Persistent donor chimaerism is consistent with disease-free survival following BMT for chronic myeloid leukaemia

Abstract

Summary:Chronic myeloid leukaemia (CML) can be treated sucAllogeneic bone marrow transplantation (BMT) is a successful treatment modality for patients with chronic myeloid leukaemia (CML). Sixty to 80 percent of patients cessfully with allogeneic bone marrow transplantation transplanted with unmanipulated BM in first chronic phase (BMT) leading to long-term disease-free survival. Leu-(CP) achieve long-term disease-free survival. 1 However, kemia relapse, however, remains a significant clinical relapse rates of 10-20% are still the most frequent cause problem. Relapse following BMT presumably results of treatment failure. 2,3 Leukaemia relapse following BMT from the expansion of small numbers of recipient leupresumably results from the inability of the conditioning kaemic cells which have survived the conditioning therregimen to eliminate all recipient leukaemic cells. Ideally, apy. In order to define patients who are at a high risk following BMT, the recipient's bone marrow should be of leukaemia relapse, a variety of techniques have been completely ablated by the conditioning regimen, facilitating employed to detect persistence of host haemopoiesis the engraftment of donor haemopoietic stem cells giving (mixed chimaerism, MC) or residual leukaemia rise to a complete donor haemopoietic chimaera. 4(minimal residual disease, MRD). However, the precise The true incidence and significance of the detection of relationship between the detection of MC and MRD mixed haemopoietic chimaerism (MC) post-BMT remains post-BMT is unknown. We have investigated chimaerunclear. 4,5 MC was initially thought to indicate an impendism and MRD status in 22 patients who were in clinical ing relapse, however, using more sensitive molecular techand haematological remission post-allogeneic BMT for niques it has become clear that MC post-BMT is not chronic phase CML. Chimaerism was assessed using uncommon, with varying percentages of recipient cells short tandem repeat PCR (STR-PCR) while BCR-ABL being detected in different study groups. [6][7][8][9][10] This variation mRNA detection using reverse transcriptase polymerase in the degree of MC is influenced by a number of factors chain reaction (RT-PCR) was performed to detect the including the sensitivity and timing of the assay, the disease presence of MRD. Seventeen patients received unmanindication for BMT, the stage of disease at time of BMT ipulated marrow (non-TCD) while in five patients a T and the choice of conditioning regimen. Several studies cell-depleted transplant (TCD) was performed as indicated that low levels of persisting recipient cells are not additional GVHD prophylaxis. Chimaerism was evaluassociated with an increased risk of leukaemic relapse. 7-10ated in 18 patients (14 non-TCD, four TCD). Mixed However, increasing levels of recipient cells over time chimaerism was an uncommon finding in recipients of (progressive mixed chimaerism) appear to predict relapse, unmanipulated BMT (21%) when compared to TCD especially in recipients of a T cell-depleted (TCD) trans-BMT (100...

Monitoring of lineage-specific chimaerism allows early prediction of response following donor lymphocyte infusions for relapsed chronic myeloid leukaemia

“…DNA was amplified using a panel of five STR primers as previously described. 15,16 Radiolabelled ␣ 32 P-dCTP was incorporated into the PCR. Following amplification, samples were electrophoresed on an 8% denaturing polyacrylamide sequencing gel and results were analysed after exposing the gel to autoradiography for 4-24 h. The routine sensitivity of the STR-PCR technique is 0.1-0.01%.…”

“…Following amplification, samples were electrophoresed on an 8% denaturing polyacrylamide sequencing gel and results were analysed after exposing the gel to autoradiography for 4-24 h. The routine sensitivity of the STR-PCR technique is 0.1-0.01%. 15,16 The STR-PCR assay is a semiquantitative one, significant increases or decreases in donor or recipient cell populations can be identified from analysis of serial samples. All results are confirmed using a second polymorphic STR-PCR marker and results are analysed by two independent observers.…”

Significance of chimerism in hematopoietic stem cell transplantation: new variations on an old theme

“…Detection of MRD depends on the disease for which HSCT has been performed, for example BCR-ABL-based RT-PCR is used for detection of MRD in patients suffering from CML. 39 …”

“…A combination of techniques has been employed to detect the persistence of host hematopoiesis (MC) as well as MRD to detect the disease relapse. These techniques involve study of a novel leukemia-specific mRNA transcript (BCR-ABL) in CML patients, 39 study of CBFb/MYH11 fusion transcripts in acute myelomonocytic leukemia (AML) patients positive for inversion 16, 48 b-globin synthesis by erythroid colonies in b-thalassemia patients and analysis of immunoglobin heavy chain (IgH) and T-cell receptor (TCR) genes in B-cell AML patients. 49 Table 3 summarizes different methods used to detect MRD for different diseases.…”

How and when should we monitor chimerism after allogeneic stem cell transplantation?

“…Most notably, the increase of autologous cells preceded elevated HbS concentration by more than 2 months. [87][88][89][90] Therefore, mixed chimerism has been considered to reduce the graft-versus-leukemia effect (GVL) in this particular group of patients. 87,88,91 In patients with acute leukemias and MDS, several early studies have left the question unanswered whether patients with mixed chimerism do have an increased risk of relapse.…”