A Myeloablative Regimen Incorporating Radiolabeled Anti-CD45 (BC8) Antibody Followed by Allogeneic Hematopoietic Cell Transplantation (HCT) for Patients with Advanced Acute Myeloid Leukemia (AML).
Authors: Nemecek Eneida R. , Pagel John M. , Rajendran Joseph G. , Fisher Darrell R. , Appelbaum Frederick R. , Press Oliver W. , Matthews Dana C. 
Published: October 2019

Abstract
The major cause of treatment failure after HCT for patients with advanced AML is disease recurrence. Augmenting systemic therapy decreases the risk of relapse, but increases nonrelapse mortality, resulting in no improvement in overall survival. We have previously demonstrated that iodine-131 [131I]-labeled anti-CD45 (BC8) antibody can deliver supplemental targeted radiation to hematopoietic tissues in patients with advanced leukemia undergoing myeloablative HCT. This report updates the results of a Phase II study of 131I-labeled BC8 antibody in combination with cyclophosphamide (CY) and total body irradiation (TBI) followed by allogeneic HCT for patients with advanced AML or MDS. Twenty-one patients, with median age of 42 (15–55) years, with AML (5 second remission, 13 relapse or refractory) or MDS (1 RAEB, 2 RAEBT) received a test infusion of 0.5 mg/kg of BC8 antibody trace-labeled with 131I. Patients underwent daily gamma camera imaging for 4 days and a marrow biopsy 24 hours after the antibody infusion to determine the estimated amount of radioactivity deposited in organs of interest. Favorable biodistribution, defined as a higher estimated radiation absorbed dose to the marrow and spleen than to any other normal organ, was observed in 20 (95%) patients. The mean estimated radiation-absorbed dose (cGy per mCi of 131I administered ± SEM) to bone marrow (8.67 ± 1.29) was 3-fold higher than to liver (3.22 ± 0.25), 17-fold higher than to kidney (0.52 ± 0.04) and 30-fold higher than to lung (0.30 ± 0.03). Seventeen patients received a therapeutic infusion of 0.5 mg/kg of antibody labeled with a median of 252 (127–389) mCi of 131I, 120 mg/kg CY over 2 days and 12 Gy TBI over 3 days followed by matched related (MRD, n=8) or unrelated donor (MURD, n=9) HCT. One MRD recipient who received 10 Gy to the liver died from pulmonary toxicity. The remaining patients have been treated at a planned dose of 8 Gy to the liver. Two of these patients required a reduction of the planned liver dose to 4 and 7 Gy respectively, to limit the marrow dose to a pre-determined maximum of 33 Gy. The estimated radiation absorbed dose (mean ± SEM) delivered to marrow was 21.4 ± 8.0 Gy and to spleen 45.4 ± 18.4 Gy. All patients experienced at least moderate mucositis. Six of 17 patients (35%) are alive and disease-free at a median of 2.8 (1–4.5) years, three of whom were in florid relapse at the time of HCT. Five patients (30%) died of relapse 37 to 266 days post HCT. Six patients (35%) died of non-relapse causes including 2 idiopathic pneumonia syndrome, 1 mucositis-induced adult respiratory distress syndrome, 1 CMV pneumonia and 2 of complications from acute GVHD. These results confirm that 131I-labeled BC8 antibody can deliver supplemental targeted radiation to marrow and spleen along with a conventional myeloablative allogeneic HCT regimen. Although the number of patients is limited, the observed disease-free survival suggests that this radioimmunoconjugate may offer the opportunity to intensify therapy to sites of leukemic involvement with acceptable toxicity.