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

Abstract

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.

188Re or 90Y‐labelled anti‐CD66 antibody as part of a dose‐reduced conditioning regimen for patients with acute leukaemia or myelodysplastic syndrome over the age of 55: results of a phase I–II study

“…The following limiting organ doses were defined: BM 35 Gy, kidney 12 Gy and liver 20 Gy. These doses were based on the experience of Matthews et al (1996) and published studies on the radiation tolerance of organs (Emami et al, 1991;Matthews et al, 1996). The therapeutic antibody was given intravenously in 1 (yttrium) or 2 (rhenium) fractions over a period of 10 min on day )14 relative to the scheduled transplantation date in order to guarantee the elimination of the nuclide.…”

Topoisomerase Ii Inhibitor‐related Acute Myeloid Leukaemia

“…Hence, the outlook for patients with therapy‐related AML remains poor even after allogeneic transplantation. One promising alternative strategy approach is to add monoclonal antibodies targeted to host haematopoietic cells in the conditioning regimen as a means of eradicating residual leukaemia ( Matthews et al , 1995 ). Another is to enhance the immune‐mediated graft vs. leukaemia effect by infusing donor lymphocytes after subablative therapy ( Giralt et al , 1997 ).…”

188Re anti‐CD66 radioimmunotherapy combined with reduced‐intensity conditioning and in‐vivo T cell depletion in elderly patients undergoing allogeneic haematopoietic cell transplantation

“…Targeted radiotherapy is one potential option to overcome this paradigm. Clinical studies have shown that monoclonal antibodies (mAb) labelled with radioactive isotopes successfully deliver higher radiation doses to the bone marrow and the spleen (Matthews et al, 1995;Bunjes et al, 2001;Pagel et al, 2006). A recent study (Ringhoffer et al, 2005) has already demonstrated the principal feasibility of the combination of radioimmunotherapy and reduced-intensity conditioning.…”