A comparative study of once‐daily versus twice‐daily filgrastim administration for the mobilization and collection of CD34+ peripheral blood progenitor cells in normal donors

Article (PDF Available)inBritish Journal of Haematology 109(4):770 - 772 · June 2000with17 Reads
DOI: 10.1046/j.1365-2141.2000.02083.x
Abstract
Eighty-one first-time normal donors underwent leukapheresis for peripheral blood progenitor cell (PBPC) collection after mobilization with filgrastim administered either twice-daily (6 µg/kg every 12 h; n = 40) or once-daily (12 µg/kg; n = 41) subcutaneously for 3 d. The groups were similar for age, donor blood volume and target CD34+ cell dose to be collected (≥ 4 × 106 CD34+ cells/kg recipient). There was no statistically significant difference in the apheresis yield of CD34+ PBPCs (× 106) per kg recipient weight (5·6 ± 3·3 vs. 5·6 ± 4·3; P = 0·94) and per litre of blood processed (30 ± 17·2 vs. 30·4 ± 19·5; P = 0·92).
770 q 2000 Blackwell Science Ltd
SHORT REPORT
A comparative study of once-daily versus twice-daily filgrastim
administration for the mobilization and collection of CD34
1
peripheral blood progenitor cells in normal donors
Paolo Anderlini, Michele Donato, Mary J. Lauppe, Yang O. Huh, Thomas G. Martin, Ka-Wah Chan,
Richard E. Champlin and Martin Ko
È
rbling Department of Blood and Marrow Transplantation and Laboratory
Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
Received 14 November 1999; accepted for publication 31 January 2000
Summary. Eighty-one first-time normal donors under-
went leukapheresis for peripheral blood progenitor cell
(PBPC) collection after mobilization with filgrastim
administered either twice-daily (6 mg/kg every 12 h;
n 40) or once-daily (12 mg/kg; n 41) subcutaneously
for 3 d. The groups were similar for age, donor blood
volume and target CD34
1
cell dose to be collected
($ 4 10
6
CD34
1
cells/kg recipient). There was no
statistically significant difference in the apheresis yield of
CD34
1
PBPCs ( 10
6
) per kg recipient weight (5´6 ^ 3´3
vs. 5´6 ^ 4´3; P 0´94) and per litre of blood processed
(30 ^ 17´2 vs. 30´4 ^ 19´5; P 0´92).
Keywords: peripheral blood progenitor cell mobilization,
filgrastim, normal donors, granulocyte colony-stimulating
factor, leukapheresis.
Recombinant human granulocyte colony-stimulating factor
(rhG-CSF)-mobilized peripheral blood progenitor cells
(PBPCs) are increasingly accepted as an alternative to
marrow for allogeneic transplantation (Goldman, 1995;
Russell et al, 1998; Appelbaum, 1999). The optimal dose
and schedule of administration for rhG-CSF in PBPC donors
are still being defined. Much of the attention has been
devoted to the rhG-CSF dose (HoÈglund et al, 1996; Stroncek
et al, 1996). Although most centres use once-daily rhG-CSF
administration, some investigators have recommended a
twice-daily schedule (Arbona et al, 1998; KroÈger et al,
1999). We report our experience in this area.
DONORS AND METHODS
Normal apheresis donors. Between April and mid-October
1999, a total of 81 consecutive first-time normal donors
received filgrastim before leukapheresis for collection of
PBPCs for allogeneic transplantation. Donors whose apheresis
products underwent complex processing immediately after
collection and second PBPC donations were not included in
this study. Protocols for collection of PBPCs for transplanta-
tion were approved by the Institutional Review Board of the
University of Texas M. D. Anderson Cancer Center, and
written informed consent was obtained from each donor.
Mobilization. The donors received an actual filgrastim
dose of either 6 mg/kg subcutaneously (s.c.) every 12 h for
3 d (April to June 1999; group A; n 40) or 12 mg/kg s.c.
daily for 3 d (July to mid-October 1999; group B; n 41).
Our overall experience with this (12 mg/kg) daily dose of
filgrastim in PBPC donors has been recently published
(Anderlini et al, 1999). On the morning of day 4, all donors
received a 6-mg/kg dose of filgrastim s.c. at least 1±2 h
before the first leukapheresis to provide a similar cumulative
filgrastim dose. Filgrastim was then continued once- or
twice-daily (at the discretion of the apheresis physician)
through completion of the PBPC collection.
Leukapheresis. Leukapheresis was performed using a Cobe
Spectra blood cell separator through bilateral peripheral
venous access. The target amount of blood to be processed
in both groups (at least during the first procedure) was set
at three times the donor's total blood volume (TBV). The
target PBPC dose to be collected was $ 4 10
6
CD34
1
cells/kg recipient body weight. Apheresis was performed
daily until the target dose was reached. The details of
British Journal of Haematology 2000, 109, 770±772
Correspondence: Paolo Anderlini, The University of Texas M. D.
Anderson Cancer Center, Department of Blood and Marrow
Transplantation, 1515 Holcombe Boulevard ± Box 24, Houston,
TX 77030, USA. E-mail: panderli@mail.mdanderson.org
immunophenotyping of the apheresis product have been
published previously (Anderlini et al, 1997). The apheresis
yields were expressed as number (n) of CD34
1
cells both per
kg of recipient and per litre of blood processed (first
apheresis) to compensate for possible differences between
the groups in donor weight and/or blood volume, as well as
apheresis duration.
Statistical analysis. Continuous variables are presented as
means ^ 1SD and were compared by two-tailed Student or
alternate t-tests. Comparisons between proportions were
performed with the Fisher's exact test. A two-tailed P-value
less than 0´05 was considered statistically significant.
RESULTS
PBPC donor demographics
The two groups were similar for donor age (group A
43 ^ 16 years vs. group B 44 ^ 13 years, P 0´59).
They were also similar for donor sex (group A male±female
20:20 vs. group B male±female 20:21).
Filgrastim-related haematological effects
The preapheresis leucocyte count in group A was slightly
higher than in group B (group A 44´5 ^ 12´6 vs. group B
39´5 ^ 13´7 10
9
/l; P 0´09).
PBPC collection and immunophenotyping data
Collection data and immunophenotyping analysis on the
apheresis product of the first procedure are displayed in
Table I. The donor total blood volume (estimated on the
basis of donor sex, height and weight) and the number of
total blood volumes processed (first apheresis) were similar
in the two groups. There was no statistically significant
difference between the two groups with regard to the
apheresis yield of CD34
1
progenitor cells (Table I). A similar
percentage of donors reached the collection target with one
procedure (group A 25:40 vs. group B 23:41; P 0´65).
DISCUSSION
The optimal dose and schedule for rhG-CSF administration
in normal donors for PBPC mobilization and collection has
not been determined. There is evidence supporting a dose±
response relationship (Hoglund et al, 1996; Stroncek et al,
1996). Whether a once-daily or a twice-daily schedule is
more effective is unclear. The rationale for twice-daily
administration is largely based on the fact that peak plasma
levels of rhG-CSF are reached about 4 h after a sub-
cutaneous filgrastim injection and decline thereafter (de
Haas et al, 1994). On the other hand, rhG-CSF plasma levels
remain elevated above baseline (about sixfold) at 24 h after
injection (de Haas et al, 1994), and filgrastim-induced
neutrophilia can last as long as 48 h after filgrastim
administration (de Haas et al, 1994). In one study, the
circulating levels of CD34
1
progenitors did not start to
decline until 5 d after single-dose filgrastim administration
(Schwinger et al, 1993).
The clinical studies published so far have been largely
inconclusive, either because of inadequate sample size (Yano
et al, 1997) or because they used different total daily rhG-
CSF doses (Arbona et al, 1998). In a report on breast cancer
patients starting leukapheresis on day 5 of filgrastim
administration, German investigators found that the split
dose schedule was more effective (Kroger et al, 1999).
However, the nature of the subjects treated, their previous
chemotherapy and radiation exposure, the use of historical
controls and the lack of data on PBPC apheresis yield per
litre of blood processed all make interpretation of their
results difficult.
To our knowledge, this study represents the largest
undertaken so far on this issue. Its sequential, although
not randomized, nature should minimize the bias related to
the use of historical controls. Our data suggest that both
filgrastim administration schedules are similarly effective for
the mobilization and collection of CD34
1
progenitor cells in
normal donors, at least when daily leukapheresis begins on
day 4 of filgrastim mobilization. In conclusion, we were
unable to show any significant advantage of twice-daily
filgrastim administration over a presumably simpler, more
convenient and `donor-friendly' once-daily schedule.
ACKNOWLEDGMENTS
We wish to thank the nurses of Station 73 (Blood and
Marrow Transplantation Clinic) and Station 79 (Apheresis),
particularly Cherlita Samaniego, for their assistance in the
education and care of the donors in this study. We also
thank Ms. Audria Winn for her secretarial assistance.
Table I. Collection and immunophenotyping data.
Variable Group A (n 40) 6 2/d Group B (n 41) 12 1/d P-value
Donor TBV (l) 4´6 ^ 1´3 4´9 ^ 0´9 0´32
No. of TBVs processed 2´8 ^ 0´2 2´8 ^ 0´3 0´66
CD34
1
( 10
6
cells/kg recipient)* 5´6 ^ 3´3 5´6 ^ 4´3 0´94
CD34
1
( 10
6
cells/l blood processed)* 30 ^ 17´2 30´4 ^ 19´5 0´92
Group A, filgrastim 6 mg/kg subcutaneously (s.c.) twice daily 3; group B, filgrastim 12 mg/kg s.c. daily 3. Both groups
received a 6-mg/kg filgrastim dose on the morning of the first apheresis.*First apheresis.TBV, total blood volume.Values
presented as means ^ SD.
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Short Report 771
REFERENCES
Anderlini, P., Przepiorka, D., Seong, D., Smith, T.L., Huh, Y.O.,
Lauppe, J., Champlin, R. & KoÈrbling, M. (1997) Factors affecting
mobilization of CD34
1
cells in normal donors treated with
filgrastim. Transfusion, 37, 507±512.
Anderlini, P., Donato, M., Chan, K.-W., Huh, Y.O., Gee, A.P., Lauppe,
M.J., Champlin, R.E. & Korbling, M. (1999) Allogeneic blood
progenitor cell collection in normal donors after mobilization
with filgrastim: the M. D. Anderson Cancer Center experience.
Transfusion, 39, 555±560.
Appelbaum, F.R. (1999) Choosing the source of stem cells for
allogeneic transplantation: no longer a peripheral issue. Blood,
94, 381±383.
Arbona, C., Prosper, F., Benet, I., Mena, F., Solano, C. & Garcia-
Conde, J. (1998) Comparison between once a day vs twice a day
G-CSF for mobilization of peripheral blood progenitor cells (PBPC)
in normal donors for allogeneic transplantation. Bone Marrow
Transplantation, 22, 39±45.
Goldman, J. (1995) Peripheral blood stem cells for allografting.
Blood, 85, 1413±1415.
de Haas, M., Kerst, J.M., van der Schoot, C., Calafat, J., Hach, C.E.,
Nuijens, J.H., Roos, D., van Oers, R.H.J. & dem Borne, E.G.K.
(1994) Granulocyte colony-stimulating factor administration to
healthy volunteers: analysis of the immediate activating effect on
circulating neutrophils. Blood, 84, 3885±3894.
HoÈglund, M., Smedmyr, B., Simonsson, B., ToÈtterman, T. &
Bengtsson, M. (1996) Dose-dependent mobilisation of
haematopoietic progenitor cells in healthy volunteers receiving
glycosylated rHuG-CSF. Bone Marrow Transplantation, 18, 19±27.
KroÈger, N., Zeller, W., Hassan, H.T., Kru
È
ger, W., Gutensohn, K.,
LoÈliger, C. & Zander, A.R. (1999) Stem cell mobilization with G-
CSF alone in breast cancer patients: higher progenitor cell yield
by delivering divided doses (2 5 mcg/kg) compared to a single
dose (1 10 mcg/kg). Bone Marrow Transplantation, 23, 125±
129.
Russell, N.H., Gratwohl, A. & Schmitz, N. (1998) Developments in
allogeneic peripheral blood progenitor cell transplantation.
British Journal of Haematology, 103, 594±600.
Schwinger, W., Mache, C., Urban, C., Beaufort, F. & Toglhofer, W.
(1993) Single dose of filgrastim (rhG-CSF) increases the number
of hematopoietic progenitors in the peripheral blood of adult
volunteers. Bone Marrow Transplantation, 11, 489±492.
Stroncek, D.F., Clay, M.E., Petzoldt, M.L., Smith, J., Jaszcz, W.,
Oldham, F.B. & McCullough, J. (1996) Treatment of normal
individuals with granulocyte-colony-stimulating factor: donor
experiences and the effects on peripheral blood CD341 cell
counts and on the collection of peripheral blood stem cells.
Transfusion, 36, 601±610.
Yano, T., Katayama, Y., Sunami, K., Deguchi, S., Nawa, J.,
Hiramatsu, Y., Nakayama, H., Arakawa, T., Ishimaru, F.,
Teshima, T., Shinagawa, K., Omoto, E. & Harada, M. (1997) G-
CSF-induced mobilization of peripheral blood stem cells for
allografting: comparative study of daily single versus divided
dose of G-CSF. International Journal of Hematology, 66, 169±178.
772 Short Report
q 2000 Blackwell Science Ltd, British Journal of Haematology 109: 770±772
    • In both autologous and allogeneic HSC transplantations, G-CSF is given for four consecutive days with apheresis beginning on the fifth day. Once daily schedule of G-CSF is found to have similar outcomes with twice daily dosing[43]. The time to begin G-CSF was also assessed in previous studies.
    [Show abstract] [Hide abstract] ABSTRACT: Hemotopoietic stem cell mobilization with cytokines alone, has still been widely accepted as the initial attempt for stem cell mobilization. Chemotherapy based mobilization can be preferred as first choice in high risk patients or for remobilization. But mobilization failure still remains to be a problem in one third of patients. Salvage mobilization strategies have been composed to give one more chance to 'poor mobilizers'. Synergistic effect of a reversible inhibitor of CXCR4, plerixafor, with G-CSF has opened a new era for these patients. Preemptive approach in predicted poor mobilizers, immediate salvage approach for patients with suboptimal mobilization or remobilization approach of plerixafor in failed mobilizers have all been demonstrated convincing results in various studies. Alternative CXCR4 inhibitors, VLA4 inhibitors, bortezomib, parathormone have also been emerged as novel agents for mobilization failure. J. Clin. Apheresis, 2015. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
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