131 I-Anti-CD45 Antibody Plus Busulfan/Cyclophosphamide in Matched Related Transplants for Acute Myeloid Leukemia in First Remission.

Patients with AML in first remission undergoing conventional matched related hematopoietic cell transplantation (HCT) have a significant risk of both relapse and non-relapse mortality following transplant. In an attempt to improve outcome by decreasing relapse, we conducted a Phase I/II study in which targeted hematopoietic irradiation delivered by 131 I-labeled anti-CD45 antibody is combined with busulfan (BU) and cyclophosphamide (CY). Patients (median age 41) received a trace (~5mCi) 131 I-labeled dose of 0.5 mg/kg anti-CD45 (BC8) murine monoclonal antibody followed by serial quantitative gamma camera imaging and a bone marrow biopsy for estimation of radiation absorbed doses to target organs (marrow and spleen) and non-target organs (liver, lung, and kidney). Fifty-two of 59 patients (88%) had a higher estimated radiation absorbed dose to marrow and spleen than to any normal organ. Forty-six of these were treated with 102 to 298 mCi 131 I delivering an estimated 5.3 to 19 (mean 11.3) Gy to bone marrow, 17 to 72 (mean 29.7) Gy to spleen, and 3.5 Gy (n = 4) to 5.25 Gy (n = 42) to the liver. Patients then received targeted BU (AUC 600–900 ng/ml), CY (120 mg/kg), and infusion of HLA-matched related marrow (n = 40) or peripheral blood stem cells (n = 6). The non-relapse mortality (NRM) was 17%, as eight patients died of transplant-related causes (sepsis-2, idiopathic pneumonia syndrome-1, viral pneumonia-3, and fungal pneumonia-2). Nine patients (20%) relapsed 3 to 38 months post-transplant, and 28 patients (61%) are surviving disease-free 7 to 124 months (median 49 months) post-transplant. For 26 patients (62%) with intermediate risk cytogenetics, 18 (69%) are surviving disease-free, with only 3 (12%) relapsing. Fifteen patients (33%) were considered high risk based on unfavorable cytogenetics or secondary AML; 7 of these 15 (46%) are surviving disease-free and 5 (33%) have relapsed. Because of the known impact of features such as age and cytogenetic risk group on post-HCT outcome, we compared our data to data from the International Bone Marrow Transplant Registry (IBMTR) on first remission AML patient conditioned with BU/CY alone prior to HCT. Over a 10-year period, 980 IBMTR patients (median age 28) were transplanted using a median BU dose of 16 mg/kg (range 8–21 mg/kg) and a median CY dose of 120 (range 62–232). Of the 509 IBMTR patients with known cytogenetics at diagnosis, 466 (92%) had intermediate-risk cytogenetics. Using a Cox regression model for overall mortality and adjusting for age and cytogenetics risk differences, the hazard for mortality among 131 I-BC8 Ab/BU/CY patients is 0.65 times that of registry patients receiving BU/CY only (95% CI 0.35 to 1.08, p = 0.09). The addition of targeted hematopoietic irradiation to conventional BU/CY is both feasible and well tolerated, and has the potential to improve survival for patients undergoing HCT for AML in first remission.