Outcome prediction in childhood acute lymphoblastic leukaemia by molecular quantification of residual disease at the end of induction

Methods to detect and quantify minimal residual disease (MRD) after chemotherapy for acute lymphoblastic leukaemia (ALL) could improve treatment by identifying patients who need more or less intensive therapy. We have used a clone-specific polymerase chain reaction to detect rearranged immunoglobulin heavy-chain gene from the leukaemic clone, and quantified the clone by limiting dilution analysis. MRD was successfully quantified, by extracting DNA from marrow slides, from 88 of 181 children with ALL, who had total leucocyte counts below 100 x 10 9/L at presentation and were enrolled in two clinical trials, in 1980-84 and 1985-89. Leukaemia was detected in the first remission marrow of 38 patients, in amounts between 6·7 x 10 -2 and 9·9 x 10 -7 cells; 26 of these patients relapsed. Of 50 patients with no MRD detected, despite study of 522-496 000 genomes, only 6 relapsed. The association between MRD detection and outcome was significant for patients in each trial. In the first trial, patients relapsed at all levels of detected MRD, whereas in the later trial, in which treatment was more intensive and results were better, the extent of MRD was closely related to the probability of relapse (5 of 5 patients with > 10 -3 MRD, 4 of 10 with 10 -3 to 2 x 10 -5, 0 of 3 with levels below 2 x 10 -5, and 2 of 26 with no MRD detected). Early quantification of leukaemic cells after chemotherapy may be a successful strategy for predicting outcome and hence individualising treatment in childhood ALL, because the results indicate both in-vivo drug sensitivity of the leukaemia and the number of leukaemic cells that remain to be killed by post-induction therapy.