Submicroscopic bone marrow involvement in isolated extramedullary relapses in childhood acute lymphoblastic leukemia: a more precise definition of "isolated" and its possible clinical implications, a collaborative study of the Resistant Disease Committee of the International BFM study group.

This study investigates the extent of bone marrow (BM) involvement at diagnosis of apparent isolated extramedullary (AIEM) relapses of childhood acute lymphoblastic leukemia (ALL) and its relation to prognosis. Sixty-four children with first AIEM relapse treated in Germany, Czech Republic, or France were included. Real-time quantitative polymerase chain reaction using T-cell receptor and immunoglobulin gene rearrangements provided a sensitive measure of submicroscopic BM involvement, which was detectable at a level of 10(-4) or higher in 46 patients and less than 10(-4) in 11 patients, and was nondetectable (sensitivity: 10(-4)) in 7 patients. In the total cohort, the probability of event-free survival (pEFS) for children with BM involvement of 10(-4) or higher was 0.30 (0.09 +/- SE) versus 0.60 (+/- 0.12) for those with less than 10(-4) (P = .13). The cumulative incidence of subsequent relapse was 0.24 (+/- 0.01) for patients with BM involvement less than 10(-4) and 0.65 (+/- 0.01) for those with 10(-4) or higher (P = .012). Restricted to central nervous system (CNS) relapses, pEFS was 0.11 (+/- 0.09) for patients with BM involvement 10(-4) or higher and 0.63 (+/- 0.17) for those with less than 10(-4) (P = .053). CNS relapses were associated with a higher (> or = 10(-4): 80%) submicroscopic BM involvement than testicular relapses (> or = 10(-4): 57%, P = .08). In summary, we show marked heterogeneity of submicroscopic BM involvement at first AIEM relapse diagnosis in children with ALL, and demonstrate its possible prognostic relevance.