The current status of T-cell depleted allogeneic stem-cell transplants in adult patients with AML

Cytotherapy (2001) Vol. 3, No. 3, 175–188

Review

The current status of T-cell depleted allogeneic stem-cell transplants in adult patients with AML D Bunjes Stem Cell Transplantation Programme, Department of Haematology/Oncology, Ulm University Hospital, FRG

Introduction Treatment results for adult patients suffering from AML have improved considerably over the past 10 years, thanks to the use of intensive consolidation therapy [1,2]. Nevertheless, a significant proportion of patients relapse or never achieve a remission, and an allogeneic stem-cell transplant (SCT) is the only curative treatment option available [3,4]. For those 60–80% of patients who achieve a remission after induction chemotherapy, the optimal consolidation therapy has not yet been defined [2–4]. In several randomized prospective trials comparing allogeneic SCT with autologous SCT and consolidation chemotherapy, the lowest relapse rates have consistently been observed after allogeneic SCT [2,5–7]. None of these trials have reported a survival advantage for patients given an allogeneic SCT as consolidation therapy in first remission, because of the high procedure-related mortality associated with an allogeneic transplant. Transplantrelated complications cause the death of 20–30% of patients with AML transplanted from an HLA-identical sibling in first CR, and this figure rises to 40–50% in patients beyond first remission [8]. Most of these procedure-related deaths are directly or indirectly caused by GvHD, which also has a dominant influence on the qualityof-life achieved after an allogeneic SCT [9,10]. A combination of cyclosporine and methotrexate 6 steroids given post-transplant is used as GvHDprophylaxis in approximately two-thirds of patients receiving an allogeneic SCT worldwide [8]. The efficacy of this combination is limited, 30–50% of patients receiving an HLA-identical sibling transplant will develop clinically relevant Grade II–IV acute GvHD and the same percentage develop chronic GvHD [11–13]. The incidence of

acute GvHD rises to 70–100% in patients given matched unrelated or mismatched family donor grafts [14–16]. Ever since the central role of T cells in the pathogenesis of GvHD was established in animal experiments in the late 1970s [17,18], the removal of T cells from the graft, i.e. T-cell depletion, has suggested itself as a potentially more effective and less toxic alternative to post-transplant immunosuppression. The initial results of the first trials of T-cell depletion in human allogeneic SCT seemed to confirm these expectations [19–23]. Provided that a ù 2 log T-cell depletion was achieved, the incidence of Grade II–IV acute GvHD was reduced to 10–20% after an HLAidentical transplant and a similar reduction in chronic GvHD was observed. Haploidentical transplants can be performed with a 10% risk of Grade II–IV acute GvHD if the graft is depleted by 3–3.5 log [24,25]. However, it rapidly became apparent that T-cell depletion was associated with a 10–60% risk of graft failure and a 2–5 fold increase in the risk of relapse [20–23,26–28]. T-cell depletion was also shown to delay immune reconstitution after SCT and to increase the risk of EBV-induced lymphoproliferative disease [29,30]. Thus, Marmont et al. concluded in 1991 that, although T-cell depletion reduced the risk of acute and chronic GvHD, it increased the risk of treatment failure for all types of leukemia [31]. Over the past 10 years, numerous investigators have attempted to define the pathogenesis of the complications associated with T-cell depletion and to develop strategies to overcome them. The following review will describe and discuss the most important of these strategies and their impact on T-cell depleted transplants for acute leukemia.

Correspondence to: D Bunjes, Stem Cell Transplantation Programme, Department of Haematology/Oncology, Ulm University Hospital, Robert Koch Strasse 8, 89081 Ulm, Germany. © 2001 ISHAGE

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The pathogenesis of graft failure and approaches to prevention The increased risk of graft failure observed in practically all studies of T-cell depletion could be caused by two general mechanisms: Stem-cell damage due to the manipulation of the graft in vitro. n Loss of a graft-enhancing effect of graft T cells, which could be due to their production of growth-stimulating cytokines, or their alloreactivity towards residual host cell. n

A multivariate analysis performed by the International Bone Marrow Transplant Registry (IBMTR) on a large number of patients receiving T-cell depleted BM grafts from HLA-identical siblings revealed three major factors with a protective effect against graft failure [31]: A TBI dose of . 11 Gy. A high dose-rate of TBI. n Post-transplant immunosuppression with cyclosporine and/or methotrexate. n n

These data clearly suggest that host anti-donor immune reactivity, normally eliminated by the T cells in the graft, is the main mechanism responsible for the graft failures observed after T-cell depleted SCT. Laboratory studies in several centers have indeed confirmed that host T cells with reactivity against donor hemopoiesis can be identified in the peripheral blood of patients with graft failure [32–41]. There is no evidence in the literature to suggest that stem-cell damage due to graft manipulation has been a significant cause of graft failure, but the possibility that T cells contribute to engraftment by producing cytokines was not excluded. Based on these in vitro studies, investigators have proposed and evaluated a number of approaches to prevent graft failures: n n n n n n n

Intensifying the chemoconditioning prior to SCT; Increasing the dose of TBI; Adding TLI to TBI; In vivo T-cell depletion with MAbs, or ATG/ALG; Giving hemopoietic growth factors, such as GM-CSF or G-CSF; Partial or selective T-cell depletion; Increasing the stem-cell dose.

The experimental basis for intensifying chemoconditioning, increasing the dose of TBI or adding TLI was mainly provided by work performed by Reisner’s group in Israel [42–46]. In these animal studies, the addition of alkylating agents, such as thiotepa or dimethylbusulfan, increasing the dose of TBI, or adding TLI, significantly reduced the risk of graft failure. These animal data were confirmed in human studies in which either additional chemotherapy or a higher dose of TBI were used. In some of these studies, however, no survival benefit was obtained, due to increased organ toxicity [26,47,48]. Adding TLI to the standard conditioning regimen has proved to be both effective and well tolerated [49–52]. In view of the importance of radioresistant host T lymphocytes, a more selective approach to inactivating or eliminating these cells in vivo, by the use of MAbs or ATG/ALG appeared to be an attractive option. Functional inactivation of host T cells using an antiLFA1 MAb was effective in preventing graft failures in children with congenital immunodeficiencies, but not in patients with leukemias [53,54]. The concept of in vivo/ex vivo T-cell depletion with MAbs, to control both GvHD and graft failure, was established in an experimental mouse model by Cobbold et al. [55], and CAMPATH-1G was found to be as effective as TBI or high-dose chemotherapy in depleting T cells in vivo [56]. This approach has been used in several studies utilizing either ATG or CAMPATH-1G for in vivo T-cell depletion. The efficacy of ATG is difficult to evaluate because in the studies in which it has been used the investigators have generally intensified chemoradiotherapy as well [57,58]. This very intensive conditioning was highly effective in preventing graft failure and was well tolerated. Proof of principle for the in vivo/ex vivo concept was provided by a study of the CAMPATH Users Group, in which the only change in the conditioning of the study group was the addition of CAMPATH-1G. This significantly reduced the risk of graft failure when compared with a historical control group [59,60]. The addition of hemopoietic growth factors after SCT has been tested in a very limited number of patients, but giving GM-CSF had no effect on the rate of graft failures after T-celldepleted SCT [61]. Several groups have performed selective or partial T-cell depletion to reduce the risk of graft failure. Depletion of only CD81 T cells did not improve engraftment [62,63], which is not surprising given the fact that

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CD81 T cells appear to have a graft-enhancing effect [64]. Partial depletion of marrow T cells, or early addback of donor T cells has been effective in terms of preventing graft failure, but has been associated with a clearly increased risk of GvHD [50,65,66]. There is ample evidence from animal studies that a high marrow-cell or stem-cell dose promotes engraftment [67,68]. In recent years there have been several reports emphasizing the importance of a high marrow cell count and/or high numbers of CD341 cells for the outcome of allogeneic stem-cell transplantation [15,69–72]. Given the limited scope for increasing the stem-cell dose in human BMT, no formal trial testing of this hypothesis has been performed. However, there is some evidence available from haploidentical SCT. Aversa et al. were able to significantly reduce the risk of graft failure by adding T-cell depleted G-CSF mobilized PBPC to T-cell-depleted haploidentical BM grafts [25,58]. The discussion has so far focused on graft failure after a T-cell depleted HLA-compatible family-donor transplant. The amount of information about the risk of graft failure after a T-cell depleted MUD transplant, or an HLA-mismatched family donor is limited. The risk of graft failure after a T-cell depleted MUD transplant seems somewhat higher than after a matched family transplant, in spite of the fact that the majority of patients received an intensified conditioning regimen and most of them were given cyclosporine post-transplant [16,73,74]. The incidence of graft failure after a MUD transplant is of the order of 10–15%, even if additional in vivo T-cell depletion is performed and high stem-cell doses are given, as shown in pediatric trials [75,76]. T-cell depletion of haploidentical marrow grafts for patients with leukemia was associated with a prohibitive graft failure rate, of up to 50% [77]. In the past 5 years several investigators have achieved significant improvements in the rate of stable engraftment in this group of patients. Two types of approach have been pursued. The Perugia group and several other groups have combined an intensified conditioning regimen, in vivo T-cell depletion with ATG and an ultra-high stem-cell dose, obtained by either adding mobilized blood stem cells to a marrow graft, or by using a large number of blood stem cells [25,78–80]. The mechanism of action of the high doses of T cells has not been completely defined, but there is some experimental evidence suggesting that donor CD341 cells are acting as veto cells for host T cells [81]. The

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alternative approach has been to combine very intensive conditioning with partial T-cell depletion and intensive post-transplant immunosuppression [82]. Both approaches have succeeded in reducing the incidence of graft failure after a T-cell depleted haploidentical stem-cell transplant to about 10%.

The pathogenesis of relapse and approaches to its prevention Within a few years of the introduction of T-cell depletion into clinical practice it became obvious that this type of GvHD prophylaxis was associated with a greatly increased risk of relapse for patients with CML in the first chronic phase [28,83]. The initial reports in patients with AML were contradictory, with some centers reporting no increase in relapse rates [20,23,84–86] and others observing a significantly higher risk of relapse [27]. Two large studies by the IBMTR using multivariate analysis then provided clear evidence that T-cell depletion is associated with an increased risk of relapse, even among patients transplanted in first remission, although the risk is very much lower than in patients with CML [31,87]. The analysis performed by Horowitz et al. [87], and the study of identical twins by Gale et al. [88], suggested that there were three different variants of the GvL effect mediated by donor T cells: A GvL effect associated with GvHD mediated by T cells with specificity for minor histocompatibility Ags shared by leukemic blasts and GvHD target tissues. n A GvL effect associated with alloreactivity, but independent of GvHD mediated by T cells with specificity for hemopoiesis-restricted minor Ags. n A GvL-effect induced by T cells with specificity for leukemia-specific Ags. n

These hypothetical mechanisms were supported by experimental studies demonstrating that T cells with these different target specificities could be found in the blood of healthy donors [89–93]. Direct proof of the potency of the GvL effect exerted by donor T cells was provided by the pioneering work of Slavin and Kolb who showed that donor lymphocytes can induce complete remissions in patients relapsing after allogeneic transplants without the help of cytoreductive chemoradiotherapy [94,95]. Although donor lymphocyte infusions (DLI) are most effective in patients with relapsed CML in chronic phase, there is clear evidence

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that they can induce complete remissions in 20–25% of patients with an AML relapse after allogeneic SCT [96–98]. These observations clearly suggest two approaches to reducing the relapse risk after T-cell depleted stem-cell transplant in patients with acute leukemia: Intensification of the conditioning regimen, by increasing the dose of TBI and/or adding additional cytoreductive drugs. n Prophylactic or preemptive use of donor lymphocytes post-transplant. n

Several investigators have chosen the first approach, usually raising the TBI dose from 12 to 14–15.75 Gy and/or adding cytotoxic drugs, such as thiotepa or high-dose cytosine arabinoside [30,57,58,86,99]. In contrast to patients given GvHD-prophylaxis with cyclosporine/ methotrexate, patients receiving T-cell depleted grafts tolerated these intensified conditioning regimens without increased organ toxicity [100,101]. The relapse rates reported in these studies for patients with AML in first remission were similar to, or lower than those receiving conventional GvHD-prophylaxis [3,8,102]. However, I would like to point out that very similar results have been achieved without the intensification of cytoreductive therapy in patients with AML in first CR [51,52,59,85]. Most of these studies provide little information about the cytogenetics of the leukemias at diagnosis, which is the most important prognostic factor for outcome after both chemotherapy and allogeneic SCT [103–106]. Therefore, the impact of T-cell depletion in this group of patients is unclear at present. The number of TD allogeneic SCT performed in patients beyond first remission is fairly small, because most investigators have considered the relapse rates reported by the IBMTR to be unacceptably high [31]. There is limited information available for patients transplanted in second remission after an intensified conditioning regimen containing high-dose TBI and thiotepa [57,58]. The relapse rates in these two studies do not appear to be significantly higher than in patients receiving a conventional transplant [3,8,107]. In our own institution we have initiated a study to intensify the conditioning regimen of patients at high risk of relapse after a TD SCT by using a radiolabeled MAb [108]. The concept of targeted radiotherapy of the BM using radiolabeled MAbs was pioneered by

investigators in Seattle and New York, using 131Ilabelled anti-CD33 and anti-CD45 antibodies [109–115]. These studies established the feasibility of this approach in the context of a conventional BMT with HLA-identical sibling donors and the results are quite encouraging [116,117]. Our study differs from the Seattle study in several important respects. In order to improve feasibility we used a 188Re-labeled anti-CD66, instead of the 131I-labeled anti-CD45 Ab, thus significantly reducing the radiation-protection requirements for the study. We included both patients with high-risk AML in first remission and patients beyond first remission in our study, and donors were not restricted to HLA-identical siblings but also included mismatched or haploidentical family donors and MUD. More than 90% of patients received G-CSF mobilized PBPC, instead of BM, and all grafts were T-cell depleted with CAMPATH-1H for HLA-compatible family donors and CD341 selection for MUD and haploidentical transplants [108]. Patients with a favorable dosimetry received a therapeutic dose of the labeled antibody prior to standard myeloablative conditioning with TBI, or busulfan plus high-dose cyclophosphamide. Over the last 3 years we have recruited a total of 42 patients with high risk AML/MDS for the study. The median age of the patients was 48 years, 17 were in first or second remission at the time of transplant and 25 in partial remission, with ø 25% blasts in the BM. Approximately half the patients received mobilized blood cells from an alternative donor. The radioimmunoconjugate provided a mean dose of 15 Gy to the marrow, the kidney was the dose-limiting normal organ. Acute toxicity was low, with a mortality of 6% at 100 days. After a median follow-up of 18 months the overall transplantrelated mortality was 22%, 26% of patients have now relapsed, 20% of those in first or second remission at the time of transplant and 30% of those not in remission (Bunjes et al., Blood, submitted). For patients transplanted in remission the actuarial probability of DFS is 67%, for those grafted in partial remission it is 30%. This approach may reduce the incidence of relapse after T-cell depleted SCT in patients with a high risk of relapse and transplant-related death. It is difficult to judge how much the use of blood stem cells may have contributed to the low relapse rate and the relatively low transplant-related mortality [70,118,119].

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The concept of using prophylactic or preemptive DLI to prevent hematological relapse has not been extensively tested in patients with acute leukemia, although it is highly effective among patients with CML in chronic phase receiving T-cell depleted grafts from HLA-identical siblings [66,120–122]. The interpretation of the data from the two studies that included AML patients is complicated by low numbers [66] and several different schedules for DLI [50]. Both studies suggest a lower relapse rate among patients transplanted in remission, but this does not reach statistical significance — even in the study with a sufficient number of patients to be statistically significant [50]. In both studies the early use of DLI was associated with a significant incidence of acute and chronic GvHD [50,66]. The same trends were observed if grafts with a fixed, low number of T cells were used [65].

The pathogenesis of immunodeficiency and approaches to its prevention The third untoward effect of T-cell-depleted SCT is a delay in immunological reconstitution. Several studies have documented that T-cell depletion delays the reconstitution of T-cell and B-cell function by approximately 6–12 months, especially in adults and in patients receiving grafts from alternative donors [29,123–127]. The most consistent findings have been a very rapid reconstitution of natural killer (NK) cell function and a long delay in the regeneration of CD41 T cells, especially CD41 CD45RA1, i.e. naive helper cells. Since CD41 counts have an influence on the risk of infection after allogeneic SCT [128], it is not surprising that several studies have appeared reporting a high incidence of and a high mortality from viral infections after T-cell depleted SCT [126,129–131]. Early T-cell regeneration after SCT is normally the result of the peripheral expansion of mature T cells in the graft [132–134], whereas late T-cell regeneration and the production of CD45RA1 T cells is dependent on thymic function [135–138]. It is therefore not surprising that T-cell depletion results in a delay in T-cell reconstitution and/or the development of a restricted T-cell repertoire [139–141]. There is no evidence to suggest that the late phase of T-cell reconstitution is compromised by T-cell depletion but, since the majority of patients receiving T-cell depleted grafts are adults and thymic function is compromised anyway, a delay in this phase can be anticipated [135,136,142–144].

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A limited number of strategies to accelerate T-cell reconstitution have so far been investigated. Early donor lymphocyte infusions have contributed to the clearance of infection in individual patients, but their overall impact on T-cell reconstitution and T-cell repertoire development has been limited and they have been associated with a significant risk of GvHD [66,123,124,141]. A number of strategies have been suggested to circumvent the problem of DLI-associated GvHD. One approach is the prophylactic or preemptive infusion of pathogen-specific T-cell lines or clones. This strategy has been tested for CMV and EBV infections, in the context of both conventional and T-cell depleted SCT [145–147]. The data reported are impressive and suggest that this is a highly effective way of protecting patients against selected pathogens. But this approach does have clear-cut limitations. It is restricted to an individual pathogen and it is extremely time-consuming, labor intensive and expensive. It is doubtful whether it is suitable for routine use in a moderately sized transplant program. An alternative is the inactivation or elimination of alloreactive T cells, either from the graft in vitro or by suicide-gene activation in vivo [148–151]. Although effective in small numbers of patients the value of these methods remains unclear at present. The application of cytokines to stimulate T-cell reconstitution after T-cell depleted allogeneic SCT has been limited to low-dose IL2 [152]. Unfortunately, no significant acceleration of T-cell reconstitution was observed. Other cytokines, which have proven effective in animal experiments, have so far not been tested in man.

The pathogenesis of EBV-associated posttransplant lymphoproliferative disease and methods for its prevention The expansion of EBV-infected human B cells is normally controlled by T-cells specific for certain viral peptides [153]. It is therefore not surprising that several single-center and registry studies have demonstrated an increased risk of EBV-associated lymphoproliferative disease (BLPD) after T-cell depleted allogeneic SCTs [30,154]. The risk seems to be higher among patients receiving mismatched family donor or MUD grafts and seems to be dependent on the method used for T-cell depletion. This complication of T-cell depletion can be effectively prevented by B-cell depletion of the graft, e.g. with CD52 Abs [154–156], or by the prophylactic

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infusion of EBV-specific donor T-cell lines [147]. A more practical approach is the monitoring of EBV-reactivation by polymerase chain reaction (PCR) and the prophylactic use of the anti-CD 20 Mab (rituximab), which is also highly effective in the treatment of this complication [157–160]. DLI are an effective alternative for the treatment of this life-threatening complication [161,162].

The role of T-cell depleted PBPC Over the past 5 years G-CSF mobilized PBPC have gradually supplanted BM as the preferred stem-cell source in HLA-identical stem-cell transplants [163–165]. Several randomized trials have consistently demonstrated that hemopoietic reconstitution is faster after PBPC grafts than after a marrow graft, whereas no difference in the incidence of acute GvHD was observed. An increase in chronic GvHD was noted in some studies, but this was not a consistent finding [118,119,166,167]. Although overall survival was not different in these studies, there is a trend towards an improved DFS in patients with advanced acute leukemias. A similar trend was observed in a recently published large registry study [168]. All of these studies were performed with unmanipulated PBPC. T-cell depleted PBPC transplants have been reported in several small and one larger trial [169–173]. In these initial trials, graft failure did not appear to be a significant problem, probably because only a moderate degree of T-cell depletion was achieved and the majority of patients were given additional GvHD prophylaxis with cyclosporine 6 methotrexate. In a recent update of the largest trial of T-cell depleted PBPC a significant incidence of graft failures (11%) was noted in patients receiving a T-cell PBPC graft from an HLA-identical donor after effective depletion with a number of CD 341 selection techniques, but without rejection prophylaxis [174]. In vivo T-cell depletion with CAMPATH-1H has been shown to be effective in preventing graft failures in HLA-identical PBPC transplants [175,176]. In our own center we have not observed a single case of graft failure in . 50 patients receiving a PBPC graft from an HLAcompatible sibling donor after in vivo/ex vivo T-cell depletion with CAMPATH-1H [85]. The incidence of both acute and chronic GvHD in some of the studies of T-cell depleted PBPC grafts has been significant; probably because of the only moderate T-cell depletion achieved with early CD341 selection techniques

[169,170]. In Ulm we have observed a significant increase in GvHD after in vivo/ex vivo T-cell depletion of PBPC grafts with CAMPATH-1H, compared with in vivo/ex vivo T-cell depletion of BM with CAMPATH1G/CAMPATH-1M [59,85]. This difference might be a reflection of the less effective T-cell depletion achieved with a lower dose of Ab (20–30 mg of CAMPATH-1H) as compared with 100 mg of CAMPATH-1G in the marrow group in the face of a 10-fold load of donor T cells. With higher in vivo doses of CAMPATH-1H, the incidence of GvHD in PBPC transplants seems comparable to that observed in BMT [176]. The impact of using T-cell depleted PBPC on other measures of outcome, such as relapse, DFS, or survival, is unknown at present. We have not been able to confirm the accelerated immunological reconstitution observed after unmanipulated PBPC transplants [177] in patients receiving PBPC grafts depleted by using CAMPATH-1H. On the contrary, our impression is that the recovery of T-cell function is possibly further delayed [85,178]. One conceivable mechanism for this functional delay could be the use of G-CSF pre-transplant to mobilize stem cells and post-transplant to accelerate neutrophil recovery after SCT. There is growing evidence that the use of G-CSF might prime donor T cells to differentiate into Type 2 T-helper cells and may also impair NK cell function [179–183]. The amount of information about PBPC transplants with grafts derived from MUD donors is very limited [184]. Of the patients reported in the study by Ringden et al. only a small subgroup received grafts T-cell depleted by CD341 selection. A significant incidence of graft failure was reported in spite of in vivo T-cell depletion with ATG. However, graft failures were limited to patients conditioned with busulfan/cyclophosphamide. This combination may not be sufficiently immunosuppressive for a T-cell depleted SCT [185]. In our center we have performed . 40 CD341 selected MUD PBPC transplants after in vivo/ex vivo T-cell depletion with ATG and CD341 selection, and have observed a residue of graft failures affecting 5–10% of patients. This incidence of graft failures is similar to that reported for patients receiving T-cell depleted PBPC grafts from haploidentical family donors [25,78–80]. The relapse rate for patients with AML in these studies was surprisingly low, in spite of the fact that the vast majority had very advanced disease at the time of transplant. One potential explanation for these observations is the appearance

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of alloreactive NK cells in the peripheral blood of patients post-transplant, which can exert a powerful antileukemic effect, at least in vitro [186]. The incidence of infections, BLPD and overall transplant-related mortality after haploidentical PBPCT seems similar to that reported for MUD marrow transplants for patients with advanced AML [15,16,69]. The introduction of PBSC represents a significant advance for patients requiring a haploidentical SCT.

Summary

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For patients with standard-risk leukemia scheduled for an HLA-identical family donor transplant, T-cell depletion of the marrow graft constitutes an acceptable, if not superior, alternative to standard GvHD prophylaxis with cyclosporine/methotrexate, provided appropriate graft rejection prophylaxis with in vivo T-cell depletion or TLI is used. Although there is no evidence available to show that T-cell depletion is superior to conventional GvHD prophylaxis, in terms of leukemia-free survival, the more effective prevention of chronic GvHD results in a better quality-of-life for surviving patients. It is unclear whether replacing BM by blood as a stem-cell source improves the overall outcome in these good-risk patients. T-cell depletion of the graft is also appropriate for patients with high-risk features grafted in first or second CR, provided that an intensified conditioning regimen is used to reduce the risk of relapse. Patients with more advanced disease with a matched family donor or MUD should only receive a T-cell depleted graft in the context of a clinical trial geared to reducing the risk of relapse. In this setting, a PBPC graft may be preferable to a BM graft. If no compatible family donor is available and a compatible unrelated donor cannot be identified within an adequate time-frame, a T-cell depleted haploidentical PBPC graft is probably the most suitable approach, provided an intensified conditioning regimen and appropriate graft rejection prophylaxis are used. The delay in immune reconstitution remains the most intractable problem associated with T-cell depleted allogeneic SCT and a major research effort will be required to address this problem.

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