Early resistance to therapy during induction in childhood acute lymphoblastic leukemia

Many patients with acute lymphoblastic leukemia (ALL) are not cured by curr ent therapy because of the development of drug resistance. It is not clear when resistance develops during the growth of the leukemic clone and whethe r resistant cells are already present at diagnosis or develop later during treatment. Twenty-two uniformly treated children with ALL were studied thro ughout induction treatment. The size of the leukemic clone in blood and mar row was estimated by limiting dilution PCR analysis, using the rearranged i mmunoglobulin heavy chain gene as a molecular marker. The decline in the nu mber of leukemic cells was biphasic in virtually all patients. For both mar row and blood, the logarithmic mean of the number of leukemic cells fell by approximately four orders of magnitude during the first 2 weeks, one order of magnitude during the third week, and not at all during the last two wee ks of induction treatment. For marrow, the median of the fraction of leukem ic cells in each patient that survived per week of treatment was 0.008 for the first 2 weeks, 0.12 for the third week, and 1.4 for the last 2 weeks; f or blood, the corresponding figures were 0.003, 0.14, and 0.69, respectivel y. In individual patients, the results for marrow and blood showed good cor relation. The biphasic decline of leukemic cell number suggests that most l eukemic cells were sensitive to treatment and were rapidly killed, leaving behind a minor but substantial population of drug-resistant cells. The most likely explanation for this phenomenon is that these resistant cells were already present at diagnosis, their resistance having originated from genet ic or epigenetic mutations during prior growth of the leukemic clone.