Prediction and reversion of post-transplant relapse in patients with chronic myeloid leukemia using mixed chimerism and residual disease detection and adoptive immunotherapy

Abstract 

In the prospective study, we examined hematopoietic mixed chimerism (using polymerase chain reaction (PCR) of variable number of tandem repeat-VNTR sequences) and minimal residual disease (MRD) status (using qualitative and in the case of positivity quantitative reverse transcriptase polymerase chain reaction (RT-PCR) for the BCR/ABL fusion mRNA) in serial peripheral blood samples taken from 25 patients after bone marrow transplantation (BMT) for chronic myeloid leukemia (CML). Increasing mixed chimerism in correlation with increasing signal of MRD was detected in 10 patients. In two patients mixed chimera status and BCR/ABL rearrangement led to hematologic relapse, in five patients molecular relapse was followed by reappearance of Ph chromosome and three patients developed molecular relapse only. Adoptive immunotherapy-donor lymphocyte infusion (DLI), interferon (INF) and discontinuation of post-transplant immunosupression-separately or in different combinations was used in nine patients with molecular, cytogenetic or hematologic relapse of CML. The results demonstrate that significant response at the molecular level can be achieved for a majority of CML patients and that using of all forms of adoptive immunotherapy controlled by MC and MRD is more efficient in patients treated in early molecular relapse-with minimal disease burdens.

Keywords: Bone marrow transplantation, Chronic myeloid leukemia, Relapse, Mixed chimerism, Minimal residual disease, BCR/ABL, Donor lymphocyte infusion

Abbreviations: AP, accelerate phase, ATG, antithymocyte globulin, BMT, bone marrow transplantation, Bu, Busulfan, CML, chronic myeloid leukemia, CC, comlete chimerism, CP, chronic phase, CsA, cyclosporin, Cy, cyclophosphamide, DLI, donor lymphocyte infusion, GVHD, graft versus host disease, GVL, graft versus leukemia, HSC, hematopoietic stem cells, IFN, interferon, inMC, increasing mixed chimerism, MC, mixed chimerism, MTX, methotrexate, MRD, minimal residual disease, PBSC, peripheral blood stem cells, PCR, polymerase chain reaction, QC-RT-PCR, quantitative competitive reverse transcriptase polymerase chain reaction, sMC, stable mixed chimerism, TBI, total body irradiation, TCD, T-cell depletion, tMC, transient mixed chimerism, VNTR, varible number of tandem repeats