Alloreactivity as therapeutic principle in the treatment of hematologie malignancies

Studies of clinical and immunologic aspects of allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning

This review has been accepted as a thesis together with six previously published papers, by the University of Copenhagen, January 12, and defended on Maj 11, 2006.

Lymphocyte Research Laboratory (now the Allo-HCT Laboratory), department of Hematology, Rigshospitalet, Copenhagen.

Correspondence: Søren Lykke Petersen, Østervang 9, 2800 Lyngby, Copenhagen, Denmark

Official opponents: Torben Barington, Hans E. Johnsen and Mogens Claësson.

3. Allogeneic hematopoietic
cell transplantation

3.1. Source of the graft

Bone marrow (BM) aspirated from the iliac crest has traditionally been the primary source of hematopoietic stem cells used in HCT. During the last decade peripheral blood stem cells (PBSC) harvested by leukapheresis following stimulation with granulocyte colony stimulating factor have become an alternative to BM. At present PBSC are more commonly used than BM in allogeneic HCT both overall and especially following nonmyeloablative or reduced-intensity conditioning regimens (Banna et al, 2004; Gratwohl et al, 2005). The contents of T cells and CD34 + cells are higher in PBSC grafts than in BM grafts (Bensinger et al, 2001; Couban et al, 2002) and the ability of PBSC to engraft under nonmyeloablative conditions may be superior to that of BM (Maris et al, 2003b). The time to neutrophil and platelet recovery is shorter following transplantation with PBSC (Ringden et al, 2002), resulting in lower platelet transfusion requirements than following bone marrow transplantation (Blaise et al, 2000; Bensinger et al, 2001; Couban et al, 2002; Ringden et al, 2002; Schmitz et al, 2002). Another possible advantage of PBSC is a more rapid reconstitution of the CD4 + T cells when compared to BM (Ottinger et al, 1996; Storek et al, 2001a; Petersen et al, 2003). Negative effects of transplantation with PBSC includes a higher risk of chronic GVHD (Cutler et al, 2001; Mohty et al, 2002; Ringden et al, 2002; Tanimoto et al, 2004; Stem Cell Trialists' Collaborative Group, 2005). The reason for this increased risk of chronic GVHD has been proposed to be related to the higher CD34 + cell dose present in the PBSC grafts (Zaucha et al, 2001; Mohty et al, 2003; Lee et al, 2003b). The risk of relapse in recipients of PBSC has in some studies been reduced when compared to the risk in BM recipients, suggesting an increased GVT effect of PBSC (Powles et al, 2000; Oehler et al, 2005; Stem Cell Trialists' Collaborative Group, 2005). In the majority of studies the survival has been similar in recipients of PBSC and BM (Blaise et al, 2000; Powles et al, 2000; Mohty et al, 2002; Ringden et al, 2002; Schmitz et al, 2002; Tanimoto et al, 2004; Oehler et al, 2005) but in a recent meta-analysis of randomized trials the overall- and disease-free survival was improved in patients with late-stage disease if they were transplanted with PBSC as opposed to BM (Stem Cell Trialists' Collaborative Group, 2005). In the protocol for allogeneic HCT with nonmyeloablative conditioning employed at Rigshospitalet, only PBSC grafts are used.

3.2. Myeloablative conditioning

Allogeneic HCT is a potentially curative treatment for otherwise lethal hematologic malignancies (Thomas et al, 1975). The rationale for the introduction of allogeneic HCT as a treatment for hematologic malignancies was the discovery in experimental animals, that allogeneic hematopoietic cells could engraft in a lethally irradiated host and regenerate the hematopoietic tissues (Little & Storb, 2002). In humans, this allowed for intensification of the antineoplastic therapy to doses that caused lethal myeloablation and led to the development of the currently used high-dose conditioning regimens consisting of cyclophosphamide (120 mg/kg) combined with either 16 mg/kg of busulfan (Santos et al, 1983) or with 12 Gy of total body irradiation (TBI) (Clift et al, 1990; Clift et al, 1991). The intensity of the conditioning regimen affects both the anti-leukemic effect and the toxicity of the transplant procedure. Increased doses of irradiation decrease the probability of relapse in patients with myeloid leukemia, but this beneficial effect is often offset by increased transplant related mortality (TRM) (Clift et al, 1990; Clift et al, 1991). The toxicity of the currently used myeloablative conditioning regimens generally restricts the use of allogeneic HCT to patients with an age below 50 to 60 years. This age limit is in contrast to the occurrence of many hematologic malignancies where the age at diagnosis is often considerably higher. In addition, a high TRM has been observed following allogeneic HCT with myeloablative conditioning in patients with chronic lymphocytic leukemia, multiple myeloma, non-Hodgkin lymphomas and Hodgkin disease further limiting the use of this treatment option in these patients (Michallet et al, 1996; Alyea et al, 2003; Peniket et al, 2003). Besides the anti-neoplastic effect of the high-dose radio-chemotherapy it became evident that the donor cells also contributed to the curative potential of allogeneic HCT. In the early animal experiments it was suggested that the donor cells possessed an anti-leukemic effect (Barnes et al, 1956). In a series of experiments performed by Barnes and Loutit (1957), mice were inoculated with leukemia and were transplanted with hematopoietic cells from mice of the same strain (syngeneic) or from mice of another strain (allogeneic). Mice that received syngeneic grafts died of leukemia, whereas recipients of allogeneic grafts survived longer and died with symptoms of GVHD but without evidence of leukemia (Barnes & Loutit, 1957). In the clinical setting it has been shown that the risk of relapse in recipients of syngeneic grafts is higher than in recipients of allogeneic grafts indicating that some degree of genetic disparity is necessary to elicit a GVT effect (Horowitz et al, 1990; Gale et al, 1994). In addition, in a number of studies, there has been a clear association between the occurrences of acute- or chronic GVHD and a lower incidence of relapse, supporting the hypothesis that the GVT effect is part of an alloresponse (Weiden et al, 1979; Weiden et al, 1981; Sullivan et al, 1989; Horowitz et al, 1990). Further evidence for the existence of a GVT effect came with the observation that DLI administered to patients with relapse of chronic myeloid leukemia following HCT could induce complete remissions without the need for additional chemotherapy (Kolb et al, 1990; Kolb et al, 1995; Slavin et al, 1995; Collins, Jr. et al, 1997). The remissions obtained in patients with relapse of chronic myeloid leukemia in chronic phase were durable and often resulted in molecular remission, defined as no detection of BCR-ABL transcripts by reverse transcriptase polymerase chain reaction (RT-PCR) (Dazzi et al, 2000b). In patients with relapse of acute leukemia or chronic myeloid leukemia in accelerated or blastic phases chances of remission were lower and the responses most often not durable (Kolb et al, 1995; Collins, Jr. et al, 1997). Donor lymphocyte infusion is often associated with development of GVHD and responses are more likely in patients who develop GVHD (Kolb et al, 1995; Collins, Jr. et al, 1997). Because GVHD following DLI can be fatal, algorithms for DLI given in gradually increased doses, have been developed (Mackinnon et al, 1995; Dazzi et al, 2000a). GVT responses following DLI takes time and in patients with chronic myeloid leukemia the time needed to achieve molecular remission is on average 4-6 months (Kolb et al, 2004). Molecular remission is desirable after allogeneic HCT, because it is highly correlated to long-term disease control. Not only in patients with chronic myeloid leukemia but also in patients with other hematologic malignancies (Olavarria et al, 2001; Corradini et al, 2003; Ritgen et al, 2004).

3.3. Nonmyeloablative and
reduced-intensity conditioning

3.3.1. Development of the conditioning regimens

Conditioning regimens that involve less radio-chemotherapy than the traditionally used myeloablative regimens have been divided in two groups: the nonmyeloablative regimens and the reduced-intensity regimens, depending on the immediate myelotoxicity induced. A truly nonmyeloablative conditioning regimen has been defined as a regimen that allowed for autologous recovery within 28 days without a transplant, did not eradicate the hematopoiesis of the host and gave rise to mixed hematopoietic chimerism upon allogeneic engraftment (Champlin et al, 2000; Baron et al, 2005a). However, this nomenclature is not strictly followed in the literature and many centers have introduced modifications to the originally described regimens further confusing the terms (Slavin, 2004). In this thesis the definitions described above have been followed which implies that the term "nonmyeloablative" refers to conditioning regimens which are mostly immunosuppressive and where complete donor hematopoietic chimerism and eradication of the malignant disease is primarily achieved by alloreactive Graft-versus-Host reactions. The term "reduced-intensity" refers to regimens, which in addition to the immunosuppressive effect have a cytoreductive element that is able to induce significant disease control and also causes severe myelosuppression.

At the FHCRC, Storb and colleagues exploited results obtained in a series of experiments using a dog model to design a TBI based nonmyeloablative conditioning regimen that could be used in the clinical setting (McSweeney & Storb, 1999). By optimizing the post-transplant immunosuppression with the combined use of cyclosporine and mycophenolate mofetil (MMF), an immunosuppressive drug more widely used in solid organ transplantation, they were able to gradually reduce the dose of TBI from 9.2 Gy to 2 Gy and still get stable engraftment of the donor cells (Storb et al, 1988; Storb et al, 1993; Storb et al, 1994; Yu et al, 1995; Storb et al, 1997; Yu et al, 1998). The majority of the dogs transplanted with this nonmyeloablative conditioning regimen became stable mixed hematopoietic chimeras and did not develop GVHD (Storb et al, 1997). The Seattle consortium, a multi-institutional group including centers in USA and Europe, carries out the human trials. The initial conditioning regimen used for HLA-identical sibling transplants consisted of 2 Gy of TBI (low-dose TBI) on day 0 combined with oral MMF 30 mg/kg/day from days 0-27 and intravenous cyclosporine 3 mg/kg/ day on days -1 and 0 followed by oral cyclosporine 12.5 mg/kg/day to day 35 with taper from day 35 to day 56 (McSweeney et al, 2001). The patients transplanted with this regimen did not develop stable mixed hematopoietic chimerism but either rejected the graft and reconstituted with autologous hematopoiesis or proceeded towards complete donor hematopoietic chimerism. To reduce the rejection incidence (16% of 102 transplants performed with this regimen) the immunosuppressive purine analog fludarabine 30 mg/m 2 was added on days -4, -3 and -2 (McSweeney et al, 2001; Storb, 2003). The regimen was subsequently modified by replacing intravenous cyclosporine on day -1 and 0 with oral cyclosporine starting on day -3 (Feinstein et al, 2003). Due to a high rate of acute GVHD the cyclosporine administration was extended to day 56 and cyclosporine was then tapered to day 77 in patients with aggressive disease and to day 180 in patients with indolent disease (Georges & Storb, 2003; Maris et al, 2004b; Baron et al, 2005b). In the unrelated donor setting the dose of MMF has been increased to 45 mg/kg/day to day 40 with taper to day 96 and cyclosporine is given at full dose to day 100 with taper to day 180 (Niederwieser et al, 2003; Maris et al, 2003b; Maris et al, 2004b; Baron et al, 2005b). Future modifications will aim at a further reduction of the incidence of acute GVHD (Baron et al, 2005b).

At the M. D. Anderson Cancer Center in Houston, the rationale behind the development of nonmyeloablative or reduced-intensity conditioning regimens has been, that the drugs used in the conditioning regimens should both be immunosuppressive and have cytoreductive activity against the underlying malignancy. In acute myeloid leukemia and myelodysplastic syndrome one of the first regimens consisted of fludarabine 120 mg/m 2 , cytarabine 8 g/m 2 and idarubicine 36 mg/m 2 (FAI) (Giralt et al, 1997; de Lima et al, 2004). Subsequently more intensive combinations of fludarabine and melphalan 140-180 mg/m 2 (FM) have been introduced (Giralt et al, 2001; de Lima et al, 2004). The FM conditioning regimen has also been used in patients with multiple myeloma, non-Hodgkin lymphomas and Hodgkin disease (Giralt et al, 2001; Giralt et al, 2002; Anderlini et al, 2005). Other conditioning regimens that have been developed for lymphoid malignancies include fludarabine 90-150 mg/m 2 with cyclophosphamide 900-2000 mg/m 2 (FCy) (Khouri et al, 1998; Khouri et al, 2001; Escalon et al, 2004; Khouri et al, 2004).

Slavin and collegues at Hadassah-Hebrew University Hospital in Jerusalem has introduced a reduced-intensity conditioning regimen consisting of busulfan 8 mg/kg, fludarabine 180 mg/m 2 and antithymocyte globulin (ATG) (Slavin et al, 1998; Or et al, 2003). This regimen, with or without modifications, has been widely used by other centers.

In most of the studies performed in the United Kingdom, in-vivo T-cell depletion with the monoclonal antibody anti-CD52 (alemtuzumab) has been included in the conditioning regimen to reduce the incidence of acute GVHD (Kottaridis et al, 2000). The remaining part of the conditioning regimen has most often been FM (Kottaridis et al, 2000; Chakrabarti et al, 2002; Chakraverty et al, 2002; Morris et al, 2004; Peggs et al, 2005) but also the busulfan/fludarabine regimen (Parker et al, 2002) and the BEAM regimen (carmustine, etoposide, cytarabine and melphalan) have been combined with alemtuzumab (Cull et al, 2000; Faulkner et al, 2004). The use of alemtuzumab leads to prolonged mixed hematopoietic chimerism in many patients and DLI is often necessary to achieve complete donor chimerism or to treat residual- or progressive disease (Kottaridis et al, 2000; Marks et al, 2002; Perez-Simon et al, 2002b; Peggs et al, 2004).

Childs and colleagues at the National Institutes of Health in Bethesda developed a nonmyeloablative regimen consisting of cyclophosfamide 120 mg/kg and fludarabine 125 mg/m 2 to transplant patients with hematologic malignancies and have also explored this approach in patients with solid tumors (Childs et al, 1999; Childs et al, 2000; Gorak et al, 2005). The initial results of allogeneic HCT in renal cell carcinoma were promising with a number of patients who responded to the treatment with tumor regression or stabilization of the disease (Childs et al, 2000). The long-term results have been more disappointing and complete responses are rare (Childs & Barrett, 2004).

Based on animal models developed to achieve stable mixed hematopoietic chimerism, Sykes and colleagues at Massachusetts General Hospital/Harvard Medical School in Boston introduced a nonmyeloablative conditioning regimen consisting of cyclophosphamide 150-200 mg/kg, thymic irradiation (7Gy) and ATG (Sykes et al, 1999; Spitzer et al, 2000; Daly et al, 2003; Dey et al, 2003). Around 30% of the recipients of HCT following this regimen rejected their grafts (Daly et al, 2003; Kraus et al, 2003; Dey et al, 2005), but interestingly sustained responses were observed in some of these patients despite the loss of donor chimerism (Dey et al, 2005).

Carella and colleagues at Ospedale San Martino in Genoa pioneered an approach that includes the use of an autologous HCT to reduce the tumor burden and then proceed to an allogeneic HCT with nonmyeloablative conditioning to control and eradicate the residual malignant cells (Carella et al, 1998; Carella et al, 2000). This approach has been further explored in multiple myeloma and NHL (Kroger et al, 2002b; Maloney et al, 2003; Galimberti et al, 2005; Gutman et al, 2005).

In addition to these regimens a number of other groups have developed nonmyeloablative or reduced-intensity conditioning regimens for allogeneic HCT. In the initial phase of development of this new treatment modality, it could be seen as an advantage to explore different ways of conditioning. Today, the numerous conditioning regimens may be a disadvantage for the collection of data needed before prospective studies comparing the results of nonmyeloablative- or reduced-intensity HCT with other treatment modalities can be initiated. The degree of myelo- and immunosuppression caused by the most used conditioning regimens is summarized in Figure 1 , which has been adapted from a figure made by Richard Champlin (Storb et al, 2001).

3.3.2. Engraftment and hematopoietic chimerism

One of the first goals of the newly developed nonmyeloablative or reduced-intensity conditioning regimens was to enable and document the engraftment of the transplanted donor cells (Giralt et al, 1997; Carella et al, 1998; Slavin et al, 1998; Childs et al, 1999; McSweeney & Storb, 1999; Sykes et al, 1999). In HCT with myeloablative conditioning the patients are severely pancytopenic for approximately two weeks. When the leukocyte count begins to rise it can generally be assumed that the leukocytes are of donor origin and the day of engraftment has therefore traditionally been defined as the first of 3 consecutive days with neutrophil counts above 0.5 × 10 9 /l (Bensinger et al, 2001). With the use of nonmyeloablative conditioning the leukopenia is milder and when the peripheral counts begin to rise, it is necessary to analyze the origin of the cells, as the patient could have rejected the graft without symptoms and recovered with autologous hematopoiesis. Methods to quantify the degree of donor chimerism are therefore essential tools in HCT with nonmyeloablative- or reduced-intensity conditioning (Antin et al, 2001). Currently, the most widely used method for chimerism analysis utilize PCR to amplify minisatellite (variable number of tandem repeats, VNTR) or microsatellite (short tandem repeats, STR) regions of the human genome that differ between the recipient and the donor (Jeffreys et al, 1985; Antin et al, 2001). We used a fluorescence-based STR-PCR method to determine the level of donor chimerism in granulocytes and in CD4 + and CD8 + T cells in 24 recipients of PBSC grafts from their HLA-identical sibling donors following nonmyeloablative conditioning (Petersen et al, 2004b). Both the kinetics of the increase in donor chimerism and the time needed to achieve complete donor chimerism, defined as > 99% donor cells, differed between the granulocytes and the T cells. The donor granulocyte chimerism was generally low for the first two weeks and then rapidly increased and complete donor chimerism was reached at a median of 42 days ( Figure 2 ) (Petersen et al, 2004b). The donor T-cell chimerism was initially higher than the donor granulocyte chimerism, but increased more gradually and the median time needed to achieve complete donor chimerism was 154 days in the CD4 + T cells and 120 days in the CD8 + T cells (Figure 2) (Petersen et al, 2004b).

The kinetics of donor hematopoietic chimerism development may potentially be influenced by several factors such as the intensity of the conditioning regimen, the post-transplant immunosuppression and the source and composition of the graft. In a study of patients transplanted with reduced-intensity conditioning regimens Pérez-Simón et al (2002a) observed that the majority of patients were complete donor chimeras in both granulocytes and in T cells within two months post-transplant. In contrast to our data Childs et al (1999) reported that complete donor T-cell chimerism occurred prior to complete myeloid chimerism. In recipients of low-dose TBI based regimens, factors that have been related to early high levels of donor T-cell chimerism includes: transplantation with PBSC grafts (Baron et al, 2004), intensive chemotherapy prior to the transplant (Baron et al, 2004), addition of fludarabine to the conditioning regimen (Panse et al, 2005) and planned autologous HCT prior to the allogeneic HCT (Panse et al, 2005). Within recipients of PBSC, high numbers of NK cells (Panse et al, 2005), CD8 + T cells (Cao et al, 2005), CD4 + T cells (Baron et al, 2005c) and CD34 + T cells (Baron et al, 2005c) in the grafts have been related to high levels of donor T-cell chimerism following the transplant and advanced donor age has been associated with low levels of donor T-cell chimerism (Panse et al, 2005). Similarly, factors that are related to the occurrence of rejection following low-dose TBI based conditioning regimens have been identified. In recipients of HLA-identical PBSC, patients who had not received intensive chemotherapy prior to the transplant had a higher risk of rejection following conditioning with 2 Gy of TBI, leading to inclusion of fludarabine into the conditioning regimen (McSweeney et al, 2001). With the use of grafts from HLA-matched unrelated donors following conditioning with 2 Gy of TBI and fludarabine, patients who received BM grafts, patients who had not received preceding chemotherapy and patients who received low numbers of CD8 + T cells or CD34 + cells had an increased risk of rejection (Maris et al, 2003b; Baron et al, 2005c). Maris et al (2004a) found that an increase of the dose of MMF from 15 mg/kg twice daily to 15 mg/kg trice daily following the transplant was associated with a decreased risk of rejection. In summary, these findings point to the existence of a balance between host and graft factors that affects the engraftment kinetics and that this balance can be manipulated, for example by changes in the conditioning regimen or in the post transplant immunosuppression.

Whether the engraftment kinetics could yield information with predictive value for clinical outcomes such as GVHD, rejection and the GVL effect has also been investigated. In the study by McSweeney et al (2001) the level of donor T-cell chimerism on day +28 predicted the subsequent occurrence of acute GVHD and rejection. In a cohort of 38 patients conditioned with 2 Gy of TBI and fludarabine, Keil et al (2003) found that a donor T-cell chimerism level of 90% or more on day 28 predicted a better progression-free survival, whereas the relation between chimerism and GVHD was not investigated. In our study of 24 patients, we were unable to document a relationship between the levels of donor T-cell chimerism early after transplant and acute GVHD, but we found a significant increased risk of acute GVHD in patients who had a donor CD8 + T-cell count above the median on day +14 ( Figure 3 ) (Petersen et al, 2004b). The data from the Seattle consortium were later extended to encompass chimerism determinations in 120 patients (Baron et al, 2004). The level of donor T-cell chimerism on day +28 predicted the occurrence of acute GVHD in this cohort and there was a suggestion that the day +14 T-cell chimerism levels could also predict the occurrence of acute GVHD (Baron et al, 2004). Patients with donor chimerism levels below 50% for the NK cells or the T cells on day +14 had a higher risk of rejection and rapid attainment of complete donor chimerism of the NK cells was predictive of improved progression-free survival (Baron et al, 2004). Recently the chimerism development of NK cells and of subsets of T cells has been investigated in 157 patients (Baron et al, 2005d). Among other findings the day +14 level of donor chimerism of the CD3 + , CD4 + and CD8 + T cells and the absolute numbers of CD4 + and CD8 + T cells of donor origin on day +14-42 all predicted the subsequent occurrence of acute GVHD grades II-IV (Baron et al, 2005d). In conclusion, these data indicate that it is possible to use early determinations of donor chimerism or absolute donor counts of leukocyte subsets to predict clinical outcomes related to alloreactivity.

3.3.3. Donor lymphocyte infusion

Following HCT with nonmyeloablative conditioning DLI is given to increase the level of donor chimerism and/or to treat relapse or progression of the malignant disease. The effect of DLI on the level of donor chimerism has been investigated in several studies. In a study by Bethge et al (2004) 16 patients were given DLI for low or falling donor T-cell chimerism and of these 6 responded. Ten patients rejected their grafts despite DLI. Dey et al (2003) observed that the level of donor T-cell chimerism had to be above 40%, if DLI should effectively convert the state of mixed chimerism into complete donor chimerism. In a study by Marks et al (2002) 35% of the recipients of DLI converted to complete donor chimerism and this response was significantly associated with the occurrence of acute- and chronic GVHD. Similarly, Peggs et al (2004) observed that 9 of 12 patients, who received DLI to increase the level of donor hematopoietic chimerism, converted to complete donor chimerism. Thus it appears that DLI can potentially convert mixed hematopoietic chimerism to complete donor chimerism. The responses are, however, highly variable and may depend on the level of donor T-cell chimerism pre-DLI. In patients with persistent or relapsing disease following the transplant, the immunosuppression is tapered in patients without GVHD, if GVHD does not occur DLI is routinely administered (Petersen et al, 2004a; Petersen et al, 2004b). Disease responses to DLI have been achieved in a variety of hematologic malignancies following HCT with nonmyeloablative or reduced conditioning (Badros et al, 2001; Marks et al, 2002; Dey et al, 2003; Dreger et al, 2003; Bethge et al, 2004; Peggs et al, 2004; Peggs et al, 2005; Kollgaard et al, 2005; Crawley et al, 2005a; Crawley et al, 2005b).

3.3.4. Toxicity

The non-hematologic toxicity of HCT with myeloablative conditioning is often the factor that limits the eligibility of the patients to receive this treatment. In addition, the patients are hospitalized and isolated in specialized wards to limit the effects of the profound myelosuppression associated with the procedure. A common goal for all the centers that were developing reduced-intensity or non-myeloablative conditioning regimens was to broaden the range of patients eligible for allogeneic HCT and therefore it was necessary to reduce the non-hematologic toxicity. The Seattle team further wanted to perform the procedure in the outpatient setting and that would require a substantial reduction in the hematologic toxicity as well. The hematologic toxicity of the regimen composed of 2 Gy of TBI and fludarabine 90 mg/m 2 is relatively mild as illustrated by median neutrophil and thrombocyte nadirs of 0.33 × 10 9 /l (range 0-1.8 × 10 9 /l) and 45 × 10 9 /l (range 4-209 × 10 9 /l) respectively in the study of 120 patients by Baron et al (2004). In a comparison to patients who received myeloablative conditioning the neutropenia in recipients of nonmyeloablative HCT was both shorter and less severe (Junghanss et al, 2002b). The median duration of neutrophil counts < 0.5 × 10 9 /l has varied between studies and was 0 days in patients with multiple myeloma (Maloney et al, 2003), where the patients received only TBI, 4 days in patients with mantle cell lymphoma where all the patients received fludarabine and TBI (Maris et al, 2004b) and 11 days in patients with chronic lymphocytic leukemia where 82% of the patients received fludarabine and TBI and where 25% of the patients had neutrophil counts < 0.5 × 10 9 /l before the transplant (Sorror et al, 2005). Thus while low pre-transplant neutrophil counts clearly affects the duration of neutropenia, the inclusion of fludarabine in the conditioning regimen may also prolong this period. In our study of 30 patients with primarily lymphoid malignancies, where 90% of the patients received fludarabine, we found that the median neutrophil and thrombocyte nadirs were 0.2 × 10 9 /l (range 0-0.9 × 10 9 /l) and 30 × 10 9 /l (range 1-88 × 10 9 /l) respectively and that the median duration of neutrophil counts < 0.5 × 10 9 /l and platelet counts < 20 × 10 9 /l were 12 days and 0 days respectively ( Figure 4 ) (Petersen et al, 2004a).

The neutropenia following the reduced-intensity regimens is more severe than following the nonmyeloablative regimens, but the duration is not necessarily longer than experienced in our study. In a study of patients conditioned with busulphan 8 mg/kg and cladribine 0.66 mg/kg or fludarabine 180 mg/m 2 the majority of the patients experienced a neutrophil count < 0.1 × 10 9 /l and the median duration of neutrophil counts < 0.5 × 10 9 /l was 9 days (Hori et al, 2004). In recipients of 150 mg/m 2 of fludarabine combined with either 140 mg/m 2 of melphalan or 10 mg/kg of busulfan all the patients became neutropenic and the median duration of neutrophil counts < 0.5 × 10 9 /l and platelet counts < 20 × 10 9 /l was 13 days and 4 days respectively (Martino et al, 2001b).

The transfusion requirements following HCT with nonmyeloablative conditioning are generally low (Weissinger et al, 2001). The patients in our study received a median of 0 (range 0-60) platelet transfusions and 3 (0-92) red blood cell transfusions during the first 60 days post-transplant (Petersen et al, 2004a). These figures are similar to the transfusion needs reported in other studies (McSweeney et al, 2001; Weissinger et al, 2001; Feinstein et al, 2003; Maloney et al, 2003). Beyond day +60, complications such as gastrointestinal GVHD, thrombotic thrombocytopenic purpura (TTP) and disease progression were the major causes of additional transfusion requirements (Petersen et al, 2004a).

Patients transplanted with nonmyeloablative and reduced-intensity conditioning regimens were generally considered ineligible for myeloablative conditioning. It is therefore difficult to compare the toxicity of the conditioning regimens because matching for age, disease status and co-morbidity is not possible. However, despite these factors which tends to favor the outcome for recipients of myeloablative conditioning the toxicity to especially the gastrointestinal system, the liver, the kidney and the hematopoietic system is significantly reduced in recipients of nonmyeloablative conditioning when compared to myeloablative conditioning (Weissinger et al, 2001; Diaconescu et al, 2004; Sorror et al, 2004; Parikh et al, 2005). In addition a decreased decline in pulmonary function and decreased occurrence of pulmonary complications such as idiopatic pneumonia syndrome and bronchiolitis obliterans have been observed following nonmyeloablative or reduced-intensity conditioning (Fukuda et al, 2003b; Chien et al, 2005; Yoshihara et al, 2005). The clinical impact of the reduced toxicity is illustrated by a decreased TRM following nonmyeloablative or reduced-intensity conditioning regimens when compared with myeloablative conditioning regimens (Diaconescu et al, 2004; Sorror et al, 2004; Alyea et al, 2005; Dreger et al, 2005; Kojima et al, 2005; Massenkeil et al, 2005; Aoudjhane et al, 2005).

3.3.5. Graft-versus-Host disease

Graft-versus-Host disease is defined by a spectrum of clinical manifestations that are the result of immunologic reactions caused by cells contained in the graft. Acute GVHD is a characteristic clinical syndrome, which includes various degrees of dermatitis, hepatitis and enteritis. The magnitude of these clinical features forms the basis for a clinical grading system where grade 0 represents no symptoms, grade I represents mild often self limiting GVHD, grade II represents moderate acute GVHD requiring immunosuppressive therapy, grade III represents severe multiorgan GVHD and grade IV represents life-threatening or fatal GVHD (Glucksberg et al, 1974; Sullivan, 1999). Acute GVHD usually develops before day +100 following HCT with myeloablative conditioning, but may be delayed in recipients of nonmyeloablative or reduced-intensity conditioning (Mielcarek et al, 2003; Taussig et al, 2003; Perez-Simon et al, 2005). Chronic GVHD is more heterogeneous in its manifestations and many of the symptoms resemble the symptoms occurring in autoimmune disorders. As for acute GVHD a staging system has been developed that divides chronic GVHD into limited and extensive (Shulman et al, 1980; Lee et al, 2003b). Limited chronic GVHD has a favorable course without treatment, whereas extensive chronic GVHD often requires long-term immunosuppressive treatment (Socie et al, 1999; Sullivan, 1999). In many studies of HCT with reduced-intensity or nonmyeloablative conditioning GVHD is a significant cause of morbidity and mortality (Slavin et al, 1998; Giralt et al, 2001; Schetelig et al, 2002; Mielcarek et al, 2003; Mineishi et al, 2003; Wong et al, 2003; Petersen et al, 2004a; Flowers et al, 2005; Kojima et al, 2005; Mielcarek et al, 2005; Perez-Simon et al, 2005; Schmid et al, 2005). We found that following nonmyeloablative HCT, the probabilities of acute GVHD grades II-IV and III-IV were 57% and 17% respectively and that the 2-year cumulative incidence of extensive chronic GVHD was 80% ( Figure 5 ) (Petersen et al, 2004a). Acute or chronic GVHD were directly responsible for 22% of the days in hospitalization and were the primary causes of death in 10% of the patients (Petersen et al, 2004a). The cumulative incidences of acute and chronic GVHD found in our study are similar to the incidences observed in the matched related setting in a study by Mielcarek et al (2003). However, in a recent study of 297 HLA-matched related transplants following low-dose TBI containing regimens, the cumulative incidences of acute GVHD grades II-IV and of extensive chronic GVHD were lower, i.e. 45% and 47%, respectively (Mielcarek et al, 2005). The incidences of acute- and chronic GVHD following nonmyeloablative or reduced-intensity conditioning varies widely between studies and in T-cell replete transplants incidences of acute GVHD grades II-IV and of chronic extensive GVHD in the range of 9-14% have been reported (Couriel et al, 2004; Miller et al, 2004).

Due to the long half-life of alemtuzumab the use of this agent as part of the conditioning regimen results in an in vivo T-cell depletion of the graft, and the recipients of these regimens therefore have very low incidences of acute and chronic GVHD following the transplant (Kottaridis et al, 2000; Chakraverty et al, 2002; Perez-Simon et al, 2002b; Faulkner et al, 2004). Donor lymphocyte infusions are frequently given following these regimens and this may increase the overall occurrence of GVHD in these patients (Marks et al, 2002; Peggs et al, 2004). Increasing age is a risk factor for development of severe acute GVHD following myeloablative conditioning (Nash et al, 1992). Because the recipients of non-myeloablative HCT are generally older than recipients of myeloablative HCT it is difficult to compare the incidences of GVHD observed following the different regimens. However, studies that were not age-matched have generally shown similar or lower incidences of acute GVHD grades II-IV in recipients of reduced-intensity or nonmyeloablative conditioning than in recipients of myeloablative conditioning and that the incidences of chronic GVHD were similar in the two groups (Mineishi et al, 2003; Sorror et al, 2004; Alyea et al, 2005; Kojima et al, 2005; Perez-Simon et al, 2005; Aoudjhane et al, 2005). In a recent age-matched study the incidence of severe (grades III-IV) GVHD was higher in recipients of reduced-intensity conditioning when compared to recipients of myeloablative conditioning, while the risk of chronic GVHD was the same (Massenkeil et al, 2005). However, DLI was more frequently given in the reduced-intensity group and was more often followed by severe acute GVHD than in the myeloablative group (Massenkeil et al, 2005). In another age-matched study the incidence of acute GVHD grades II-IV were lower in the recipients of nonmyeloablative conditioning than in recipients of myeloablative conditioning, but the incidence of chronic GVHD showed no difference based on the conditioning regimen (Mielcarek et al, 2003). In our studies we have used conventional guidelines (Sullivan, 1999) to diagnose and grade acute and chronic GVHD in order to compare the observed incidences to other studies. These conventional criteria are, however, challenged by the finding that acute GVHD can occur beyond day +100 in recipients of nonmyeloablative or reduced-intensity HCT (Mielcarek et al, 2003; Taussig et al, 2003; Perez-Simon et al, 2005). In addition, the toxicity profile caused by GVHD is different based on the conditioning regimen with more skin and gut morbidity occurring in the nonmyeloablative group than in the myeloablative group 6-12 months post transplant (Mielcarek et al, 2003). To fully compare the morbidity caused by GVHD following nonmyeloablative and myeloablative HCT new grading criteria are needed, which focus on the symptoms of GVHD rather than the time of occurrence (Mielcarek et al, 2003). The effect of GVHD on survival and disease progression has been investigated in several studies of HCT with nonmyeloablative or reduced-intensity conditioning. The occurrence of acute GVHD is generally associated with increased TRM and decreased survival. In most studies a negative effect of acute GVHD on the survival has been observed for the more severe forms, i.e. grades III-IV (Mineishi et al, 2003; Corradini et al, 2005; Schmid et al, 2005; Shimazaki et al, 2005; Crawley et al, 2005a). In a recent study of 322 patients with various hematologic malignancies it was found that acute GVHD grades II-IV negatively affected the progression-free survival and increased the non-relapse related mortality (Baron et al, 2005b). In that study extensive chronic GVHD increased the progression-free survival and decreased the risk of progression or relapse (Baron et al, 2005b). A similar beneficial effect of chronic GVHD on the risk of relapse or on the progression-free survival has also been observed in other studies (Dreger et al, 2003; Perez-Simon et al, 2003; Mohty et al, 2004; Gerull et al, 2005; Blaise et al, 2005). In a recent study the effects on survival of no chronic GVHD, limited chronic GVHD and extensive chronic GVHD were analyzed separately (Crawley et al, 2005a). Both limited and extensive chronic GVHD were associated with a better progression-free survival but the highest progression-free survival was observed in the patients with limited chronic GVHD (Crawley et al, 2005a) and similar observations have been done by others (Corradini et al, 2005; Schmid et al, 2005).

In conclusion, whereas acute GVHD and especially severe acute GVHD is most often only associated with increased toxicity following nonmyeloablative or reduced-intensity HCT, the occurrence of chronic GVHD seems to be associated with a beneficial GVL effect, that can potentially override the toxic effects of this complication and increase the survival.

3.3.6. Immune reconstitution

Myeloablative conditioning induces a period of approximately two weeks of severe granulocytopenia, where the patients are at risk of bacterial infections. In addition, functional defects of the recovering granulocytes increase the risk of bacterial infections for several months (Zimmerli et al, 1991). While NK cells recover to normal values within one to two months both T- and B-cell recovery may be delayed for several months or even years (Petersen et al, 2003; Auletta & Lazarus, 2005). Low counts of CD4 + T cells and of B cells following allogeneic HCT are associated with an increased risk of infections and failure to mount cytomegalovirus (CMV) specific T-cell responses after the transplant is associated with decreased survival (Storek et al, 1997; Storek et al, 2000; Boeckh et al, 2003). Studies of long-term survivors of allogeneic HCT indicate that the function of the thymus is critical for the T-cell reconstitution and different strategies to enhance the thymopoiesis have therefore been explored (Storek et al, 2001b; van den Brink et al, 2004). As radiation has a negative effect on the thymopoiesis (Chung et al, 2001), it has been speculated that a reduction in the doses of radio-chemotherapy included in the conditioning regimen would limit the thymic damage and allow for a more rapid reconstitution of naïve T cells following nonmyeloablative or reduced-intensity HCT than after myeloablative HCT. Data to support this hypothesis has been presented by several groups (Friedman et al, 2001; Chao et al, 2002; Jimenez et al, 2005), but other groups have found that T-cell reconstitution following nonmyeloablative HCT occurs primarily by peripheral expansion with limited contribution of recent thymic emigrants (Bahceci et al, 2003; Larosa et al, 2005). The toxicity to the thymus induced by the conditioning regimen is not the only factor that influences the T-cell reconstitution following HCT. The use of alemtuzumab or ATG as part of the conditioning regimen has been associated with delayed T-cell reconstitution because of the in vivo T-cell depletion induced by these antibodies (Chakrabarti et al, 2002; Fallen et al, 2003; Saito et al, 2003; Dodero et al, 2005). In addition to the immediate role of the conditioning regimen, factors such as age and GVHD and its treatment may affect both T and B cell reconstitution (Weinberg et al, 2001; Storek et al, 2001c; Storek et al, 2002; Fallen et al, 2003; Petersen et al, 2003; Omazic et al, 2005). We studied the numbers of T, B and NK cells in the peripheral blood of 15 recipients of nonmyeloablative conditioning and transplantation with PBSC (Petersen et al, 2003). The NK cells and CD8 + T cells reached normal values quite rapidly, whereas the levels of CD4 + T cells and of B cells were reduced for 9-12 months ( Figure 6 and Figure 7 ) (Petersen et al, 2003). These observations are similar to the findings in other studies of patients transplanted with low-dose TBI containing regimens (Baron et al, 2003; Busca et al, 2003; Maris et al, 2003a) and indicate that the patients have severe immune deficiencies for up to one year post transplant. When we compared the lymphocyte subset counts at four months and at one year to the counts in 13 recipients PBSC following myeloablative conditioning we observed no difference in the NK- or T-cell counts between the two groups and lower B-cell counts at four months but not at 12 months in the nonmyeloablative group (Petersen et al, 2003). Others have also observed that most of the lymphocyte subsets reconstituted at similar rates in recipients of nonmyeloablative and myeloablative conditioning (Busca et al, 2003; Maris et al, 2003a). Maris et al (2003a) found that recipient T cells that survive the conditioning regimen are likely to contribute to the protection against CMV in the early period post transplant. However, it was also found that the naïve T-cell counts were reduced in the nonmyeloablative transplant recipients at one year post-transplant (Maris et al, 2003a). It is thus clear that the reconstitution of B and T cells following HCT is a dynamic process that is dependent on many factors, and firm conclusions on whether nonmyeloablative or reduced-intensity conditioning enhance the reconstitution of the adaptive immune system must await further research.

3.3.7. Infection and other complications

The management of infections is an important issue in patients undergoing allogeneic HCT with nonmyeloablative or reduced-intensity conditioning. During the first year following nonmyeloablative HCT we observed that 17% of the hospitalization days were due to known infections and 14% were due to fever/pneumonia of unknown origin (Petersen et al, 2004a). Early after transplant the reduced severity of the neutropenia in recipients of nonmyeloablative conditioning has translated into a lower rate of infections when compared to myeloablative conditioning (Junghanss et al, 2002b; Maris et al, 2003a; Diaconescu et al, 2004; Sorror et al, 2004). However when the observation period is extended infectious complications continue to occur (Mohty et al, 2000; Martino et al, 2001a; Daly et al, 2003; Maris et al, 2003a) and the incidence of invasive fungal infections may be similar or even higher in recipients of nonmyeloablative or reduced-intensity HCT (Martino et al, 2001a; Junghanss et al, 2002b; Fukuda et al, 2003a; Kojima et al, 2004). Conflicting results exist concerning the risk of CMV activation following different conditioning regimens. Martino et al (2001a) observed a reduction in the risk of both CMV reactivation and overt CMV disease in recipients of reduced-intensity conditioning when compared to the risk following myeloablative conditioning whereas others did not find such a difference (Saito et al, 2003; Schetelig et al, 2003a). In a study by Junghanss et al (2002a) it was observed that though the incidence of CMV disease was initially very low after nonmyeloablative HCT, the onset of CMV disease was delayed when compared to myeloablative HCT leading to similar 1-year incidences with the two types of conditioning. Finally, the use of alemtuzumab as part of the conditioning regimen appears to be associated with a high incidence of CMV reactivation perhaps due to a delay in T-cell reconstitution (Chakrabarti et al, 2002; Dodero et al, 2005). Besides infections and GVHD, engraftment syndrome which was diagnosed in three patients and TTP which developed in seven patients, were some of the more serious complications encountered in the first 30 recipients of HLA-identical nonmyeloablative HCT at Rigshospitalet (Petersen et al, 2004a). Engraftment syndrome is characterized clinically by fever, erythrodermatous rash and hypoxia with or without pulmonary infiltrates and hepatic- and renal dysfunction may also accompany the syndrome (Spitzer, 2001). Engraftment syndrome is related to the neutrophil recovery, involves release of inflammatory cytokines and has been observed following both autologous and allogeneic HCT (Spitzer, 2001; Gorak et al, 2005). Others have also observed engraftment syndrome in recipients of nonmyeloablative HCT, and though the patients usually respond to treatment with steroids, the syndrome has been associated with increased TRM and a shorter overall survival (Spitzer et al, 2000; Gorak et al, 2005). Thrombotic thrombocytopenic purpura is a syndrome consisting of microangiopathic hemolysis, thrombocytopenia and microvascular thrombosis (Sadler et al, 2004). The clinical symptoms are related to the tissue ischemia or infarction caused by the microvascular thrombi and includes neurologic abnormalities and abdominal or chest pain often accompanied by renal insufficiency (Sadler et al, 2004; Ho et al, 2005). In TTP after allogeneic HSCT there is generally no severe von Willebrand factor-cleaving protease (ADAMTS 13) deficiency (van der Plas et al, 1999; Elliott et al, 2003; Vesely et al, 2003). Plasma exchange, which is the treatment of choice in idiopathic TTP (Sadler et al, 2004) is rarely successful in transplant associated TTP and therefore not recommended (Ho et al, 2005). The pathophysiology of transplant associated TTP is poorly understood but endothelial damage caused by the conditioning regimen (Hahn et al, 2004) or as a result of Graft-versus-Host reactions (Biedermann et al, 2002; Ganster et al, 2004; Martinez et al, 2005) may be involved. The mortality following this complication is often considerable (Fuge et al, 2001; Ruutu et al, 2002; Shimoni et al, 2004; Martinez et al, 2005). Both the diagnostic criteria for TTP and the reported incidences of this complication have varied between studies (George et al, 2004; Ho et al, 2005). We used the criteria published by Ruutu et al (2002) i.e. the simultaneous occurrence of all of the following: (1) red blood cell fragmentation, (2) hemolysis, (3) the need for red blood cell transfusions, (4) de novo or prolonged thrombocytopenia (5) negative, or at most, marginally positive laboratory tests for disseminated intravascular coagulation. Ruutu et al (2002) found a 2-year cumulative incidence of TTP of 6.7% in recipients of myeloablative HCT whereas we observed a 1-year cumulative incidence of 26% (Petersen et al, 2004a). Other groups have described the occurrence of TTP following HCT with nonmyeloablative- or reduced-intensity (Corradini et al, 2002; Elliott et al, 2003; Shimoni et al, 2004; Kornacker et al, 2005). In the study by Shimoni et al (2004) the cumulative incidence of TTP was 23% in recipients of reduced conditioning HCT and was not significantly higher than the incidence in recipients of myeloablative conditioning (16%). The factors that have been found to increase the risk of TTP includes acute GVHD, age, transplantation with a matched unrelated donor and female gender (Fuge et al, 2001; Daly et al, 2002; Ruutu et al, 2002; Elliott et al, 2003; Hahn et al, 2004; Shimoni et al, 2004; Petersen et al, 2004a; Martinez et al, 2005).

In conclusion TTP is a serious complication following allogeneic HCT and the occurrence may be related to GVHD or to the same risk factors as known for GVHD (Elliott et al, 2003; Martinez et al, 2005). The development of TTP may thus depend both on the kind of conditioning regimen, the GVHD prophylaxis and the patient population and further research is needed to clarify whether the incidence of TTP is higher following nonmyeloablative or reduced-intensity HCT than following myeloablative HCT.

3.3.8. Hospitalization

McSweeney et al (2001) showed that allogeneic HCT with nonmyeloablative conditioning could be performed as an outpatient procedure as 53% of the eligible patients did not require hospitalization during the first 2 months post-transplant and the remaining patients were hospitalized for a median of 8 days (range 1-35 days). At Rigshospitalet we have also attempted to perform the transplants in the outpatient setting (Petersen et al, 2004a). We found that 22% of the eligible patients were treated entirely as outpatients during the first 2 months and that the median hospitalization requirements for the remaining patients were 8 days (range 1-61 days) (Petersen et al, 2004a). However, the patients continued to be admitted beyond two months post transplant. In the 17 patients who had a follow-up of more than 1 year the median time spend in hospital was 44 days (range 4-151 days) and in addition they had a median of 52 (range 23-73) outpatient visits (Petersen et al, 2004a). This observation illustrates that though the transplant itself can be performed as an outpatient procedure, both the patients and the treating institution must be prepared on the possibibily that complications may result in a considerable number of admissions. In line with this result, the 1-year cost of the total transplant procedure did not differ between recipients of nonmyeloablative and of myeloablative HCT as treatment for acute myeloid leukemia (Cordonnier et al, 2005). Though the patients in the nonmyeloablative group had a significantly shorter duration of the initial hospitalization period, the total number of hospitalization days was not different and the costs in the period from 6-12 months post transplant were higher in the nonmyeloablative group than in the myeloablative group (Cordonnier et al, 2005).

3.3.9. Survival and disease control

When the survival following allogeneic HCT with nonmyeloablative or reduced-intensity conditioning is evaluated it is important to remember that the patients transplanted were ineligible for conventional myeloablative HCT due to age or co-morbidity. In addition many of the patients were heavily pretreated. The initial studies were conducted as feasibility studies and often included patients with various hematologic malignancies. In the study we performed, the overall survival at two years was 68% with a progression-free survival of 43%, a TRM of 22% and a relapse related mortality of 13% ( Figure 8 A ) (Petersen et al, 2004a). These figures are comparable with the results of a 305 HLA-identical transplants after nonmyeloablative conditioning reported by the Seattle consortium (Sandmaier et al, 2003). The patients in our study had received a median of 4 (range 1-10) chemotherapy regimens prior to the transplant, 50% had received an autologous HCT and only 20% were in complete remission at the time of transplant (Petersen et al, 2004a). The results thus indicate that nonmyeloablative HCT represents a feasible treatment option for patients with advanced hematologic malignancies that are ineligible to receive HCT with myeloablative conditioning.

During the last few years a number of studies have been published with disease specific survival data available ( Tables 1-8 ). It is difficult to compare the results of these studies because of differences in the patient populations and differences in the conditioning regimens. Some of the larger studies (Robinson et al, 2002; Dreger et al, 2003; Robinson et al, 2004; Aoudjhane et al, 2005; Crawley et al, 2005a; Crawley et al, 2005b) performed by the European Group for Blood and Marrow Transplantation (EBMT) includes patients previously reported in studies from single institutions. The general tendency in the studies summarized in Table 1-8 is that disease control can be achieved, but the follow up in most studies is rather short. The TRM is generally low but it is not negligible. Traditionally the day +100 TRM has been used to compare different studies of HCT with myeloablative conditioning. Because of the substantial number of complications observed during the first year post transplant after nonmyeloablative or reduced-intensity HCT, the day +100 TRM may not fully estimate the toxicity related to the procedure, and the longest period for which TRM has been reported is therefore included in Tables 1-8. Though the number of patients in our study was small we found that the number of relapses were higher in patients with multiple myeloma than in patients with other mature B-cell malignancies ( Figure 8B ) (Petersen et al, 2004a). When examining Tables 1-5 rather high incidences of relapse have been observed in both multiple myeloma and non-Hodgkin lymphomas, whereas the relapse rate in chronic lymphocytic leukemia generally appears lower. Whether this is due to differences in the susceptibility of the diseases to the GVT effect is to early to conclude. However, the 3-year progression-free survival of 21% in 229 patients with multiple myeloma reported recently (Crawley et al, 2005a) indicates that further progress in the treatment of this disease is warranted. In the study by Crawley et al (2005a) chemoresistant disease negatively affected both the overall- and progression-free survival, a finding which is in line with the finding by Kröger et al (2004a) that relapse after a prior autologous HCT, predicted for an increased relapse rate and decreased overall- and progression-free survival. It has also been observed that patients who had received many cycles of chemotherapy had a lover progression-free survival than the less heavily pretreated patients (Gerull et al, 2005). Table 1 Table 2 Table 3

In summary these data indicate that the disease control in multiple myeloma following nonmyeloablative or reduced-intensity HCT is limited in patients with advanced disease. Trials of the tandem approach where an autologous HCT is closely followed by an allogeneic HCT are ongoing and will hopefully elucidate whether the initial promising results of this schedule (Kroger et al, 2002b; Maloney et al, 2003; Galimberti et al, 2005) will lead to durable remissions.

From the studies summarized in Tables 1-8 it is not possible to determine whether one specific conditioning regimen compares favorably to other regimens with respect to the clinical outcome. It is also difficult to determine whether the outcome of these studies is better or worse than the outcome following conventional chemotherapy or following myeloablative HCT, because no randomized studies exist. Retrospectively, the role of the conditioning regimen for the clinical outcome has been examined. In patients with acute myeloid leukemia and myelodysplastic syndrome a similar overall survival was observed in recipients of the nonmyeloablative FAI regimen and in recipients of the reduced-intensity FM regimen, Table 7 (de Lima et al, 2004). The number of relapses were higher in the FAI group while the TRM was higher in the FM group (de Lima et al, 2004) indicating that both the toxicity and the anti-neoplastic effect of the conditioning regimen may affect the clinical outcome. In a study by Aoudjhane et al (2005) 315 patients with acute myeloid leukemia who had received different nonmyeloablative- or reduced-intensity conditioning were matched to 407 recipients of myeloablative conditioning. There was no difference in the overall and progression-free survival between the two groups. Again the TRM was reduced in recipients of nonmyeloablative or reduced-intensity conditioning but this advantage was offset by a higher rate of relapse (Aoudjhane et al, 2005). In contrast, Scott et al (2006) found no difference in relapse rate or progression-free survival between patients transplanted with myeloablative or nonmyeloablative conditioning for myelodysplastic syndrome or acute myeloid leukemia.

In patients with chronic myeloid leukemia, Crawley et al (2005b) found that the progression-free survival was higher in patients conditioned with fludarabine, busulfan and ATG (Slavin et al, 1998) when compared to the survival in recipients of other conditioning regimens. Comparable results for overall and progression-free survival between recipients of nonmyeloablative or reduced-intensity HCT and of myeloablative HCT have also been reported in patients with chronic lymphocytic leukemia (Dreger et al, 2005) and in cohorts of patients with various hematologic malignancies (Alyea et al, 2005; Kojima et al, 2005). In contrast the results of HCT with nonmyeloablative or reduced-intensity conditioning in acute lymphoblastic leukemia have generally been dismal due to high rates of relapse (Kassim et al, 2005). Table 4 Table 5 Table 6 Table 7 Table 8

There are no randomized studies available where nonmyeloablative or reduced-intensity HCT has been compared to conventional chemotherapy. However, Mohty et al (2005) investigated the outcome in patients with acute myeloid leukemia who were potential candidates for HCT with reduced-intensity conditioning. The patients were transplanted if they had an HLA-identical sibling donor but received chemotherapy if no donor was available. The results of this genetic randomization showed a higher 4-year leukemia-free survival in the donor group when compared to the no donor group (Mohty et al, 2005).

In conclusion, more research is needed to establish the role of HCT with nonmyeloablative or reduced-intensity conditioning in the treatment of patients with hematologic malignancies. We now know that responses can be obtained in a variety of diseases, but important issues such as whom to transplant, and when to transplant is currently uncertain. Though prospective comparative studies are needed to address these issues, other kinds of research is also important to improve the results of HCT with reduced-intensity or nonmyeloablative conditioning. Though the TRM in most studies is lower following the nonmyeloablative or reduced-intensity conditioning regimens compared to myeloablative conditioning regimens, it is not negligible as shown in Tables 1-8. Relapse of the malignant disease also continues to be a significant problem in most studies. In HCT with nonmyeloablative conditioning the alloreactive responses of the donor cells represents the only potentially curable principle of the procedure, and at the same time these responses are responsible for a large part of the morbidity and the mortality associated with the treatment. It is thus important to investigate the biological mechanisms involved in GVHD and the GVT effect. The knowledge obtained may then be used to design treatment protocols that reduce the pathology related to alloreactivity without compromising the GVT effect.

4. Biology of alloreactive responses

4.1. Hematopoietic chimerism and tolerance

In murine and canine models, stable mixed hematopoietic chimerism has been achieved in HCT with nonmyeloablative conditioning regimens (Sharabi & Sachs, 1989; Storb et al, 1997; Sykes et al, 1997). This state of stable mixed hematopoietic chimerism was associated with specific donor-host tolerance exemplified by the lack of GVHD and the ability of donor skin grafts to survive while third party skin grafts were rejected (Sharabi & Sachs, 1989; Storb et al, 1997; Sykes et al, 1997; McSweeney & Storb, 1999). One of the initial goals of HCT with nonmyeloablative conditioning in humans was to obtain stable mixed hematopoietic chimerism and bi-directional donor-host tolerance as in the animal models. If individuals could be tolerized to donor antigens by this procedure it could be beneficial in recipients of solid organ transplantation, obviating the need for life long pharmacologic immunosuppression (Spitzer et al, 1999). Stable mixed hematopoietic chimerism by itself would be curable in a number of non-malignant hematologic diseases as well as creating a platform for immunologic interventions such as DLI to treat malignant diseases (McSweeney & Storb, 1999). The relationship between mixed chimerism and tolerance appears to be more complex in humans than in the animal models. Childs et al (1999) first reported that complete donor T-cell chimerism was necessary before alloresponses could occur. We found, in line with other reports, that acute GVHD could occur in the setting of mixed T-cell chimerism, indicating that mixed T-cell chimerism does not protect against alloreactivity in humans (Mattsson et al, 2001; Dey et al, 2003; Baron et al, 2004; Petersen et al, 2004b). With the onset of acute GVHD, both CD4 + and CD8 + donor T-cell chimerism increased and the CD8 + T cells of recipient origin disappeared faster in patients with acute GVHD grades II-IV than in patients without clinical significant acute GVHD (Petersen et al, 2004b). These findings support the hypothesis that alloreactive donor T cells can contribute to the elimination of recipient hematopoietic tissues through GVH reactions (Kolb et al, 1997; Pelot et al, 1999; Storb et al, 1999). Not only GVHD but also GVT reactions may occur in the context of mixed chimerism in humans (Dey et al, 2003; Baron et al, 2004). In the study by Baron et al (2004) approximately half of the patients were still mixed T-cell chimeras at the time when they achieved complete remission.

4.2. The Graft-versus-Tumor effect

Intensive research has been performed into the mechanisms involved in the GVT effect. There is growing evidence that mHags are some of the primary target molecules and that alloreactive T cells specific for these mHags are the effector cells (Fontaine et al, 2001; Bleakley & Riddell, 2004). As mHags are peptides derived from polymorphic proteins one would expect a vast number of mHags to be present in any transplant situation. However, only 16 molecules have been identified as mHags in humans so far (Bleakley & Riddell, 2004). One of the intriguing aspects of the GVT effect is that while it is often associated with GVHD, it can occur in the absence of GVHD. One possible explanation for this observation could be related to the tissue distribution of the different mHags. The majority of the identified mHags has an ubiquitous tissue distribution and mismatch for these antigens may therefore be associated with reactivity against both malignant cells and normal host tissues (Bleakley & Riddell, 2004). In contrast, the expression of mHags such as HA-1 and HA-2 are confined to cells of hematopoietic origin (de Bueger et al, 1992). Disparity for these antigens could therefore lead to an alloresponse directed against both normal and malignant hematopoietic cells while sparing the non-hematopoietic tissues of the host, which clinically would be observed as a GVT effect without GVHD (Mutis et al, 1999b; Dickinson et al, 2002; Marijt et al, 2003). This explanation may be overly simplistic because disparity for HA-1 has in some studies been implicated in the development of GVHD (Goulmy et al, 1996; Tseng et al, 1999; Mutis et al, 1999a; Lin et al, 2001). Inflammatory cytokines, released during an alloresponse, can mediate acute GVHD in mice that lack expression of alloantigen on the epithelial cells (Teshima et al, 2002) and inflammation may induce expression of mHags, normally restricted to the hematopoietic tissues, on non-hematopoietic cells (Kloosterboer et al, 2005). This indicates that the separation of GVHD and the GVT effect may be difficult to achieve in the clinical setting. Recently, it has been shown that many of the mHags identified in humans are derived from proteins implicated in tumorigenesis and that solid tumors may aberrantly express mHags such as HA-1 (Klein et al, 2002; Spierings et al, 2004; Tykodi et al, 2004). These observations may encourage further development of allogeneic HCT as immunotherapy not only for hematologic malignancies but also for solid tumors, for example by post-transplant vaccination or infusion of mHag specific T cells (Tykodi et al, 2004; Hambach & Goulmy, 2005). Alloreactive NK cells have also been implicated in GVT responses following HCT, especially in recipients of T-cell depleted grafts. The activity of NK cells is influenced by killer-cell immunoglobulin-like receptors (KIRs) present on the surface of the NK cells. This receptor family includes inhibitory receptors that recognize HLA class I alleles known as KIR epitopes (Parham & McQueen, 2003). According to the missing self recognition model, the NK cells of an individual carries inhibitory KIRs specific for the HLA class I molecules of the individual, and interaction between the inhibitory KIRs and HLA class I on the surface of autologous cells sends a negative signal to the NK cell, which prevents killing of the autologous cells. In contrast, allogeneic cells, which express other HLA class I alleles fail to interact with the inhibitory KIRs on the NK cells of the individual and are killed (Karre, 2002). In haploidentical HCT the donor and the recipient only share one set of HLA class I alleles and the recipient cells will therefore fail to express KIR epitopes that can interact with the inhibitory KIRs on the donor NK cells. In this transplant setting, where extensive T-cell depletion is used, it has been shown that NK-cell alloreactivity plays an important role in the eradication of acute myeloid leukemia (Ruggeri et al, 1999; Ruggeri et al, 2002). Interestingly the patients with KIR epitope incompatibility did not develop GVHD, and by using murine models the authors showed that this could be due to elimination of the recipient APC by the alloreactive NK cells (Ruggeri et al, 2002). Besides the control of NK-cell activity that is based on the interaction between KIRs and HLA class I, NK-cell activity is also influenced by HLA class I independent mechanisms (Kumar & McNerney, 2005). It is therefore possible for an individual to harbor potentially autoreactive NK cells that carries KIRs for which the individual have no corresponding HLA-alleles and thus KIR epitope incompatibility may also be present in HLA-identical HCT (Shilling et al, 2002; Dupont & Hsu, 2004). That NK-cell alloreactivity may play a role in HLA-identical HCT is suggested by a recent study, where patients who lacked one or more of the HLA class I alleles for the inhibitory KIRs of the donors had a lower relapse incidence than patients with KIR epitope compatibility (Hsu et al, 2005).

4.3. Pathophysiology of Graft-versus-Host Disease

While the pathophysiology of chronic GVHD remains poorly characterized, acute GVHD has been thoroughly investigated in animal models and a three-step model has been proposed by Ferrara and colleagues (Reddy & Ferrara, 2003; Ferrara et al, 2005). In the first phase of the process, tissue damage by the conditioning regimen results in the translocation of lipopolysaccharide (LPS) from the intestinal lumen to the circulation and release of inflammatory cytokines such as tumor necrosis factor (TNF)- α and interleukin (IL)-1 (Hill et al, 1997; Hill & Ferrara, 2000). One of the effects of LPS and the inflammatory cytokines is to induce maturation and activation of host APC such as dendritic cells, leading to an increased expression of MHC, costimulatory and adhesion molecules on the APC surface, which in turn enhances donor T-cell activation (Matzinger, 2002; Reddy & Ferrara, 2003; Shlomchik, 2003). Recent studies has highlighted the role of host APC as being essential for donor T-cell activation and initiation of GVHD, but APC of donor origin may intensify and propagate ongoing GVHD and thus contribute to the pathology of GVHD (Shlomchik et al, 1999; Teshima et al, 2002; Matte et al, 2004; Merad et al, 2004; Tivol et al, 2005). When T cells are activated in the second phase of the process, they upregulate the expression of the IL-2 receptor, proliferate and secrete cytokines such as IL-2 and interferon (IFN)- γ (Th1 cytokines) and/or IL-4, IL-5, IL-10 and IL-13 (Th2 cytokines) (Mosmann et al, 1986; Ferrara et al, 2005). The exact role of these and other cytokines in this process named the "cytokine storm" which accompanies acute GVHD is not completely elucidated. However, acute GVHD is primarily a Th1 response where IL-2 is essential for continuous proliferation and amplification of the response. And where IFN- γ lowers the amount of LPS needed to induce production of inflammatory cytokines by macrophages and thereby creates a vicious circle of increasing inflammation (Ferrara et al, 2005). In the third phase of the process, cells in the target tissues of GVHD, which are primarily the skin, liver, gut and lymphohematopoietic tissues, are destroyed by direct killing by donor cytotoxic T cells using the Fas/Fas ligand or the perforin/granzyme pathways (Graubert et al, 1997; van den Brink & Burakoff, 2002; Reddy & Ferrara, 2003) and by the toxicity of inflammatory cytokines such as IL-1 and TNF- α (Teshima et al, 2002).

4.4. Cytokines in alloreactive responses

Though acute GVHD is characterized as a Th1 response, the Th1/ Th2 paradigm is not applicable to all aspects of alloreactivity. Interleukin-4 has been shown to be necessary for activating alloreactive CD4 + T cells by an APC dependent mechanism (Bagley et al, 2000) and IL-2 is involved in the development of tolerance (Nelson, 2004). However, T cells that have been experimentally manipulated to express a Th2 phenotype, characterized by the production of IL-4 and IL-10 when stimulated, have been shown to inhibit development of acute GVHD in murine models (Fowler et al, 1994a; Fowler et al, 1994b; Krenger et al, 1995). In addition, human studies have shown that high pre-transplant frequencies of donor IL-2 producing helper T lymphocyte precursors (HTLp) reacting against recipient antigens are associated with an increased risk of acute GVHD (Theobald et al, 1992; Schwarer et al, 1993; Russell, 2002) and with a lower risk of relapse (Russell et al, 2001). Similarly high frequencies of anti-recipient IL-4 producing HTLp have been related to a reduced risk of acute GVHD and an increased risk of relapse (Imami et al, 1998). The combined determination of IL-2 and IL-4 producing HTLp frequencies would potentially give a more accurate estimate of the degree of alloreactivity that could be expected after allogeneic HCT in each donor/recipient combination. With the aim of performing simultaneous determination of IL-2 and IL-4 producing HTLp frequencies by limiting dilution analysis (LDA), we utilized the CTLL-2 bioassay and the CT.h4S bioassay to study the secretion of IL-2 and IL-4 in HLA-mismatched mixed lymphocyte cultures (MLCs) (Petersen et al, 2002). The results showed that though we were able to optimize the CT.h4S bioassay to measure IL-4 concentrations as low as 5 pg/ml, we failed to detect IL-4 in most of the MLCs that were performed with 5 × 10 4 responder cells and incubated for 3 days (Petersen et al, 2002). High amounts of soluble IL-4 receptor produced by activated T cells could in theory be responsible for this lack of IL-4 detection. To test this hypothesis we used an enzyme linked immunosorbent assay (ELISA) to detect soluble IL-4 receptor, but did not detect significant amounts of this molecule in the MLC supernatants (Petersen et al, 2002). Finally we performed large MLCs with 1 × 10 6 responder cells and found that whereas 3-6 days of incubation was optimal for IL-2 detection, the optimal incubation period for IL-4 detection was 12 days or more.

In conclusion we found that a combined IL-2/IL-4 HTLp assay was not practical due to low frequencies of IL-4 producing cells in response to HLA-mismatched stimulator cells and due to differences in the optimal incubation period needed to detect the two cytokines (Petersen et al, 2002). The secretion of IL-4 in response to HLA-identical stimulator cells was not investigated in the study mentioned above. However, with the use of real-time quantitative RT-PCR we did not detect significant amounts of IL-4 mRNA in HLA-identical MLCs performed with 5 × 10 4 responder cells and incubated for 3 days (Petersen et al, 2006).

In vitro methods such as LDA, flowcytometry with intracellular staining and enzyme linked immunospot (ELISPOT) assays have been used after allogeneic HCT to quantify cytokine secreting cells and their relation to the development of GVHD. By using LDA we found that the frequencies of IL-2 producing cells that reacted against recipient antigens were higher in patients with acute GVHD grades II-IV than in patients without clinical significant acute GVHD ( Figure 9 ) (Petersen et al, 2005). This finding confirms that it is possible to quantify the degree of ongoing alloreactivity by use of LDA of IL-2 producing cells following HCT (Nierle et al, 1993; Bunjes et al, 1995). However, due to frequent occurrence of inhibition of the IL-2 production and to the subsequent complexity of the computational analysis, we found that the assay was not suitable as a routine tool in allogeneic HCT (Petersen et al, 2005).

In studies performed with ELISPOT or flowcytometry with intracellular staining, both IFN- γ and IL-4 have been implicated in the development of GVHD (Guo et al, 2004; Hirayama et al, 2005; Takabayashi et al, 2005). Higher frequencies of INF- γ producing cells have been found in patients with acute GVHD when compared to patients without acute GVHD (Guo et al, 2004; Hirayama et al, 2005). The results are more inconsistent for IL-4, one study showing higher frequencies in patients with acute GVHD when compared to patients without GVHD (Hirayama et al, 2005), one study showing no difference (Guo et al, 2004) and one study showing lower frequencies of IL-4 producing cells in patients with acute GVHD (Takabayashi et al, 2005). Other methods that have been employed in the study of cytokines and development of GVHD have included determination of cytokine gene expression in cells from the peripheral blood, measurement of cytokines and cytokine receptors in serum, plasma or culture supernatants and investigation of polymorphisms in the genes that controls the production of cytokines or the expression of cytokine receptors.

We performed a longitudinal study of the gene expression of IL-2, IL-4, IL-10, IL-18, TNF- α and transforming growth factor β (TGF- β ) in peripheral blood mononuclear cells obtained from 21 recipients of HCT with nonmyeloablative conditioning (Petersen et al, 2006). We used real-time quantitative RT-PCR to determine the levels of cytokine mRNA in cells that were unstimulated or stimulated with irradiated recipient-, donor- or third-party mononuclear cells. The results of the study showed that the composition of the responder cells was likely to influence the results (Petersen et al, 2006). This finding may not be surprising but is important in studies of samples obtained from recipients of HCT, as the cell composition of these samples varies widely because of the differences in the reconstitution of monocytes and lymphocytes following HCT. In addition, we observed that on day +14 the levels of IL-10 mRNA in response to stimulation with irradiated recipient- or donor cells were higher in patients without acute GVHD than in patients with acute GVHD grades II-IV ( Figure 10 ) (Petersen et al, 2006). The IL-10 mRNA detected on day +14 was likely to originate from the recipient cells and the patients who experienced progression or relapse of the malignant disease had higher pre-transplant levels of IL-10 mRNA than patients who did not relapse. Based on these findings we concluded that IL-10 might inhibit alloreactivity following allogeneic HCT potentially affecting both the occurrence of GVHD and the GVL effect (Petersen et al, 2006).

The data in the literature concerning the levels of IL-10 post transplant and the occurrence of GVHD are conflicting. In some studies high post-transplant levels of IL-10 have been related to the development of tolerance (Bacchetta et al, 1994) and a low incidence of acute GVHD (Tanaka et al, 1997; Ju et al, 2005). In other reports increased IL-10 levels have been observed before or during acute GVHD (Carayol et al, 1997; Hempel et al, 1997; Remberger & Ringden, 1997; Liem et al, 1998; Takatsuka et al, 1999; Remberger et al, 2003; Visentainer et al, 2003). The major biological function of IL-10 is to oppose inflammatory responses (Moore et al, 2001) and it is therefore difficult to determine whether IL-10 observed during an inflammatory response such as acute GVHD contribute to the response or is secreted as a regulatory mechanism. High spontaneous IL-10 production by MNC pre-transplant has been associated with a low incidence of acute GVHD (Baker et al, 1999; Holler et al, 2000) and though the genetic control of IL-10 production needs further elucidation (Mullighan & Bardy, 2004; Lin et al, 2005), studies of gene polymorphisms in the IL-10 promoter region have suggested that recipients who are intermediate or high IL-10 producers are protected against severe acute GVHD (Middleton et al, 1998; Cavet et al, 1999; Cavet et al, 2001; Socie et al, 2001; Lin et al, 2003; Dickinson et al, 2004). A recent study by Lin et al (2005) further substantiates the role of IL-10 in regulation of the development of acute GVHD. In that study there was a synergistic relationship between the recipient IL-10 genotype and the IL-10 receptor- β genotype of the donor, suggesting that both cytokine production and the receptor properties are important for regulation of alloreactivity by IL-10 following allogeneic HCT (Lin et al, 2005).

4.5. Regulatory cell populations
and alloreactivity

During the last decade one topic in immunology that has received much interest is the regulation of immuneresponses. The interest was prompted by the characterization of a subset of CD4 + T cells that inhibited autoimmunity in mice. These cells were termed regulatory T cells (T reg ) and were characterized by constitutive surface expression of CD25 (the α chain of the IL-2 receptor) (Sakaguchi et al, 1995; Sakaguchi, 2004). Resting T cells normally do not express CD25 but the expression of this molecule on the cell surface is upregulated upon activation. The CD4 + CD25 + T reg originally characterized underwent differentiation in the thymus, had limited potential for proliferation and inhibited the proliferation of CD4 + CD25 - T cells and CD8 + T cells in vitro by a cell-contact dependent mechanism, which involved down regulation of the IL-2 production (Suri-Payer et al, 1998; Thornton & Shevach, 1998; Jordan et al, 2001; Piccirillo & Shevach, 2001). In humans, CD4 + CD25 + T reg with similar characteristics have also been found (Ng et al, 2001). More recently, it has been shown that expression of the forkhead family transcription factor Foxp3 is critical for the generation and function of T reg (Fontenot et al, 2003; Hori et al, 2003; Khattri et al, 2003). In addition it has been shown that CD4 + CD25 + T reg can be generated in the periphery under certain conditions (Karim et al, 2004) and that T reg can be expanded in vitro while retaining their inhibitory capacity (Hoffmann et al, 2004). In addition to the CD4 + CD25 + T reg , several other T-cell subsets with regulatory properties have been identified, including CD4 + T cells that produce high levels of IL-10 (Groux et al, 1997), CD8 + T-cell populations (Jiang & Chess, 2000; Xystrakis et al, 2004) and NK-T cells (Kronenberg, 2005). In the field of HCT, regulatory T-cell populations have been shown to inhibit GVHD in animal models (Zeng et al, 1999; Taylor et al, 2002; Edinger et al, 2003; Trenado et al, 2003; Xystrakis et al, 2004). In humans, Meignin et al (2005) observed no differences in the numbers of CD4 + CD25 + T reg in the blood or in the expression of Foxp3 in sorted CD4 + CD25 + T reg between patients with and without chronic GVHD. Clark et al (2004) found higher absolute numbers of T reg in patients with chronic GVHD than in patients without GVHD and Sanchez et al (2004) observed a similar trend. On the contrary Miura et al (2004) observed lower levels of Foxp3 in peripheral blood mononuclear cells from patients with acute and chronic GVHD than from patients without GVHD, and Zorn et al (2005) confirmed this finding in a larger study of patients with chronic GVHD and also found low frequencies of CD4 + CD25 + T reg in patients with chronic GVHD. Thus more studies are needed before definite conclusions can be made about the relationship between the numbers of CD4 + CD25 + T reg and GVHD development.

Depletion of CD25 + cells by CD25-specific immunotoxin infusions early after transplant has been attempted with the aim of depleting T cells activated by alloantigens and thereby reducing the incidence of GVHD (Martin et al, 2004). The results suggested that this procedure could actually increase the incidence of acute GVHD grades III-IV because the concomitant administration of cyclosporine inhibited the expression of CD25 on the surface of the alloreactive cells and caused a selective depletion of cells with a constitutively high expression of CD25 such as T reg (Martin et al, 2004).

An alternative way to study cell interactions in immune responses is by LDA (Lefkovits & Waldmann H, 1999; Hernandez-Fuentes et al, 2003; Bonnefoix et al, 2005). We performed LDA of IL-2 producing cells using responder cells obtained from patients during the first year following HCT with myeloablative or nonmyeloablative conditioning. In a substantial number of the assays performed, there were deviations from single-hit kinetics and signs of inhibition of the IL-2 production (Petersen et al, 2005). In limiting dilution analysis studies inhibition has been observed previously when mixtures of effector and inhibitory cells are present in the responder cell population, and mathematical models have been developed to calculate the frequencies of the different cell subsets (Fey et al, 1983; Dozmorov et al, 1995; Dozmorov et al, 1996; Dozmorov & Miller, 1996; Lefkovits & Waldmann H, 1999; Dozmorov et al, 2000; Portugal et al, 2001; Bonnefoix et al, 2003; Bonnefoix et al, 2005). Inhibition of alloresponses has previously been observed in LDA experiments with responder cells from recipients of HCT (Rosenkrantz et al, 1990; Kraus et al, 2003) but computational analysis of these cell interactions has not been attempted in a large number of samples. We used a non-linear model to analyze the LDA results and this data analysis suggested the presence of an inhibitory cell population in the responder cells (Petersen et al, 2005). Inhibition occurred throughout the first year post-transplant and was not restricted by factors such as type of graft, conditioning regimen or chimerism status. Inhibition was more often present with high frequencies of IL-2 producing cells suggesting a physiologic role of the supposed inhibitory cell population in down-regulation of immune responses ( Figure 11 ) (Petersen et al, 2005) We do not know the phenotype of the inhibitory cell population proposed by our analysis, but CD4 + , CD25 + T reg can inhibit CD4 + , CD25 - T-cell responses to alloantigens in a similar manner as we have observed (Ng et al, 2001; Bonnefoix et al, 2005).

In conclusion, both animal models and human studies indicate that regulatory cell populations may affect alloresponses following HCT, but further studies are needed to clarify the exact role of these cells. If this goal is achieved, one possible therapeutic application of regulatory cells could be infusion of in vitro expanded T reg for treatment of GVHD.

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Alloreactivity as therapeutic principle in the treatment of hematologic malignancies

1. Introduction

2. Alloreactivity

3. Allogeneic hematopoietic cell transplantation