PNNL

Abstract

Patients with acute myeloid leukemia in first remission undergoing conventional matched related hematopoietic cell transplantation have a significant risk of both relapse and non-relapse mortality following transplant. We conducted a Phase I/II study in which targeted hematopoietic irradiation delivered by 131I-labeled anti-CD45 antibody was combined with busulfan (BU) and cyclophosphamide (CY) to improve outcome by decreasing relapse. Patients received a trace (5mCi) 131I-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 to estimate radiation absorbed doses to target organs (marrow and spleen), non-target organs (liver, lung, and kidney), and the remainder tissues. 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 patients were treated with 102 to 298 mCi 131I 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 (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 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; 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-transplant outcome, we compared our data to data from the International Bone Marrow Transplant Registry on first remission acute myeloid leukemia patient conditioned with BU/CY alone prior to hematopoietic cell transplantation. Over a 10-year period, 980 Registry 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 Registry 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 131I-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 hematopoietic cell transplantation for acute myeloid leukemia in first remission.