British Medical Bulletin

British Medical Bulletin Advance Access first published online on September 11, 2006
This version published online on October 5, 2006
British Medical Bulletin, doi:10.1093/bmb/ldl005

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Allogeneic haematopoietic stem cell transplantation: current status and future outlook

Johan Aschan

Center for Allogeneic Stem Cell Transplantation and Division of Hematology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden

Correspondence to: Johan Aschan, Department of Medicine, M54, Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden. Tel.: +46 8 585 800 00; fax: +46 8 774 87 25; e-mail: johan.aschan{at}karolinska.se

	Abstract

Top Abstract Introduction Donors Stem cell sources Conditioning Supportive care Infections GVHD Relapse Individualization Novel indications Mesenchymal stem cells Conclusions References

 
Allogeneic haematopoietic stem cell transplantation (allo-SCT) is an established treatment of haematological malignancies and other immunohaematopoietic disorders. The use of unrelated donors and cord blood (CB) grafts has increased the possibilities of finding a donor, and results are approaching those after sibling donor transplants. The use of peripheral blood stem cells (PBSCs), instead of bone marrow, results in faster engraftment and increased risk of chronic graft-versus-host disease (GVHD). High-dose myeloablative (MA) conditioning is recently challenged by reduced-intensity conditioning (RIC) for older patients and those with comorbidity. Better diagnostic tools and novel anti-microbial drugs have reduced morbidity and mortality from infections. A major problem is disease relapse. Early detection of minimal residual disease or recurrent recipient haematopoietic cells allows early intervention with immunotherapy. Donor lymphocyte infusions (DLIs) have not only an anti-leukaemic effect but also an anti-tumour effect against a variety of solid organ tumours. New indications such as metastatic solid tumours are investigated. Mesenchymal stem cells (MSC) may enhance engraftment and have immunomodulatory effects.

Keywords: allogeneic haematopoietic stem cell transplantation • unrelated donors • peripheral blood stem cells • leukaemia • reduced-intensity conditioning • graft-versus-host disease • relapse

	Introduction

Top Abstract Introduction Donors Stem cell sources Conditioning Supportive care Infections GVHD Relapse Individualization Novel indications Mesenchymal stem cells Conclusions References

 
The first attempt to treat a patient suffering from a haematological malignancy with high-dose chemoradiotherapy followed by allogeneic haematopoietic stem cell transplantation (allo-SCT) was performed by Thomas et al. in 1957 [1]. This treatment concept was developed from the findings during the Second World War that irradiation destroyed the bone marrow function. Further studies during the 1950s showed that irradiated animals could be saved from irreversible pancytopenia by transfusion of bone marrow from another animal, and shortly thereafter, animal models in leukaemia paved the way for the first treatment of humans with end-stage leukaemia. After the discovery of the human leucocyte antigens (HLAs), matching between donors and patients became possible. The first long-term survivors after bone marrow transplantation were patients with severe combined immunodeficiency transplanted in 1968 [2]. After the demonstration by Thomas et al. that some patients with end-stage leukaemia could be saved with allo-SCT from HLA-identical donors, the number of transplants performed worldwide increased [3]. Today >20 000 transplants are performed yearly with >200 000 transplants performed overall. Apart from the discovery of the HLA system, prevention of graft-versus-host disease (GVHD), better supportive care and, most important, transplantation in remission had a major impact on the success.

Established indications are acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL). For acute leukaemia with high-risk features, allo-SCT is indicated in first remission (CR 1), otherwise in more advanced stages. Transplantation in later stages increases both the risk of leukaemia relapse and the risk of transplantation-related complications. Despite the introduction of tyrosine kinase inhibitors such as imatinib mesylate, allo-SCT is still the only curative treatment for chronic myeloid leukaemia (CML). Usually, younger patients are therefore early considered for allo-SCT, but most patients are referred to transplantation after failure of tyrosine kinase inhibitor treatment. Other haematological malignancies indicated for allo-SCT are myelodysplastic syndrome (MDS), chronic lymphocytic leukaemia (CLL) with high-risk features such as purine analogue resistance or deletion (17p), selected patients with high-risk lymphoma and selected patients with myelofibrosis and other myeloproliferative disorders with poor prognosis. Studies with allo-SCT in multiple myeloma are ongoing, and besides trials, autologous single or double transplantations are the established form of transplantation for this disorder. Non-malignant diseases curable with allo-SCT are severe aplastic anaemia (SAA) and haemoglobinopathies. In some rare forms of inherited errors of metabolism, haematopoietic cells derived from the donor stem cells can produce the missing enzyme and thereby correct the disease [4].

	Donors

Top Abstract Introduction Donors Stem cell sources Conditioning Supportive care Infections GVHD Relapse Individualization Novel indications Mesenchymal stem cells Conclusions References

 
Generally, the ideal donor is a sibling with the same two HLA haplotypes as the recipient. The recipient’s twin is from an immunological point of view the most suitable donor, but allo-SCT between twins, that is, syngeneic transplant, is associated with an increased risk of relapse [5].

In rare cases, an HLA-identical family member besides siblings can be found. In addition, partially HLA-identical family members can be used with the success approaching that of matched siblings. In many countries, the number of siblings is decreasing. This leads to a lower probability to find a suitable family donor, and as only 30% of all patients have a family donor, the use of HLA-matched unrelated donors (MUD) has increased during the last decades [6]. Large registers of unrelated volunteer donors are established, and today, 10 million donors are available worldwide. With this number of potential donors, many patients will have a well-matched donor identified. However, the chance is depending upon the ethnic background as most donors are Caucasians. Efforts are currently focusing on recruitment of donors from other ethnic groups.

Initially, tissue typing was performed phenotypically. Recently, genetic methods have replaced the phenotypic method, and the number of alleles identified has increased substantially. The importance of matching for HLA classes A, B and DR is well known, and with the increasing numbers of unrelated donor transplants performed, the knowledge is increasing concerning the importance of matching for classes C, DQ and DP. Mismatching for classes C and DQ has been associated with both rejection and GVHD [7]. Therefore, many centres are aiming for 10/10 match regarding HLA-A, B, C, DR and DQ. Due to improved tissue typing and better matching, transplant results with unrelated donors have improved and are close to the results after sibling donor transplantation [8].

	Stem cell sources

Top Abstract Introduction Donors Stem cell sources Conditioning Supportive care Infections GVHD Relapse Individualization Novel indications Mesenchymal stem cells Conclusions References

 
For many years, bone marrow aspirated from the iliac crest was the main source of haematopoietic stem cells for transplantation. In autologous transplantation, peripheral blood stem cells (PBSCs) totally replaced aspirated bone marrow during the 1990s. A similar trend has been seen in allo-SCT during the last decade for patients with haematological malignancies. After 5–6 days injection of granulocyte colony-stimulating factor (G-CSF), high number of stem cells can be harvested from the blood by aphaeresis [9]. The PBSC graft has a higher number of nucleated cells, CD34- and CD3-positive cells as well as natural killer cells compared with the bone marrow graft and results in faster engraftment of neutrophils and platelets. Despite the high number of T-cells, the incidence of acute GVHD is similar to that after transplantation of bone marrow. Probably at least in part due to a shift from Th-1 to Th-2 cells. However, chronic GVHD is more common, and, therefore, PBSC is less often used for patients with non-malignant disorders as they do not benefit from the graft-versus-leukaemia (GVL) effect correlated with chronic GVHD. Patients with advanced leukaemia seem to benefit from PBSC grafts [10].

PBSC was until recently only used in sibling transplantations because of the suspected high risk for acute GVHD. As most studies showed similar incidence of acute GVHD with PBST as with bone marrow, PBSC was introduced in transplantation with unrelated donors, and preliminary findings are similar to those after sibling transplantation [11].

On the contrary, younger patients had a better outcome with bone marrow instead of PBSC [12].

Early trials with G-CSF-stimulated bone marrow shows interesting results with rapid engraftment and a low incidence of GVHD. Further studies are required before this method of graft donation can be regarded clinical routine.

The cord blood (CB), normally wasted during delivery, is rich of haematopoietic stem cells and can be used as a stem cell source for allo-SCT. In many countries, banks of cryopreserved CB units are established, and today >100 000 units are available for transplantation and >4200 transplants with CB grafts have been performed. Advantages with CB are the rapid availability and the reduced risk for GVHD due to the relative deficiency of mature T cells. Therefore, some degree of mismatch can be allowed. Drawbacks are a higher incidence of graft failure and a slower engraftment resulting in more infections. The number of nucleated cells and CD34 cells per kilogram bodyweight of the recipient is approximately one log lower compared with bone marrow as stem cell source. Several studies have shown the importance of a high CB cell dose, and more than 2 x 10⁷ nucleated cells/kg is recommended. This limits the use of CB for adult patients. However, different ways have been explored to increase the cell number: the pooling of two units or in vitro expansion being most explored. Although, the in vitro expansion is theoretically appealing, the clinical breakthrough is still awaited. On the contrary, the pooling of two units has been performed with promising results [13, 14].

	Conditioning

Top Abstract Introduction Donors Stem cell sources Conditioning Supportive care Infections GVHD Relapse Individualization Novel indications Mesenchymal stem cells Conclusions References

 
The purpose of the conditioning given before transplantation is to eradicate the underlying disease and suppress the patient’s immune system to allow engraftment of donor stem cells. Ideally, this should be achieved without any major toxicity. However, this is impossible and there is always a balance between the cytotoxic effect and side effects. More than 35 years ago, the combination of cyclophosphamide (CY) 60 mg/kg/day for two consecutive days (in total 120 mg/kg) and total body irradiation (TBI) was introduced. This is still the gold standard to which every other conditioning is compared [15].

As not all transplant centres have access to irradiation, and to avoid possible side effects from TBI, such as pneumonitis, cataracts, secondary tumours, endocrinological disturbances and decreased growth in children, busulfan (BU) was substituted for TBI. Sixteen milligram per kilogram of BU given during four successive days before CY has been used together with 120–200 mg/kg of CY [16]. BU + CY increased the risk of veno-occlusive disease (VOD) of the liver, haemorrhagic cystitis, chronic GVHD, obstructive bronchiolitis and alopecia in a randomized trial compared with CY + TBI, but patients given BU + CY had a lower incidence of cataract [17]. Randomized trials have mainly included patients with AML and CML. Except one study, survival was similar [18]. Pharmacological monitoring of BU concentrations is important in particular to reduce toxicity and perhaps to reduce the relapse risk. An intravenous (IV) preparation of BU is today available, and non-randomized studies show a reduced risk of VOD and a lower transplantation-related mortality (TRM) [19]. However, it is not shown that IV BU is better compared with oral BU with targeted steady-state concentrations.

In children with ALL, a small randomized trial showed better event-free survival with TBI compared with BU, and this was confirmed in a large retrospective analysis [20, 21]. Therefore, TBI is preferred for children with ALL, but for the youngest children below the age of 3, TBI should be avoided as it is correlated with severe side effects on the development of the central nervous system. Despite the lack of randomized studies among adult ALL patients, many centres recommend TBI in the conditioning for ALL.

Investigators in Seattle showed excellent survival in patients with SAA given 200 mg/kg of CY in combination with anti-thymocyte globulin (ATG), and this is now the most common conditioning in this disorder.

Reduced-intensity conditioning

Despite the fact that increased intensity of the conditioning reduces the risk of leukaemic relapse, the survival is not improved because increased toxicity results in higher TRM [22]. Together with the knowledge that the new donor-derived immune system has a strong anti-leukaemic effect, researchers have developed new conditioning regimens. The concept of the so-called reduced-intensity conditioning (RIC) relies on the donor T-cell-mediated graft-versus-malignancy effect rather than on the cytotoxic effect of the conditioning. In RIC, the main purpose of the conditioning is to be immunosuppressive to abrogate the immunologic resistance to allogeneic engraftment. After transplantation, donor lymphocyte infusion (DLI) can further enhance the anti-tumour effect. DLI was first given to patients with relapse of CML after conventional allo-SCT with remarkable effect and has thereafter been used to treat relapse of almost all haematological malignancies [23]. This less-toxic approach allows transplantation in elderly patients and in those with comorbidity, patients who are considered contraindicated for myeloablative (MA) conditioning [24]. Many different RIC regimens have been used although the majority include a purine analogue. One of the most used regimens consists of only 2 Gy TBI, in many patients combined with fludarabine. This is probably the most reduced regimen that has shown engraftment. An important part of this regimen is the use of post-grafting immunosuppression with cyclosporine (CsA) and mycophenolate mofetil. Because there is an inverse correlation between the intensity of the conditioning and the incidence of graft failure, one risk with this regimen is poor engraftment. This risk is at least in part depending on previous treatment and time from treatment, reflecting the state of immunocompetence in the recipient at the time of transplantation. This RIC protocol has enabled outpatient transplantation, but later referrals because of infections and GVHD are common [25].

Other protocols widely used are fludarabine + BU 8 mg/kg + ATG, fludarabine + melphalan and fludarabine + CY [26, 27].

RIC has been used for patients with a variety of malignant and non-malignant disorders. Early experiences suggest that patients with high tumour burden, in particular if the disease is rapidly progressing, have a poor outcome. Many patients who have failed autologous SCT can now be offered an allogeneic transplantation with RIC. Consequently, the number of transplants for lymphomas, including Hodgkin’s lymphoma and CLL, is increasing with this novel transplant technique.

Another interesting concept is the tandem autologous—RIC allogeneic transplantation [28]. The rationale is to separate the high-dose cytotoxic treatment from the allogeneic immunotherapy, and to do this with a low TRM, both from the autologous and from the allogeneic RIC transplantation. Early results from patients with multiple myeloma is encouraging, and the European Group for Blood and Marrow Transplantation (EBMT) recently closed a prospective study comparing this concept with single, or double, autologous SCT on the basis of the availability of a matched sibling donor, so-called biological randomization. Results are not yet reported.

Prospective randomized trials comparing RIC with conventional MA conditioning are lacking, and retrospective studies are difficult because patients are not comparable due to differences in age and comorbidities. Conflicting results exist regarding the incidence of GVHD, but most studies have shown a reduced TRM. One study suggests a higher relapse risk in CLL [29].

	Supportive care

Top Abstract Introduction Donors Stem cell sources Conditioning Supportive care Infections GVHD Relapse Individualization Novel indications Mesenchymal stem cells Conclusions References

 
During the pancytopenic phase after MA conditioning, patients are extremely susceptible to infections and are therefore kept in protected environment such as laminar airflow rooms or reversed isolation. Prophylactic treatment against bacteria, virus and fungi is routinely given. Recently, home care shortly after allo-SCT was shown to be safe and even resulted in a lower TRM [30]. In addition, transfusion of erythrocytes and platelets together with analgesics and enteral or parenteral nutrition is most often required. Different regimens to reduce the incidence of hepatic complications have been tried. Oral ursodeoxycholic acid was shown to protect from liver toxicity, and N-acetylcystein is currently being investigated. Erythropoietin and G-CSF have been used after allo-SCT to hasten erythrocyte and neutrophil recovery. Erythropoietin was evaluated in a randomized trial and decreased the need for erythrocyte transfusions but increased the cost compared with transfusions. G-CSF accelerates neutrophil recovery but may delay platelet engraftment. Some studies have reported an increased risk of GVHD with the use of G-CSF after allo-SCT, in particular if bone marrow is the stem cell source [31]. However, conflicting data exist.

	Infections

Top Abstract Introduction Donors Stem cell sources Conditioning Supportive care Infections GVHD Relapse Individualization Novel indications Mesenchymal stem cells Conclusions References

 
Early after allo-SCT, gram-positive bacteria such as alfa-streptococci and coagulase-negative staphylococci are common pathogens causing bacteraemia. Resistant staphylococci and enterococci are an emerging problem. Fungal infections with non-albicans candida and moulds are also a clinical problem as diagnosis is difficult and often late. Novel diagnostic tools for fungal infections are needed, and a polymerase chain reaction (PCR)-based method is being evaluated. Previously, amphotericine B was the only available alternative for treatment of fungal infections. As amphotericine B treatment is associated with considerable side effects, liposomal preparations were developed. Those were shown to be effective and less toxic but at a considerable cost. Lately, new anti-fungal drugs such as caspofungin and the newer azoles, voriconazole and posaconazol, have increased the treatment arsenal.

After the pancytopenic phase, cytomegalovirus (CMV) is a common infectious problem. Previously, CMV pneumonia was a major obstacle to a successful allo-SCT. Today, mortality from CMV is rare. With modern diagnostic methods based on early antigen detection or the PCR technique, CMV viraemia can often be diagnosed and treated before disease develops. Reactivations of latent virus in a CMV seropositive patient or transmission from a CMV seropositive donor to a seronegative patient are the most common causes of CMV infection. Therefore, it seems important to match for the CMV serology status between the donor and the patient. With the use of filtered blood products or CMV seronegative blood donors, the risk of infection from blood products is minimal. There is a trend for later CMV infections with RIC and immune intervention with DLI. Furthermore, treatment options have improved with ganciclovir, foscarnet, cidofovir and valganciclovir.

Epstein–Barr virus (EBV) may cause a lymphoproliferative disease after allo-SCT. Risk factors include the use of ATG and unrelated donors. Monitoring EBV viraemia by PCR enables early treatment with rituximab, DLI or EBV-specific cytotoxic T cells.

	GVHD

Top Abstract Introduction Donors Stem cell sources Conditioning Supportive care Infections GVHD Relapse Individualization Novel indications Mesenchymal stem cells Conclusions References

 
Acute and chronic GVHD are major complications after allo-SCT. The pathophysiology of acute GVHD is currently rather well understood [32]. Much less is known about the mechanism of chronic GVHD. In the acute form, donor T cells recognize recipient HLA molecules after presentation by recipient antigen-presenting cells. This releases interleukin (IL)-2 and activates cytotoxic T cells, natural killer cells and macrophages. Further stimulation by interferon gamma enhances the activation of T cells and natural killer cells. Main targets are skin, gut and liver. The major risk factor for GVHD is HLA disparity, but also female donor to male patient, in particular if the female donor is immunized, certain HLA alleles and host environment have been reported as important.

Chronic GVHD generally appears from 3 months to 1 year after allo-SCT. It resembles several autoimmune disorders such as scleroderma and Sjögrens disease. Symptoms include lichenoid and scleroderma skin changes, mucositis, sicca syndrome, keratoconjunctivitis, oesophageal and vaginal strictures, cholestatic hepatic dysfunction, bronchiolitis obliterans and myositis. Many patients suffer from wasting and immunodeficiency, which increases the risk for infections, in particular from gram-positive bacteria. Chronic GVHD may present in three different forms: it may occur as part of a continuous spectrum, with acute GVHD merging into chronic GVHD without a disease-free interval (progressive onset) or it can occur after a period during which no clinical GVHD has been evident (quiescent) or it can arise without preceding acute GVHD, the so-called de novo onset. Patients with a progressive course of chronic GVHD developing directly after acute GVHD have an inferior prognosis compared with patients with ‘de novo onset’.

To reduce the risk of GVHD prevention is given. The most efficient prevention is to deplete the graft from T cells before it is infused. However, T-cell depletion is correlated with an increased risk of graft rejection and leukaemia relapse.

A short course of three to four doses of methotrexate (MTX) in combination with CsA is the most used immunosuppression today. The addition of prednisolone or replacement of MTX by prednisolone is also used. In particular, with CB transplants, MTX is avoided as it is myelotoxic and prolongs time to engraftment. Tacrolimus, a calcineurin inhibitor like CsA, replaced CsA in prospective randomized trials and resulted in a lower incidence of GVHD although survival was similar. The combination of tacrolimus and sirolimus, a macrolide immunosuppressant, shows promising early results [33]. However, no prospective randomized trial exists so far.

As ATG is eliminated slowly, it will remain in the circulation at effective concentrations for several weeks. This means that the addition of ATG given to the patient before transplantation affects both T cells in the patient and also the infused T cells in the graft inoculum. ATG was shown to reduce the incidence of GVHD and improve survival in unrelated donor transplants [34]. An important side effect is increased risk of infections. This is dose dependent, and the optimal dose is currently not known.

If acute GVHD develops, high-dose prednisolone treatment is standard of care. Most patients respond to this treatment, but in steroid refractory patients, mortality is high. Second-line treatment consists of ATG or other T-cell anti-bodies, anti-bodies against IL-2 or the IL-2 receptor, antibodies against tumour necrosis factor (TNF) or combinations of antibodies. In addition, psoralen and ultraviolet light and extracorporeal photopheresis have been tried.

Treatment of chronic GVHD consists of CsA and steroids. In non-responding patients, tacrolimus, thalidomide, mycophenolate mofetil, sirolimus and 1 Gy of total lymphoid irradiation may be used.

	Relapse

Top Abstract Introduction Donors Stem cell sources Conditioning Supportive care Infections GVHD Relapse Individualization Novel indications Mesenchymal stem cells Conclusions References

 
With better supportive care and more efficient prevention of GVHD, relapse of the underlying malignancy is today the single most common cause of treatment failure after allo-SCT. The risk correlates strongly with the disease, disease status at time of transplantation and method of GVHD prevention. Patients in first remission of acute leukaemia or first chronic phase (CP) of CML have a relapse risk of 20–30% increasing to 40–60% if transplanted in later remission or second CP. Patients not in remission or with chemorefractory disease may have a relapse risk exceeding 70%. Because there is an inverse correlation between the incidence of GVHD and relapse, more efficient immunosuppression, for example, T-cell depletion or the combination of CsA and MTX, will increase the relapse risk. Both the dose and the treatment length of CsA are important. With a low dose and a shorter duration, the relapse risk is decreased [35]. However, severe GVHD should be prevented because of its high mortality. Best survival is seen with a mild acute and limited chronic GVHD [5].

Documentation of the potent anti-tumour effect of the new donor-derived immune system has been shown for a variety of haematological malignancies and solid tumours. Although relapse after allo-SCT can be treated with DLI, only patients with CML have a good prognosis. Acute leukaemia relapsing after allo-SCT may respond, but in most patients, the response is usually only temporary. In CML, patients with molecular relapse, that is, recurrence of the bcr/abl transcript detected by PCR, have a better response compared with patients with haematological relapse. With more advanced forms of CML relapse, accelerated phase or blastic transformation, the response is even worse. It is, therefore, of importance to detect relapse as early as possible to increase the possibility of successful immunotherapy after allo-SCT. Ideally, you can monitor a uniform disease-specific marker, such as bcr/abl in CML. However, in many malignancies, either there is no specific marker or you have to develop a patient-specific primer. For example, in ALL, you can construct clone-specific primers for rearrangement in the T-cell receptor, a time- and labour-intensive work. As an alternative to a disease-specific marker, you can analyse the existence of patient haematopoiesis, for example, by PCR using variable number of tandem repeats. After allo-SCT, the goal is to induce complete donor haematopoietic chimerism. If patient haematopoiesis is reappearing or progressing, it may predict relapse, in particular, if the progress is in the leukaemia cell lineage [36]. Adoptive immunotherapy, by tapered immunosuppression or DLI, based on minimal residual disease or mixed haematopoietic chimerism may prevent relapse and improve leukaemia-free survival after allo-SCT.

Chimerism analyses are also important to predict and analyse graft rejection and the risk for GVHD. T-cell-mixed chimerism was significantly correlated with a decreased risk of severe acute GVHD and death by GVHD [37].

Side effects of DLI are GVHD and pancytopenia. DLIs with escalating doses have a lower incidence of GVHD but are equally effective compared with high-dose bulk DLI [38].

	Individualization

Top Abstract Introduction Donors Stem cell sources Conditioning Supportive care Infections GVHD Relapse Individualization Novel indications Mesenchymal stem cells Conclusions References

 
A common trend in recent years is the individualization of the transplant procedure. With a variety of conditioning regimens, stem cell sources and different methods of GVHD prevention, the complexity has increased substantially. Conditioning regimen depends on both the disease and the age and comorbidity of the patient. If a MA conditioning is given, it should have a strong cytotoxic effect against the particular disease. All MA regimens have a strong immunosuppressive effect. RIC varies considerably in its cytotoxic and immunosuppressive effect. Many centres have developed their one protocol, but some centres are using different protocols depending on the diagnosis and the risk for graft rejection. Stem cell source is also dependent on the diagnosis and conditioning regimen. With non-malignant disorders, PBSC is preferred as chronic GVHD should be avoided. Also with RIC, PBSC is the first choice because it is important with a high stem cell dose to overcome allograft resistance. Furthermore, the method of GVHD prevention depends on diagnosis, conditioning regimen and stem cell source. For example, non-malignant diseases should be given the most effective prevention while a recipient of a CB graft should be recommended to omit MTX in the GVHD prophylaxis to hasten engraftment.

	Novel indications

Top Abstract Introduction Donors Stem cell sources Conditioning Supportive care Infections GVHD Relapse Individualization Novel indications Mesenchymal stem cells Conclusions References

 
Immunotherapy with allo-SCT has been used in patients with metastatic solid tumours. A graft-versus-tumour effect has been shown for renal carcinoma, adenocarcinoma of the colon and metastatic carcinoma of the breast, ovary, prostate and pancreas. The largest experience is from metastatic renal cancer. Patients received RIC to have a low TRM. Responses were shown including a few complete ones [27]. Good prognostic factors were less than three metastatic sites and Karnofsky score 70. Patients who received DLI and developed chronic GVHD had a better survival, 70% at 3 years after allo-SCT [39]. Survival and tumour response will probably be better if allo-SCT is done earlier in the course of the disease when tumour load is lower. Future studies will show the place of allo-SCT in patients with solid tumours.

	Mesenchymal stem cells

Top Abstract Introduction Donors Stem cell sources Conditioning Supportive care Infections GVHD Relapse Individualization Novel indications Mesenchymal stem cells Conclusions References

 
Mesenchymal stem cells (MSC) are multipotent non-haematopoietic cells that can be derived from bone marrow, fat and several foetal tissues and have the capacity to differentiate in vitro and in vivo into different mesenchymal lineages such as bone, cartilage, adipose, tendon and bone marrow stroma. MSC can reduce alloreactivity and inhibit T-cell proliferation in mixed lymphocyte cultures and after mitogen stimulation in vitro. Although the exact mechanism of immunomodulation is not known, it was recently shown that adult MSC may also be immunosuppressive in vivo as infusion of haploidentical MSC reversed severe acute GVHD [40]. Furthermore, MSC can maintain and expand lineage-specific colony-forming units from CD34+ cells in long-term cultures and can also promote engraftment of unrelated haematopoietic stem cells in animal models. Further controlled studies are needed to evaluate the role of MSC in the allo-SCT setting.

	Conclusions

Top Abstract Introduction Donors Stem cell sources Conditioning Supportive care Infections GVHD Relapse Individualization Novel indications Mesenchymal stem cells Conclusions References

 
Allo-SCT has developed from an experimental treatment for patients with end-stage leukaemia to a routine procedure for patients with a variety of haematological disorders. With large registers of unrelated donors and the use of CB grafts, it is today possible to offer an allo-SCT not only to patients with an HLA-identical sibling but to most patients in need of transplantation. PBSCs are increasingly used for patients with malignancies as they result in a faster haematological recovery, and a strong GVL effect correlated with the increased incidence of chronic GVHD. With the use of RIC, older patients and those with comorbidity can be offered a potential curative allo-SCT. Relapse is a major problem, but with early detection of mixed haematopoietic chimerism or minimal residual disease, immune intervention with DLI may decrease the risk. Further studies are needed to find the place for allo-SCT in the treatment of patients with metastatic solid tumours.

Accepted for publication June 21, 2006.

	References

Top Abstract Introduction Donors Stem cell sources Conditioning Supportive care Infections GVHD Relapse Individualization Novel indications Mesenchymal stem cells Conclusions References

 

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