Importance of Mixed Chimerism to Predict Relapse in Persistently BCR/ABL Positive Long Survivors After Allogeneic Bone Marrow Transplantation for Chronic Myeloid Leukemia

Abstract

Determination of hematological chimerism could be helpful in understanding the biology of leukemic relapse after allogeneic bone marrow transplant (BMT) for chronic myeloid leukemia (CML), because the detection of malignant residual cells carrying the bcr/abl message by qualitative RT-PCR is of limited value in predicting disease progression for individual patients. We have studied the chimerism pattern and the bcr/abl status by Southern-blot in 15 CML patients (M/F:6/9) transplanted with unmanipulated BM from HLA identical sibling donors, persistently bcr/abl positive by RT-PCR. The median age of the series was 31 years (18-49) and disease status at BMT was: chronic phase: 11, accelerated phase: 3 and blast crisis: 1 patient. Of the 15 patients, 9 are alive and in complete remission (CR), 4 have died in CR and 2 are alive but suffered relapse at + 19 and +26 months post-BMT. The median follow-up is 81 months (13,7-168). Rearrangement of the BCR gene was performed by Southern-blot using P32-labeled transprobe-1. PCR analysis of chimerism was assessed using primers for the following VNTR loci: D1S80, D1S111, 33.1, APO-B, YNZ-22, lambdag3 and DXS52. Seventy-nine samples were analyzed (median per patient 5 (range 2-9)). Thirteen patients showed complete chimerism and lacked BCR rearrangement over time by Southern-blot. The 2 patients who relapsed showed mixed chimera status from +9 and +5 months respectively until the end of the study. Persistent BCR rearrangement was observed in these 2 patients from +12 and +11 months respectively. Our data suggest that mixed chimerism may predict hematologic or cytogenetic relapse by several months in those patients who are persistently PCR-positive post-BMT.

Serial quantification of lymphoid and myeloid mixed chimerism using multiplex PCR amplification of short tandem repeat-markers predicts graft rejection and relapse, respectively, after allogeneic transplantation of CD34+ selected cells from peripheral blood

“…[2][3][4][5][6][7][8] The predictive value of MC in an individual patient for either graft rejection or relapse is controversial. [9][10][11][12] Some studies indicate that MC is associated with these complications, [13][14][15][16][17][18][19][20][21][22][23] while others do not corroborate this finding. 24,25 The lack of association of MC with graft rejection and relapse in some studies might be because of the fact that chimerism was not analysed in the cell subsets responsible for these complications.…”

“…After a median (range) follow-up of 15 (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25) Table 1. )…”

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

“…Our MC rate was not substantially lower than those reported after complete T cell depletion and it was found to be greater than that seen after unmanipulated grafts, especially in CML transplanted in chronic phase 26,27 (approximately 20%) as compared to 64% in our patients.…”

Sequential monitoring of chimerism and detection of minimal residual disease after allogeneic blood stem cell transplantation (BSCT) using multiplex PCR amplification of short tandem repeat-markers

“…6,8,9,[33][34][35] Although persistent recipient cells are not necessarily associated with an increased relapse rate, 36 several reports have shown, that the incidence of recurrent disease is significantly increased in the group of patients with unstable mixed chimerism showing increasing host signals compared to patients presenting with stable complete chimerism or patients with mixed chimerism turning into complete chimeras. 24 In this situation it is of critical importance to have a quantitative method for the evaluation of chimerism to provide useful information which could serve as a basis for clinical decision making.…”