Minimal Residual Disease Status Before Allogeneic Bone Marrow Transplantation Is an Important Determinant of Successful Outcome for Children and Adolescents With Acute Lymphoblastic Leukemia

Abstract

The efficacy of allografting in acute lymphoblastic leukemia (ALL) is heavily influenced by remission status at the time of transplant. Using polymerase chain reaction (PCR)-based minimal residual disease (MRD) analysis, we have investigated retrospectively the impact of submicroscopic leukemia on outcome in 64 patients receiving allogeneic bone marrow transplantation (BMT) for childhood ALL. Remission BM specimens were taken 6 to 81 days (median, 23) before transplant. All patients received similar conditioning therapy; 50 received grafts from unrelated donors and 14 from related donors. Nineteen patients were transplanted in first complete remission (CR1) and 45 in second or subsequent CR. MRD was analyzed by PCR of Ig or T-cell receptor δ or γ rearrangements, electrophoresis, and allele-specific oligoprobing. Samples were rated high-level positive (clonal band evident after electrophoresis; sensitivity 10−2 to 10−3), low-level positive (MRD detected only after oligoprobing; sensitivity 10−3 to 10−5), or negative. Excluding 8 patients transplanted in CR2 for isolated extramedullary relapse (all MRD−), MRD was detected at high level in 12 patients, low level in 11, and was undetectable in 33. Two-year event-free survival for these groups was 0%, 36%, and 73%, respectively (P < .001). Follow-up in patients remaining in continuing remission is 20 to 96 months (median, 35). These results suggest that MRD analysis could be used routinely in this setting. This would allow identification of patients with resistant leukemia (who may benefit from innovative BMT protocols) and of those with more responsive disease (who may be candidates for randomized trials of BMT versus modern intensive relapse chemotherapy).

Residual leukaemia after bone marrow transplant in children with acute lymphoblastic leukaemia after first haematological relapse or with poor initial presenting features

“…The quality of remission before BMT may impact upon outcome (Giona et al, 1994;Mehta et al, 1994). Three studies have shown that a low level of disease before transplant correlates with successful outcome (Knechtli et al, 1998a;Uzunel et al, 2001;Van der Velden et al, 2001). This conclusion cannot be drawn from our data.…”

“…In contrast, the other studies were not as restrictive in patient selection. The transplant regimen also did not include T-cell depletion, as performed in two other studies (Knechtli et al, 1998a;Van der Velden et al, 2001). Knechtli et al (1998b) also analysed the post-engraftment behaviour of residual leukaemia after allo-BMT in 71 children with ALL using a semi-quantitative PCR-based method on bone marrow samples taken at four different times post BMT.…”

Modelling a minimal residual disease‐based treatment strategy in childhood acute lymphoblastic leukaemia

“…For intensive therapy, data are scarcer. Knechtli et al (1998) studied MRD before allogeneic transplantation in 64 children with ALL. The relapse rates for MRD prior to transplantation were 100% for an MRD 10 )2 ) 10 )3 , 64% for an MRD 10 )3 ) 10 )5 and 37% for an MRD < 10 )5 .…”

Minimal residual disease prior to stem cell transplant for childhood acute lymphoblastic leukaemia

“…Each of these studies has shown MRD burden pre-SCT to be an independent prognostic factor in prediction of relapse. Analysis identified MRD to be an independent prognostic factor in multivariate analysis in Bader et al (2002) and Knechtli et al (1998) (P < 0AE01). Although formal metaanalysis is invalidated by differences in transplant protocol and MRD method, some clinically useful conclusions can be inferred from pooling the results of these studies.…”

“…Three published studies have examined the correlation between MRD burden prior to conditioning and relapse after SCT in more than 100 children transplanted for ALL in remission (Knechtli et al, 1998;Van der Velden et al, 2001;Bader et al, 2002). Knechtli et al (1998) used polymerase chain reaction (PCR) analysis of antigen receptor genes and allele-specific probing (a technique capable of detection of one leukaemic cell in 10 000 normal cells) to estimate MRD a median of 23 d pre-BMT in 64 children (19 CR1, 39 CR2, two CR3 or beyond) transplanted in a single centre predominantly from unrelated donors. The level of MRD was defined as either high positive [presence of a band on polyacrylamide gel electrophoresis (PAGE)], low (negative by PAGE but positive on radio-labelled probing) or negative.…”