Increasing mixed haematopoietic chimaerism after BMT with total depletion of CD4+ and partial depletion of CD8+ lymphocytes is associated with a higher incidence of relapse

Abstract

Summary:In this study we analysed the incidence and clinical impact of the persistence of host haemopoiesis (mixed chimaerism, MC) after allogeneic BMT in 35 consecutive patients with haematologic malignancies using a total CD4؉ cell-depleted graft with an adjusted dose of CD8 ؉ cells (1 ؋ 10 8 /kg). Chimaerism was assessed by PCR amplification of VNTRs in 30 evaluable patients: 19 non-CML and 11 CML cases which were also evaluated for the BCR-ABL transcript by RT-PCR. All but one had complete engraftment with a donor profile early post-BMT. At the end of the study period, 12 of 30 patients displayed MC (40%). The overall diseasefree survival for MC patients was clearly unfavourable when compared to those who exhibited a donor profile (24.7% vs 100%, P = 0.005). However, we found that only two of five patients with MC in the non-CML group relapsed, whereas a clear correlation could be made between MC and relapse in CML (seven showed MC, preceding cytogenetic or haematological relapse in six of them, which displayed a prior BCR-ABL mRNA positivity). In addition, a quantitative-PCR approach enabled us to demonstrate that increasing amounts of MC are invariably associated with subsequent relapse, whereas a low stable level of host or complete donor haemopoiesis is consistent with clinical complete remission. Although these results suggest that the clinical impact of MC may depend on the underlying disease, it is compatible with the concept that the graftversus-leukaemia effect against CML is mainly exerted by donor CD4 ؉ lymphocytes. Elimination of this cellular subset may be responsible for the inability of the graft to prevent a progressive increase in the tumor cell burden. Keywords: MC; BMT; T cell depletion; relapse Bone marrow transplantation (BMT) is the treatment of choice for many patients with haematologic malignancies. malignant clone by the conditioning regimen followed by the infusion of healthy donor marrow cells which re-establish normal haematologic and immune functions. However, the differences in post-transplant relapses between allogeneic and autologous or syngeneic BMT, 2,3 and especially between in vitro T cell-depleted and unmanipulated allogeneic BMT, [3][4][5] indicate that allogeneic donor T cells play a pivotal role in the eradication of malignant cells, the socalled graft-versus-leukaemia (GVL) effect, and may be crucial for the development of complete donor haematopoiesis. Furthermore, graft failure and development of mixed chimaerism (MC, the coexistence of recipient and donor haematopoiesis) are more common after T cell-depleted BMT when compared with conventional transplants. 6-8The true incidence and significance of the detection of MC post-BMT remain unclear.6-10 However, with the use of increasingly sensitive molecular techniques for the detection of residual recipient cells, MC is frequently observed post-allogeneic BMT, 6-13 although more important than simple documentation of the incidence of MC is an assessment of its relevance in relation to clinical outcome, particularly any ...

Monthly prospective analysis of hematopoietic chimerism after allogeneic hematopoietic cell transplantation

“…1,2,10,13 As for the relapse of leukemia, several studies have suggested that MC after allogeneic HCT was correlated with relapse in chronic myelogenous leukemia (CML). [14][15][16][17] In cases of acute leukemia, the findings were not consistent among studies, with some studies suggesting a correlation of MC with relapse [18][19][20][21] while others failed to show such a correlation. 6,8,9,14,17,22 In most studies, the timing of the assay of HpC after HCT was not controlled and the data were analyzed retrospectively.…”

“…[14][15][16][17] In cases of acute leukemia, the findings were not consistent among studies, with some studies suggesting a correlation of MC with relapse [18][19][20][21] while others failed to show such a correlation. 6,8,9,14,17,22 In most studies, the timing of the assay of HpC after HCT was not controlled and the data were analyzed retrospectively. 2,[9][10][11][17][18][19] In a series of 163 consecutive adult patients who underwent allogeneic HCT in our hospital, we monitored the status of HpC using a sensitive PCR-based method at monthly intervals in a prospective manner.…”

“…6,8,9,14,17,22 In most studies, the timing of the assay of HpC after HCT was not controlled and the data were analyzed retrospectively. 2,[9][10][11][17][18][19] In a series of 163 consecutive adult patients who underwent allogeneic HCT in our hospital, we monitored the status of HpC using a sensitive PCR-based method at monthly intervals in a prospective manner. We conducted this study to (1) identify pre and post transplant variables that may determine the chances of having MC at 1, 2, and 3 months after allogeneic HCT, and (2) evaluate the clinical significance of having MC early after allogeneic HCT especially in terms of graft failure and relapse of leukemia.…”

Prognostic value of hematopoietic chimerism in patients with acute leukemia after allogeneic bone marrow transplantation: a prospective study

“…[1][2][3][4][5] Several studies suggested that MC after allogeneic BMT may correlate with relapse in chronic myelogenous leukemia (CML). [4][5][6][7][8] These studies showed that increasing proportions of recipient cells over time are highly associated with subsequent relapse while low levels of persisting recipient cells are not associated with an increased risk of relapse. In cases of acute leukemia, however, the significance of MC as a predictive marker for relapse is less clear.…”

“…[1][2][3][4][5][6][7][8] Such mixed chimerism (MC) in the hematopoietic system was suggested to be a marker of immune tolerance as well as closer tissue matching between the donor and recipient on the basis of a decreased incidence of graftversus-host disease (GVHD). [1][2][3][4][5] Several studies suggested that MC after allogeneic BMT may correlate with relapse in chronic myelogenous leukemia (CML).…”