Peripheral Blood Stem Cells for Allogeneic Transplantation: A Review

Abstract

Peripheral blood stem cells (PBSCs) have become increasingly popular for use in hematopoietic stem cell transplantation. PBSCs are readily collected by continuous-flow apheresis from patients and healthy donors after the administration of s.c. recombinant colony-stimulating factors with only minimal morbidity and discomfort.Although the precise identification of PBSCs remains elusive, they can be phenotypically identified as a subset of all circulating CD34+ cells. There are important phenotypic and biologic distinctions between PBSCs and bone marrow (BM)-derived progenitor cells. PBSCs express more lineage-specific antigens but are less metabolically active than their BM-derived counterparts.The use of PBSCs for allogeneic transplantation has been compared to BM in several randomized trials and cohort studies. The use of PBSCs in leukemia, myeloma, non-Hodgkin's lymphoma, and myelodysplasia has resulted in shorter times to neutrophil and platelet engraftment at the expense of increased rates of chronic graft-versus-host disease. The increase in graft-versus-host disease is mainly due to a log-fold increase in donor T cells transferred with the graft. Relapse rates after transplantation may be lower after PBSC transplantation but a convincing survival advantage has not been demonstrated overall. It is possible that a stronger graft-versus-tumor effect may exist with PBSCs when compared with BM although the mechanisms leading to this effect are not clear.

Full text

DOI: 10.1634/stemcells.19-2-108
2001;19;108-117 Stem Cells
Corey Cutler and Joseph H. Antin Peripheral Blood Stem Cells for Allogeneic Transplantation: A Review
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Peripheral Blood Stem Cells for Allogeneic Transplantation: A Review
COREY CUTLER, JOSEPH H. ANTIN
Department of Adult Oncology, Dana-Farber Cancer Institute and Department of Medicine,
Brigham and Women’s Hospital, Boston, Massachusetts, USA
Key Words. Peripheral blood stem cell · CD34+· Allogeneic · Transplantation · Hematologic malignancies · Apheresis
ABSTRACT
Peripheral blood stem cells (PBSCs) have become
increasingly popular for use in hematopoietic stem cell
transplantation. PBSCs are readily collected by contin-
uous-flow apheresis from patients and healthy donors
after the administration of s.c. recombinant colony-
stimulating factors with only minimal morbidity and
discomfort.
Although the precise identification of PBSCs remains
elusive, they can be phenotypically identified as a subset of
all circulating CD34+cells. There are important pheno-
typic and biologic distinctions between PBSCs and bone
marrow (BM)-derived progenitor cells. PBSCs express
more lineage-specific antigens but are less metabolically
active than their BM-derived counterparts.
The use of PBSCs for allogeneic transplantation has
been compared to BM in several randomized trials and
cohort studies. The use of PBSCs in leukemia, myeloma, non-
Hodgkin’s lymphoma, and myelodysplasia has resulted in
shorter times to neutrophil and platelet engraftment at the
expense of increased rates of chronic graft-versus-host dis-
ease. The increase in graft-versus-host disease is mainly due
to a log-fold increase in donor T cells transferred with the
graft. Relapse rates after transplantation may be lower after
PBSC transplantation but a convincing survival advantage
has not been demonstrated overall. It is possible that a
stronger graft-versus-tumor effect may exist with PBSCs
when compared with BM although the mechanisms leading
to this effect are not clear. Stem Cells 2001;19:108-117
STEM CELLS 2001;19:108-117 www.StemCells.com
Correspondence: Joseph H. Antin, M.D., Dana-Farber Cancer Institute, 44 Binney St., Boston, Massachusetts 02115, USA.
Telephone: 617-632-2525; Fax: 617-632-5175; e-mail: Joseph_Antin@dfci.harvard.edu Received December 21, 2000;
accepted for publication January 8, 2001. ©AlphaMed Press 1066-5099/2001/$5.00/0
INTRODUCTION
Since the first report detailing the use of peripheral
blood-derived stem cells (PBSCs) was published [1], there
has been rapid expansion in the clinical use of these cells as
well as a concomitant increase in an understanding of their
basic biology.
PBSC transplantation (PBSCT) has become increas-
ingly common in the autologous setting, with PBSC largely
replacing bone marrow (BM) as the preferred stem cell
source due largely to quicker engraftment kinetics and ease
of collection. The use of PBSC in allogeneic transplantation
has increased greatly as well, albeit more cautiously.
In this review, we will discuss the identification and
immunophenotypic characteristics of PBSCs, describe
methods for collection of these cells and discuss outcome
issues such as engraftment kinetics and graft-versus-host
disease (GVHD). The clinical experience of PBSCT in var-
ious hematological malignancies with both traditional and
nonmyeloablative approaches will be discussed in detail.
IDENTIFICATION OF PBSCS
Hematopoietic stem cells are normally found in very
limited numbers in the peripheral circulation (less than
0.1% of all nucleated cells). It is logical that progenitor
Stem Cells
Concise Review
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Cutler, Antin
109
cells circulate in the periphery, as this ensures an even dis-
tribution of hematopoiesis within the BM. The movement
of PBSCs in the circulation and homing of PBSCs to the
BM are beyond the scope of this review.
PBSCs represent a subpopulation of all CD34+cells found
in the circulation. Although morphologically difficult to iden-
tify, these cells can be distinguished to some degree by their
immunophenotypic patterns. PBSCs are CD34+/CD38–and do
not express a full complement of either myeloid or lymphoid
lineage-specific markers (Lin–) but do express the Thy-1
differentiation antigen. These CD34+/CD38–/Lin–/Thy-1+
cells are the cells responsible for initiating long-term culture
initiating colony (LTC-IC) assays [2].
PBSCs that are mobilized by colony-stimulating factors
(i.e., recombinant human [rHuG-CSF]) are neither phenotyp-
ically nor immunologically identical to BM-derived stem
cells. In comparison with BM-derived stem cells, mobilized
PBSCs have been found to express more lineage-specific dif-
ferentiation antigens (i.e., CD13, CD33), have a lower pro-
portion of cells in S phase (i.e., are less active in cellular
cycling) and are less metabolically active (in rhodamine
retention assays and by demonstrating less CD71 positivity)
[3]. Furthermore, PBSCs demonstrate higher clonogenicity
in LTC assays [3].
Currently, the most reproducible method of stem cell
quantification after collection is by flow cytometric evalua-
tion of CD34+cell numbers. Enumeration of CD34+/CD38–,
CD34+/CD33–, and CD34+/Thy-1+cell subsets may prove
to be a more useful technique of estimation of stem cell
numbers [4]. The percentage of colony-forming units-gran-
ulocyte-macrophage from a stem cell harvest has also been
used to estimate stem cell numbers. This method is much
less reliable and can vary widely due to differences in cul-
ture technique and media as well as several human factors.
Furthermore, not all transplantation centers are equipped to
perform these labor-intensive cultures, which require 10 to
14 days of incubation. The standardized method for enu-
merating CD34+cell counts has been published in greater
detail elsewhere [2, 5].
MOBILIZATION AND COLLECTION OF PBSCS
Levels of pluripotent hematopoietic stem cells rise up to
50-fold in the recovery phase after myelosuppressive
chemotherapy and can be collected for autologous trans-
plantation. In order to achieve circulating levels high enough
to ensure a harvest capable of reconstituting a mature
hematopoietic system after allogeneic donation, healthy
donors must be “primed” with hematopoietic growth fac-
tors, using either rHuG-CSF or rHuGM-CSF. The use of
growth factors during the recovery phase after chemother-
apy may or may not increase the total number
of PBSCs that can be collected in the autologous setting.
Combined priming with both nonmyeloablative chemo-
therapy and CSF is not routinely performed in healthy donors.
CSF doses of between 2 and 24 µg/kg administered s.c.
daily have been given to healthy donors [6-8], including
donors over the age of 60 years [9]. The induced leucocy-
tosis, when maintained at levels below 70,000 cells/µl, has
not been shown to be detrimental to the donor’s health for
short periods of time, however, important morbidity,
including splenic rupture and death, have rarely been
reported [10, 11]. Common minor side effects caused by the
administration of growth factors include bone pain, myal-
gias, headache, and fever, which respond to mild analgesics
in over 80% of cases. Longer follow-up (up to six years)
has confirmed the safety of administration of rHuG-CSF to
healthy donors [11, 12].
PBSCs are obtained by apheresis, generally via periph-
eral venous access; occasionally central venous access may
be required. Up to two to three donor blood volumes are
processed per session by extracorporeal continuous-flow
apheresis machines. Stem cells and granulocytes are sepa-
rated from the red blood cell and plasma fractions of blood
by centrifugation and the latter two components are returned
to the donors during the apheresis procedure itself. The
process generally requires between three and five hours per
session. The target range of peripheral stem cells of 2 ×106
cells/kg (recipient weight) can generally be achieved in one to
two sessions.
The efficacy of stem cell collection comparing BM and
PBSCs has been examined. In a randomized trial, a single
PBSC apheresis procedure yielded 3.7 times more CD34+
cells than a standard BM harvest. Furthermore, BM har-
vests were 6.8 times more likely to be insufficient for trans-
plantation (defined as less than 2 ×106cells/kg of recipient
weight, p< 0.001) [13].
Potential risks associated with stem cell apheresis proce-
dure include complications related to central line placement
when necessary (such as pneumothorax) and cytopenias due
to the apheresis procedure itself. Leukopenia or lymphope-
nia frequently occur and can last a variable period of time.
Thrombocytopenia (<100 ×109cells/l) is not uncommon,
however, bleeding complications are extraordinarily rare.
Similarly, anemia that requires transfusion is very uncom-
mon. Anderlini et al. provide a complete review of donor
safety issues [14].
PBSC donation is generally preferred by donors over
traditional BM donation, which entails either general or
spinal anesthesia, a brief hospital stay, and more post-proce-
dure discomfort. Several phase II studies measuring outcomes
(including quality of life and anxiety scores) comparing the
two procurement procedures confirmed this fact [15, 16].
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PBSCs for Allogeneic Transplantation
ENGRAFTMENT AND KINETICS
The prolonged and profound cytopenias encountered
after transplantation account for much of the morbidity and
mortality associated with the procedure. Typical delays to
neutrophil recovery after autologous BM transplantation
(BMT) range from 14 to 21 days. After allogeneic BMT, the
time to engraftment is longer and more variable, ranging from
14 to 28 days and in part may be related to post-transplant
immunosuppressive agents, such as methotrexate.
A convincing reduction in time to engraftment after both
autologous and allogeneic PBSCT when compared to tradi-
tional BMT has been demonstrated. In the allogeneic setting,
neutrophil engraftment (to 0.5 ×109cells/l on two consecutive
days) occurred between one and six days earlier with PBSCT
when compared with BMT in randomized trials (mean time to
engraftment: 14 versus 15 days and 15 versus 21 days) [17,
18]. Unsupported platelet counts of 20 ×109/l occurred
between four and seven days earlier (mean time to platelet
engraftment: 15 versus 19 days and 11 versus 18 days) [17,
19]. The results of a large database review are consistent with
the results of the randomized trials (mean time to neutrophil
engraftment 14 versus 19 days, mean time to platelet engraft-
ment 18 versus 25 days, p< 0.001 for both comparisons) [20].
Typical doses of CD34+stem cells used for PBSCs are
2×106cells/kg of recipient body weight or greater. Doses
lower than this threshold are associated with prolonged
cytopenias and increased early mortality [21].
A relationship between the dose of CD34+stem cells
delivered with the transplant and the tempo of hematologic
recovery has been demonstrated for both BMT [21] as well
as PBSCT [22]. The use of higher doses of CD34+cells may
lead to quicker engraftment, particularly when doses are
greatly increased [23, 24]. Platelet recovery appears to be
more sensitive to CD34+doses than neutrophil recovery [24].
Efforts to enrich PBSCT by ex-vivo CD34+cell selection
(positive selection) have resulted in increased rates of GVHD,
possibly by altering the cytokine expression patterns of trans-
planted cells or changing lymphocyte subsets delivered with
the graft [25]. These efforts do not appear to alter engraftment
kinetics significantly [25, 26]. Negative selection (T cell
depletion) clearly leads to lower rates of GVHD, at the
expense of a slightly higher incidence of graft rejection.
Other strategies used to shorten the time to engraftment
include the use of combined PBSCT and BMT [27] and the
use of rHuG-CSF-mobilized BM for transplantation [28-30].
The latter approach may have the advantage of GVHD rates
similar to traditional BMT [29] and neutrophil engraftment
kinetics similar to those of PBSCT [30].
The earlier engraftment seen after PBSCT has lead to
earlier discharge from hospital [17, 19, 31] and total lower
immediate costs associated with the transplant procedure
[18, 32]. The reduction in costs associated with the proce-
dure is primarily due to fewer dollars spent on hospital room
charges, blood products and other supportive measures. The
costs of stem cell mobilization and collection procedures,
however, are greater for PBSCT than for traditional BMT,
primarily due to the use of recombinant human hematopoi-
etic growth factors [32]. Long-term cost issues are more dif-
ficult to predict and will be influenced by GVHD outcomes
after PBSCT (see below).
GVHD
Acute GVHD results from the complex interaction of
donor T cells and recipient organs and involves recogni-
tion of minor histocompatibility antigens in an inflamma-
tory milieu. Tissue damage from conditioning regimens,
infections, and the underlying illness may provide an envi-
ronment that fosters T cell recognition of susceptible tis-
sues. Clinical injury is thought to derive from direct T cell
injury through perforin/granzyme, Fas/Fas ligand interac-
tions, and the effects of inflammatory cytokines [33]. It
may be due in part to conditioning-induced tissue damage,
transmigration of endotoxin across damaged gut mucosa,
and dysregulation of inflammatory cytokines.
Acute GVHD occurs within the first weeks following
transplantation. Chronic GVHD occurs later, and is arbitrar-
ily defined as the presence or persistence of GVHD beyond
100 days since transplantation. The occurrence and severity
of GVHD is related to the degree of HLA-mismatching
between donor and recipient, the type of conditioning regi-
men used, the use of degree of immunosuppression of the
recipient (GVHD prophylaxis), the viral exposure of the
donor and recipient, the underlying malignant disease, and
to the passage of mature, immunocompetent T cells with the
stem cell transplant [34]. PBSCT contain roughly a log-fold
increase in the concentration of CD3+T cells when com-
pared to BMT. This large increase in T cell dose is largely
responsible for the increased risk of GVHD seen after
PBSCT. PBSCs were avoided for years because of concerns
over the higher risk of GVHD, however, these concerns
appear to be less severe than originally anticipated.
The incidence and severity of GVHD after PBSCT may
be influenced by rHuG-CSF administered to donors prior to
stem cell collection. Polarization of T cells to the Th2 class
has been demonstrated to occur in response to rHuG-CSF in
mouse models [35, 36]. This polarization is related to the
subtype of antigen-presenting cell (dendritic cell) initiating
the immune response. rHu-G-CSF has been shown to
increase the circulating numbers of type 2 dendritic cells,
which in turn influence the predominance of a Th2 cellular
response and elucidated cytokines [37, 38]. Th2 cells are
considered GVHD neutral in comparison to Th1 cells.
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There have been five randomized controlled trials [17-
19, 39, 40] and many cohort studies [20, 31, 41-50] that
have examined the relative risks (RR) of acute and chronic
GVHD after PBSCT when compared to traditional BMT
(Table 1). No single trial has concluded that the incidence of
acute GVHD incidence is higher after PBSCT when com-
pared to traditional BMT. Only one of the trials, however,
was statistically powered to detect small differences in the
incidence of acute GVHD [40]. RR for acute GVHD after
PBSCT varied from 0.67 to 1.5 compared to BMT [43, 44].
In a meta-analysis of 15 trials, a small but statistically sig-
nificant increase in the RR of acute GVHD after PBSCT
was demonstrated (RR 1.13, 95% confidence interval [CI]
1.01-1.26) [51].
It has been accepted clinically that the incidence of
chronic GVHD after PBSCT may be higher than after tra-
ditional BMT. The literature regarding this subject has been
controversial, with some studies finding evidence support-
ing [18, 20, 49, 50] and others not supporting this hypothe-
sis [19, 39, 40]. In a meta-analysis, a 1.5-fold increase in
RR was noted when the results of 13 trials were combined
(RR 1.48, 95% CI 1.20-1.81) [51]. In addition to being
more prevalent after PBSCT, chronic GVHD was more
likely to be extensive when compared with BMT (RR 1.58,
95% CI 1.24-2.00) [51]. This increase in chronic GVHD
was related to the increased dose of T cells delivered with
the graft in a regression model [51].
The occurrence of acute GVHD has been linked to higher
treatment-related morbidity and early mortality, however,
chronic GVHD has been shown to be protective against
relapse [51, 52] and may be associated with better long-term
survival, particularly when used in high-risk patients [20, 40].
It remains to be determined whether the reduction in hospital
stay during the acute phase is cost-effective compared with
the increased costs and morbidity of chronic GVHD.
USE OF PBSCS FOR SPECIFIC HEMATOLOGICAL
MALIGNANCIES
Autologous stem cell grafting has been used with vary-
ing degrees of success in chronic myelogenous leukemia
(CML) [53, 54], acute leukemia [55], myelodysplasia [56],
and multiple myeloma [57]. The potential advantages of allo-
geneic transplantation include the security of a contaminant-
free graft and the possibility of a unique graft-versus-tumor
effect. The use of PBSC when compared to BM may lead to
a reduction in relapse rates after transplantation, due to an
enhanced graft-versus-tumor effect. An overall improvement
in survival has not been demonstrated, however, there may
be a trend towards better outcomes after PBSCT in patients
with high-risk disease.
Acute and Chronic Leukemia
BMT for acute myelogenous leukemia (AML) is recom-
mended for patients with refractory/resistant leukemia,
patients in second clinical remission, and patients with high-
risk cytogenetic features in first remission. The Medical
Research Council AML10 trial revealed significant differ-
ences in long-term disease-free survival when autologous
Table 1. RR of acute and chronic GVHD after PBSCT versus BMT
Study Study design nRR of acute RR of chronic
GVHD (95% CI) GVHD (95% CI)
Powles [19] Single institution blind randomized 39 1.06 (0.55-2.01) 1.52 (0.60-3.83)
Blaise [18] Multicenter randomized 101 1.06 (0.67-1.66) 1.82 (1.10-3.00)
Bensinger [40] Multicenter randomized 172 1.19 (0.92-1.54) 1.19 (0.85-1.67)
Vigorito [39] Single institution randomized 37 1.42 (0.38-5.33) 1.34 (0.75-2.39)
Schmitz [17] Multicenter randomized 66 1.13 (0.70-1.80) 1.50 (0.38-6.00)
Champlin [20] Retrospective database cohort 824 1.19 (0.91-1.56) 1.30 (1.00-1.70)
Russell [46] Retrospective cohort 87 1.50 (0.75-3.00) 1.76 (1.26-2.46)
Üstün[50] Cohort with historical controls 80 1.03 (0.51-2.06) 3.65 (1.75-7.58)
Scott [47] Cohort with historical controls 24 1.00 (0.39-2.58) 3.33 (0.47-23.47)
Solano [48] Retrospective cohort 74 NA 1.89 (0.97-3.68)
Bacigalupo [42] Retrospective cohort 97 1.25 (0.85-1.84) 0.99 (0.90-1.09)
Lemoli [44] Cohort with historical controls 30 1.50 (0.29-7.73) 1.40 (0.57-3.43)
Pavletic [45] Cohort with historical controls 43 1.20 (0.67-2.15) NA
Bensinger/Storek [43, 49] Cohort with historical controls 74 0.67 (0.40-1.13) 1.67 (1.09-2.54)
Azevedo [41] Cohort with historical controls 38 1.11 (0.59-2.10) NA
Study, year of publication = the first author and the year of publication; n= study sample size; 95% CI = 95% confidence intervals for RR assessments;
RR = relative risk.
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PBSCs for Allogeneic Transplantation
transplantation was compared with consolidative chemother-
apy in individuals without an HLA-matched sibling [55].
At least one trial has demonstrated higher long-term sur-
vival after allogeneic transplantation compared with autol-
ogous transplantation [58], but others have demonstrated
equivalence [57, 59]. Allogeneic transplantation has
become the standard of care for patients with high-risk
cytogenetic features in first remission, patients with resis-
tant or refractory disease and patients in second remission,
provided the patient is a candidate for the procedure and a
suitable donor is available. Acute lymphoblastic leukemia
is treated largely the same way in the adult population.
In stable phase CML, allogeneic transplantation is cur-
rently the curative therapy of choice when feasible.
Autologous transplantation with Philadelphia chromosome-
negative-purged marrow or stem cells has recently re-
emerged as an investigational treatment option [60], but
there is no established benefit of autologous transplantation
over interferon-based therapy.
PBSCT has been used most extensively in acute and
chronic leukemias. In a prospective, randomized trial com-
paring allogeneic BMT and PBSCT in 111 patients, Blaise
et al. did not demonstrate significantly different overall and
leukemia-free survival between PBSCT and BMT groups
[18]. The trial did demonstrate the expected significantly
decreased time to neutrophil and platelet engraftment after
PBSCT. The rate of chronic GVHD was noted to be signif-
icantly higher after PBSCT when compared with BMT
(30% versus 55%, p< 0.03).
In a study reported by Schmitz et al., the authors reported
the outcomes of 66 patients with acute or chronic leukemia
who received BMT or PBSCT from HLA-matched siblings
[17]. The majority of patients entered in this trial had low-risk
disease, referring to AML in first remission or CML in
chronic, stable phase. The mean time to platelet recovery (>20
×109/l) was reduced by four days after PBSCT when com-
pared to BMT. No differences in rates of GVHD or overall
survival were reported in this trial.
Multiple Myeloma
Autologous BMT for multiple myeloma has been
shown to be superior to traditional chemotherapy, offering
both a disease-free and overall survival advantage [61].
However, autologous transplants are frequently contami-
nated by residual tumor cells when assessed by sensitive
molecular techniques [53, 62]. The risk of contamination as
well as the demonstration of a pronounced graft-versus-
myeloma effect [63, 64] has prompted the study of allo-
geneic stem cell sources as an alternative to autologous
cells. This approach is not without risk; the Cancer and
Leukemia Group B recently has had to stop accrual to a trial
of non-T cell-depleted allogeneic transplantation in myeloma
due to concerns over toxicity.
Majolino et al. described 10 patients (including four who
had already received PBSC autografts) undergoing allogeneic
PBSCT for multiple myeloma [65]. The median time to
engraftment was 13 days. Eight of 10 patients had a complete
remission (CR) while the remaining two patients had a partial
remission (PR). None of the patients achieving CR had evi-
dence of recurrence of myeloma 7 to 28 months after trans-
plantation. Two patients died of treatment-related causes.
Corradini et al. described the molecular remission status
of 51 patients after autografting or allogeneic transplantation
with either BM or PBSCs [66]. All 17 patients who received
allografts entered a CR state after transplantation. In patients
with molecular markers available, there was a significantly
increased proportion of patients who achieved a molecular
remission after allogeneic transplantation compared to
autologous transplantation. Furthermore, only one of five
allogeneic BMT patients became polymerase chain reac-
tion-negative for clonal immunoglobulin gene rearrange-
ments compared with six of nine patients who received
allogeneic PBSCT. Similarly, Cavo et al. described five
patients who had both complete clinical and molecular
remissions after PBSCT from HLA-matched siblings [67].
Myelodysplasia
Allogeneic transplantation is the only therapy for
myelodysplastic syndromes (MDS) with curative potential
available today. Patients with fewer cytogenetic abnormali-
ties [68], less latency since the time of diagnosis [69], and
patients with refractory anemia or refractory anemia with
ringed sideroblasts [70, 71] have better outcomes after trans-
plantation. The International Prognostic Scoring System
score is also useful for predicting outcome after transplanta-
tion [72]. The optimal timing of stem cell transplantation for
this disease is not yet known.
The experience in transplantation with PBSC for MDS
is more limited than that for the acute and chronic
leukemias. Patients with MDS have comprised only a small
proportion of patients in trials comparing PBSCT and BMT
and therefore no conclusions can be drawn on the relative
advantages and disadvantages of PBSCT.
Non-Hodgkin’s Lymphoma (NHL)
Autologous transplantation for relapsed intermediate and
high-grade NHL has clear survival advantages over
chemotherapy [73]. Allogeneic transplantation has been used
for patients with relapse after BMT or refractory disease. In a
preliminary report by Körbling et al., four patients with
refractory NHL underwent allogeneic PBSCT from HLA-
matched siblings [74]. Three patients had a CR and the fourth,
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Cutler, Antin
113
a PR. One patient died of infectious complications 82 days
after transplantation and the other three patients were reported
to be alive greater than 31 to 100 days post-transplant.
Khouri et al. studied the effects of allogeneic transplan-
tation in patients with mantle cell lymphoma, an intermedi-
ate-grade lymphoma with a uniformly poor prognosis [75].
Sixteen patients were studied, 11 of whom received allo-
geneic PBSCs as a stem cell source. Nine patients remained
alive at the time of publication, with eight patients in CR.
Molecular minimal residual disease was assessed in seven
patients. Five of the seven patients had no evidence of mole-
cular residual disease between 3 and 30 months after trans-
plantation. Five of seven patients had evidence of chronic
GVHD. Other case reports have documented the efficacy of
allogeneic PBSCT for NHL [76, 77].
A graft-versus-lymphoma effect has been noted in both
animal models [78] and human studies [75-77]. In a murine
model of NHL, Ito and Shizuru demonstrated a unique graft-
versus-lymphoma activity which was separable from GVHD
effects and mediated by CD8+T cells and perforin-dependent
cytolysis [78].
BM Aplasia and Donor Lymphocyte Infusion (DLI)
The use of unstimulated PB buffy coat cells for aplastic
anemia was first reported by Storb et al. in 1982 [79]. At this
time, the addition of buffy coat cells to BMT increased the
risk of GVHD, likely as a result of the immense T cell load
in the buffy coat compared with the relative sparse concen-
tration of progenitor cells. Graft rejection was diminished
and survival for patients treated with both marrow and buffy
coat cells was improved compared with marrow alone; how-
ever, it was not clear whether this improvement could be
attributed to the stem cells infused or prevention of graft
rejection by the infusion of large numbers of allogeneic
T cells [80].
More recently, infusions of buffy coat cells, referred to
as DLI have been used as post-transplantation immunother-
apy for malignant disease. Given at variable times after
transplantation of allogeneic BM or PBSC, DLI can induce
potent graft-versus-tumor effects and is useful as treatment
for relapsed malignancies or pre-emptive therapy for preven-
tion of relapse. The procedure is associated with a 50% risk
in acute GVHD and a 20% risk of marrow aplasia [81]. The
effects of DLI are most prominent in CML, where single
infusions of donor lymphocytes have induced long-lasting
remissions in relapsed patients [82].
Despite the infusion of hematopoietic progenitor cells
with the lymphocyte population, even rHuGM-CSF-mobilized
donor lymphocytes are not completely protective against mar-
row aplasia when used in relapsed CML [81]. This implies that
aplasia seen after DLI may not be solely due to destruction of
native hematopoietic elements, but also involves suppression
of donor engraftment and hematopoiesis.
Nonmyeloablative Transplantation and PBSCs
The DLI experience led to the notion that a transplanta-
tion could rely primarily on the immune system of the
donor to eradicate the leukemia and that sublethal condi-
tioning might allow stable engraftment. Clearly, depending
on whether the targeted disease was a stem cell disorder
(e.g., CML) or a disease in which stem cells are not
involved (e.g., NHL), it may or may not be necessary to
establish complete chimerism of hematopoiesis. The first
trial of nonmyeloablative or reduced-intensity conditioning
followed by allogeneic PBSCT was reported by Khouri et
al. in 1998 [83]. This technique employs the graft-versus-
tumor effect as the primary therapeutic modality and omits
high-dose conditioning regimens. Instead, low-dose
immunosuppressive regimens containing drugs such as the
nucleoside analogue fludarabine, generally in combination
with cyclophosphamide or busulfan, are used to permit
donor progenitor cell engraftment even without host myelo-
ablation. The graft-versus-host/graft-versus-leukemia
response might result in eradication of host hematopoiesis,
therefore it is necessary to include a source of stem cells to
sustain hematopoiesis.
Potential advantages of a nonmyeloablative approach
to allogeneic transplantation include the inclusion of an
older patient population and patients with other comorbid
conditions that would be otherwise excluded from allo-
geneic transplantation. As well, the procedure itself is not
limited by chemotherapy-induced toxicity and can often be
performed in an outpatient setting. Rates of GVHD after
nonmyeloablative transplantation are similar to those seen
after myeloablative transplantation.
In the first published phase II study [83], 15 patients
with lymphoid malignancies were transplanted following
nonmyeloablative conditioning. Eleven of 15 patients
demonstrated evidence of donor-derived hematopoiesis at
one month post-transplant. Mixed chimerism (defined as the
coexistence of recipient and donor-derived hematopoiesis)
was noted in most subjects. DLIs in the post-transplant set-
ting were able to convert some patients from mixed chimeric
hematopoiesis to full donor-derived hematopoiesis.
A nonmyeloablative approach to PBSCT for NHL was
explored by Nagler et al. [84]. Nineteen patients with heav-
ily-pretreated NHL were given a nonmyeloablative condi-
tioning regimen consisting of fludarabine, busulfan, and
antithymocyte globulin. Eight of the 19 patients were alive
between 15 and 37 months post-transplant. There were four
patients who relapsed after treatment. An attempt at post-
transplantation immunomodulation with immunosuppressive
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PBSCs for Allogeneic Transplantation
therapy withdrawal and/or DLI was not successful at
inducing remissions in these patients.
CONCLUSIONS AND FUTURE DIRECTIONS
PBSCs are now commonly used as the stem cell source
for allogeneic transplantation. These cells are readily col-
lected from the peripheral circulation when mobilized with
hematopoietic growth factors. Efforts to increase the yield
of donor harvests are now focusing on the optimal timing of
stem cell procurement and on the use of novel hematopoi-
etic growth factors (such as flt-3 ligand) to increase the effi-
cacy of mobilization of the stem cell compartment into the
peripheral circulation.
Although the time to engraftment of PBSCs appears to
be shorter than BM-derived stem cells, newer BM mobiliza-
tion techniques may obviate this difference in the future. The
specific biological factors leading to a more rapid engraft-
ment are yet to be identified fully and represent a gap in the
basic understanding of stem cell biology.
Although the incidence of GVHD was initially thought to
be similar for both BMT and PBSCT, recent evidence from
ongoing clinical trials and a meta-analysis has demonstrated
that both acute and chronic GVHD occur with greater fre-
quency after PBSCT than BMT. Efforts to control GVHD
with novel immunophyllin inhibitors and other immunomodu-
latory agents may reduce rates of GVHD after both procedures
to minimize treatment-related mortality and long-term mor-
bidity. The ability to harness the useful effects of the graft-ver-
sus-tumor activity and separate them from GVHD will further
increase the beneficial effects of high-dose therapy and stem
cell transplantation. The addition of post-transplantation cellu-
lar immunotherapy with either donor lymphocyte or dendritic
cell preparations may enhance graft-versus-tumor activity.
The role of PBSCT for individual malignancies remains
to be determined. At the present, it is reasonable to reserve
the use of PBSC to clinically high-risk scenarios, such as sec-
ond remission AML or CML in blast crisis, where PBSCT
has shown a survival advantage over BMT in a database
review. For low-risk malignant conditions such as stable
phase CML, it is reasonable to continue using BM-derived
stem cells for transplantation until clinical trials demonstrate
the superiority of one stem cell source over the other.
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DOI: 10.1634/stemcells.19-2-108
2001;19;108-117 Stem Cells
Corey Cutler and Joseph H. Antin Peripheral Blood Stem Cells for Allogeneic Transplantation: A Review
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