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Blood, Vol. 94 No. 7 (October 1), 1999:
pp. 2192-2199
By
From the Division of Clinical Research, Fred Hutchinson Cancer
Research Center and Department of Medicine, University of Washington,
Seattle, WA.
We conducted a phase I-II clinical trial to test the hypothesis that
removal of CD4 cells from an HLA-mismatched unrelated marrow graft
would substantially reduce the risk of grades III-IV graft-versus-host
disease (GVHD) and that retention of a specified number of CD8 cells in
the graft would be sufficient to prevent rejection. Patients were
eligible for this study when an HLA-A, -B, or -DRB1-matched unrelated
donor could not be identified. HLA matching of the donor and recipient
was based on typing of HLA-A and -B antigens by serologic methods and
by typing of HLA-DRB1 alleles by molecular methods, and donors were
selected when disparity was limited to a single HLA-DRB1 allele or a
single HLA-A or -B antigen. Twenty-seven patients with hematologic
malignancy or aplastic anemia were prepared to receive a transplant
with conventional regimens of cyclophosphamide and fractionated total
body irradiation, and a standard regimen of methotrexate and
cyclosporine was given for GVHD prophylaxis. CD4 cells were removed
from the donor marrow, and the numbers of CD8 cells were adjusted
systematically in graded steps for successive patients, depending on
the occurrence of grades III-IV GVHD or graft failure in previously
enrolled patients. Removal of CD4 cells did not cause graft rejection
or appreciably decrease the risk of grades III-IV GVHD. Depletion of
CD8 cells was associated with an increased risk of rejection with
either HLA-DRB1 disparity or with HLA-A or -B disparity. With either type of disparity, the risk of grades III-IV GVHD is likely to be
higher than 15% at any dose of CD8 cells associated with less than 5%
risk of graft failure. The absence of graft failure associated with CD4
depletion supports the hypothesis that donor CD4 cells are not
essential for preventing marrow graft rejection in humans. The
correlation between graft failure and the number of CD8 cells in the
donor marrow supports the hypothesis that donor CD8 cells help to
prevent marrow graft rejection.
CURRENTLY AVAILABLE posttransplant
immunosuppressive regimens do not provide optimal protection against
graft-versus-host disease (GVHD) after marrow transplantation from an
HLA-nonidentical family member or from an unrelated
donor.1,2 Clinical studies have shown that GVHD can be
prevented by removing T cells from the donor marrow, but this approach
has been associated with an increased risk of graft failure, among
other significant complications affecting survival.3
Immunologic rejection mediated by small numbers of recipient lymphoid
cells that survive the conditioning regimen is a likely cause of graft
failure associated with removal of T cells from the donor
marrow.3 Laboratory studies have shown that donor T cells
prevent rejection by eliminating or inactivating recipient T cells that
survive the conditioning regimen.4,5 This occurs
primarily through the generation of cytotoxic effectors that recognize
alloantigens expressed by recipient T cells.6
In murine marrow transplant models, both CD4 cells and CD8 cells of the
donor can cause GVHD, but donor CD8 cells were at least 5-fold more
effective than donor CD4 cells for preventing marrow graft rejection
mediated by recipient T cells.4 In humans, removal of CD8
cells from the donor marrow is associated with an increased risk of
graft failure in HLA-identical sibling recipients.7 Taken
together, these studies suggest that donor CD8 cells play a critically
important role in preventing allogeneic marrow graft rejection. Based
on these considerations, we designed a clinical trial to determine
whether removal of CD4 cells from HLA-mismatched unrelated donor marrow
could safely and substantially reduce the risk of grades III-IV GVHD
when a specified number of CD8 cells is retained in the graft to
prevent rejection.
Patient and donor selection.
Patients were eligible for this study if they had a hematologic
malignancy deemed to have less than 5% chance of cure by conventional therapy but potentially curable by treatment with high-dose
cyclophosphamide and total body irradiation followed by allogeneic
marrow transplantation. Patients with severe aplastic anemia were also
eligible. Patients were ineligible if they were older than 55 years of
age or had previously received greater than 3,000 cGy whole brain
irradiation or greater than 1,500 cGy to the chest or abdomen, or any
involved field irradiation to these areas within 6 months before transplantation.
Transplantation procedures and supportive care.
Patients were prepared to receive a transplant with 60 mg of
cyclophosphamide per kg body weight for 2 days and either 13.2 Gy total
body irradiation (TBI) given in 1.2 Gy fractions 3 times daily
(n = 12) or 13.5 Gy TBI given in 1.5 Gy fractions twice daily
(n = 15). Intrathecal methotrexate was given for prevention of
central nervous system (CNS) malignancy and local field irradiation was
given for prevention of testicular relapse in patients who were at risk
of these complications. Cyclosporine and methotrexate were given for
GVHD prophylaxis.11 Trimethoprim-sulfamethoxazole was given
before transplantation and after engraftment for prophylaxis against
Pneumocystis carinii pneumonia. Nineteen patients
were hospitalized in isolation rooms with laminar airflow and received oral nonabsorable antibiotics for prevention of bacterial and fungal
infection. Six of the remaining eight patients were hospitalized in
rooms with high-efficiency particulate air-filtered air and positive-pressure ventilation. Antibiotics were given intravenously for
prevention of bacterial infection whenever the absolute neutrophil count was less than 500/µL. All patients received fluconazole for
prevention of fungal infection.12 Amphotericin was given whenever fungal infection was suspected. Acyclovir was given during the
first 30 days after transplantation to prevent herpes simplex reactivation in seropositive patients.13 Patients who were
seronegative for cytomegalovirus (CMV) received leukopoor filtered
blood products or blood products from donors who were
CMV-seronegative.14 CMV-seropositive patients were treated
with ganciclovir whenever weekly blood tests for CMV pp65 antigen were
positive.15 Gamma globulin was given intravenously at
weekly intervals for the first 90 days after transplantation whenever
the serum immunoglobulin G (IgG) level was less than 400 mg/dL.
Recombinant human granulocyte colony-stimulating factor (G-CSF) was
given at the discretion of the attending physician if the absolute
neutrophil count did not surpass 100/µL by day 21 after transplantation.
Marrow treatment.
Marrow was aspirated by conventional methods at the donor center and
transported to the Fred Hutchinson Cancer Research Center (FHCRC;
Seattle, WA) according to procedures of the National Marrow Donor
Program (Minneapolis, MN). At the time of arrival, red blood cells were
depleted and mononuclear cells were enriched by centrifugation using a
COBE Spectra machine (Cobe, Lakewood, CO). CD4 cells and CD8 cells were depleted by an immunomagnetic procedure using clinical grade monoclonal antibodies prepared in the FHCRC Biologics Production Shared Resource. Antibodies were used with paramagnetic polystyrene beads (Dynal, Lake Success, NY) and the MaxSep device (kindly donated
by Baxter Healthcare Corporation, Irvine, CA) under an Investigational
Device Exemption from the Food and Drug Administration. The
CD4-specific murine IgM antibody 66.116 was conjugated to Dynabeads M-450 (Dynal) by overnight incubation at pH 9.5. The CD8-specific murine IgG2a antibody 51.117 was bound to
Dynabeads M-450 coated with sheep antimouse IgG. The immunomagnetic
separation steps are summarized in Fig 1.
CD34 cells, CD4-bright cells, and CD8-bright cells were enumerated
before and after the immunomagnetic separation by flow cytometry after
direct immunofluorescent staining with commercially available
antibodies (Becton Dickinson, San Jose, CA). For enumeration of
CD4-bright cells, 100,000 events were analyzed with subtraction for 0%
to 0.021% (mean, 0.0048%) background after staining with an
isotype-matched irrelevant control antibody.
Study design, endpoints, and statistical analysis.
This phase I-II clinical trial was undertaken to determine whether
removal of CD4 cells from the marrow graft can substantially reduce the
risk of grades III-IV acute GVHD after transplantation from an
unrelated donor with MHC-class II (HLA-DRB1) or MHC-class I (HLA-A or
-B) disparity. Because we anticipated that removal of CD4 cells might
not be sufficient to prevent grades III-IV GVHD, the study was further
designed to determine whether the number of CD8 cells in the graft
could be adjusted in a way that reduced the risk of grades III-IV GVHD
to 15% or less (equivalent to results with HLA-identical sibling
donors) without increasing the risk of rejection to more than 5% in
patients given conventional regimens of cyclophosphamide and
fractionated TBI before transplantation together with methotrexate and
cyclosporine after transplantation.
Results of marrow treatment.
From the immunomagnetic separation procedure, the mean recovery of
nucleated cells was 46.8% (range, 17% to 73%), and the mean recovery
of CD34-positive cells was 67.8% (range, 34% to 110%). The final
processed grafts contained 5.88 (range, 1.3 to 28.3) × 107 nucleated cells and 2.75 (range, 0.4 to 6.3) × 106 CD34-positive cells per kg recipient body weight.
Before the immunomagnetic separation, the grafts contained 16.6 (range,
5.4 to 41.1) × 106 CD4-bright cells per kg recipient body
weight. In 7 of the processed marrows, no CD4-bright cells were
detected by flow cytometric analysis of 1.0 × 105 events
(Tables 1 and
2). In the
remaining 20 marrows, the immunomagnetic separation procedure achieved
an average 3.37 (range, 1.5 to 5.0) log depletion of CD4-bright cells.
The median number of residual CD4-bright cells in the graft was
3.0 × 103/kg recipient body weight, and the highest
number administered was 2.1 × 105/kg (Tables 1 and
2).
Incidence of graft failure and grades III-IV GVHD as correlated with
the numbers of various cell types in the processed marrow.
Engraftment could not be evaluated in 2 patients (UPN 8650 and 8125)
who died, respectively, on days 4 and 12 after transplantation. Among
the 25 patients who could be evaluated, 5 had failure of initial
engraftment, and 20 had evidence of initial engraftment manifested by
an increase in absolute neutrophil counts to levels greater than
500/µL for at least 3 days (Tables 1 and 2). The median interval time
from the marrow infusion to granulocyte recovery in these 20 patients
was 23.5 days (range, 18 to 28 days). Five of these patients were
treated with G-CSF to accelerate engraftment. One patient (UPN 9022)
had initial engraftment followed by graft failure at 63 days after
transplantation (Table 2).
Chimerism studies.
In 1 of the 5 patients with failure of initial engraftment, blood cells
were predominantly of donor origin, and in the other 4, blood cells
were predominantly of recipient origin. Chimerism studies documented
the presence of donor cells in the peripheral blood or marrow during
the first 100 days after transplantation in each of the 20 patients who
had initial engraftment. In 7 of these cases, recipient cells were also
detected on at least 1 occasion. In 2 of the 7, the presence of
recipient cells was associated with evidence of recurrent malignancy
after transplantation. In the other 5 cases, the persistence of
recipient cells was not associated with either recurrent malignancy or
graft failure. The patient with late graft failure had only donor cells
detectable in the marrow 4 days before he died.
Platelet engraftment.
Nine of the 20 patients who had neutrophil engraftment also had
recovery of self-sustained platelet counts at levels greater than
20,000/µL during the first 3 months after transplantation and were
independent of platelet transfusion support. Five of these patients
later developed thrombocytopenia, which could have been related to CMV
infection or chronic GVHD. Eleven of the 20 patients who had neutrophil
engraftment remained persistently thrombocytopenic and required
continued platelet transfusion support. Seven of the 11 died between
days 39 and 77 after transplantation without having recovered
self-sustained platelet counts at levels greater than 20,000/µL, and
1 patient with recurrent malignancy remained thrombocytopenic until he
died on day 243 after transplantation. In the remaining 3 patients,
platelet counts eventually recovered to levels greater than 20,000 µL
between 4 and 12 months after transplantation. Recovery of
self-sustained platelet counts correlated strongly with higher numbers
of nucleated cells in the final processed marrow (P = .009)
and showed a trend for correlation with the number of CD34 cells
(P = .12).
Infections.
No patient developed a lymphoproliferative disorder caused by
Epstein-Barr virus. Fungal infections were notably frequent among
patients in this study. One of the 2 patients who died during the first
2 weeks after transplantation had pulmonary infection with Candida
glabrata and Aspergillus with no pretransplant
history of fungal infection. Three of the 5 patients with failure of
initial engraftment had Aspergillus or Fusarium
infection. One of these patients had a pretransplant history of
pulmonary Aspergillus infection. Eight of the 20 patients with
initial engraftment had documented fungal infection. Three had
Candida infection, 3 had Aspergillus infection, 1 had
both Candida and Aspergillus infection, and 1 had both
Candida and Nocardia infection. Only 1 of these 8 patients had a pretransplant history of suspected fungal infection. Two
of the cases with isolated Candida infection were related to a
nosocomial outbreak caused by contamination of parenteral fluids with
C parapsilosis. Development of fungal infection in engrafted
patients showed a trend for correlation with lower numbers of CD4 cells
in the final processed marrow (P = .14).
Recurrent malignancy.
Six of the 20 patients with initial engraftment had recurrent
malignancy after transplantation. Two patients with acute leukemia in
relapse at the time of transplantation had recurrent disease diagnosed
on days 47 and 145 after transplantation. Among the other 7 patients
with acute leukemia, 6 died without recurrent malignancy between 4 and
118 days after transplantation, and 1 died without recurrent malignancy
on day 817. The other 4 patients with recurrent malignancy after
transplantation had CML. One was in first chronic phase at the time of
transplantation, 2 were in accelerated phase, and 1 was in chronic
phase after blast crisis. In 2 of these 4 patients, the disease
progressed despite discontinuation of immunosuppressive treatment. In 1 patient, the disease resolved after immunosuppressive treatment was
stopped, and in 1 patient the disease was controlled by treatment with
interferon. Among the other 7 patients with CML who engrafted, 6 died
without recurrent malignancy between 39 and 180 days after
transplantation, and 1 remains alive and well without recurrent
malignancy nearly 3 years after transplantation.
Causes of death, chronic GVHD, and current status.
Four of the 5 patients with failure of initial engraftment died: 1 with
fungal infection after a successful second transplant; 1 with fungal
infection after unsuccessful second and third transplants; 1 with
recurrent CML after spontaneous autologous reconstitution; and 1 with
hemorrhage and bacterial enteritis. The patient with late graft failure
died with systemic Pseudomonas infection. Sixteen of the 19 durably engrafted patients died: 8 with infection (3 bacterial, 2 fungal, 2 CMV, and 1 P carinii); 1 with acute GVHD; 2 with
chronic GVHD (and 2 with chronic GVHD as a contributing cause of death
in patients who died with infection); 4 with recurrent malignancy (2 CML, 1 ALL, and 1 AML); and 1 with unknown causes. Excluding UPN 9994 who was diagnosed with recurrent malignancy on day 82, 8 (73%) of 11 engrafted patients who survived for at least 100 days after
transplantation developed clinical extensive chronic GVHD. Four
patients remain alive: 1 with donor engraftment and chronic GVHD after
a second transplant following rejection of the first transplant (UPN
9202); 1 with donor engraftment and resolved GVHD without recurrent CML
(UPN 8670); 1 with donor engraftment and cytogenetic recurrence of CML,
which resolved after immunosuppressive treatment was discontinued (UPN
8532); and 1 with donor engraftment and cytogenetic evidence of
recurrent CML currently being treated with interferon (UPN 7850).
Results of this study suggest that with the use of conventional
pretransplant and posttransplant immunosuppressive regimens, removal of
CD4 cells from the graft does not cause rejection but also does not
appreciably decrease the risk of grades III-IV GVHD after
HLA-mismatched unrelated marrow transplantation. Depletion of CD8 cells
was associated with an increased risk of rejection with either DRB1
disparity or with HLA-A or -B disparity. In both groups, the risk of
grades III-IV GVHD is likely to be higher than 15% at any dose of CD8
cells associated with less than 5% risk of graft failure. The
correlation between graft failure and the number of CD8 cells in the
donor marrow supports the hypothesis that donor CD8 cells help to
prevent marrow graft rejection. With the conditioning regimens of
cyclophosphamide and 13.2 to 13.5 Gy TBI and the posttransplant
immunosuppressive regimen of methotrexate and cyclosporine used for
patients enrolled in this study, however, at least 5.0 × 106 donor CD8 cells/kg recipient body weight were needed to
prevent rejection of a marrow graft with either HLA-DRB1 or HLA-A or -B disparity. With the use of more intensive conditioning regimens, more
effective posttransplant immunosuppression, or possibly with larger
numbers of stem cells in the graft, lower numbers of donor CD8 cells
might be sufficient to prevent rejection without causing acute GVHD.
We thank Kale Slechta and Dr Torstein Egeland for preclinical testing;
Beth Macleod for processing the marrow grafts; Andrew Yamane and Mari
Malkki for HLA class I allele typing; Lori Hubbard and Tracey Stevens
for assistance with donor searches; Jennie Lorenz and Amy Mellon for
data management; Alison Sell for assistance with Food and Drug
Administration correspondence and preparation of the manuscript; and Dr
Shelly Heimfeld and Jeanie Bjerke for critical review of the
manuscript. Marrow from unrelated donors was procured with the
assistance of the National Marrow Donor Program and other marrow donor registries.
Submitted October 26, 1998; accepted April 21, 1999.
Supported by Grant Nos. AI33484, CA15074, CA18029, HL36444, and CA18221
from the National Institutes of Health, Department of Health and Human Services.
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.
Address reprint requests to Paul J. Martin, MD, Fred Hutchinson Cancer
Research Center, 1100 Fairview Ave N, D2-100, Seattle, WA 98109-1024;
e-mail: pmartin{at}fhcrc.org.
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|
TOP
ABSTRACT
INTRODUCTION
1" and "
A prospective, randomized, double-blind study.
J Infect Dis
171:1545, 1995