Radioimmunotherapy with bismuth-213 as conditioning for nonmyeloablative allogeneic hematopoietic cell transplantation in dogs: A dose deescalation study

Background. Using a canine model of nonmyeloablative hematopoietic cell transplantation (HCT), the authors demonstrated that pretransplant radioimmunotherapy with the alpha-emitter bismuth-213 (Bi-213) coupled to anti-CD45 or anti-T-cell receptor alphabeta (TCRalphabeta) monoclonal antibodies (mAb), together with postgrafting immunosuppression with mycophenolate mofetil (MMF) and cyclosporine A (CsA), achieved stable engraftment of dog leukocyte antigen (DLA)-identical marrow. Engraftment was achieved with doses of 3.6 to 8.8 mCi/kg Bi-213, but signs of liver toxicity were noted in all dogs. To find a safe and effective dose for further trials, the authors performed a dose deescalation study in 15 dogs with 2.7 to 0.8 mCi/kg Bi-213. Methods. Bi-213 was linked to the mAb using the metal-binding chelate CHX-A"-DTPA. All dogs received three to six injections of Bi-213 linked to anti-CD45 or anti-TCRalphabeta mAb followed by marrow grafts from DLA-identical littermates and postgrafting MMF and CsA. Results. During follow-up of greater than 30 weeks, engraftment remained stable in all evaluable dogs conditioned with 1.4 to 2.1 mCi/kg Bi-213-anti-CD45 or 2.0 to 2.7 mCi/kg Bi-213-anti-TCRalphabeta. Only one dog conditioned with 1.5 mCi/kg Bi-213-anti-TCRalphabeta had stable engraftment, whereas two rejected their grafts. In both groups, all dogs conditioned with less than 1.3 mCi/kg Bi-213 rejected their grafts. No signs of graft-versus-host disease or other toxicities were noted. Only mild and transient elevation of liver function tests occurred in 4 of 15 dogs. Conclusions. This study demonstrates that dose deescalation of radioimmunotherapy with Bi-213 labeled to anti-CD45 or anti-TCRalphabeta as conditioning for nonmyeloablative HCT minimizes toxicity without compromising engraftment. With a dose of 2 mCi/kg Bi-213, further trials using radioimmunotherapy with Bi-213 for nonmyeloablative HCT seem feasible.