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Blood, Vol. 91 No. 9 (May 1), 1998:
pp. 3148-3155
High CD34+ Cell Counts Decrease Hematologic Toxicity of
Autologous Peripheral Blood Progenitor Cell Transplantation
By
Nicolas Ketterer,
Gilles Salles,
Michel Raba,
Daniel Espinouse,
Anne Sonet,
Pierre Tremisi,
Charles Dumontet,
Isabelle Moullet,
Assia Eljaafari-Corbin,
Eve-Marie Neidhardt-Berard,
Fadhela Bouafia, and
Bertrand Coiffier
From the Service d'Hématologie, Centre Hospitalier Lyon-Sud,
Hospices Civils de Lyon and UPRES-JE 1879 "Hémopathies
Lymphoïdes malignes", Université Claude Bernard,
Pierre-Bénite; and Etablissement de Transfusion Sanguine de Lyon,
Lyon, France.
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ABSTRACT |
Optimal numbers of CD34+ cells to be reinfused in
patients undergoing peripheral blood progenitor cell (PBPC)
transplantation after high-dose chemotherapy are still unknown.
Hematologic reconstitution of 168 transplantations performed in
patients with lymphoproliferative diseases was analyzed according to
the number of CD34+ cells reinfused. The number of days
from PBPC reinfusion until neutrophil recovery (>1.0 × 109/L) and unsustained platelet recovery (>50 × 109/L) were analyzed in three groups defined by the number
of CD34+ cells reinfused: a low group with less than or
equal to 2.5 × 106 CD34+ cells/kg, a high
group with greater than 15 × 106 CD34+
cells/kg, and an intermediate group to which the former two groups were
compared. The 22 low-group patients had a significantly delayed neutrophil (P < .0001) and platelet recovery (P < .0001). The 41 high-group patients experienced significantly shorter
engraftment compared with the intermediate group with a median of 11 (range, 8 to 16) versus 12 (range, 7 to 17) days for neutrophil
recovery (P = .003), and a median of 11 (range, 7 to 24)
versus 14 (range, 8 to 180+) days for platelet recovery (P < .0001). These patients required significantly less platelet
transfusions (P = .002). In a multivariate analysis, the
amount of CD34+ cells reinfused was the only variable
showing significance for neutrophil and platelet recovery. High-group
patients had a shorter hospital stay (P = .01) and tended to
need fewer days of antibotic administration (P = .12). In
conclusion, these results suggest that reinfusion of greater than 15 × 106 CD34+ cells/kg after high-dose
chemotherapy for lymphoproliferative diseases further shortens
hematopoietic reconstitution, reduces platelet requirements, and may
improve patients' quality of life.
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INTRODUCTION |
THE PLACE OF high-dose chemotherapy with
autologous stem cell support has been well established these last years
in a number of selected hematologic malignancies.1-5 The
use of mobilized peripheral blood progenitor cells (PBPC) has replaced
conventional bone marrow transplantation and is nowadays the main
source for hematopoietic rescue.6 This change in stem cell
source has many reasons, including ease of collection and more rapid
hematologic recovery with PBPC compared with bone
marrow.7-9 Moreover, PBPC may constitute the only available
source of hematopoietic stem cells when bone marrow is hypoplastic
because of numerous previous treatments or pelvic
irradiation10 and may eventually reduce the risk of tumor
cell contamination.11,12
Until a few years ago, mononuclear cell (MNC) count, as well as
determination of colony-forming unit-granulocyte-macrophage (CFU-GM)
yield, were commonly the most useful indicators of harvest quality.13-15 Unfortunately, this last assay was poorly
standardized and poorly reproducible between different laboratories and
thus not always comparable from one institution to
another.16 The determination by flow cytometry of the
subset of peripheral blood cells expressing the CD34 antigen
(CD34+ cells) is commonly used today to assess the
progenitor cell content and correlates quite well with the progenitors
assays.17 Moreover, the CD34+ cell count has
been shown to be a good predictor of engraftment kinetics, especially
for platelets.18-20 The optimal level of CD34+
cell count to be reinfused has still not been well determined, even if
some investigators have proposed 2 or 2.5 × 106
cells/kg as the minimal threshold for rapid
reconstitution,6,21,22 with a greater risk for delayed
platelet engraftment under this limit.21,23 However, other
factors like prior chemotherapy regimens have also been shown to
predict time to engraftment in some reports.24
If an agreement usually exists concerning the need of a minimal number
of CD34+ cell count to be reinfused after high-dose
chemotherapy, the level of the optimal threshold has not yet been
determined. Few trials including large numbers of homogeneous patients
are available and the hypothetical benefit of a higher threshold is
still unknown. To assess this question, we retrospectively analyzed 168 consecutive high-dose therapy regimens with PBPC transplantations
performed for lymphoproliferative diseases between June 1994 and
December 1996, and we explored in these patients the role of the amount of CD34+ cells reinfused on hematopoietic reconstitution.
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MATERIALS AND METHODS |
Patients.
Between June 1994 and December 1996, 153 patients (97 men, 56 women)
with a median age of 49 years (range, 15 to 66) were treated at the
Centre Hospitalier Lyon-Sud with high-dose therapy and PBPC transplant
for lymphoproliferative diseases (Table 1). Approval was obtained from
the Institutional Review Board for these studies. Informed consent was
provided according to the Declaration of Helsinki. Patients were
selected for intensive chemotherapy because of first line treatment
failure for Hodgkin's disease (HD) or non-Hodgkin's lymphoma (NHL),
because of NHL with two or three unfavorable prognostic criteria
according to the age-adjusted International Prognosis Index (IPI) at
diagnosis,25 or because of stage 3 multiple myeloma (MM).
Additional inclusion criteria included an Eastern Cooperative Oncology
Group (ECOG) performance status less than 2 and evidence of adequate
hepatic, renal, and cardiac function.
Among the 153 patients analyzed, 15 were treated twice with high-dose
therapy. Two patients (one NHL and one HD) received two PBPC
transplantations because of relapse more than 1 year after a first
intensification, whereas 13 patients received a sequential
intensification with two PBPC reinfusions (Table 1). Considering that
the main aim of this study was to evaluate the influence of the
CD34+ cell count in the harvest on engraftment, we took
into account in this analysis the total of the 168 PBPC
transplantations performed during this period. However, for response
and survival assessment, each sequential intensification was analyzed
only once. In both patients who received a second PBPC transplantation
because of a relapse after a first intensification, only the first PBPC
transplant was considered for response and survival evaluation.
Disease status was assessed at harvest with physical examination and
computerized tomography (CT) scan. Bone marrow biopsy was performed in
all but three patients who had a previous bone marrow involvement. When
patients had no previous history of tumor cell bone marrow involvement
and achieved partial or complete remission before transplant, bone
marrow was considered as being not involved at time of transplant. Bone
marrow infiltration by lymphoma was designated as minimal when tumor
cells represented less than 10% of the biopsy.
Mobilization regimen and collection of PBPC.
PBPC were collected in 109 patients after high-dose chemotherapy
consisting of cyclophosphamide 5.25 g/m2 alone or
cyclophosphamide 4.5 g/m2 plus etoposide 450 mg/m2, the cytostatic agents being given in both regimens
in three divided doses over 24 hours, followed by the administration of a hematopoietic growth factor, granulocyte colony-stimulating factor
(G-CSF), or GM-CSF. Thirty-seven patients were mobilized with standard
chemotherapy and growth factor, generally consisting in the last course
of induction regimen and seven patients had a mobilization with G-CSF
alone. When a second mobilization procedure was needed, the second
harvest was collected after mobilization with G-CSF alone at doses of 5 to 20 µg/kg/d.
Leukaphereses usually started on the first day when leukocyte count in
the peripheral blood reached 1.0 × 109/L. Since June
1996, daily measurements of peripheral blood CD34+ cells
were performed and leukaphereses started when this count reached
20/µL. When platelet count was less than 30 × 109/L
on the day before the first leukapheresis, patients were transfused with irradiated platelets. When mobilization was performed with hematologic growth factor alone, leukaphereses started on the fifth day
of their administration. Leukaphereses were achieved with
continuous-flow blood cell separators, Baxter CS3000 (Baxter Healthcare
Ltd, Berkshire, UK) or COBE Spectra (COBE Laboratories Ltd, Gloucester,
UK). The total volume processed in each leukapheresis was between 2 to
3 blood mass volume at a flow rate of 40 to 60 mL/minute. Aphereses
were usually performed until enough cells were collected to ensure the
harvest of 2.5 × 106 CD34+ cells/kg to be
reinfused, given an eventual loss of 20% of the cells after thawing.
The median number of leukaphereses per harvest was three (range, 1 to
6). The final product was then cryopreserved in the patient's serum
with 10% dimethyl sulfoxide (DMSO) in the vapor phase of liquid
nitrogen.
Measurement of progenitor cell content.
The percentage of CD34+ cells in thawed apheresis
suspensions was determined using three parameter flow cytometry using
side scatter, CD34-phycoerythrin (PE) and CD45 fluorescein
isothiocyanate (FITC), as previously reported by Donaldson et
al.26 Briefly, 50 µL of each suspension was incubated
with PE-conjugated anti-CD34 monoclonal antibody (MoAb) (Human
Progenitor Cell Antigen-2 [HPCA-2]; Becton Dickinson, Oxford, UK) and
FITC-conjugated anti-CD45 MoAb (Becton Dickinson) for 30 minutes at
4°C. A control sample was labelled with PE-conjugated
IgG1 and FITC-conjugated IgG1 MoAb. After
incubation, red blood cells were lysed with fluorescence-activated cell
sorting (FACS) lysing solution (Becton Dickinson) and washed twice with
phosphate-buffered saline. Flow cytometry was performed using the
FACScan (Becton Dickinson, Mountain View, CA). Initial gating to
exclude CD45 negative events was performed and only CD34+,
CD45+ events with low side scatter were considered to be
progenitor cells. In the CD45+ gate, 50,000 events were
acquired. The absolute numbers of CD34+ hematopoietic
progenitor cells were calculated by multiplying the percentage of
positive cells by the total nucleated cell content, as determined by
conventional automated cell counting (Minos STX, ABX
International, Paris, France).
Before August 1995, the clonogenic assays for CFU-GM were not uniform
in all patients. After this period, clonogenic assays were performed
using the Methocult SFH 4435 (Terry Fox Laboratories, Vancouver,
Canada). Cells were seeded at 40 × 103 cells/plate on
each of two culture dishes (3 × 35 mm) and the dishes were
incubated at 37°C in a 5% CO2 humidified incubator. The growth of CFU-GM was scored on day 14.
Conditioning regimen.
Fifty-nine patients (35%) received total body irradiation
(TBI)-containing conditioning regimens, which consisted of
cyclophosphamide 120 mg/kg, etoposide 900 mg/m2, and 10 Gy
fractionated TBI in 49 cases and melphalan 140 mg/m2
combined with 10 to 12 Gy fractionated TBI in 10 cases. A
total of 109 patients (65%) received conditioning regimens without
TBI, which consisted of carmustine 300 mg/m2, etoposide 800 mg/m2, aracytine 800 mg/m2, and melphalan 140 mg/m2 (BEAM) in 68 patients, melphalan 200 mg/m2 in 18 patients, ICE (ifosfamide 12 g/m2,
carboplatine 1,500 mg/m2, and etoposide 1,500 mg/m2) in 18 patients, and other regimens in five patients.
PBPC were reinfused 2 days after the last day of chemotherapy in BEAM
or melphalan regimens and 3 days after ICE therapy. In case of
cyclo/etoposide/TBI or melphalan/TBI, PBPC were reinfused on the last
day of irradiation. All but two patients received a hematopoietic
growth factor (G- or GM-CSF) after PBPC transplant, which was
discontinued when neutrophil count was greater than 1.0 × 109/L.
Toxicity.
Hematologic toxicity was defined from the day of the PBPC reinfusion
(day 0). The time to absolute neutrophil count (ANC) greater than 0.1, 0.5, or 1.0 × 109/L was defined as the number of days
from day 0 for the neutrophils to increase and to be stable at least 3 days over these values. The time to platelets over 20, 50, or 100 × 109/L was defined as the number of days for
platelets to be stable over these values without any transfusions.
Platelets were routinely transfused in case of thrombopenia under 20 × 109/L or when hemorrhage occurred and consisted
mainly of single donor apheresis product. Transfusions of red blood
cell units were performed when hemoglobin values decreased to less than
80 g/L, or above this limit when symptomatic anemia occurred. The total
number of blood products administered was registered during the entire
hospital stay and during the 2 months after reinfusion of PBPC.
Duration of hospital stay was determined from day 0 until discharge of the patient from the sterile unit or from any specialized medical unit. Antibiotherapy was given for any clinical or
microbiological infection, or for a persistent undocumented fever above
38°C.
Response.
Response assessment was evaluated at harvest, then 3 months after
transplant with clinical examination, CT scan, bone marrow aspirate,
and biopsy. A complete response (CR) was defined as the disappearance
of all sites of disease including bone marrow. Partial response (PR)
was defined as a reduction of more than 50% in the product of the two
largest diameters of each measurable lesion, or as the persistence of
bone marrow infiltration as the only residual site of disease. Stable
disease (SD) was defined as a reduction of less than 50% in these
measures. Progressive disease (PD) was defined as the appearance of a
new lesion or as the increase in size of any preexistent lesion.
Statistical analysis.
Distributions of clinical characteristics or variables among patient
subgroups as defined by the number of CD34+ cells reinfused
were compared using the Pearson chi-squared test. Patients who had not
achieved a platelet count of 20, 50, or 100 × 109/L
at day 180 were designated as 180+ in the median range. Patients who
died before engraftment were censored on the date of death and were
designated on the graphs by a plus sign. Rates of neutrophil and
platelet recovery were estimated using the product-limit method of
Kaplan-Meier and compared using a log-rank test. Associations between
prognostic factors and hematopoietic recovery were evaluated using a
log-rank test. Multivariate analyses were performed using the Cox
hazards regression model. The supportive care was graded using the
number of red blood cells and platelet units transfused, the length of
antibiotic administration, and hospital stay, and the differencies
among subgroups were assessed using the Mann-Whitney U test.
| |
RESULTS |
Patient characteristics.
Of the 168 transplantations performed, three groups of patients were
constituted according to the number of CD34+ cells
reinfused (Table 1). First, the upper
quartile of the distribution of CD34+ cells reinfused was
arbitrarily identified and included 41 patients (24%) who received
greater than or equal to 15 × 106 CD34+
cells/kg. This group was designated as the high CD34+
group. Patients who did not receive the number considered as a safe
threshold (>2.5 × 106 CD34+
cells/kg) were then identified. These 22 patients (13%) who were still
intensified because of the adverse prognosis of their disease constituted the low CD34+ group. The remaining 105 patients
(63%) composed the intermediate CD34+ group and received
greater than 2.5 × 106, but less than 15 × 106 CD34+ cells/kg. The intermediate
CD34+ group was then considered as the reference group to
which either the low CD34+ group or the high
CD34+ group were respectively compared.
Table 2 shows the most important
characteristics of patients at transplant and their distribution
according to the reinfused CD34+ cell count. When compared
with the intermediate group, the low group was characterized by a
significantly higher number of patients who received at least 6 months
of chemotherapy (73% v 45%, P = .02), and by more
patients previously treated with fludarabine (27% v 9%,
P = .01). When compared with the intermediate group, less
patients in the high group had received at least three previous chemotherapy regimens (27% v 49%, P = .02). No other
variables related to previous treatment and to disease status at
transplant were significantly different in the three patient subgroups.
The proportion of patients receiving TBI-containing regimens did not
differ significantly between the three groups (P = .44). After
reinfusion of PBPC, growth factors (G-CSF in 107 patients, GM-CSF in 59 patients) were started at day 1 (n = 31), day 7 (n = 130), or later (n = 5) for a median time of 6 days (range, 1 to 17). Two patients did not
receive any growth factor. Onset of hematopoietic growth factor
administration was not significantly different in these three
subgroups. However, when compared with the intermediate group, patients
reinfused with a low number of CD34+ cells had a longer
period of growth factor administration (median of 9 days v 6 days, P = .009), while the difference was not significant when
compared with the high CD34+ group (median, 5 days;
P = .18).
PBPC reinfused.
Considering the total group of patients, the median count of MNC and
CD34+ cells reinfused were respectively 3.6 × 108/kg and 6.86 × 106/kg (Table 2). The
median number of CFU-GM, evaluated for the last 100 patients with the
Methocult assay was 114 × 104/kg. The median numbers
of CD34+ cells reinfused in the three subgroups were
respectively 1.5, 5.85, and 21.6 × 106/kg, whereas
interestingly, the median numbers of MNC reinfused were very similar.
Hematopoietic recovery.
Table 3 shows for all patients and for the
three CD34+ cell dose subgroups the median time, range,
10th and 90th percentile of neutrophil and platelet recovery. The
median time to achieve an ANC greater than 0.1, 0.5, or 1.0 × 109/L was respectively 10, 11, and 12 days. In the low
CD34+ group patients, the median time to achieve a
neutrophil count greater than 1.0 × 109/L was 1 day
longer as compared with the intermediate-group patients, a difference
which is still highly significant (P < .0001). When compared
with the intermediate CD34+ group, higher CD34+
cell dose allowed to significantly further shorten neutrophil engraftment by 1 day (P = .003). The probability of achieving an ANC greater than 1.0 × 109/L according to the
three CD34+ cell counts is shown in Fig 1.
As shown in Table 3, when the thresholds of 0.1 and 0.5 ANC were
considered, the differences between the groups were essentially similar
and significant. The median time to achieve an unsustained platelet
count greater than 20, 50, or 100 × 109/L was
respectively 10, 14, and 17 days for all patients. The difference for
the three thresholds was highly significant between each group (P
< .0001). Figure 2 shows the probability of
achieving a platelet count greater than 50 × 109/L
according to the CD34+ cell count reinfused. Moreover, 81%
of the intermediate-group patients achieved a platelet count greater
than 100 × 109/L at day 30 as compared with 28% of
the low and 97% of the high-group patients (P < .0001 and
=.01, respectively). When considering patients evaluated at day 100 (n = 141), significantly more patients failed to recover 50 or 100 × 109/L platelets in the low group as compared with the
intermediate group (20% v 2% and 60% v 18%,
P = .002 and .0001, respectively). When comparing the high and
the intermediate groups, the proportion of patients below the 50 or 100 × 109/L platelet thresholds was 0% versus 2% and
3% versus 14% (P = .4 and .058, respectively).
View larger version (12K):
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| Fig 1.
Time to recovery to an ANC greater than 1.0 × 109/L in intermediate CD34+ group patients
(dashed line) compared with low CD34+ group patients
(solid line) (P < .0001) and with high CD34+
group patients (dotted line) (P = .003). Of note, the time is shown on a logarithmic scale.
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View larger version (13K):
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| Fig 2.
Time to recovery to a platelet count greater than 50 × 109/L in intermediate CD34+ group patients
(dashed line) compared with low CD34+ group patients
(solid line) (P < .0001) and with high CD34+
group patients (dotted line) (P < .0001). Of note, the time
is shown on a logarithmic scale.
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Factors influencing hematopoietic recovery.
When comparing the low and intermediate groups, CD34+ cell
dose was in univariate analysis a significant factor (P < .0001) influencing neutrophil recovery (Table 4). The
other significant variables were the duration of cumulative treatments
before harvest (P = .003), the line of treatment (P =
.04), and the previous use of fludarabine (P = .03), whereas
alkylating agents exposure was of borderline significance (P = .059). The CD34+ cell dose was the only variable
significantly influencing platelet recovery (P < .0001). These five variables were then considered for multivariate
regression analysis. When comparing the low and intermediate-group
patients, CD34+ cell dose remained the only independent
variable significantly influencing neutrophil recovery (P =
.02).
When comparing the high group and intermediate groups, the
CD34+ cell dose was the only variable showing significance
in univariate analysis for neutrophil and platelet engraftment (P
= .003 and < .0001, respectively), and multivariate analysis was
therefore not performed.
The analysis of factors influencing hematopoietic recovery was
essentially similar when other thresholds for platelet (20 or 100 × 109/L) or neutrophil (0.1 or 0.5 × 109/L) recovery were considered (not shown).
Supportive care and clinical toxicity.
Table 5 shows the influence of the amount
of CD34+ cells reinfused on patients' supportive care. The
median number of red blood cell transfusions was not significantly
different between the three subgroups. In contrast,
patients in the intermediate CD34+ group required a median
number of two platelet transfusions, as compared with three for the low
group and one for the high-group patients (P = .001 and .002, respectively). When compared with the intermediate group, the median
time of antibiotic administration was 2 days longer in the low group
and 1 day shorter in the high group (P = .009 and .12, respectively). Furthermore, when compared with the intermediate group,
low-group patients had a longer hospital stay, whereas high-group
patients had a significantly shorter hospital stay (P = .0002 and .01, respectively).
Considering all other nonhematologic toxicities, we did not observe any
significant differences between the three subgroups of patients (not
shown), except for infections that occured within the 30 days after
PBPC transplantation in 41% of the low group as compared with 21% of
the intermediate-group patients (P = .05).
We observed four treatment-related deaths. In the low CD34+
group, one patient reinfused with 1.62 × 106
CD34+ cells/kg died of intracerebral bleeding at day 97. In
the intermediate CD34+ group, three patients died of
treatment-related toxicity, two early (one of fatal cardiac failure and
one after venoocclusive disease) and one at day 105 of septicemia.
Response and survival.
Three months after transplant, 150 patients were assessable for
response and three had died. Ninety-six patients (63%) achieved a CR,
30 (20%) a PR, three (2%) had a SD and 21 patients (14%) relapsed.
At the time of analysis, 48 patients (31%) had progressed. The median
follow-up for these patients was 14 months, but it was at least 6 months for all patients without relapse. To assess the potential
influence of the CD34+ cell count reinfused on disease
outcome, we examined in each group the rate of early relapses defined
as disease progression within 6 months after the reinfusion of PBPC.
Among the 24 patients who progressed during this period, we observed
four early relapses (18%) in the low CD34+ group as
compared with 15 (14%) in the intermediate CD34+ group
(P = .89) and five (12%) in the high CD34+ group
(P = .79).
| |
DISCUSSION |
This report analyzes the influence of the amount of reinfused
CD34+ cells on hematologic recovery in 168 intensified
patients. Among them, 22 (13%) received less than or equal to
2.5 × 106 CD34+ cells/kg, a
level lower than our planned threshold, whereas 41 (24%) received
CD34+ cell doses greater than 15 × 106/kg.
The present study confirms that patients who received less than or
equal to 2.5 × 106 CD34+ cells/kg had
significantly later hematopoietic engraftment when compared with those
receiving greater than 2.5 × 106 cells/kg. In a trial
including 61 patients, Haas et al18 had already shown that
a dose of at least 2.5 × 106 CD34+
cells/kg was required for a safe engraftment. Bensinger et
al19 have proposed the same minimal threshold, but
suggested that a higher limit value could be better for platelet
recovery. Other investigators have recommended a minimal threshold of 2 × 106 CD34+ cells/kg to provide rapid
engraftment.21,22 Only a small study found no correlation
between CD34+ cell count and platelet recovery, but
consisted of no more than two patients receiving less than 2.5 × 106 CD34+ cells/kg.27 In the
present study, a significant proportion of patients reinfused with less
than or equal to 2.5 × 106 CD34+ cells/kg
experienced delayed hematologic recovery, particularly significant for
platelets, with a median time that was 5 days longer to achieve an
unsustained platelet count greater than 50 × 109/L. Even if an absolute value cannot be determined, the
definition of a minimal threshold is probably clinically helpful,
considering that 95% of the present patients receiving more than 2.5 × 106 CD34+ cells/kg achieved an ANC
greater than 1.0 × 109/L in less than 15 days and an
unsustained platelet count greater than 20 × 109/L in
less than 14 days. However, as already reported,23 this data confirms that PBPC transplant is still feasible with moderate toxicities even for patients with lower CD34+ cell dose in
harvest. This option must therefore always be weighed with the patient
considering the potential benefit provided by intensified treatment, as
compared with the increased risk of delayed platelet engraftment and
longer hospitalization.
The most interesting point of this report is to indicate that after
excluding the patients reinfused with less than or equal to 2.5 × 106 CD34+ cells/kg from the analysis, patients
reinfused with a very high CD34+ cell dose showed better
hematopoietic engraftment and especially faster platelet recovery.
Until now, no study had clearly shown that reinfusion of a high number
of CD34+ cells could bring an additional clinical benefit,
as compared with the reinfusion of an adequate progenitor cell count.
Kiss et al20 reported in 27 patients the existence of a
threshold effect between rapid and slow engraftment of 5 × 106 CD34+ cells/kg. In a large study including
heterogeneous patients with various diseases, Weaver et
al28 also defined an optimal CD34+ cell dose of
more than 5.0 × 106/kg and have shown a 95%
probability of rapid engraftment above this limit. Moreover, this study
suggested a dose-effect relationship for platelets up to doses of 10 × 106 CD34+ cells/kg, a finding also
reported by others.29-31 However, in many of these studies,
the group of patients receiving a higher number of CD34+
cells was compared with another group that included several patients receiving less than optimal numbers of CD34+ cells. In the
present study, the median time for an unsustained platelet count
greater than 20 × 109/L in the high CD34+
group was only 8 days, all patients achieving this count at 13 days.
The dose-effect relationship between CD34+ cell dose and
platelet recovery was also valid for the thresholds of 50 and 100 × 109/L platelets. When considering long-term
platelet recovery, a higher proportion of patients recovered 100 × 109/L platelets at day 100 in the high group when
compared with the intermediate group.
In the high CD34+ group patients, the benefit was also
clear for platelet requirements, with a median number of one
transfusion and a very narrow range, only one patient needing three
platelet transfusions. Moreover, high CD34+ cell count
allowed to further shorten the duration of hospitalization and tended
to decrease the number of days with antibiotics. This reduction in
supportive care due to more rapid platelet recovery might allow
significant cost savings. Of note, the number of aphereses performed to
obtain the PBPC harvest was not significantly different in both groups
(not shown).
While CD34+ cell dose appears as the strongest predictor of
engraftment, several other conditions such as duration of previous treatments and number of chemotherapy regimens have been reported to
favor delayed neutrophil or platelet recovery.24,28 In the present study comprising only patients with lymphoid malignancies, CD34+ cell dose remained, after multivariate analysis, the
only independent variable significantly influencing either neutrophil
or platelet engraftment, whatever the patient group.
Some data have shown that tumor cells could be mobilized in peripheral
blood after chemotherapy and G-CSF,32 and that tumor cells
may be found in the CD34+ population in follicular lymphoma
and MM.33,34 Even if the biologic significance of PBPC
tumor cell contamination remains uncertain, the benefit of the
reinfusion of large cell numbers might be questionable, considering the
putative risk of tumor cell reinfusion. In the present study, however,
the administration of high CD34+ cell doses did not
correlate with a higher rate of early relapses within the 6 months
after PBPC transplantation.
In conclusion, the present study suggests that compared with the
reinfusion of adequate CD34+ cell count defined as PBPC
harvest containing more than 2.5 × 106
CD34+ cells/kg, the reinfusion of more than 15 × 106 CD34+ cells/kg after high-dose chemotherapy
further shortens hematopoietic engraftment. Indeed, it markedly
improves platelet independence and seems to shorten the duration of
hospitalization. The hypothesis that reinfusion of high
CD34+ cell count is cost effective and may contribute to a
better quality of life has to be analyzed in further studies. It will
also be interesting to investigate whether high CD34+ cell
doses improve long-term hematopoietic recovery, as late impairment of
progenitor cell compartment has been documented in patients after
autologous transplantation.35,36
| |
FOOTNOTES |
Submitted August 22, 1997;
accepted December 11, 1997.
Supported by the Comité Départemental du Rhône de la
Ligue contre le Cancer (Lyon, France). N.K. was supported by the
Communauté de Travail des Alpes Occidentales (COTRAO) and by the
Fondation Michel Clavel (Lyon, France).
Address reprint requests to Gilles Salles, MD, Service
d'Hématologie, Centre Hospitalier Lyon-Sud, 69495 Pierre-Benite
Cedex, France.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
| |
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Abstract
Introduction
Abstract