Relationship between minimal residual disease measured by multiparametric flow cytometry prior to allogeneic hematopoietic stem cell transplantation and outcome in children with acute lymphoblastic leukemia

Abstract

BackgroundThe presence of minimal residual disease detected by polymerase chain reaction techniques prior to allogeneic hematopoietic stem cell transplantation has proven to be an independent prognostic factor for poor outcome in children with acute lymphoblastic leukemia. Design and MethodsThe aim of this study was to ascertain whether the presence of minimal residual disease detected by multiparametric flow cytometry prior to allogeneic hematopoietic stem cell transplantation is related to outcome in children acute lymphoblastic leukemia. Minimal residual disease was quantified by multiparametric flow cytometry at a median of 10 days prior to hematopoietic stem cell transplantation in 31 children (age range, 10 months to 16 years) with acute lymphoblastic leukemia. Thirteen patients were transplanted in first remission. Stem cell donors were HLA-identical siblings in 8 cases and matched unrelated donors in 23. Twenty-six children received a total body irradiation-containing conditioning regimen. According to the level of minimal residual disease, patients were divided into two groups: minimal residual diseasepositive (≥0.01%) (n=10) and minimal residual disease-negative (<0.01%) (n=21). ResultsEstimated event-free survival rates at 2 years for the minimal residual disease-negative andpositive subgroups were 74% and 20%, respectively (P=0.004) and overall survival rates were 80% and 20%, respectively (P=0.005). Bivariate analysis identified pre-transplant minimal residual disease as the only significant factor for relapse and also for death (P<0.01). ConclusionsThe presence of minimal residual disease measured by multiparametric flow cytometry identified a group of patients with a 9.5-fold higher risk of relapse and a 3.2-fold higher risk of death than those without minimal residual disease. This study supports the strong relationship between pre-transplantation minimal residual disease measured by multiparametric flow cytometry and outcome following allogeneic hematopoietic stem cell transplantation and concur with the results of previous studies using polymerase chain reaction techniques.Key words: minimal residual disease, hematopoietic stem cell transplantation, polymerase chain reaction. Citation: Elorza I, Palacio C, Dapena JL, Gallur L, Sanchez de Toledo J, and Diaz de Heredia C.Relationship between minimal residual disease measured by multiparametric flow cytometry prior to allogeneic hematopoietic stem cell transplantation and outcome in children with acute lymphoblastic leukemia. Haematologica 2010;95:936-941. doi:10.3324/haematol.2009 Relationship between minimal residual disease measured by multiparametric flow cytometry prior to allogeneic hematopoietic stem cell transplantation and outcome in children with acute lymphoblastic leukemia

Impact of pretransplant minimal residual disease after cord blood transplantation for childhood acute lymphoblastic leukemia in remission: an Eurocord, PDWP–EBMT analysis

“…To this date, the impact of MRD before transplantation in childhood ALL has only been addressed in studies with a relatively small number of patients. 19,26,27 In this study, including 170 patients with a median follow-up of 4 years, we have shown that MRD before UCBT is a strong predictive Leukemia Free Survival Figure 2. The estimated 4-year probability of LFS in children with ALL in remission by MRD status before UCBT.…”

Prognostic and therapeutic implications of minimal residual disease at the time of transplantation in acute leukemia

“…Nevertheless, these studies uniformly found excellent long-term outcomes for patients without detectable MRD (that is, 'MRD À ' patients) undergoing myeloablative AlloHCT, with 2-5 year estimates of EFS, relapse-free survival and OS often in the 70-80% range, and more recent series suggesting even better outcomes. [29][30][31][34][35][36][37][39][40][41][42][43][46][47][48][49] Almost without exception, the outcomes for patients with detectable MRD (that is, 'MRD þ ' patients) were significantly inferior, with long-term estimates of EFS of 0-30% and OS of 30-50%, respectively. Although data are more limited for AutoHCT, available information suggests that MRD À patients may have relatively good disease control that appears to approach that seen after AlloHCT, at least in the subset of leukemias that do not harbor the Philadelphia chromosome; on the other hand, MRD þ ALL patients experience exceedingly high rates of relapse after AutoHCT.…”

“…53,57,61,62 However, MRD appears to bear significance as an independent prognostic marker, as suggested by multivariate regression modeling in many of the studies. [27][28][29]36,37,39,[42][43][44][47][48][49]53,54,57,[59][60][61] The association between MRD and risk of BM relapse is likely 'dose-dependent' in ALL 27,28,36,37,41,42,44,47,63 and, possibly, AML, 53,54,60 while MRD assessments may fail to predict extramedullary relapse accurately. 32,45 Interestingly, evidence from logistic regression models suggests that the relative level of MRD has more impact on survival in ALL than in AML.…”

The assessment and appraisal of regenerative medicines and cell therapy products: an exploration of methods for review, economic evaluation and appraisal

“…110,111,189 These studies have shown, to varying degrees, that MRD status prior to HSCT appears to be an important prognostic determinant of long-term RFS and OS, with MRD-negative (< 0.01% marrow blasts) patients experiencing superior survival compared with MRD-positive (> 0.01% to 5% marrow blasts) patients, including within studies of children with relapsed ALL. These data support the assumption of a continuous relationship between MRD level prior to HSCT and 5-year survival probability.…”

“…Similar findings were reported in a study that included a slightly larger sample of those post second or later relapse (n = 18). 110 Based on these and other studies, there is the suggestion of benefits through MRD-directed therapies, although controlled trials are needed to define their value. 109 Immunotherapies are showing promise and are being investigated.…”