Granulocyte colony-stimulating factor recruitment of CD34+ progenitors to peripheral blood: impaired mobilization in chronic granulomatous disease and adenosine deaminase--deficient severe combined immunodeficiency disease patients.
Peripheral blood (PB) CD34+ cells mobilized by granulocyte colony-stimulating factor (G-CSF) administration are potentially useful for transplantation and as a target of gene transfer for therapy of hematopoietic disorders. Efficient harvest and planning for clinical use of PB CD34+ cells ideally requires foreknowledge of the expected mobilization kinetics and yield. We developed a sensitive flow cytometric assay for accurately enumerating CD34+ cells throughout the range seen at baseline to peak mobilization. We used this assay to assess the kinetics of G-CSF-mediated mobilization of CD34+ cells to PB in normal volunteers and in patients with chronic granulomatous disease (CGD) or adenosine deaminase (ADA)-deficient severe combined immunodeficiency disease (SCID). Two dose levels of G-CSF were examined (5 and 10 micrograms/kg/d for 7 days). Both doses were well tolerated. For normal subjects and patients an increase in PB CD34+ cells was first detected only preceding the third dose of G-CSF (day 3), peaked transiently on day 5 or 6, and then decreased thereafter despite additional doses of G-CSF. With 32 normal volunteers mean peak CD34+ cell counts were 57 and 76 cells/mm2 of blood (5 and 10 micrograms doses, respectively), whereas for 18 CGD patients the mean peaks were 31 and 40 cells/mm2 of blood. For 2 ADA-deficient SCID patients studied at a G-CSF dose of 5 micrograms/kg/d, the average peak was 16 cells/mm2 of blood. For both of these patient groups mobilization of CD34+ cells to PB was impaired compared with similarly treated normal subjects (P < .05). By contrast to the kinetics of the CD34+ cell mobilization, the absolute neutrophil count (ANC) increased markedly by 6 hours after the first dose of G-CSF and then increased steadily through day 8. At days 5 and 6 (peak mobilization of CD34+ cells) the mean ANC of CGD and ADA patients was only slightly lower ( < or = 15%) than that seen with normal subjects, whereas the difference in CD34+ cell mobilization was > 48%. Thus, ANC is not a reliable surrogate to predict peak PB CD34+ cell counts and direct enumeration of PB CD34+ counts should be undertaken in decisions regarding timing and duration of apheresis to harvest a specific number of these cells. Finally, unexpected, but significant differences in the PB CD34+ cell mobilization between normal subjects and patients with inherited disorders can occur and underscores the importance of establishing the expected mobilization of PB CD34+ cells in the planning of treatment approaches using these cells.
Sekhsaria
S
S
Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institute of Health, Bethesda, MD 20892, USA.
Fleisher
T A
TA
Vowells
S
S
Brown
M
M
Miller
J
J
Gordon
I
I
Blaese
R M
RM
Dunbar
C E
CE
Leitman
S
S
Malech
H L
HL
D000243:Adenosine Deaminase / Q000172:deficiency*; D000293:Adolescent; D000328:Adult; D000368:Aged; D018952:Antigens, CD34 / Q000032:analysis; D001853:Bone Marrow / Q000187:drug effects*; D001854:Bone Marrow Cells; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D006105:Granulomatous Disease, Chronic / Q000097:blood* / Q000473:pathology / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D007958:Leukocyte Count / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D012680:Sensitivity and Specificity; D016511:Severe Combined Immunodeficiency / Q000097:blood* / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000628:therapy; D013997:Time Factors
D018952:Antigens, CD34; D016179:Granulocyte Colony-Stimulating Factor; D000243:Adenosine Deaminase