Graft-versus-leukaemia following allogeneic bone marrow transplantation: emergence of cytotoxic T lymphocytes reacting to host leukaemia cells

Abstract

Cytotoxic T lymphocyte precursor (CTLp) frequency assays were examined in patients with chronic myeloid leukaemia (CML) following bone marrow transplantation (BMT) using recipient lymphocytes or CML cells as targets in a 51Cr release cytotoxicity assay. Eighteen patients were studied; 11 received marrow from a fully HLA A, B and DR matched sibling donor, and six from matched unrelated donors or a partially matched sibling (one patient). Two of the unrelated donor transplant recipients received marrow depleted of T lymphocytes, and the remainder received unmanipulated marrow and cyclosporin with or without methotrexate as prophylaxis against graft-versus-host disease (GVHD). Donor cells tested before BMT did not generate CTL against the patients' leukaemia, but up to 9 months after BMT a low frequency of CTLp directed against the patients' CML cells (Lk-CTLp) was detected in all patients. The Lk-CTLp frequency was significantly lower than the frequency of CTLp directed against the recipients' PHA transformed pretransplant lymphocytes (Ly-CTLp) (p less than 0.05). Lk-CTLp showed MHC restricted cytotoxicity and did not demonstrate cytotoxicity in an NK assay. The Lk-CTLp frequency correlated with both GVHD severity and relapse: severe GVHD was only seen with Lk-CTLp frequencies greater than 1:400,000, while leukaemic relapse was only observed in two patients with Lk-CTLp frequencies less than 1:400,000. These results show that a low frequency of alloreactive cells of presumed donor origin with cytotoxic potential against residual leukaemia normally circulate after BMT. Their relationship with the graft-versus-leukaemia phenomenon and their cross-reaction with GVHD reacting cells remain to be determined.