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REVIEW ARTICLE
From the Department of Adult Oncology, Dana-Farber
Cancer Institute, Brigham and Women's Hospital, Harvard Medical
School, Boston, MA.
Despite significant progress in the past 20 years,
graft-versus-host disease (GVHD) remains a significant cause of
morbidity and mortality after allogeneic hematopoietic stem cell
transplantation (HSCT). T-cell depletion (TCD) of the donor graft
offers the potential for prevention of GVHD without the morbidity
associated with immunosuppressive drugs such as methotrexate and
cyclosporine. Most early trials documented that TCD could substantially
limit acute and chronic GVHD. However, this reduction in GVHD did not
translate into improved overall survival because of unexpected high
rates of graft failure, Epstein-Barr virus-associated
lymphoproliferative disorders, and disease recurrence after TCD bone
marrow transplantation. Despite the problems associated with TCD, great
interest remains in developing and improving this technology,
particularly for recipients of HLA-mismatched grafts. If advances in
graft engineering can accomplish the goal of GVHD prevention without
adversely affecting engraftment, immunocompetence, and antileukemic
activity, then substantial improvements in overall transplant outcome
can be realized.
GVHD can be classified as acute or chronic based on timing of
onset and clinical features. Acute GVHD usually develops within the
first 2 months of bone marrow transplantation (BMT) and affects mainly
the skin, gastrointestinal tract, and liver. When pharmacologic immunosuppression is used as GVHD prophylaxis after myeloablative transplantation, moderate to severe acute GVHD (grades II-IV) occurs in 25% to 60% of matched related donor transplant recipients, and up to 45% to 70% in unrelated donor recipients.1-5
Acute GVHD is also emerging as a major complication after allogeneic nonmyeloablative stem cell transplantation.6 Development
of grade II to IV acute GVHD is associated with decreased survival in
patients after allogeneic BMT.7,8
Chronic GVHD has a later onset than acute GVHD and is often clinically
distinct. Patients can manifest sclerodermatous skin changes,
keratoconjunctivitis, sicca syndrome, lichenoid oral mucosal lesions,
esophageal and vaginal strictures, liver disease, and pulmonary
insufficiency.9 Despite immunosuppressive agents, approximately 30% to 50% of patients will develop chronic GVHD after
myeloablative HLA-identical sibling BMT. The incidence of chronic GVHD
may be even higher after allogeneic transplantation using unmanipulated
peripheral blood stem cells (PBSCs).10,11 Although limited
chronic GVHD often resolves spontaneously with minimal intervention,
extensive chronic GVHD requires prolonged immunosuppressive treatment
and is associated with significant morbidity and mortality. More than
50% of patients with extensive chronic GVHD will die, mostly secondary
to infections resulting from severe immune dysfunction.12
Acute GVHD is believed to occur in 3 phases: (1) tissue damage
from conditioning, (2) donor T-cell activation, and (3) inflammatory effectors. In the earliest phase, inflammatory cytokines are released from host tissue in response to damage by the pretransplantation conditioning regimen.13 These cytokines, including
interleukin-1 (IL-1) and tumor necrosis factor- Several clinical studies have attempted to interrupt the cytokine
cascade as a strategy to prevent GVHD. Unfortunately, a blinded
randomized trial of IL-1 receptor antagonist versus placebo did not
demonstrate any benefit for IL-1 blockade in acute GVHD prevention.15 Another trial of recombinant human IL-11 to
reduce Th1 cytokine production was halted due to unacceptable
toxicity.16 Thus, although interruption of the "cytokine
storm" may prevent GVHD in murine models, it appears to be
insufficient in humans, and T cells remain the prime target for current
therapeutic strategies in GVHD prophylaxis.
Current approaches for the prevention and treatment of GVHD
involve direct blockade of T-cell function. These include the down-regulation of T lymphocytes by inhibiting cellular proliferation (methotrexate), inhibition of de novo purine synthesis (mycophenolate mofetil), suppression of IL-2 secretion by blocking calcineurin activity (cyclosporine, FK-506), interfering with downstream growth signaling pathways (sirolimus), and reduction of T-cell
responsiveness by blocking the IL-2 receptor (daclizumab).
However, the most effective means of GVHD prophylaxis is depletion of T
cells from the donor inoculum. In many instances, TCD can dramatically
reduce the incidence of GVHD even in the absence of posttransplantation immunosuppressive therapy.
In 1968, Dicke and colleagues reported that irradiated mice
receiving transplants with spleen cell fractions depleted of small lymphocytes enjoyed 80% to 100% survival without evidence of GVHD, whereas mice given fractions containing increasing numbers of lymphocytes all died from severe GVHD.17 Subsequently,
Reisner and coworkers demonstrated similar results with mouse bone
marrow and spleen cell suspensions depleted of T cells by soybean or peanut agglutinination.18 In the 1970s, antithymocyte
globulin (ATG) was tried as a method of TCD, but with limited success
because early ATG preparations were also toxic to hematopoietic cells. This problem was later circumvented through the absorption of ATG with
spleen or liver suspensions to remove antibodies against stem
cells.19 Using absorbed ATG, animals successfully received transplantations with minimal to no GVHD, across both major and minor
histocompatibility barriers.20-25 In the late 1970s, it
became clear from murine models that even minor alloantigen differences could stimulate GVHD, and that contamination of the marrow with as few
as 0.3% T lymphocytes (3 × 104 cells) could be
sufficient to cause lethal GVHD.23 In 1981, Vallera and
colleagues reported on the first use of a monoclonal antibody,
anti-Thy-1.2, for ex vivo TCD in a murine transplant model.26 In that study, however, many animals still died
from complications of GVHD after a few months. This led to the eventual realization that antibody alone is insufficient to abrogate GVHD and
that addition of rabbit complement would confer superior protection. The importance of complement would be confirmed in subsequent human
studies using monoclonal antibodies for TCD.
Because animal studies had shown that pharmacologic
immunosuppression was not necessary after TCD, it was anticipated that TCD transplants in humans without cyclosporine and methotrexate would
be associated with less mucositis, renal failure, infections, and other
complications of conventional BMT. Furthermore, it was hoped that the
lower incidence of GVHD would translate into improved long-term
survival. From 1981 to 1986, hundreds of TCD transplantations were
performed worldwide using various methods of TCD. Although these trials
confirmed a low incidence of acute and chronic GVHD, they also revealed
new and important limitations associated with TCD BMT. These included
an increased incidence of graft rejection, delayed immune
reconstitution, increased posttransplantation lymphoproliferative disorders (LPDs), and increased rate of disease relapse.
Methods of TCD
T-cell dose in TCD BMT
The advantages and disadvantages of TCD are listed in Table
1 and discussed in more detail
below.
GVHD prevention HLA-identical sibling transplantation. In 1981, Rodt and coworkers reported on the use of absorbed human ATG as TCD in HLA-compatible sibling transplants and demonstrated that only 2 of 12 patients developed mild skin GVHD.33 In contrast, concurrent TCD studies using murine monoclonal antibodies alone reported GVHD rates of approximately 50%.35,36 These results prompted investigators to add complement in hopes of enhancing lymphocytolysis and improving GVHD outcome. Studies in the mid-1980s confirmed that TCD using monoclonal antibodies plus rabbit complement, which removed 2 to 3 logs of T lymphocytes, uniformly decreased the incidence of clinically significant GVHD to 10% to 20% after matched sibling transplantation.37,39,41-43 In the late 1980s and early 1990s, similar results were reported in larger phase II trials of TCD using anti-CD5, -CD6, and -CD8 antibodies plus complement, CAMPATH-1, or immunotoxins.49,54,61-64 In some of these studies, the low incidence of GVHD was achieved even in the absence of immunosuppression after transplantation.49,54 Studies of HLA-identical sibling PBSC transplantation using CD34+ selection have reported great variation in acute GVHD incidence from 8% to 100%.65-69 This variability was likely influenced by factors such as the number of CD3+ cells infused, immunosuppressive agents given after transplantation, and type of CD34+ selection device used. Other TCD methods are also being investigated with PBSC transplantation. Hale and associates have recently reported that HLA-matched sibling PBSC transplantation purged with CAMPATH-1H or CAMPATH-1G is associated with only 4% and 11% incidence of grade II to IV acute GVHD, respectively.70Alternative donor transplantation.
Retrospective data from the National Marrow Donor Registry (NMDR) have
demonstrated that TCD is a significant negative predictor for the
development of grade III to IV acute GVHD after unrelated BMT.71 The International Bone Marrow Transplant Registry
(IBMTR) recently reported on 1868 leukemia patients who
received allogeneic marrow transplants from donors other than
HLA-identical siblings. The incidence of grade II to IV GVHD was
between 34% and 38% in the TCD group, as compared to 57% in the
non-TCD group (P < .0001).72 HLA-matched
unrelated marrow transplants depleted of T cells with anti-CD6
monoclonal antibody plus complement as the sole form of GVHD
prophylaxis is associated with an approximately 40% incidence of grade II to IV GVHD.73 A similar result has been
reported for TCD using the Organ dysfunction after TCD BMT T-cell depletion appears to be associated with less organ toxicity early after transplantation compared to conventional BMT. The incidence of hepatic veno-occlusive disease has been reported to be only 3.1% after TCD BMT, and only 1.2% among patients receiving total body irradiation (TBI) as part of their conditioning.80 This reduction in hepatotoxicity may be due to the fact that the TCD patients are spared from injurious effects of methotrexate or cyclosporine/tacrolimus. Alternatively, decreases in alloreactivity may lead to lower levels of circulating cytokines, which could damage hepatic endothelium. Finally, because TCD patients may have earlier neutrophil recovery in the absence of methotrexate, they are also less likely to require antibiotics such as amphotericin that could have deleterious effects on hepatorenal function.T-cell depletion has also been associated with decreased pulmonary complications after BMT. Breuer and coworkers have reported that fatal interstitial pneumonitis occurred in only 6 of 80 (7.5%) consecutive allogeneic BMT where TCD was used as GVHD prophylaxis.81 In another series, the incidence of life-threatening pulmonary complications within the first 60 days of BMT was 8% among those who received TCD as the sole form of GVHD prophylaxis, but 33% among those who received cyclosporine and methotrexate (P < .0001).82 In this study, the protective effect of TCD against pulmonary complications was independent of acute GVHD in multivariate analysis, perhaps implicating deleterious effects of GVHD prophylactic medications. Transplant-related mortality Because TCD protects against GVHD and reduces organ dysfunction after BMT, one would expect these benefits to translate into lower transplant-related mortality (TRM). In a number of series, TRM after TCD BMT has indeed been quite low, ranging from 2% to 15%.49,83-86 However, other TCD studies have reported TRM rates from 20% to 32% even after matched sibling transplantations, with many deaths being secondary to graft failure, infections, and Epstein-Barr virus (EBV)-associated LPDs.54,87-89 This variability highlights the fact that elements other than GVHD, such as the intensity of conditioning, posttransplantation immunosuppression, graft failure, and immune reconstitution, also contribute significantly to TRM. It further reinforces the point that for a TCD regimen to be successful, it must do more than just protect against GVHD. It must also preserve graft-versus-leukemia (GVL) activity and engraftment potential and spare patients from excessive transplant-related toxicity.
Graft failure Prior to the advent of TCD, graft failure after allogeneic BMT was uncommon, occurring in 1% to 5% of patients having transplantations for leukemia.90,91 In contrast, most TCD BMT series in the 1980s and early 1990s reported higher rates of graft failure.31,32,40,41,43-46,51,52,61,87,92-99 In some of these studies, the incidence of graft failure was as high as 50% to 70%.92,99 In an analysis from the IBMTR of more than 3000 patients who received TCD or non-TCD BMT for leukemia, TCD was associated with a 9-fold increased risk for graft failure compared to unmanipulated marrow transplantation (P < .0001).100A number of studies have retrospectively analyzed risk factors associated with graft failure after TCD. Aside from HLA disparity, one important factor appears to be the dose of TBI administered before transplantation. Patients who are conditioned with higher doses of TBI consistently have lower incidence of graft failure compared to those who receive lower TBI doses.92,99,101,102 In addition, donor-recipient sex disparity, male donor gender, donor age over 25 years, and absence of posttransplantation immunosuppression, have also been reported to be significant risk factors for graft failure.95,99,100 Graft failure after TCD BMT can occur as 3 distinct patterns.92 These include (1) failure of initial engraftment, (2) partial or full initial engraftment followed by graft rejection within 2 weeks of BMT, and (3) delayed graft failure that can occur months after BMT. The pathophysiologic mechanisms behind these different patterns are not well understood, although it is widely accepted that early graft failure after TCD transplantation results primarily from immunologic rejection of donor hematopoietic elements by host lymphoid elements that have survived the conditioning process. Direct evidence for the role of the host immune system have come from the identification of host T lymphocytes from patients at the time of graft rejection, which exhibit donor-specific cytotoxic activity,103-112 and which suppress donor proliferation of granulocyte-macrophage colony-forming units and erythroid colony forming units in vitro.93,104 Clinical evidence further supporting this model includes observations that genetic disparity between donor and recipient correlates with graft rejection and that increased immunosuppression, either through the conditioning regimen or posttransplantation immunosuppressive agents, appears to protect against graft failure.92,95,99-102,113 It does not appear that failure of initial engraftment is caused by injury to hematopoietic progenitors or auxiliary cells during marrow manipulation, because autologous marrows purged with monoclonal antibodies and complement engraft without difficulty.61,99,114-116 Viral infections, such as cytomegalovirus (CMV) or human herpes virus 6, may contribute to graft failure after BMT.117-121 Although TCD BMT patients may have a higher risk of CMV reactivation after transplantation,122-125 direct clinical evidence implicating this and other viruses to graft failure after TCD transplantation is limited. Other clinical observations also offer insight into the pathophysiology of graft failure. Many studies have reported that mixed lymphoid and myeloid chimerism is more common after TCD BMT and that such chimerism may be associated with graft failure.99,102,126-130 Viable host-derived hematopoietic cells can often be recovered from patients after TCD marrow transplantation,131,132 and their coexistence with the donor graft implies a state of immune tolerance between the graft and host. This may be especially true for patients who have persistent stable mixed chimerism with fully functional hematopoietic grafts. For patients whose mixed chimerism is transient, however, it is possible that graft failure could result when host lymphoid tolerance of the graft is broken. At the current time, it is unknown whether the mixed chimeric state is a cause of graft rejection or an effect of the graft rejection process itself. The higher incidence of graft failure associated with donor-patient gender disparity has led researchers to investigate gender-specific antigens as potential targets for graft rejection. Studies suggest that female patients receiving grafts from male donors may be at higher risk for graft rejection because female recipient T lymphocytes can recognize male-specific minor antigens in the donor graft. The H-Y antigens encoded on the Y chromosome have been implicated as targets for this process. During rejection of male stem cell grafts, H-Y-specific CTL clones have been isolated from the peripheral blood of female recipients.110 Multiple H-Y antigens are believed to be involved in graft rejection. Known H-Y epitopes recognized by HLA-A2-restricted CTL clones include peptides derived from the SMCY and DFFRY genes.133-135 More recently, a third H-Y epitope that is recognized by HLA-B60-restricted CTL clones has been localized to the UTY gene on the Y chromosome.136 The identification of these H-Y antigens could prove useful in the selection of donor recipient pairs for stem cell transplantation and could be especially relevant in female recipients who may have been sensitized to male antigens through prior blood transfusions. Because graft rejection is felt to be mediated by residual host T cells that have escaped myeloablation, early preventive strategies were focused on intensifying the myeloablative regimen. Some investigators also believed that intensive conditioning regimens would empty out the host marrow and increase "hematopoietic space" for the incoming donor graft. High doses of cytarabine, thiotepa, and anthracyclines have been incorporated into standard ablative regimens and have reduced the rate of graft failure after TCD BMT.89,137-141 However, these were also more likely to be associated with increased regimen-related toxicity. Other researchers have investigated the addition of total lymphoid irradiation (TLI) as a strategy against graft failure. Although TLI has been shown to reduce graft failure after conventional BMT for aplastic anemia,142-144 its benefits are less clear after TCD BMT. Although single-arm studies of TCD BMT have reported a low incidence of graft failure when TLI was included in the conditioning regimen,87,145,146 an older prospective randomized trial of TCD transplantation failed to show any benefit.147 An alternative method of immunosuppression commonly used to reduce graft failure after TCD BMT is the simultaneous depletion of host immune cells using ATG or CAMPATH-1 at the time of transplantation. Studies in animals from the late 1980s showed that in vivo depletion of recipient lymphocytes using anti-T-cell monoclonal antibodies could prevent rejection of the TCD marrow even across major histocompatibility barriers.148,149 The presumed mechanism behind this observation was that the treatment eliminated host lymphocytes that were active in the graft rejection process. In 1994, Hale and his associates adapted this approach to humans and reported that simultaneous donor and host TCD with CAMPATH-1 reduced the incidence of graft failure to less than 10%, without compromising GVHD prophylaxis.87 In their subsequent series of 70 AML patients receiving transplants from HLA-identical sibling donors using this combined TCD approach, the incidence of graft failure was only 6%, significantly lower than that with donor marrow TCD alone.86 Another widely applied strategy for reducing graft failure involves
limited or selective TCD. The premise of this approach arose from the
belief that most early methods of TCD had attempted to deplete as many
T lymphocytes from the marrow as possible and that the exhaustive
depletion nonspecifically removed ancillary marrow elements that were
necessary to sustain engraftment. It was thus postulated that by
selectively purging only certain subsets of T cells, such as mature T
lymphocytes, but sparing NK cells, immature thymocytes, monocytes, and
other hematopoietic elements, one could maintain the protective effects
against GVHD without increasing the risk for graft failure. Several
selective antibody-purging methods have been successfully used. Studies
using anti-CD5 immunotoxins, anti-CD6, and anti-TCR T-cell add-back to the marrow inoculum has been studied as a means of reducing graft rejection after TCD BMT. Using centrifugal elutriation technique for T-cell separation, Wagner and coworkers have shown the reintroduction of T lymphocytes to a dose of 0.5 × 106 cells/kg protects against GVHD while maintaining engraftment at over 95%.59 Researchers have also added back donor T cells to marrow that had been T depleted using CAMPATH-1. However, these studies are problematic because of an increased risk of severe GVHD as the number of T cells added back is increased.153,154 Dose escalation of CD34+ stem cells may be an effective strategy for overcoming graft failure after TCD BMT. Preclinical models have shown that mice given "megadoses" of TCD marrow could engraft despite sublethal doses of conditioning irradiation.155 In human studies, the addition of CD34+ cells to TCD marrow to augment stem cell dose has permitted reliable engraftment in leukemia patients despite full HLA haplotype mismatches.60,79 Delayed immune reconstitution Regeneration of the immune system after allogeneic BMT is a slow process that is often protracted by the presence of GVHD and its treatment. Peripheral blood T- lymphocyte counts do not normalize until 3 to 12 months after BMT,156 and their functional recovery frequently takes even longer.157-159 In vitro studies of T cells after BMT have demonstrated reduced proliferative response to mitogenic stimuli, abnormal cytotoxic T-cell effector function, and impaired ability to collaborate with B cells in immunoglobulin synthesis.157,160-166 Because of this delayed immune reconstitution, patients after allogeneic BMT remain susceptible to opportunistic infections for months to years.After allogeneic BMT, regeneration of T-cell populations occurs by both thymic-dependent and thymic-independent pathways. The former pathway involves the positive or negative selection of thymocytes in the thymus and produces a T-cell population with a diverse T-cell receptor (TCR) repertoire. In contrast, the thymicindependent pathway, which reconstitutes the T-cell compartment by expansion of T cells infused along with the graft, produces a T-cell population with limited TCR diversity. Although the thymic- dependent pathway appears to be important in the regeneration of T cells after chemotherapy in children, it may be less active in adults whose thymuses are involuted.167,168 However, even in adults, the host thymus is required after BMT for the reconstitution of CD4+ and CD8+ naïve subsets, and maintenance of TCR diversity.169 Immune recovery after TCD BMT has been studied in a number of transplant centers using various methods of TCD.163,165,170-175 After allogeneic BMT, NK cells appear to be the first lymphoid subset to emerge, usually within 2 to 3 weeks after transplantation, followed by B cells (3-6 months) and T cells (3-12 months). Phenotypic analyses reveal that total lymphocyte numbers are usually higher early after BMT in recipients of conventional marrow compared to TCD grafts. Furthermore, the reconstituted T-cell compartment is predominantly of the CD8+ subset, and most TCD BMT patients will have a deficit in CD4+ cells, with an inverted CD4+ to CD8+ ratio for up to 2 years.165 The number of CD4+ cells normalizes at 7 to 9 months after conventional BMT, but this process is delayed after TCD BMT.170 Functional recovery of T cells appears to be impaired after TCD BMT as well. Welte and colleagues reported that in recipients of TCD marrow, the proliferative response of peripheral blood mononuclear cells to exogenous IL-2 stimulation remained abnormal for up to 6 months, compared to only 1 month for recipients of conventional BMT.163 Similarly, the proliferative response of T cells to mitogenic stimulation can be impaired for over 18 months after TCD BMT.165 As another reflection of their decreased function, T lymphocytes from recipients of TCD BMT have significantly restricted variability in their TCR repertoires.173,175 This may be explained in part by the fact that the T-cell compartment after BMT is expanded mainly from lymphocytes cotransfused with the marrow, and therefore recipients of TCD transplants would have many fewer precursors with which to reconstitute their repertoire than recipients of conventional BMT. In support of this hypothesis, TCR analyses have shown the peripheral T-lymphocyte pool after TCD BMT to be the progeny of a limited number of precursors.173 The delayed reconstitution of CD4+ cells and impaired recovery of T-cell repertoire diversity have led many to speculate that TCD BMT recipients may be at higher risk for opportunistic infections. Although there is little reported evidence to suggest an increased risk of bacterial or fungal infections after TCD transplantation, a number of studies have demonstrated a higher probability of reactivation for viruses such as CMV,122,124,125 and EBV, leading to EBV-associated B-cell lymphoproliferative disorders (EBV-LPDs).54,176,177 EBV-LPDs Although EBV-LPDs are well known in immunosuppressed patients after solid organ transplantation, it is surprisingly uncommon after BMT except in the TCD setting, where its incidence has been reported to be between 5% to 30%.54,176,177 Recipients of TCD transplants using HLA-mismatched or unrelated donor marrow appear to be at particularly high risk,138,176,178 as are patients with severe GVHD and those treated with certain anti-T-cell monoclonal antibodies.54,176,179 EBV-LPDs are felt to arise mainly from infected donor B cells that have been cotransplanted with the allograft. However, there have been cases of EBV lymphoma in B cells from EBV-seronegative donors, suggesting that de novo infection in transplant recipients or reactivation of EBV in recipient cells can occur.Although combinations of IFN- Spurred by the advances in the understanding and treatment of EBV-LPDs, researchers have in recent years concentrated their efforts on prevention of this disease. B-cell depletion of the donor graft has been investigated as a strategy to reduce EBV-LPDs after TCD BMT. Cavazzana-Calvo and colleagues have shown that combined ex vivo depletion of B and T cells from the graft using monoclonal antibodies effectively prevented EBV-LPDs and improved survival compared to control patients who received TCD grafts without B-cell purging.190 Similarly, Hale and Waldman have reported that TCD BMT using CAMPATH-1 was associated with a minimal risk for EBV-LPDs.191 They attributed this risk reduction to the fact that CAMPATH-1 depletes both T and B cells, thereby removing donor B cells that are potentially infected with EBV from the donor marrow.191 Finally, the prophylactic administration of EBV-specific CTLs has been shown to reduced the incidence of EBV-LPDs after TCD BMT.185,186 Leukemia relapse The higher incidence of leukemia relapse associated with TCD BMT was first suggested in a prospective randomized trial which included 40 patients with acute and chronic leukemia.44 Of the 20 patients randomized to the TCD arm, 7 had clinically apparent relapse, compared to only 2 in the control (non-TCD) arm.44 Although not statistically significant, this difference prompted researchers to investigate the possibility of higher disease relapse associated with TCD. Multiple retrospective studies have subsequently demonstrated that leukemia relapse is indeed more frequent after TCD BMT, especially for CML.8,100,126,192-196The increased rate of leukemia relapse after TCD BMT has been linked, as least in part, to the reduction in GVHD and concomitant loss of the GVL activity. In recipients of T-cell-replete marrow, patients who develop clinically significant GVHD have a lower incidence of leukemia relapse compared to those who do not develop GVHD.197-199 Additional evidence linking T cells and GVL activity comes from studies using donor lymphocyte infusions in patients with CML who have relapsed after BMT, where complete response rates of 70% to 80% have been attained.200,201 TCD BMT for CML. An increased rate of relapse has been observed in virtually all studies using TCD of HLA-identical sibling bone marrow on patients with CML.100,126,192,193 The risk of relapse after matched related TCD BMT for CML chronic phase has been estimated to be 5- to 6-fold higher than that after conventional BMT.100,192 This relative risk has been reported to be as high as 18 for TCD transplantations done in accelerated phase CML.193 However, the increase in CML relapse is not as apparent after TCD transplantation using matched unrelated marrow.199,202-204 In one series, the 3-year probability of relapse for CML chronic phase was only 8% for recipients of unrelated TCD allografts, compared to 47% for those who received TCD marrow from HLA identical siblings.204 TCD BMT for acute leukemia. Unlike CML, TCD appears to have only a modest effect on the relapse rate of patients receiving transplants for acute leukemia. Reported rates of relapse after TCD BMT for acute myelogenous leukemia (AML) in first remission have ranged from 0% to 31% in different centers and are at least partly influenced by factors such as intensity of conditioning, extent and method of TCD, patient selection, and posttransplantation immunosuppression.83,89,205-207 Retrospective data from the IBMTR, which included 731 TCD and 2480 non-TCD BMTs for leukemia, have shown that TCD is associated with a 1.7- to 2.0-fold increased risk for recurrence in patients with acute lymphoblastic leukemia (ALL) in any phase and in patients with AML undergoing transplantation in relapse or first remission.100 However, in a small randomized trial comparing TCD with methotrexate and cyclosporine as GVHD prophylaxis for leukemia patients undergoing HLA-matched related BMT, a higher relapse rate was observed after TCD BMT only in patients with CML, but not in patients with acute leukemia.208 Leukemic relapse after alternative donor TCD BMT.
There have been conflicting reports on whether TCD adversely affects
leukemia-free survival after alternative donor transplantation. In an
analysis of 462 patients from the NMDP, TCD was associated with a
significant increased risk for leukemia relapse at 2 years.71 More recently, Champlin and colleagues reported
on the IBMTR experience from 870 patients who underwent T-depleted
unrelated or mismatched donor BMT for leukemia.72 They
discovered that the leukemia-free survival for patients whose grafts
were depleted with "narrow specificity" antibodies (eg, anti-CD5,
CD6, anti-TCR TCD BMT for lymphoma/myeloma. Although studies have shown lower lymphoma and myeloma relapse after allogeneic BMT than autologous transplantation,209-214 use of allogeneic BMT has been restricted in these diseases primarily because of disproportionately high rates of transplant-related mortality. Because TCD is associated with less toxicity, it has been suggested that TCD transplants may be particularly beneficial in these conditions. Small studies of matched sibling TCD BMT for non-Hodgkin lymphoma (NHL) and multiple myeloma (MM) have indeed demonstrated low rates of treatment-related toxicity and mortality.151,215 However, whether TCD will protect against relapse and improve overall survival remains unknown.
Selective TCD Although both GVL activity and GVHD are initiated by T cells in the donor graft, evidence suggests that different subsets of T lymphocytes may be involved in these processes and that GVL activity could exist in the absence of GVHD.216,217 In animal models, both donor CD4+ and CD8+ cells play a significant role in GVHD, but donor CD4+ cells in the absence of CD8+ cells can still mediate GVL activity.218 Based in part on these observations, Champlin and colleagues have shown that CD8+ depletion followed by posttransplantation cyclosporine can reduce the incidence and severity of GVHD without compromising GVL activity. In their initial study of 36 leukemia patients given CD8+-depleted matched sibling grafts, 2 (8%) developed grade III to IV GVHD, and only 3 (11%) had leukemia relapse at 2 years.62 In a follow-up double-blind randomized trial, the cyclosporine plus CD8+depletion arm experienced significantly less grade II to IV GVHD compared to the control arm receiving cyclosporine alone (20% versus 80%, P < .004), and the leukemia relapse rates were similar between the 2 groups.219Additional evidence to suggest that GVL activity can be separated from GVHD has emerged from studies of DLI given for relapsed disease after BMT. Although many DLI series have demonstrated an association between development of GVHD and antileukemic response, it is clear that in a number of patients, remission can be attained in the absence of GVHD. The GVHD/GVL dichotomy is further evidenced in DLI studies using CD8+ depletion. CD8+-depleted DLI has been shown to significantly reduce the incidence of GVHD, but retain GVL activity and clinical responses in patients with relapsed CML.220,221 Although studies of CD8+ depletion have been encouraging, the pathophysiologic differences between GVHD and GVL are likely more complicated than just CD4 and CD8 cells. Definitive dissection of the anatomic subsets underlying GVHD and GVL remains a crucial but elusive goal for investigators hoping to reduce disease relapse after TCD BMT. Cytokine stimulation Another strategy aimed at decreasing disease relapse rates after TCD BMT has been the administration of IL-2 after transplantation to stimulate activity of NK cells. Evidence has emerged to suggest that NK cells may be important mediators of antileukemic activity. Baker and coworkers have recently reported in murine models that CD8+ NK/T cells expanded in culture with IL-2, IFN- , and anti-CD3 monoclonal antibody exhibit potent cytotoxic activity against syngeneic
and allogeneic tumor targets both in vitro and in vivo.222 When allogeneic mice across major histocompatibility barriers received
these expanded CD8+ NK/T cell transplants, little GVHD was
observed despite doses up to 20 × 106 cells. In
contrast, when the same donor-recipient pairs were given transplants
with 2.5 × 106 splenocytes rich in T cells, all
developed acute GVHD and died within 20 days. Evidence for NK cell
alloreactivity in GVL has also been suggested in human studies.
Addition of IL-2 to peripheral blood lymphocytes collected from CML
patients after allogeneic BMT has been shown to induce an NK cell
cytolytic response against cryopreserved leukemic cell
targets.223,224 In an analysis of 20 patients who received
allografts grafts mismatched at the HLA-C or Bw4
allele in the direction of GVHD, Ruggeri and coworkers were able
to isolate donor versus recipient alloreactive NK cell clones at a high
frequency early after transplantation, even though none of these
patients had clinical evidence of GVHD.225 They further
demonstrated that these alloreactive NK cell clones could lyse the
patients' pretransplantation cryopreserved leukemia cells in vitro,
suggesting that GVL activity mediated by NK cells exists in these
patients without GVHD.
Interleukin-2 is known to stimulate both NK cells and activated T cells at high concentrations. However, IL-2 at low doses appears to stimulate NK cells preferentially. As such, it has been postulated that administration of low doses of IL-2 may enhance GVL activity through NK cell stimulation without inducing GVHD. Prolonged infusion of low-dose recombinant IL-2 following TCD allogeneic BMT has been shown to be well tolerated and results in a marked increase in NK cell numbers.226 Mononuclear cells taken from patients after low-dose IL-2 treatment have also been shown to possess substantially enhanced in vitro cytolytic activity against tumor cell lines.226 In a pilot clinical trial, the prolonged infusion of IL-2 of at least 4 weeks after TCD BMT appeared to lower the incidence of disease relapse relative to historical controls.227 Although promising, these preliminary results have yet to be tested in randomized studies. DLI Adoptive immunotherapy using DLI has also emerged as a potential approach to compensate for the higher rate of leukemia relapse after TCD BMT. Sehn and colleagues have retrospectively analyzed the outcomes of 46 CML patients who underwent TCD allogeneic BMT, and compared them to 40 similar patients who received non-TCD allogeneic transplants using cyclosporine and methotrexate.84 They found that, as expected, the TCD group had a lower incidence of GVHD and treatment-related mortality, but a higher probability of hematologic or molecular relapse compared to the non-TCD group. However, most of the patients suffering relapse were successfully salvaged with DLI, compensating for the initial higher relapse rate associated with TCD. Similarly, Drobyski and coworkers reported that despite a high cumulative incidence of CML relapse (49%) at 3 years after TCD BMT, the 5-year overall survival rate in their cohort was 80% because most patients having relapse achieved durable remissions with DLI therapy.85 Taken together, these results suggest that TCD BMT followed by posttransplantation DLI at disease relapse could be a reasonable option for patients with CML, especially for those with concurrent comorbidity or advanced age who would otherwise be suboptimal candidates for non-TCD BMT.
Functional TCD/induction of T-cell anergy Instead of focusing on removal of anatomic subsets, some investigators have turned their attention to TCD techniques in which only alloreactive T cells are removed from the graft. In one such system, donor T cells are coincubated with recipient mononuclear cells in vitro. After a defined interval, alloreactive cells are identified by expression of activation markers, such as CD25 or CD69, and are physically separated from the remaining cells by immunomagnetic cell sorting.228,229 Using this method, Koh and colleagues have shown that approximately 90% of the alloreactive component could be purged while preserving more than 70% residual immunity as measured by third-party alloantigen response.228 It is postulated that this method would preferentially purge alloreactive lymphocytes from the graft that are responsible for GVHD, but retain nonreactive T cells, which may improve posttransplantation immune reconstitution and enhance engraftment.As an extension of functional TCD, other investigators have attempted to induce anergy in donor T cells prior to transplantation as a means of reducing GVHD. Murine marrow transplant studies have shown that GVHD could be reduced even across major genetic barriers by treating the recipient with CTLA4-Ig, an agent that blocks the CTLA4-BB1 (also called CD28-B7) interaction between T lymphocytes and antigen-presenting cells.230,231 Blockade of this and other costimulatory pathways (LFA-1/ICAM, CD40-CD40L) have since been shown to deactivate T cells and induce a state of alloimmune tolerance after BMT.231-233 A recent study in pediatric patients has suggested that costimulatory signal blockade using CTLA-Ig may reduce GVHD after HLA-mismatched BMT.234 If differential targets for GVHD and GVL can be identified, it may be possible to expose donor marrow in vitro to GVHD targets in the presence of CTLA4-Ig to induce GVHD specific anergy, while preserving the T-cell response to tumor antigens for a full GVL effect. Delayed T-cell add-back/prophylactic DLI The success of DLI in salvaging CML patients after BMT has led many researchers to investigate the potential of using delayed T-cell add-back to eliminate residual disease after TCD BMT. The attraction of this approach is that it allows one to reap the benefits of TCD early after BMT (ie, decreased GVHD and transplant-related toxicity), and yet be able to restore the GVL effect at a later time with DLI. Alyea and colleagues have recently conducted a trial of delayed T-cell add-back in 14 patients with MM after TCD allogeneic BMT.235 Of the 11 patients who had persistent myeloma 6 months after transplantation, 10 responses (6 complete, 4 partial) were observed after DLI, and the 2-year progression-free survival for the 14 patients who received DLI was significantly improved compared to a comparable historical cohort who received TCD BMT without DLI. After nonmyeloablative stem cell transplantation, the GVL effect induced by DLI may be sufficient to prevent relapse in leukemic patients with minimal residual disease.236Even though DLI is performed when the patient is further removed from conditioning therapy and the associated inflammatory cytokine milieu, GVHD remains a major complication. Existing data on DLI show a GVHD incidence between 40% and 80%, and an attendant mortality of nearly 20%. The solution to this GVHD problem may lie in the correct timing and dosing of lymphocytes with the T-cell add-back, but neither of these parameters is known at this time. In patients given DLI for relapsed disease, GVHD incidence and severity have been decreased without loss of GVL by lowering the dose of lymphocytes infused,237 or by selectively depleting CD8+ cells from the lymphocyte pool.221,238 For prophylactic DLI to be viable, it must reduce relapse rates without inducing GVHD. This may be possible by using DLI with a fixed number of selected T cells. A randomized trial of prophylactic DLI 6 months after TCD BMT has attempted to address this issue. Patients were randomized to receive either unselected or CD8+-depleted lymphocytes, adjusted to a CD4+ dose of 1.0 × 107 CD4+ cells/kg. None of 9 patients receiving CD8+-depleted lymphocytes developed GVHD, compared to 6 of 9 patients receiving unselected cells (P = .003). All patients experienced conversion to complete donor chimerism, and relapse rates were similarly low in both groups.244 In recent years, researchers have introduced the herpes simplex thymidine kinase (HSTK) gene into donor T cells as a novel approach for controlling GVHD after DLI. The insertion of this "suicide" gene into donor T lymphocytes renders them susceptible to destruction with ganciclovir, and therefore provides a reliable means of eliminating these cells should severe GVHD develop after the infusion.239,240 The use of suicide gene therapy may also be applicable in conjunction with TCD BMT. Tiberghien and coworkers have recently shown that HSTK gene-modified T lymphocytes infused along with TCD marrow at the time of transplantation did not interfere with engraftment.241 More significantly, they were able to demonstrate long-lasting circulation of the gene-modified cells after transplantation, and in 2 of 3 patients, GVHD response on treatment with ganciclovir.241 A case of chronic cutaneous GVHD responsive to ganciclovir has also been recently reported in a patient who had received T cells bearing the HSTK gene at the time of BMT.242 Vaccine strategies As new leukemia antigens are identified that are potential targets for the GVL response, allogeneic tumor vaccines may be developed to stimulate specific antileukemic activity without GVHD. As an example, a recently identified peptide (PR1) from the serine protease proteinase 3, which is aberrantly expressed in myeloid leukemias, may serve as a specific target for the GVL response.243 Investigators have successfully isolated PR-1-specific CTLs from the peripheral blood of patients with CML. PR-1-specific CTLs were found in 11 of 12 patients who responded to IFN therapy, but none of the 7 patients who did not respond. Furthermore, 6 of 8 patients who responded to allogeneic BMT had PR-1-specific CTLs in their blood, but in the one patient who relapsed after BMT, no PR-1-specific CTL could be detected.243 Based on these results, clinical trials of a PR-1 peptide vaccine are currently being conducted in patients with myeloid leukemia, and adoptive cellular therapy using PR-1-specific CTLs may one day replace DLI as a method for eradicating leukemia cells without GVHD after TCD transplantation.
It is frustrating that after 2 decades, we have not been able to establish the role of TCD in transplantation. We still do not have a clear idea of who should receive a TCD BMT, or how marrow or stem cells should be purged. It remains unclear whether additional medications are needed to promote engraftment or control GVHD, or what the nature and timing of immunomodulating manipulations to reduce the risk of relapse should be. There have been no definitive randomized trials to answer these questions to date, partly because researchers have not been able to agree on a single TCD strategy or the best way to engineer a graft. The optimal number of T cells to include in the graft remains unknown and may in fact vary among donor-recipient pairs. It would be ideal to be able to manipulate different lymphoid subgroups responsible for GVHD and GVL. Being able to do so will be critical to the future success of allogeneic stem cell transplantation.
Submitted June 8, 2001; accepted July 27, 2001.
Supported in part by NIH grant AI29530.
R.J.S. is a clinical scholar of the Leukemia Society of America.
© 2001 by The American society of Hematology
Reprints: Robert J. Soiffer, Dana-Farber Cancer Institute, 44 Binney St, D1B58, Boston, MA 02115; e-mail: robert_soiffer{at}dfci.harvard.edu.
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Introduction
Graft-versus-host disease
(TNF-
T-cell receptor antibody
T10B9 in unrelated marrow transplants for
patients with chronic myelogenous leukemia (CML).
