Prognostic Significance of Minimal Residual Disease (MRD) in Children with High Risk Acute Lymphoblastic Leukemia(ALL) A Children's Oncology Group Study.

Abstract

MRD is known to be an important prognostic factor in childhood ALL. In POG 9906 we studied a select group of 271 patients with NCI high risk precursor B-ALL further defined by an age/sex/WBC algorithm (Shuster et al. Cancer Res Therapy Control 9:101, 1999) to select those at highest risk; historical data suggested that patients selected by this algorithm would account for about 12% of patients and have a 44% 4y EFS. Patients with Ph+ ALL or favorable genetics (TEL-AML1 translocation or trisomies 4 and 10) were excluded. All patients received 4-drug induction with vincristine, prednisone, L-asparaginase and daunomycin, plus intrathecal methotrexate, and consolidation with cyclophosphamide, ara-C and 6-MP followed by 2 cycles of interim maintenance and delayed intensification similar but not identical to so-called “augmented BFM”. MRD was measured in peripheral blood on day 8 (PB) and in bone marrow at day 29 (BM) by 4-color flow cytometry as previously described (Leukemia 17:1566, 2003). BM MRD data were available on 240 patients, and PB data on 243. At cutoffs of 1%, 0.1% and .01%, MRD in BM was associated with increased relapse rate (p=.0002). At a cutoff of .01%, 83/240 (35%) patients were MRD positive; these had 3 y EFS of 58±6% compared to 79±5% for MRD negative patients (p=.0008). The EFS of the 28 patients with MRD >1% was 44±14%. There were numerous (25/52) extramedullary events, mostly in CNS. MRD predicted 17/27 marrow relapses but only 8/25 other relapses (p=.03). Overall, 21% of MRD positive patients (>.01%) had a marrow relapse compared to 6% of MRD negative ones. Day 8 PB MRD was also prognostic, with the 49 MRD negative patients having a 3 y EFS of 89±6% compared to 70±5% for the 194 patients with MRD >.01% (p=.008). End induction BM MRD is a strong prognostic factor even among patients with especially high risk ALL and is a better predictor of marrow than of extramedullary relapse. Absence of MRD in day 8 PB identifies a subgroup of approximately 20% of these high risk patients who have an exceptionally good EFS, particularly given their very poor expected outcome. [Display omitted]