title: Residual bone marrow leukemic progenitor cell burden after induction chemotherapy in pediatric patients with acute lymphoblastic leukemia.
abstract: We used highly sensitive multiparameter flow cytometry and blast colony assays to quantify the leukemic progenitor cell (LPC) burden of postinduction chemotherapy bone marrows from newly diagnosed and relapsed pediatric patients with acute lymphoblastic leukemia (ALL). Of 890 newly diagnosed patients, 243 (27%) had detectable LPC in the postinduction bone marrow samples with an average (mean +/- SE) LPC content of 22+/-9 LPC/10(6) mononuclear cell (MNC; range, 0-7199/10(6) MNC; median, 0/10(6) MNC). By comparison, 24 of 50 (48%) patients with relapsed ALL had detectable LPC in their postinduction bone marrow specimens (P = 0.003), and their average LPC content was 202+/-139 LPC/10(6) MNC. Fewer patients with B-lineage ALL (170 of 786; 22%) than patients with T-lineage ALL (73 of 104; 70%) harbored residual LPC in their postinduction bone marrow specimens (P < 0.0001). This correlation with immunophenotype was independent of the National Cancer Institute risk classification. Similarly, 19 of 44 (43%) patients with relapsed B-lineage ALL versus 5 of 6 (83%) patients with relapsed T-lineage ALL harbored residual LPC in their postinduction bone marrow specimens (P = 0.09). Among newly diagnosed patients, those with high-risk ALL seemed to have larger numbers of residual LPC in their bone marrow after induction chemotherapy than those with standard risk ALL (53+/-26, n = 286 versus 7+/-1, n = 604, P = 0.04). LPC of patients with standard risk ALL who had a slow early marrow response at day 7 seemed to be more resistant to the three-drug induction chemotherapy than patients who had a rapid early marrow response. Overall, the order of chemosensitivity of LPC was: newly diagnosed standard risk B-lineage > newly diagnosed higher risk B-lineage > newly diagnosed standard risk T-lineage > newly diagnosed higher risk T-lineage > relapsed B-lineage > relapsed T-lineage. Notably, LPC- patients whose end-of-induction remission bone marrow specimens had zero LPC had an excellent early event-free survival outcome. Within the standard and high-risk subsets, LPC- patients had a 2.6-fold lower and 2.4-fold lower incidence of events, respectively, than LPC+ patients. At 6 months, 12 months, as well as 24 months, the ranking order for better event-free survival was: standard risk, LPC- > high risk, LPC- > standard risk, LPC+ > high risk, and LPC+.
authors.affiliation: Children's Cancer Group ALL Biology Reference Laboratory, Parker Hughes Institute, St. Paul, Minnesota 55113, USA.
authors.forename: F M
authors.initials: FM
authors.lastname: Uckun
authors.forename: L
authors.initials: L
authors.lastname: Stork
authors.forename: N
authors.initials: N
authors.lastname: Seibel
authors.forename: M
authors.initials: M
authors.lastname: Sarquis
authors.forename: C
authors.initials: C
authors.lastname: Bedros
authors.forename: H
authors.initials: H
authors.lastname: Sather
authors.forename: M
authors.initials: M
authors.lastname: Sensel
authors.forename: G H
authors.initials: GH
authors.lastname: Reaman
authors.forename: P S
authors.initials: PS
authors.lastname: Gaynon
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001853:Bone Marrow / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D002986:Clinical Trials as Topic; D005434:Flow Cytometry; D006801:Humans; D016130:Immunophenotyping; D007223:Infant; D018365:Neoplasm, Residual; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis / Q000188:drug therapy / Q000473:pathology*; D012074:Remission Induction