title: Regeneration pattern of precursor-B-cells in bone marrow of acute lymphoblastic leukemia patients depends on the type of preceding chemotherapy.
abstract: Immunofluorescence stainings for the CD10 antigen and terminal deoxynucleotidyl transferase (TdT) can be used for the detection of leukemic blasts in CD10+ precursor-B-acute lymphoblastic leukemia (precursor-B-ALL) patients, but can also provide insight into the regeneration of normal precursor-B-cells in bone marrow (BM). Over a period of 15 years, we studied the regeneration of CD10+, TdT+, and CD10+/TdT+ cells in BM of children with (CD10+) precursor-B-ALL during and after treatment according to three different treatment protocols of the Dutch Childhood Leukemia Study Group (DCLSG) which differed both in medication and time schedule. This study included a total of 634 BM samples from 46 patients who remained in continuous complete remission (CCR) after treatment according to DCLSG protocols VI (1984-1988; n = 8), VII (1988-1991; n = 10) and VIII (1991-1997; n = 28). After the cytomorphologically defined state of complete remission with CD10+ and CD10+/TdT+ frequencies generally below 1% of total BM cells, a 10-fold increase in precursor-B-cells was observed in protocol VII and protocol VIII, but not in protocol VI. At first sight this precursor-B-cell regeneration during treatment resembled the massive regeneration of the precursor-B-cell compartment after maintenance treatment, and appeared to be related to the post-induction or post-central nervous system (CNS) therapy stops in protocols VII and VIII. However, careful evaluation of the distribution between the 'more mature' (CD10+/TdT-) and the 'immature' (CD10+/TdT+) precursor-B-cells revealed major differences between the post-induction/post-re-induction precursor-B-cell regeneration (low 'mature/immature' ratio: generally <1.0), the post-CNS treatment regeneration (moderate 'mature/immature' ratio: 1.2-2.8), and the post-maintenance regeneration (high 'mature/ immature' ratio: 5.7-7.6). We conclude that a therapy stop of approximately 2 weeks is already sufficient to induce significant precursor-B-cell regeneration even from aplastic BM after induction treatment. Moreover, differences in precursor-B-cell regeneration patterns are related to the intensity of the preceding treatment block, with lower 'mature/immature' ratios after the highly intensive treatment blocks. This information is essential for a correct interpretation of flow cytometric immunophenotyping results of BM samples during follow-up of leukemia patients. Particularly in precursor-B-ALL patients, regeneration of normal precursor-B-cells should not be mistaken for a relapse.
authors.affiliation: Department of Immunology, University Hospital Rotterdam/Erasmus University Rotterdam, The Netherlands.
authors.forename: E G
authors.initials: EG
authors.lastname: van Lochem
authors.forename: Y M
authors.initials: YM
authors.lastname: Wiegers
authors.forename: R
authors.initials: R
authors.lastname: van den Beemd
authors.forename: K
authors.initials: K
authors.lastname: Hählen
authors.forename: J J
authors.initials: JJ
authors.lastname: van Dongen
authors.forename: H
authors.initials: H
authors.lastname: Hooijkaas
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D001215:Asparaginase / Q000008:administration & dosage / Q000494:pharmacology; D001402:B-Lymphocytes / Q000187:drug effects* / Q000473:pathology; D014408:Biomarkers, Tumor / Q000032:analysis; D002454:Cell Differentiation; D002455:Cell Division / Q000187:drug effects; D002648:Child; D004253:DNA Nucleotidylexotransferase / Q000032:analysis; D003907:Dexamethasone / Q000008:administration & dosage / Q000494:pharmacology; D004341:Drug Evaluation; D005260:Female; D005434:Flow Cytometry; D006410:Hematopoiesis / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D016130:Immunophenotyping; D008297:Male; D008853:Microscopy; D009363:Neoplasm Proteins / Q000032:analysis; D018365:Neoplasm, Residual; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology; D015260:Neprilysin / Q000032:analysis; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000473:pathology*; D014750:Vincristine / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D014750:Vincristine; D003907:Dexamethasone; D004253:DNA Nucleotidylexotransferase; D015260:Neprilysin; D001215:Asparaginase