Predictive value of minimal residual disease befor allo-HSCT in children and adolescents with high-risk acute myeloid leukemia
Allogeneic haemopoietic stem cell transplantation (allo-HSCT) – is an effective option in the treatment of high risk patients with acute myeloid leukemia (AML). The relapse after allo-HSCT occurs in about 20-50% of patients, depending on status of the disease and negative prognostic factors. Minimal residual disease (MRD) is a powerful and independent predictor of subsequent relapse, which is detected using polymerase chain reactions or multiparametric flow cytometry. Presented clinical data demonstrated the high prognostic significance of the measured MRD in adults before allo-HSCT. However, impact of pre-transplantation MRD status in children and adolescents with AML is not well elucidated. The goal of this study was to evaluate the impact of pre-transplantation MRD on overall survival (OS), event-free survival (EFS), transplant-related mortality (TRM), relapse-free survival (RFS), relapse incidence (RI) and primary graft failure in transplantation in children and adolescents with AML.
Materials and methods
From 2008 to 2018 a total of 95 AML pediatric patients of R. M. Gorbacheva Memorial Institute received allo-HSCT in complete clinical-hematological remission. Most of the patients received AML-BFM 2004 as primary treatment. We used WHO 2008 criteria (review 2016) to assign cytogenetic risk. All subsequent patients eligible for this study underwent bone marrow (BM) aspiration or biopsy prior to allo-HSCT. Among these patients, 79 were assessed for MRD before HSCT and were considered in this retrospective analysis. MRD was examined with immunophenotyping or polymerase chain reaction/ cytogenetic. The median age was 10 years (1-18). Patients were divided into 2 groups: 1 group – MRD-positive n=33 (42%), 2 group – MRD-negative n=46 (58%). Allo-HSCT was performed in first remission in 23 (70%) MRD-positive patients and 35 (76%) MRD-negative patients. High cytogenetic risk accounted for 14/30 (46%) MRD-positive and 16/40 (40%) MRD-negative patients (p=0.7). Equal number of secondary (n=4; 12% and n=4; 8%, respectively, p=0.7) AML, and also extramedullary (n=6; 18% and n=6; 13%, respectively, p=0.5) disease were observed in both groups. Different in intensity regimes of conditioning were used in equal proportions in both groups (RIC/MAC): 18/15 (1.2) in MRD-positive patients, 25/21 (1.2) in MRD-negative patients. Probabilities of OS, EFS, RFS, TRM were estimated by using the Kaplan-Meier method. Relapse of leukemia and death was accepted as event in EFS. Cumulative RI and primary graft failure – by using Mann-Whitney U-test.
Transplant engraftment was identified in 71 (90%) of patients. Graft failure occurs in the 4 patients of each group (12% for MRD-positive и 8% for MRD-negative. P=0.6). At the median follow up 3 years OS were 63,6% for MRD-positive and 69,6% for MRD-negative patients (p=0,7); the 3-year EFS were 45,5% and 65,2% respectively (p=0,1). The cumulative RI was higher for MRD-positive (n=14) than for patients MRD-negative (n=8) patients (42% and 17% respectively; p=0,01). RFS were also different in the both groups (57,6% and 82.6%; р=0.02). TRM were similar for MRD-positive patients compared with MRD-negative patients (15.2% and 17.4% respectively; p=0.6). Resistant relapse was the reason of death in 13/26 (50%) patients. Nine (27%) MRD-positive and 5 MRD-negative (10%) patient were treated with prophylactic/preventive hypomethylating agent ± IDL in posttransplantation period. One MRD-positive patient experienced a relapse after epigenetic therapy.
These data demonstrated, that pre-transplantation MRD is associated with increased risk of relapse in children and adolescents with AML (RI-p=0.01; RFS- p=0.02). MRD-positive patients had similar OS (p=0.7), EFS (p=0.1) to patients with MRD-negative status, because relapse had not decisive role for survival.
Acute myeloid leukemia, minimal residual disease, allo-HSCT, children.