Cytoreduction with iodine-131-anti-CD33 antibodies before bone marrow transplantation for advanced myeloid leukemias JM Burke, PC Caron, EB Papadopoulos, CR Divgi, G Sgouros, KS Panageas, RD Finn, SM Larson, RJ O’Reilly, DA Scheinberg and JG Jurcic Departments of Medicine, Radiology, Medical Physics, and Biostatistics, Memorial Sloan-Kettering Cancer Center and the Weill Medical College of Cornell University, New York, NY, USA Summary: The monoclonal antibodies M195 and HuM195 target CD33, a glycoprotein found on myeloid leukemia cells. When labeled with iodine-131 ( 131 I), these antibodies can eliminate large disease burdens and produce prolonged myelosuppression. We studied whether 131 I-labeled M195 and HuM195 could be combined safely with busulfan and cyclophosphamide (BuCy) as conditioning for allogeneic BMT. A total of 31 patients with relapsed/refractory acute myeloloid leukemia (AML) (n ¼ 16), accelerated/ myeloblastic chronic myeloid leukemia (CML) (n ¼ 14), or advanced myelodysplastic syndrome (n ¼ 1) received 131 I-M195 or 131 I-HuM195 (122–437 mCi) plus busulfan (16 mg/kg) and cyclophosphamide (90–120 mg/kg) fol- lowed by infusion of related-donor bone marrow (27 first BMT; four second BMT). Hyperbilirubinemia was the most common extramedullary toxicity, occurring in 69% of patients during the first 28 days after BMT. Gamma camera imaging showed targeting of the radioisotope to the bone marrow, liver, and spleen, with absorbed radiation doses to the marrow of 272–1470 cGy. The median survival was 4.9 months (range 0.3–90+ months). Three patients with relapsed AML remain in complete remission 59+, 87+, and 90+ months following bone marrow transplantation (BMT). These studies show the feasibility of adding CD33-targeted radioimmunotherapy to a standard BMT preparative regimen; however, randomized trials will be needed to prove a benefit to intensified conditioning with radioimmunotherapy. Bone Marrow Transplantation (2003) 32, 549–556. doi:10.1038/sj.bmt.1704201 Keywords: acute myelocytic leukemia; chronic myeloid; leukemia; monoclonal antibodies; radioimmunotherapy Allogeneic bone marrow transplantation (BMT) from an HLA-matched sibling donor results in long-term disease- free survival in approximately 50% of patients with both acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). 1 However, outcomes remain poor in patients with advanced forms of these diseases. In patients with relapsed AML or AML refractory to induction chemotherapy, allogeneic BMT results in long-term disease-free survival in only 20% of cases. 2 In patients with CML in accelerated phase, BMT from an HLA- matched sibling produces long-term remission in 20–40% of patients. 3–5 In patients with CML in blast crisis, under 20% of patients achieve long-term disease-free survival. 3–5 Both therapy-related toxicity and relapse of disease contribute to morbidity and mortality after BMT. The two most commonly used preparative regimens in large trials of BMT for myeloid leukemias are total body irradiation plus cyclophosphamide (TBI/Cy) and busulfan plus cyclophosphamide (BuCy). 6–16 Previously, investigators have attempted to improve patient outcomes by intensifying the conditioning before BMT. Methods that have been studied include increasing the dose of TBI, 17–19 modifying the chemotherapy regimen, 16 or targeting radiation to the marrow using monoclonal antibodies. 20–23 M195 is a murine IgG2a antibody that targets CD33, a cell-surface glycoprotein present on most myeloid leukemia cells as well as on committed myelomonocytic and erythroid progenitor cells. 24 The therapeutic efficacy of unconjugated M195 is limited by its lack of intrinsic antileukemic activity and by the development of human anti-mouse antibodies (HAMA) in many patients. 25 To overcome these problems, a humanized version of M195 (HuM195) was constructed by grafting complementarity- determining regions of M195 onto the variable framework and constant region of a human IgG1 antibody. 26 A phase I trial of HuM195 showed similar pharmacology to murine M195 but without significant immunogenicity. 27 By delivering radioisotopes directly to targeted tumor cells, radioimmunotherapy offers the potential to increase the cytotoxicity of unlabeled antibodies. In a phase I trial, 24 patients with advanced myeloid leukemias were treated with escalating doses of M195 labeled with iodine-131 ( 131 I). 28 At doses above 135 mCi/m 2 , profound myelosup- pression occurred, allowing eight patients to proceed to BMT. Three of these patients achieved complete remission (CR). This early study demonstrated that 131 I-M195 can Received 27 November 2002; accepted 16 April 2003 This work was supported by National Institutes of Health Grants PO1 CA33049 and RO1 CA55349. Correspondence: Dr JG Jurcic, 1275 York Ave., Box 458, New York, NY 10021, USA. E-mail: jurcicj@mskcc.org Bone Marrow Transplantation (2003) 32, 549–556 & 2003 Nature Publishing Group All rights reserved 0268-3369/03 $25.00 www.nature.com/bmt