Phase I trial of alpha-particle immunotherapy with ²²⁵Ac-lintuzumab and low-dose cytarabine in patients age 60 or older with untreated acute myeloid leukemia.

Objectives: ²²⁵Ac-lintuzumab is a radioimmunoconjugate composed of ²²⁵Ac, which emits 4 α-particles, linked to a humanized anti-CD33 monoclonal antibody. An initial phase I trial showed that a single infusion of ²²⁵Ac-lintuzumab is safe at doses ≤ 111 kBq/kg and has activity in relapsed/refractory acute myeloid leukemia (AML). We conducted a multicenter, phase I dose-escalation trial to determine the maximum tolerated dose (MTD), toxicity, and biological activity of fractionated-dose ²²⁵Ac-lintuzumab in combination with low-dose cytarabine (LDAC).

Methods: Patients 蠅 60 years with untreated AML not candidates for intensive chemotherapy were eligible. Patients received LDAC 20 mg twice daily for 10 days every 4-6 weeks for up to 12 cycles. During Cycle 1, 2 fractions of ²²⁵Ac-lintuzumab were given 1 week apart, beginning 4-7 days following completion of LDAC. To prevent radiation-induced nephrotoxicity, patients were given furosemide while receiving ²²⁵Ac-lintuzumab then spironolactone for 1 year afterward. Four dose levels of ²²⁵Ac-lintuzumab were studied using a 3+3 design.

Results: Eighteen patients (median age, 77 years; range, 68-87) completed therapy. Twelve (67%) had prior myelodysplastic syndrome (MDS), for which 10 (83%) received therapy with hypomethylating agents (n=9) or allogeneic hematopoietic cell transplantation (n=1). Eleven patients (61%) had intermediate-risk and 7 (39%) had poor-risk AML. Median CD33 expression was 81% (range, 30-100%). ²²⁵Ac-lintuzumab was given at 18.5 (n=3), 37 (n=6), 55.5 (n=3), or 74 (n=6) kBq/kg/fraction. Two patients had dose-limiting toxicity (grade 4 thrombocytopenia with marrow aplasia for > 6 weeks following therapy), one each in the 37 and 74 kBq/kg/fraction cohorts. Although the MTD was not reached, 74 kBq/kg/fraction was chosen as the phase II dose to limit prolonged myelosuppression. Hematologic toxicities included grade 4 neutropenia (n=5) and thrombocytopenia (n=9). Grade 3/4 non-hematologic toxicities included febrile neutropenia (n=6), pneumonia (n=5), sepsis (n=3), other infections (n=3), atrial fibrillation/syncope (n=1), transient creatinine elevation (n=1), fatigue (n=1), hypokalemia (n=1), mucositis (n=1), and rectal hemorrhage (n=1). Thirty- and 60-day mortality rates were 0% and 17%, respectively. Eleven of 14 patients (79%) evaluated after Cycle 1 had bone marrow blast reductions (mean reduction, 66%; range, 19-100%). Two CR, 1 CR with incomplete platelet recovery (CRp), and 2 CR with incomplete blood count recovery (CRi) were seen for an overall response rate of 28%. Only patients receiving 蠅 37 kBq/kg/fraction responded (Table). All responses occurred after 1 cycle of therapy, in contrast to historical data with LDAC alone, where the median time to response was 3 cycles. Median progression-free survival (PFS) for all patients was 2.7 months (range, 1.0-16.9). Median overall survival (OS) was 5.6 months (range, 1.6-32+). Median response duration was 9.1 months (range, 4.1-16.9). Peripheral blood blast counts were a strong predictor of response. Among 36 patients treated in the current and initial phase I trials, responses were seen in 8 of 19 patients (42%) with blast counts < 200/µL, compared with 0 of 17 patients with blast counts 蠅 200/µL (P=0.002). This difference is likely due to decreased marrow targeting in patients with higher circulating blast counts when the subsaturating antibody doses used in these trials are given.

Conclusion: Fractionated-dose ²²⁵Ac-linutuzmab can be safely combined with LDAC and induce remission in older patients with untreated AML. A phase II trial of ²²⁵Ac-lintuzumab at 74 kBq/kg/fraction using hydroxyurea, if necessary, to lower peripheral blast counts prior to administration to determine response rate, PFS, and OS in this patient population is in progress. Research Support: Actinium Pharmaceuticals, Inc. provided ²²⁵Ac-lintuzumab and funded this trial.