Early Responses to Chemotherapy of Normal and Malignant Hematologic Cells Are Prognostic in Children With Acute Lymphoblastic Leukemia

Abstract

Improved cure rates for children with acute lymphoblastic leukemia (ALL) have resulted from better relapse prediction, using clinical and laboratory features at diagnosis, and more intensive therapy in high-risk patients. More recently, measurements of the variation in the response of malignant lymphoblasts to chemotherapy in vivo have further improved relapse prediction. It is unknown whether the variation in the response of nonmalignant hematologic cells after chemotherapy correlates with the response of lymphoblasts or risk of relapse. We retrospectively evaluated myelosuppression during induction and consolidation chemotherapy in 227 children uniformly treated for ALL on consecutive Australian and New Zealand Children's Cancer Study Group protocols. The early response to treatment was assessed in a representative subset (n = 62) by determining minimal residual disease (MRD) level by molecular techniques on the end-of-induction bone marrow sample. We found that a slow rate of myeloid recovery at the end of induction chemotherapy, reflected in a low absolute neutrophil count (ANC), was highly predictive of relapse (P < .0001). Additionally, patients with a high end-of-induction MRD level had a high risk of relapse (P = .001). Multivariate analysis confirmed the independent prognostic significance of MRD and ANC at the end of induction chemotherapy (P < .05). There was no significant association between other measures of myelotoxicity and MRD or relapse. We conclude that the responses of normal myeloid cells and malignant lymphoblasts to chemotherapy predict outcome by distinct mechanisms. While these results are promising, their use in the clinical setting needs to be examined in a future randomized controlled trial.