Characterization of lineage‐specific chimaerism in patients with acute leukaemia and myelodysplastic syndrome after allogeneic stem cell transplantation before and after relapse

Abstract

Summary. Recently, we have shown that patients with acute leukaemias and myelodysplastic syndromes (MDS), who showed increasing mixed chimaerism (MC) upon serial PCR analysis after transplant, have a signi®cantly increased risk of relapse. To determine whether the increasing MC in these patients is caused by the reappearance of normal recipient haematopoiesis or by the reoccurrence of malignant cells, we puri®ed different leucocyte subpopulations and analysed these subfractions with regard to their donor±recipient ratio by a PCR-based method for the analysis of minisatellite DNA regions. In 14 patients [eight acute lymphoblastic leukaemia (ALL), three acute myelogenous leukaemia (AML) and three MDS] subfractions were analysed when increasing MC was ®rst noted upon serial analysis of the peripheral blood. In seven of these 14 patients (four ALL, two AML and one MDS), subfractions were characterized at the time of frank haematological relapse. In all 14 patients investigated with increasing MC, recipient cells were detected in different mononuclear cell subpopulations. In patients characterized during frank relapse, two distinct distribution patterns were found. Patients who relapsed before day 300 (one ALL, two AML and one MDS) showed recipient-derived (normal) cells in addition to blast populations in different mononuclear subsets as well as granulocytes. In patients with acute leukaemias who relapsed after day 300 (two ALL and one AML), only leukaemic cells were found that were of recipient origin, whereas all other haematopoietic cell lines were donor derived.These data show that persistent MC in the early posttransplant period is caused predominantly by normal recipient haematopoietic cells. This ®nding further supports the hypothesis that a state of mixed haematopoietic chimaerism may reduce the clinical graft-versus-leukaemia (GVL) effect of alloreactive donor-derived effector cells in patients with acute leukaemias and MDS, and thus facilitate the proliferation of residual malignant cells that may have survived the preparative regimen.

Leukemia lineage-specific chimerism analysis is a sensitive predictor of relapse in patients with acute myeloid leukemia and myelodysplastic syndrome after allogeneic stem cell transplantation

“…This finding of complete donor chimerism in all cell subsets analyzed, except the leukemia-affected cell lineage, has been noted before. 52,53 The only patients with MC in the T cell fraction at the time of relapse in this study were those with an aberrant CD7 expression before SCT. It has been suggested that immune escape by clonal evolution of the leukemia is a common occurrence in patients who relapse with myeloid leukemias after SCT.…”

Increasing mixed chimerism defines a high-risk group of childhood acute myelogenous leukemia patients after allogeneic stem cell transplantation where pre-emptive immunotherapy may be effective

“…42 However, this increase of normal autologous cells very reliably predicts relapse and can therefore be taken as a decisive signal that development of relapse has commenced without a chance for self-limitation.…”

Allogeneic bone marrow transplantation for infants with acute leukemia or myelodysplastic syndrome

“…20 Optimization of conditioning 21 and posttransplantation therapy 22 may also improve outcome. New approaches under investigation include use of monoclonal antibodies, 23 monitoring of minimal residual disease 24 and chimerism status, 25 and use of immunotherapy after BMT. [26][27][28] As expected, the WBC count at the time of diagnosis was high, and CNS disease and 11q23 abnormalities were common in this cohort of infants.…”