Development of a marrow transplant regimen for acute leukemia using targeted hematopoietic irradiation delivered by 131I-labeled anti-CD45 antibody, combined with cyclophosphamide and total body irradiation.
In an attempt to decrease the relapse rate after bone marrow transplantation (BMT) for advanced acute leukemia, we initiated studies using 131I-labeled anti-CD45 antibody (BC8) to deliver radiation specifically to hematopoietic tissues, followed by a standard transplant preparative regimen. Biodistribution studies were performed in 23 patients using 0.5 mg/kg trace 131I-labeled BC8 antibody. The BC8 antibody was cleared rapidly from plasma with an initial disappearance half-time of 1.5 +/- 0.2 hours, presumably reflecting rapid antigen-specific binding. The mean radiation absorbed doses (cGy/mCi131I administered) were as follows: marrow, 7.1 +/- 0.8; spleen, 10.8 +/- 1.4; liver, 2.7 +/- 0.2; lungs, 2.1 +/- 0.1; kidneys, 0.7 +/- 0.1; and total body, 0.4 +/- 0.03. Patients with acute myelogenous leukemia (AML) in relapse had a higher marrow dose (11.4 cGy/mCi) than those in remission (5.2 cGy/mCi; P = .001) because of higher uptake and longer retention of radionuclide in marrow. Twenty patients were treated with a dose of 131I estimated to deliver 3.5 Gy (level 1) to 7 Gy (level 3) to liver, with marrow doses of 4 to 30 Gy and spleen doses of 7 to 60 Gy, followed by 120 mg/kg cyclophosphamide (CY) and 12 Gy total body irradiation (TBI). Nine of 13 patients with AML or refractory anemia with excess blasts (RAEB) and two of seven with acute lymphocytic leukemia (ALL) are alive disease-free at 8 to 41 months (median, 17 months) after BMT. Toxicity has not been measurably greater than that of CY/TBI alone, and the maximum tolerated dose has not been reached. This study demonstrates that with the use of 131I-BC8 substantially greater doses of radiation can be delivered to hematopoietic tissues as compared with liver, lung, or kidney, which may improve the efficacy of marrow transplantation.
Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle 98104.
D C
DC
Matthews
F R
FR
Appelbaum
J F
JF
Eary
D R
DR
Fisher
L D
LD
Durack
S A
SA
Bush
T E
TE
Hui
P J
PJ
Martin
D
D
Mitchell
O W
OW
Press
D000293:Adolescent; D000328:Adult; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics; D001853:Bone Marrow / Q000000981:diagnostic imaging; D016026:Bone Marrow Transplantation / Q000379:methods*; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000627:therapeutic use*; D005260:Female; D006410:Hematopoiesis / Q000528:radiation effects*; D006801:Humans; D007074:Immunoglobulin G; D007165:Immunosuppression Therapy / Q000379:methods*; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use; D007668:Kidney / Q000000981:diagnostic imaging; D015470:Leukemia, Myeloid, Acute / Q000628:therapy*; D017493:Leukocyte Common Antigens / Q000276:immunology*; D008099:Liver / Q000000981:diagnostic imaging; D008168:Lung / Q000000981:diagnostic imaging; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000628:therapy*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000628:therapy*; D016499:Radioimmunotherapy / Q000379:methods*; D011877:Radionuclide Imaging; D013154:Spleen / Q000000981:diagnostic imaging; D014018:Tissue Distribution; D014916:Whole-Body Irradiation
D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D007457:Iodine Radioisotopes; D003520:Cyclophosphamide; D017493:Leukocyte Common Antigens