January 2001, Volume 15, Issue 1, Pages 134 - 140

Original Manuscript

Quantification of minimal residual disease in children with oligoclonal B-precursor acute lymphoblastic leukemia indicates that the clones that grow out during relapse already have the slowest rate of reduction during induction therapy V de Haas1,2, OJHM Verhagen2, AEGKr von dem Borne3, W Kroes4, H van den Berg1 & CE van der Schoot2,3 1Emma Kinderziekenhuis AMC, University of Amsterdam, Amsterdam, The Netherlands     2Central Laboratory of the Netherlands Red Cross Blood Transfusion Service and Laboratory of Experimental and Clinical Immunology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands     3Department of Hematology, Academic Medical Centre, Amsterdam, The Netherlands     4Department of Cytogenetics, Academic Medical Centre, Amsterdam, The Netherlands     Correspondence to: CE van der Schoot, Department of Experimental Immunohematology, Central Laboratory of The Netherlands Red Cross Blood Transfusion Service, Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands; Fax: 31 20 5123474

Keywords

acute lymphoblastic leukemia (ALL);   minimal residual disease (MRD);   antigen receptor rearrangements;   oligoclonality;   clonal evolution

Abstract

Antigen receptor gene rearrangements are applied for the PCR-based minimal residual disease (MRD) detection in acute lymphoblastic leukemia (ALL). It is known that ongoing rearrangements result in subclone formation, and that the relapsing subclone(s) can contain antigen receptor rearrangement(s) that differ from the rearrangements found in the major clone(s) at diagnosis. However, the mechanism leading to this so-called clonal evolution is not known, particularly at which time point in the disease the relapsing subclone obtains its (relative) therapy resistance. To obtain insight in clonal evolution, we followed the kinetics of several subclones in three oligoclonal ALL patients during induction therapy. Clone-specific nested PCR for immunoglobulin heavy chain or T cell receptor gene rearrangements were performed in limiting dilution assays on bone marrow samples taken at diagnosis, at the end of induction therapy and at possible relapse in three children with oligoclonal B-precursor ALL. We demonstrated that in all three patients the subclones were behaving differently in response to therapy. Moreover, in the two patients who relapsed, the clones that grew out during relapse showed the slowest regression or even evoluated during induction therapy and the clones that were not present at relapse showed good response to induction therapy. These results support the hypothesis that at least in some patients already at diagnosis or in the very first weeks, subclones have important differences in respect to resistance. Hence, these data give experimental evidence for the need to develop, during the first months after diagnosis, quantitative PCR assays for at least two different Ig/TCR gene rearrangement targets for every ALL patient. Leukemia (2001) 15, 134-140.

Received 26 April 1999; Accepted 22 August 2000

^© Macmillan Publishers Ltd 2001