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).

Minimal residual disease status determined by multiparametric flow cytometry pretransplantation predicts the outcome of patients with ALL receiving unmanipulated haploidentical allografts

“…In this largest sample study, we extended the established MRD experience in the MDST, MUDT, and CBT settings and showed that, in unmanipulated haplo‐SCT modality, ( a ) pre‐MRD status was associated with a higher incidence of relapse as well as lower LFS and OS; ( b ) the levels of pre‐MRD were also correlated with CIR, LFS, and OS; and ( c ) a scoring system that could be used in predicting transplant outcomes, including relapse, LFS, and OS, was effectively established based on pre‐MRD. Our study adds novel evidence, suggesting that the incorporation of MRD platforms into the monitoring of patients with ALL pretransplantation is a transformative approach in the risk stratification of cases with this clinically challenging disease.…”

“…Currently, the detection of minimal residual disease (MRD) has been successfully used for hematological relapse prediction and MRD‐guided treatment of acute lymphoblastic leukemia (ALL) . Numerous studies have demonstrated that MRD evaluation during remission induction and consolidation therapy provides unique and valuable information and is the most important prognostic variable in many studies of adult and pediatric ALL .…”

“…In allo‐SCT settings, the importance of pretransplantation MRD (pre‐MRD) status is gaining appreciation based on several publications showing significantly inferior outcomes for ALL patients with positive pre‐MRD, and possibly, the clinical benefit accrued by an allo‐SCT in ALL patients with a suboptimal MRD response to initial induction chemotherapy . However, these studies, with heterogeneous conditioning regimen, stem cell source, and graft‐vs‐host disease (GVHD) prophylaxis, mainly focused on human leukocyte antigen (HLA)‐matched related (MSDT) and unrelated donor transplantation (MUDT) as well as cord blood transplantation (CBT) . With the increased use of haploidentical SCT (haplo‐SCT) in ALL patients, it is becoming increasingly imperative to determine the role of pre‐MRD studies may assume in prognostication of patients with ALL who underwent haplo‐SCT.…”

Minimal residual disease detection after allogeneic stem cell transplantation is correlated to relapse in patients with acute lymphoblastic leukaemia

“…The MRD status before SCT was not correlated with relapse in this study, which may be explained by the low number of MRD‐negative patients. Other studies with larger MRD‐negative groups have clearly shown an association between MRD positivity before SCT and a subsequent relapse after SCT (Knechtli et al , 1998a; van der Velden et al , 2001; Bader et al , 2002). In our previous study (Uzunel et al , 2001), we also showed that the combination of acute and chronic GVHD was significantly associated with lower risk of relapse.…”

“…Most of these studies, using conventional chemotherapy, have shown that MRD status after induction therapy is one of the most significant prognostic factors. In the stem cell transplantation (SCT) setting, we and others have reported the importance of detecting and quantifying MRD before SCT (Knechtli et al , 1998a; Uzunel et al , 2001; van der Velden et al , 2001; Bader et al , 2002). Patients with persistent MRD before SCT had a higher risk of relapse after SCT compared with MRD‐negative patients.…”