Detailed clonality analysis of relapsing precursor B acute lymphoblastic leukemia: implications for minimal residual disease detection

Genetic instability has important implications for detection of minimal res idual disease (MRD) when the target is a clonal genetic marker revealed at diagnosis. A successful MRD detection approach requires a stable marker and for lymphoid leukemias clonal rearrangements of immunoglobulin (Ig) and T cell receptor (TCR) genes are commonly used. In the present study, Ig heavy chain (IgH) and TCR (gamma and delta) genes were studied in 18 consecutive , relapsing precursor-B ALL patients. At least one clonal rearrangement was found in all cases at presentation (IgH 94%, TCR gamma 39% and TCR delta 2 8%). An altered rearrangement pattern between diagnosis and relapse was dem onstrated in 14 patients (78%). At least one stable molecular target was fo und in 13 out of 18 cases (72%). Clonal differences between diagnostic and relapse samples were explained by: (1) loss of original rearrangements; (2) V-H to DJ(H), joining; (3) V-H gene replacement; (4) appearance of new rea rrangements. In two cases with apparently new IgH gene rearrangements at re lapse extended sequencing of the diagnostic samples revealed minor clonal r earrangements identical to the relapse clones. Interestingly, one patient d isplayed instability on both the IgH and TCR gene loci, whereas a stable Ig kappa rearrangement was found at presentation and relapse. These data show that clonal diversity is common in precursor-B ALL and strongly suggest th at MRD detection should include multiple gene targets to minimize false-neg ative samples. Even so, five of our 18 relapse cases (28%) lacked stable cl onal markers and should have been unsuitable for MRD detection. (C) 2001 El sevier Science Ltd. All rights reserved.