Residual bone marrow leukemic progenitor cell burden after induction chemotherapy in pediatric patients with acute lymphoblastic leukemia.

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+.

[1]  D. Stram,et al.  Bone Marrow Leukemic Progenitor Cell Content in Pediatric T-Lineage Acute Lymphoblastic Leukemia Patients with an Isolated Extramedullar First Relapse , 2001, Leukemia & lymphoma.

[2]  D. Stram,et al.  Paucity of leukemic progenitor cells in the bone marrow of pediatric B-lineage acute lymphoblastic leukemia patients with an isolated extramedullary first relapse. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[3]  L. Foroni,et al.  INVESTIGATION OF MINIMAL RESIDUAL DISEASE IN CHILDHOOD AND ADULT ACUTE LYMPHOBLASTIC LEUKAEMIA BY MOLECULAR ANALYSIS , 1999, British journal of haematology.

[4]  W. Hiddemann,et al.  Leukaemia‐associated immunophenotypes (LAIP) are observed in 90% of adult and childhood acute lymphoblastic leukaemia: detection in remission marrow predicts outcome , 1999, British journal of haematology.

[5]  N. Heerema,et al.  Treatment outcome and prognostic factors for infants with acute lymphoblastic leukemia treated on two consecutive trials of the Children's Cancer Group. , 1999, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  C. V. D. Schoot,et al.  Real-time quantitative PCR for the detection of minimal residual disease in acute lymphoblastic leukemia using junctional region specific TaqMan probes , 1998, Leukemia.

[7]  M. Kami,et al.  Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood , 1998, The Lancet.

[8]  W. Hop,et al.  Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood , 1998, The Lancet.

[9]  H. Cavé,et al.  Clinical Significance of Minimal Residual Disease in Childhood Acute Lymphoblastic Leukemia , 1998 .

[10]  P. Steinherz,et al.  Survival after relapse in childhood acute lymphoblastic leukemia , 1998, Cancer.

[11]  D. Catovsky,et al.  Detection of minimal residual disease in B‐lineage acute lymphoblastic leukaemia by quantitative flow cytometry , 1998, British journal of haematology.

[12]  H. Sather,et al.  Response of children with high-risk acute lymphoblastic leukemia treated with and without cranial irradiation: a report from the Children's Cancer Group. , 1998, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[13]  Elaine Coustan-Smith,et al.  Immunological detection of minimal residual disease in children with acute lymphoblastic leukaemia , 1998, The Lancet.

[14]  N. Heerema,et al.  Biology and treatment of childhood T-lineage acute lymphoblastic leukemia. , 1998, Blood.

[15]  M. Cleary,et al.  E2A-PBX1 chimeric transcript status at end of consolidation is not predictive of treatment outcome in childhood acute lymphoblastic leukemias with a t(1;19)(q23;p13): a Pediatric Oncology Group study. , 1998, Blood.

[16]  J. Hancock,et al.  Minimal residual disease analysis for the prediction of relapse in children with standard‐risk acute lymphoblastic leukaemia , 1998, British journal of haematology.

[17]  C. Pui,et al.  Recent advances in the biology and treatment of childhood acute lymphoblastic leukemia , 1997, Current opinion in hematology.

[18]  H. Sather,et al.  Clinical features and treatment outcome of children with myeloid antigen positive acute lymphoblastic leukemia: a report from the Children's Cancer Group. , 1997, Blood.

[19]  H. Sather,et al.  Clinical features and treatment outcome of children with biphenotypic CD2+ CD19+ acute lymphoblastic leukemia: a Children's Cancer Group study. , 1997, Blood.

[20]  A. Kasprzyk,et al.  Increased sensitivity of minimal residual disease detection by interphase FISH in acute lymphoblastic leukemia with hyperdiploidy , 1997, Leukemia.

[21]  D. Johnston,et al.  Measurement of residual leukemia during remission in childhood acute lymphoblastic leukemia. , 1997, The New England journal of medicine.

[22]  H. Sather,et al.  Improved clinical outcome for children with T-lineage acute lymphoblastic leukemia after contemporary chemotherapy: a Children's Cancer Group Study. , 1996, Leukemia & lymphoma.

[23]  L. Robison,et al.  Incidence of cancer in children in the United States. Sex‐, race‐, and 1‐year age‐specific rates by histologic type , 1995, Cancer.

[24]  G. Masera,et al.  Relapse after first cessation of therapy in childhood acute lymphoblastic leukemia: a 10-year follow-up study. Italian Association of Pediatric Hematology-Oncology (AIEOP). , 1995, Medical and pediatric oncology.

[25]  W. Hiddemann,et al.  Chemotherapy in 998 unselected childhood acute lymphoblastic leukemia patients. Results and conclusions of the multicenter trial ALL-BFM 86. , 1994, Blood.

[26]  R. Gelber,et al.  Treatment of childhood acute lymphoblastic leukemia: results of Dana-Farber Cancer Institute/Children's Hospital Acute Lymphoblastic Leukemia Consortium Protocol 85-01. , 1994, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[27]  F. Uckun,et al.  Pretransplantation burden of leukemic progenitor cells as a predictor of relapse after bone marrow transplantation for acute lymphoblastic leukemia. , 1993, The New England journal of medicine.

[28]  M. Hancock,et al.  Treatment of acute lymphoblastic leukemia : 30 years' experience at St. Jude Children's Research Hospital , 1993 .

[29]  P. Martiat,et al.  Long-term follow-up of residual disease in acute lymphoblastic leukemia patients in complete remission using clonogeneic IgH probes and the polymerase chain reaction. , 1993, Blood.

[30]  J. Silber,et al.  Residual disease at the end of induction therapy as a predictor of relapse during therapy in childhood B-lineage acute lymphoblastic leukemia. , 1992, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[31]  F. Uckun,et al.  Autologous bone marrow transplantation in high-risk remission B-lineage acute lymphoblastic leukemia using a cocktail of three monoclonal antibodies (BA-1/CD24, BA-2/CD9, and BA-3/CD10) plus complement and 4-hydroperoxycyclophosphamide for ex vivo bone marrow purging. , 1992, Blood.

[32]  R Hartmann,et al.  Six-year experience with a comprehensive approach to the treatment of recurrent childhood acute lymphoblastic leukemia (ALL-REZ BFM 85). A relapse study of the BFM group. , 1991, Blood.

[33]  J. Peto,et al.  Results of Medical Research Council Childhood Leukaemia Trial UKALL VIII (Report to the Medical Research Council on behalf of the Working Party on Leukaemia in Childhood) , 1991, British journal of haematology.

[34]  J. Ledbetter,et al.  Autologous bone marrow transplantation in high-risk remission T-lineage acute lymphoblastic leukemia using immunotoxins plus 4-hydroperoxycyclophosphamide for marrow purging. , 1990, Blood.

[35]  C. Bartram,et al.  Detection of minimal residual disease in acute lymphoblastic leukemia by in vitro amplification of rearranged T-cell receptor delta chain sequences. , 1989, Blood.

[36]  M. Borowitz,et al.  Prognostic importance of the pre-B-cell immunophenotype and other presenting features in B-lineage childhood acute lymphoblastic leukemia: a Pediatric Oncology Group study. , 1989, Blood.

[37]  B. Lange,et al.  Detection of minimal disease in hematopoietic malignancies of the B-cell lineage by using third-complementarity-determining region (CDR-III)-specific probes. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[38]  F. Galibert,et al.  In vitro amplification of T cell gamma gene rearrangements: a new tool for the assessment of minimal residual disease in acute lymphoblastic leukemias. , 1989, Leukemia.

[39]  A. Hagenbeek,et al.  Nonhomogeneous distribution of leukemia in the bone marrow during minimal residual disease. , 1987, Blood.

[40]  M. Greaves.  Differentiation-linked leukemogenesis in lymphocytes. , 1986, Science.

[41]  J. H. Scarffe,et al.  Cancer Medicine , 1982, British Journal of Cancer.

[42]  H. Sather,et al.  Prognostic significance of the CD10+CD19+CD34+ B-progenitor immunophenotype in children with acute lymphoblastic leukemia: a report from the Children's Cancer Group. , 1997, Leukemia & lymphoma.

[43]  C. Pui,et al.  Recent advances in the biology and treatment of childhood acute lymphoblastic leukemia , 1997, Current opinion in hematology.

[44]  RobertW. Miller,et al.  Childhood cancer , 1995, Cancer.

[45]  J. Harbott,et al.  [Concept and interim result of the ALL-BFM 90 therapy study in treatment of acute lymphoblastic leukemia in children and adolescents: the significance of initial therapy response in blood and bone marrow]. , 1994, Klinische Padiatrie.

[46]  Z. Estrov,et al.  Persistence of self-renewing leukemia cell progenitors during remission in children with B-precursor acute lymphoblastic leukemia. , 1994, Leukemia.

[47]  G. Paolucci,et al.  [Treatment of acute lymphoblastic leukemia]. , 1971, Minerva pediatrica.