac linked to a humanized anti-CD33 monoclonal antibody. ²²⁵Ac emits 4 α-particles and has a 10 day half-life. A Phase 1 trial to evaluate fractionated-doses of ²²⁵Ac-lintuzumab in combination with low-dose cytarabine was previously conducted. Responses were seen at doses of ≥1 µCi/kg/fraction, and 2 µCi/kg/fraction was chosen as the phase 2 dose to limit myelosuppression. Responding pts had peripheral blasts <200 /µL which likely leads to more effective drug delivery to bone marrow. (ASH, 2016, Abstract 4050). We report preliminary results of a multicenter, phase 2 study to determine the response rate, progression-free survival (PFS), and OS after fractionated-dose ²²⁵Ac-lintuzumab monotherapy in older AML pts unfit for induction chemotherapy.

Patients and Methods: Pts ≥ 60 years with untreated AML and ECOG PS 0-3 were enrolled. Pts with antecedent hematologic disorders (AHDs) were eligible, including those with prior AHD therapy. Pts 60 to 74 years of age were required to have significant cardiac, pulmonary, renal or hepatic impairment. Any pt ≥ 75 years of age was eligible. Expression of CD33 on > 25% of blasts was required. Pts were required to have a peripheral blast count <200/µL within 7-10 days of the first dose. Pretreatment with hydroxyurea was allowed to lower peripheral blast counts if necessary. Two doses of 2 µCi/kg of ²²⁵Ac-lintuzumab were administered on Days 1 and 8. G-CSF was administered starting 10 days after the 2^nd dose of ²²⁵Ac-lintuzumab, and spironolactone was given for 1 year to prevent possible radiation-induced nephrotoxicity.

Results: Thirteen pts were treated, and preliminary data are available on 9 with median age 75 years (range, 65-82) and PS median 2 (0-1 in 2 pts, 2 in 3 pts, & 3 in 2 pts). Six (67%) had prior treatment for AHDs (5 MDS, 1 atypical CML). At baseline, 5 pts had ANC ≥ 500/µL, only 2 had ANC ≥ 1000/µL, and only 1 had platelets > 50,000/µL. Available cytogenetic data were limited, but 1 had intermediate and 3 had adverse cytogenetics by MRC criteria. The median baseline bone marrow blast percentage was 26% (range, 20-88%) with a median CD33 expression of 67% (range, 33-91%).

Myelosuppression was seen in all evaluable pts including grade 4 thrombocytopenia with marrow aplasia for > 6 weeks following therapy in 3 pts. The only Grade >3 non-hematologic toxicities reported in ≥1 pt were pneumonia and cellulitis. Veno-occlusive disease did not occur. The 30-day mortality rate was 33% (disease progression, acute on chronic respiratory failure, and post-traumatic intracranial hemorrhage after a fall).

Objective responses were documented in 5 of the 9 pts (56%): 2 Complete Remissions with incomplete platelet count recovery (CRp) and 3 Complete Remissions with incomplete hematologic recovery (CRi). Among the responders, 2 pts had adverse cytogenetics including one with t-AML, and 3 pts had no AHD. Two pts had resistant disease.

Median time to neutrophil recovery (ANC ≥ 500/µL) was 36 days (range 20-60) from the first dose of ²²⁵Ac-lintuzumab. The two pts with CRp had neutrophil recovery at Days 60 and 36. Two of the pts with CRi had not reached ANC ≥ 500/µL when they expired from infection on days 65 and 56, and the third is at day 66+ without ANC recovery. Since pts with AHDs may not have capacity to recover to normal neutrophil production, pts without AHDs may be more informative. Of the 3 pts without AHDs, 1 had ANC recovery at Day 36, 1 had death from infection at Day 56 without ANC recovery, and 1 is pending ANC recovery at Day 66+. No pts reached platelet counts > 20,000/µL without transfusions.

Conclusions: Preliminary data from this Phase 2 trial of ²²⁵Ac-lintuzumab monotherapy at 2 µCi/kg/fraction document a 56% response rate in older pts unfit for intensive therapy, many with AHDs. As myelosuppression at this dose was considered to be longer than acceptable in this population, accrual to this study will continue at 1.5 µCi/kg/fraction with the goal to shorten recovery times. Data on additional patients treated at that dose will be presented.