Detection of Minimal Residual Disease in Adult Acute Lymphoblastic Leukemia by Analysis of Gene Rearrangements and Correlation with Early Relapses

Abstract

While more than 75% of the adult patients with acute lymphoblastic leukemia (ALL) achieve a complete remission after treatment with intensive chemotherapy, about 40% of them relapse within five years. These relapses are probably due to residual leukemic cells. Gene rearrangements are used as markers of clonality and thereby monoclonal leukemic lymphoid cells can be detected with high sensitivity. In this study, we have applied the analysis of gene rearrangements to detect minimal residual disease in patients considered to be in complete remission. Serial bone marrow samples were studied in 35 patients before and four weeks after initiation of a standardized induction chemotherapy. Gene probes for the joining regions of the human immunoglobulin heavy chain and the constant regions of the human T-cell receptor β-chain were used. In five of the 35 patients, the same gene rearrangements found before therapy persisted and indicated residual disease. Four of them relapsed within a median time of 10 weeks. Six of the 30 other patients without detectable gene rearrangements after induction therapy also relapsed, but median time to relapse was 30 weeks. Two of them had a relapse in the central nervous system without detectable bone marrow infiltration. Our data suggest that minimal residual disease, detected by analysis of gene rearrangements, is associated with a high early relapse rate. Analysis of gene rearrangements at the time of assessing the response to primary therapy seems to be of prognostic value in ALL and may contribute to a stratification of further therapy.