Regeneration pattern of precursor-B-cells in bone marrow of acute lymphoblastic leukemia patients depends on the type of preceding chemotherapy.
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.
van Lochem
E G
EG
Department of Immunology, University Hospital Rotterdam/Erasmus University Rotterdam, The Netherlands.
Wiegers
Y M
YM
van den Beemd
R
R
Hählen
K
K
van Dongen
J J
JJ
Hooijkaas
H
H
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
D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D014750:Vincristine; D003907:Dexamethasone; D004253:DNA Nucleotidylexotransferase; D015260:Neprilysin; D001215:Asparaginase