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ADC Online First, published on July 12, 2014 as 10.1136/archdischild-2013-304832
Review
Recent advances in the management of graft-versus-host disease S Dhir,1 M Slatter,2 R Skinner1,2 1
Department of Paediatric and Adolescent Haematology/ Oncology, Great North Children’s Hospital, Newcastle upon Tyne, UK 2 Children’s Haemopoietic Stem Cell Transplant Unit, Great North Children’s Hospital, Newcastle upon Tyne, UK Correspondence to Dr R Skinner, Department of Paediatric and Adolescent Oncology/BMT, Great North Children’s Hospital, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, UK; [email protected] Received 28 March 2014 Revised 21 June 2014 Accepted 23 June 2014
ABSTRACT Graft-versus-host disease (GvHD) remains a significant hurdle in overcoming the morbidity and mortality associated with haemopoietic stem cell transplantation in children. Better understanding of its pathobiology is facilitating the development of biomarkers for the severity of acute GvHD and treatment response, and has led to the introduction of a more prognostically relevant grading system for chronic GvHD. These enable stratification of appropriate prophylactic and treatment strategies according to the risk profiles of individual patients. Steroid-refractory acute GvHD has a poor prognosis, but early reports of the use of new immunosuppressive drugs and especially cellular treatments with extracorporeal photopheresis and mesenchymal stem cells suggest improved short-term outcomes and offer the promise of increased longer-term survival rates.
INTRODUCTION
To cite: Dhir S, Slatter M, Skinner R. Arch Dis Child Published Online First: [please include Day Month Year] doi:10.1136/ archdischild-2013-304832
Haemopoietic stem cell transplantation (HSCT) is a well-established curative treatment for many otherwise fatal or life-limiting haematological, immunological or metabolic diseases in children, but graft-versus-host disease (GvHD) continues to limit the procedure’s success nearly 50 years after it was first described. This article will demonstrate how improved understanding of the pathobiology is leading to the emergence of pharmacological and cellular strategies that offer hope for improved control of GvHD. Furthermore, the identification of predictive biomarkers for an increased risk of GvHD and refinements in clinical assessment that allow clearer identification of higher-risk patients constitute two contrasting but complementary advances in the overall management of GvHD. The prevention and treatment of GvHD have become more challenging with the greater use of alternative donors and stem cell sources since unrelated and mismatched donors and peripheral blood stem cells (PBSCs) are more likely to cause GvHD.1 Over the last 10 years, several consensus documents published after a series of meetings convened by the US National Institutes of Health (NIH) have addressed the assessment and management of GvHD. Since the historical 100-day post-transplant distinction between acute and chronic GvHD has become blurred, the consensus group proposed a new classification based primarily on the clinical presentation (table 1),2 although there is still uncertainty about the value of distinguishing between classic chronic GvHD and overlap syndrome.3 Donor–host disparities in major and minor histocompatibility antigens are central to the pathogenesis of acute GvHD (aGvHD). The ideal donor is
matched at allele level between donor and recipient at both antigens at each of the human leucocyte antigen (HLA) A, B, C (class I) and DRB1 and DQB1 (class II) loci. HLA alleles are highly polymorphic and finding matches from unrelated donors (URDs), especially in ethnic minority groups, may be challenging. Most units now seek 10/10 (all 10 alleles match) matches, but a few look for a 12/12 match (also matching at DPB1*). The ideal type and degree of HLA matching desirable is dependent on various factors like donor type, stem cell source, indication for transplant and the recipient’s current medical status. The development of aGvHD involves three distinct phases (figure 1).1 Tissue damage related to chemotherapy/radiotherapy conditioning treatment damages and activates host tissues, leading to the release of inflammatory cytokines especially tumour necrosis factor-α (TNF-α) and interleukin-1, which increase the expression of major histocompatibility complex (MHC) antigens on host antigenpresenting cells. This sets the scene for enhanced alloreactivity (immunologically mediated reactivity of donor cells directed against recipient cells) characterised by donor T-cell activation and clonal expansion, with secretion of interleukin-2 (IL-2) and interferon-γ, which recruits and stimulates cytotoxic T-lymphocytes and macrophages. Regulatory T cells (Tregs) act as a counterbalance by limiting the activation and expansion of donor T cells. Finally, target cell apoptosis and direct tissue destruction is mediated by these immune effector cells in a proinflammatory response triggered by stimulatory molecules such as lipopolysaccharides that have translocated across damaged gut mucosa. The ensuing ‘cytokine storm’ amplifies the inflammatory milieu and resultant damage. This complex interwoven pathogenesis leads to both opportunities and complexity in prevention and management by offering multiple targets for pharmacological intervention while explaining the limited success of strategies that focus on one target only. The pathogenesis of chronic GVHD (cGVHD) is believed to involve autoimmune and alloimmune dysregulation, leading to disordered immunological reactivity against autologous (self ) and allogeneic (donor) antigens. However, incomplete understanding of the effector mechanisms is a major factor impeding the targeted development of improved therapeutic strategies.
ACUTE GVHD The reported incidence of aGvHD in children varies widely from 20% to 80%, depending principally on the major risk factors of HLA-matching and donor type (matched or mismatched, sibling,
Dhiremployer) S, et al. Arch Dis Child 2014;0:1–8. doi:10.1136/archdischild-2013-304832 1 Copyright Article author (or their 2014. Produced by BMJ Publishing Group Ltd (& RCPCH) under licence.
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Review Table 1 Classification of acute and chronic graft-versus-host disease (GvHD)
Category Acute GvHD Classic acute GvHD Persistent, recurrent or late-onset acute GvHD Chronic GvHD Classic chronic GvHD Overlap syndrome
Timing of symptoms
Presence of Presence of acute GvHD chronic GvHD features features
≤100 days >100 days
Yes Yes
No No
No time limit No No time limit Yes
Yes Yes
Adapted with permission from Filipovich et al.2
other related or unrelated donor) and stem cell source (bone marrow, peripheral blood or umbilical cord blood), and to a lesser extent donor age (older adult donors are associated with a higher risk of aGvHD) and sex (multiparous female donors higher risk).4 In order of frequency, aGvHD predominantly
affects the skin, gastrointestinal tract and liver.4 Skin involvement commonly starts as an erythematous maculopapular rash on the palms and soles, but can involve any part of the skin and (when severe) lead to bullae formation. The differential diagnosis includes engraftment rash, infections (especially viral) and drug reactions, and may require clarification by skin biopsy. Gastrointestinal aGvHD presents with secretory diarrhoea (copious and sometimes bloody in severe cases) and may cause abdominal pain, nausea, vomiting and anorexia. The differential diagnosis includes mucositis, while endoscopy and biopsy may be needed to exclude infection. Hepatic aGvHD usually presents with cholestatic jaundice and raised liver enzymes (typically γ-glutamyl transpeptidase) and may have to be differentiated from hepatic veno-occlusive disease, viral infections, sepsis and drug toxicity. Hepatitic aGvHD with prominent transaminitis is rarer still but well described. Rarely, liver biopsy may be necessary, but the risk of dangerous bleeding is significant. With the significant improvements in post-HSCT supportive care in the last two decades, particularly reducing infectionrelated mortality,5 there is greater focus on preventing and
Figure 1 The three-phase model of the pathogenesis of acute graft-versus-host disease. The key steps are (1) host antigen-presenting cell (APC) activation, (2) donor T-cell activation, (3) cellular and inflammatory effector phase (Copied with permission from Ferrara et al1). 2
Dhir S, et al. Arch Dis Child 2014;0:1–8. doi:10.1136/archdischild-2013-304832
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Review managing GvHD. Guidelines for the diagnosis and management of acute and chronic GvHD were published in 2012 by the British Committee for Standards in Haematology (BCSH) and the British Society for Blood and Marrow Transplantation (BSBMT).6–8 The authors stated that the recommendations were applicable to adults and children, but highlighted the importance of careful consideration of disease-associated comorbidities and treatment toxicities in children.7 A working group of the European Group for Blood and Marrow Transplantation and the European LeukaemiaNet has recently published recommendations for prophylaxis and treatment of GvHD in adults in an attempt to standardise practice.9 The group acknowledged the existence of divergent views concerning GvHD management in paediatric practice but is planning to develop standardised recommendations for children. The American Society of Blood and Marrow Transplantation (ASBMT) has also recently published recommendations for first-line and second-line treatment of aGvHD but does not specifically mention children.10 The strategies used for prophylaxis of aGvHD depend on the nature of the conditioning regimen, donor type, stem cell source and degree of HLA mismatch. Prophylaxis in myeloablative (full-intensity conditioning, aimed at eradicating all residual malignant and marrow haemopoietic cells) HSCTs usually comprises ciclosporin A for approximately 2–12 months (depending on the underlying disease being transplanted) with or without a short course of intravenous methotrexate (usually 3–4 doses). Tacrolimus is preferred to ciclosporin in many non-European centres, although published evidence comparing these calcineurin inhibitors (CNIs) is lacking in children. Pre-HSCT anti-T-cell serotherapy with either antithymocyte globulin or alemtuzumab (CAMPATH) is usually added for URD transplants and also provides additional prophylaxis against graft rejection. Prophylaxis for reduced-intensity HSCTs (with less intensive conditioning treatment that does not fully eradicate malignant and haemopoietic cells and instead relies on immunological antihost and antitumour effects) usually comprises ciclosporin and mycophenolate mofetil (MMF), although some centres prefer a corticosteroid to MMF; again, serotherapy is usually added for URD HSCTs. Despite these common themes, there are wide variations in drug scheduling and dosing.9 There are some patients for whom no suitably matched related or unrelated donor can be found. Haploidentical parental HSCT is feasible and various T-cell depletion (TCD) strategies have been used to minimise GvHD and maximise sustained engraftment and early immune reconstitution. Historical methods to remove viable T-lymphocytes include in vitro CAMPATH-1M antilymphocyte antibody, soy lectin and sheep red cell rosetting. Recently, European centres performing TCD HSCT have used CD34 stem cell selection, most commonly the Miltenyi Clini-MACS system that uses an organic iron bead/anti-CD34 antibody conjugate to isolate purified CD34 stem cells through a magnetic column.11 However, this method also depletes grafts of beneficial stromal cells, so an alternative is to specifically deplete T-lymphocytes and B-lymphocytes while retaining CD34 cells together with engraftment-enhancing CD34− progenitors, natural killer, dendritic and graft-facilitating cells. γδ T cells normally represent 1–10% of blood lymphocytes. Although they can destroy intracellular and extracellular pathogens, they are not MHC-restricted and are therefore unlikely to cause GvHD. Depletion of T-cell α/β receptor (TCRαβ) and CD19 cells, with selection of TCRγδ T cells, is a new technique preserving the graft-versus-leukaemia effect with promising results in haploidentical HSCT.12 13 Dhir S, et al. Arch Dis Child 2014;0:1–8. doi:10.1136/archdischild-2013-304832
Box 1 shows first-line, second-line and third-line treatment options for acute GvHD. The modified Glucksberg clinical grades,14 which have been shown to correlate with overall survival in adults,15 are usually employed to stratify treatment for aGvHD. The components of first-line management have changed little over the last 30 years. Grade I aGVHD is managed by continuing the prophylactic CNI and adding topical steroids (and sometimes topical tacrolimus) to affected skin, while systemic immunosuppression with intravenous methylprednisolone 2 mg/kg/day is added for grades II–IV, although a recent adult trial suggested that 1 mg/kg/day is sufficient for grade II.16 Higher steroid doses offer no additional benefit and contribute to increased toxicity.17 In gastrointestinal aGvHD, the addition of nonabsorbable steroids (budesonide and beclomethasone) may facilitate reduction of systemic steroid doses.7 Unfortunately, a complete response to steroid treatment is seen in only about 70% of cases of aGvHD.17 However, newer treatments have been introduced for the treatment of steroid-refractory aGvHD, usually defined as failure to respond to 5 days of methylprednisolone and CNI, or deterioration after 3 days.7 9 18 It has been known for over 20 years that aGvHD refractory to initial treatment is associated with a survival rate of 50% of children with refractory cGvHD in a phase II trial, it causes a high incidence of serious infections.35 Recent small uncontrolled studies suggest that imatinib may improve sclerodermatous or pulmonary cGvHD,36 37 while rituximab may benefit skin and musculoskeletal cGvHD.38 Third-line treatments include MMF, high-dose steroid pulses and methotrexate. 6
RECENT DEVELOPMENTS Extracorporeal photopheresis ECP is an apheresis-based immunomodulatory therapy that has been used for over 20 years for the treatment of cutaneous T-cell lymphoma. It is now being used for a widening number of indications including solid organ allograft rejection, autoimmune-mediated disorders and GvHD. The patient’s blood is leukapheresed and centrifuged to separate out the leukocyte-enriched buffy coat, which is then injected with a photosensitising drug 8-methoxypsoralen and exposed to ultraviolet-A (UVA) irradiation. The photoactive buffy coat is then reinfused into the patient. Due to the large volume of extracorporeal blood required, until recently the procedure was limited to patients of over 40 kg. However, the Therakos Cellex device uses continuous flow separation technology with reduced extracorporeal blood volumes and shorter treatment times. With the addition of blood priming to the machine, patients weighing as little as 8 kg have been safely treated. Studies are ongoing to fully elucidate the mechanism of action against GvHD. Exposure to UVA light results in apoptosis of peripheral blood mononuclear cells, and it is thought that when these are reinfused, dendritic cells are involved in processing them, provoking anti-inflammatory cytokine responses and the generation of specific Tregs that suppress the effector T cells causing GvHD.39 Side effects are few and mainly related to central venous catheter infection and thrombosis. Care has to be taken to avoid hypotension particularly in young children and hypocalcaemia when citrate anticoagulation is used. A prospective randomised controlled trial demonstrated favourable results of a 12-week course of ECP in cGvHD, with further improvement when continued for 24 weeks.40 41 There is less published evidence for the treatment of aGvHD, but one trial in 59 patients with steroid-refractory aGvHD gave ECP on two consecutive days weekly until response and thereafter every 2–4 weeks until maximal response. In total, 82% with skin GvHD, 61% with liver and 61% with gut involvement had a complete response.42 Available evidence thus indicates that ECP is a valuable option for treatment of acute and chronic GvHD with proven safety in children.43 The main advantage is that it allows reduction in other immunosuppressive therapy that lessens the risk of immunosuppression-related morbidity and mortality.
Mesenchymal stromal cells MSCs are multipotent progenitors found in bone marrow, adipose tissue and also fetal membranes and umbilical cord blood (UCB). They have important immunoregulatory properties, including inhibition of T-cell proliferation, release of soluble factors and promotion of Tregs. They are hypoimmunogenic and do not need to be HLA-matched to the recipient. Their use as treatment for steroid-refractory aGvHD was pioneered by Le Blanc,44 and prospective studies demonstrated efficacy in paediatric and adult patients with aGvHD.45 Commercial preparations are now available. Most studies have used MSCs as second-line therapy in steroid-refractory aGvHD, but a phase II randomised multicentre study evaluated two different doses of MSCs given in combination with methylprednisolone for the initial therapy for aGvHD. Thirty-two adults with grade II–IV aGvHD were randomised to receive two doses of either two or eight million MSCs/kg each. The first MSCs infusion was given within the 48 h following diagnosis of grade II–IV aGvHD, and the second three days later. A total of 94% of patients achieved a complete (77%) or partial (16%) Dhir S, et al. Arch Dis Child 2014;0:1–8. doi:10.1136/archdischild-2013-304832
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Review response. Response rates were comparable in patients given two or eight million MSCs/kg.46 Further studies are needed to inform on the optimal timing and dose of MSCs to treat aGvHD. Efficacy is less convincing in patients with cGvHD.47 Cotransplantation of MSCs at the time of HSCT has been shown in some small studies to have a possible effect on reducing the incidence of aGvHD, suggesting a role in prevention as well as treatment of aGvHD.48
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Biomarkers The development of biomarkers that can potentially predict which patients are likely to develop GvHD or to respond to first-line treatment is an exciting advance that is likely to become increasingly available. A panel of four informative biomarkers (TNF receptor-1, IL-2 receptor, IL-8 and hepatocyte growth factor) was found to have diagnostic and prognostic value for aGvHD.49 In addition, GvHD target organ-specific biomarkers have been identified. Elafin is a specific marker for skin GvHD50 and regenerating islet-derived 3α for gut GvHD.51 When measured in serum samples obtained from the day of transplant (day 0), day 14 and day 28 of treatment, concentrations of these six GvHD biomarkers were predictive of the likelihood of treatment response and survival.52 There is increasing evidence for the role of genetic polymorphisms affecting the function of gene products. For example, two single-nucleotide polymorphisms in the heparanase gene associated with high recipient heparanase levels correlated with extensive cGvHD53 and polymorphisms in the PARP1 gene have been associated with a higher risk of cGvHD.54
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CONCLUSION Improved understanding of the pathobiology of acute and chronic GvHD should lead to the development of more refined preventive and therapeutic strategies. Measurement of biomarkers may enable prophylaxis and treatment to be tailored for individual patients, while increasing availability and use of ECP and MSCs may improve the currently poor outcomes of patients with steroid-resistant acute and chronic GvHD. Competing interests None. Provenance and peer review Commissioned; externally peer reviewed.
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Dhir S, et al. Arch Dis Child 2014;0:1–8. doi:10.1136/archdischild-2013-304832
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Recent advances in the management of graft-versus-host disease S Dhir, M Slatter and R Skinner Arch Dis Child published online July 12, 2014
doi: 10.1136/archdischild-2013-304832
Updated information and services can be found at: http://adc.bmj.com/content/early/2014/07/12/archdischild-2013-304832.full.html
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References
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ADC Online First, published on July 12, 2014 as 10.1136/archdischild-2013-304832
Review
Recent advances in the management of graft-versus-host disease S Dhir,1 M Slatter,2 R Skinner1,2 1
Department of Paediatric and Adolescent Haematology/ Oncology, Great North Children’s Hospital, Newcastle upon Tyne, UK 2 Children’s Haemopoietic Stem Cell Transplant Unit, Great North Children’s Hospital, Newcastle upon Tyne, UK Correspondence to Dr R Skinner, Department of Paediatric and Adolescent Oncology/BMT, Great North Children’s Hospital, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, UK; [email protected] Received 28 March 2014 Revised 21 June 2014 Accepted 23 June 2014
ABSTRACT Graft-versus-host disease (GvHD) remains a significant hurdle in overcoming the morbidity and mortality associated with haemopoietic stem cell transplantation in children. Better understanding of its pathobiology is facilitating the development of biomarkers for the severity of acute GvHD and treatment response, and has led to the introduction of a more prognostically relevant grading system for chronic GvHD. These enable stratification of appropriate prophylactic and treatment strategies according to the risk profiles of individual patients. Steroid-refractory acute GvHD has a poor prognosis, but early reports of the use of new immunosuppressive drugs and especially cellular treatments with extracorporeal photopheresis and mesenchymal stem cells suggest improved short-term outcomes and offer the promise of increased longer-term survival rates.
INTRODUCTION
To cite: Dhir S, Slatter M, Skinner R. Arch Dis Child Published Online First: [please include Day Month Year] doi:10.1136/ archdischild-2013-304832
Haemopoietic stem cell transplantation (HSCT) is a well-established curative treatment for many otherwise fatal or life-limiting haematological, immunological or metabolic diseases in children, but graft-versus-host disease (GvHD) continues to limit the procedure’s success nearly 50 years after it was first described. This article will demonstrate how improved understanding of the pathobiology is leading to the emergence of pharmacological and cellular strategies that offer hope for improved control of GvHD. Furthermore, the identification of predictive biomarkers for an increased risk of GvHD and refinements in clinical assessment that allow clearer identification of higher-risk patients constitute two contrasting but complementary advances in the overall management of GvHD. The prevention and treatment of GvHD have become more challenging with the greater use of alternative donors and stem cell sources since unrelated and mismatched donors and peripheral blood stem cells (PBSCs) are more likely to cause GvHD.1 Over the last 10 years, several consensus documents published after a series of meetings convened by the US National Institutes of Health (NIH) have addressed the assessment and management of GvHD. Since the historical 100-day post-transplant distinction between acute and chronic GvHD has become blurred, the consensus group proposed a new classification based primarily on the clinical presentation (table 1),2 although there is still uncertainty about the value of distinguishing between classic chronic GvHD and overlap syndrome.3 Donor–host disparities in major and minor histocompatibility antigens are central to the pathogenesis of acute GvHD (aGvHD). The ideal donor is
matched at allele level between donor and recipient at both antigens at each of the human leucocyte antigen (HLA) A, B, C (class I) and DRB1 and DQB1 (class II) loci. HLA alleles are highly polymorphic and finding matches from unrelated donors (URDs), especially in ethnic minority groups, may be challenging. Most units now seek 10/10 (all 10 alleles match) matches, but a few look for a 12/12 match (also matching at DPB1*). The ideal type and degree of HLA matching desirable is dependent on various factors like donor type, stem cell source, indication for transplant and the recipient’s current medical status. The development of aGvHD involves three distinct phases (figure 1).1 Tissue damage related to chemotherapy/radiotherapy conditioning treatment damages and activates host tissues, leading to the release of inflammatory cytokines especially tumour necrosis factor-α (TNF-α) and interleukin-1, which increase the expression of major histocompatibility complex (MHC) antigens on host antigenpresenting cells. This sets the scene for enhanced alloreactivity (immunologically mediated reactivity of donor cells directed against recipient cells) characterised by donor T-cell activation and clonal expansion, with secretion of interleukin-2 (IL-2) and interferon-γ, which recruits and stimulates cytotoxic T-lymphocytes and macrophages. Regulatory T cells (Tregs) act as a counterbalance by limiting the activation and expansion of donor T cells. Finally, target cell apoptosis and direct tissue destruction is mediated by these immune effector cells in a proinflammatory response triggered by stimulatory molecules such as lipopolysaccharides that have translocated across damaged gut mucosa. The ensuing ‘cytokine storm’ amplifies the inflammatory milieu and resultant damage. This complex interwoven pathogenesis leads to both opportunities and complexity in prevention and management by offering multiple targets for pharmacological intervention while explaining the limited success of strategies that focus on one target only. The pathogenesis of chronic GVHD (cGVHD) is believed to involve autoimmune and alloimmune dysregulation, leading to disordered immunological reactivity against autologous (self ) and allogeneic (donor) antigens. However, incomplete understanding of the effector mechanisms is a major factor impeding the targeted development of improved therapeutic strategies.
ACUTE GVHD The reported incidence of aGvHD in children varies widely from 20% to 80%, depending principally on the major risk factors of HLA-matching and donor type (matched or mismatched, sibling,
Dhiremployer) S, et al. Arch Dis Child 2014;0:1–8. doi:10.1136/archdischild-2013-304832 1 Copyright Article author (or their 2014. Produced by BMJ Publishing Group Ltd (& RCPCH) under licence.
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Review Table 1 Classification of acute and chronic graft-versus-host disease (GvHD)
Category Acute GvHD Classic acute GvHD Persistent, recurrent or late-onset acute GvHD Chronic GvHD Classic chronic GvHD Overlap syndrome
Timing of symptoms
Presence of Presence of acute GvHD chronic GvHD features features
≤100 days >100 days
Yes Yes
No No
No time limit No No time limit Yes
Yes Yes
Adapted with permission from Filipovich et al.2
other related or unrelated donor) and stem cell source (bone marrow, peripheral blood or umbilical cord blood), and to a lesser extent donor age (older adult donors are associated with a higher risk of aGvHD) and sex (multiparous female donors higher risk).4 In order of frequency, aGvHD predominantly
affects the skin, gastrointestinal tract and liver.4 Skin involvement commonly starts as an erythematous maculopapular rash on the palms and soles, but can involve any part of the skin and (when severe) lead to bullae formation. The differential diagnosis includes engraftment rash, infections (especially viral) and drug reactions, and may require clarification by skin biopsy. Gastrointestinal aGvHD presents with secretory diarrhoea (copious and sometimes bloody in severe cases) and may cause abdominal pain, nausea, vomiting and anorexia. The differential diagnosis includes mucositis, while endoscopy and biopsy may be needed to exclude infection. Hepatic aGvHD usually presents with cholestatic jaundice and raised liver enzymes (typically γ-glutamyl transpeptidase) and may have to be differentiated from hepatic veno-occlusive disease, viral infections, sepsis and drug toxicity. Hepatitic aGvHD with prominent transaminitis is rarer still but well described. Rarely, liver biopsy may be necessary, but the risk of dangerous bleeding is significant. With the significant improvements in post-HSCT supportive care in the last two decades, particularly reducing infectionrelated mortality,5 there is greater focus on preventing and
Figure 1 The three-phase model of the pathogenesis of acute graft-versus-host disease. The key steps are (1) host antigen-presenting cell (APC) activation, (2) donor T-cell activation, (3) cellular and inflammatory effector phase (Copied with permission from Ferrara et al1). 2
Dhir S, et al. Arch Dis Child 2014;0:1–8. doi:10.1136/archdischild-2013-304832
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Review managing GvHD. Guidelines for the diagnosis and management of acute and chronic GvHD were published in 2012 by the British Committee for Standards in Haematology (BCSH) and the British Society for Blood and Marrow Transplantation (BSBMT).6–8 The authors stated that the recommendations were applicable to adults and children, but highlighted the importance of careful consideration of disease-associated comorbidities and treatment toxicities in children.7 A working group of the European Group for Blood and Marrow Transplantation and the European LeukaemiaNet has recently published recommendations for prophylaxis and treatment of GvHD in adults in an attempt to standardise practice.9 The group acknowledged the existence of divergent views concerning GvHD management in paediatric practice but is planning to develop standardised recommendations for children. The American Society of Blood and Marrow Transplantation (ASBMT) has also recently published recommendations for first-line and second-line treatment of aGvHD but does not specifically mention children.10 The strategies used for prophylaxis of aGvHD depend on the nature of the conditioning regimen, donor type, stem cell source and degree of HLA mismatch. Prophylaxis in myeloablative (full-intensity conditioning, aimed at eradicating all residual malignant and marrow haemopoietic cells) HSCTs usually comprises ciclosporin A for approximately 2–12 months (depending on the underlying disease being transplanted) with or without a short course of intravenous methotrexate (usually 3–4 doses). Tacrolimus is preferred to ciclosporin in many non-European centres, although published evidence comparing these calcineurin inhibitors (CNIs) is lacking in children. Pre-HSCT anti-T-cell serotherapy with either antithymocyte globulin or alemtuzumab (CAMPATH) is usually added for URD transplants and also provides additional prophylaxis against graft rejection. Prophylaxis for reduced-intensity HSCTs (with less intensive conditioning treatment that does not fully eradicate malignant and haemopoietic cells and instead relies on immunological antihost and antitumour effects) usually comprises ciclosporin and mycophenolate mofetil (MMF), although some centres prefer a corticosteroid to MMF; again, serotherapy is usually added for URD HSCTs. Despite these common themes, there are wide variations in drug scheduling and dosing.9 There are some patients for whom no suitably matched related or unrelated donor can be found. Haploidentical parental HSCT is feasible and various T-cell depletion (TCD) strategies have been used to minimise GvHD and maximise sustained engraftment and early immune reconstitution. Historical methods to remove viable T-lymphocytes include in vitro CAMPATH-1M antilymphocyte antibody, soy lectin and sheep red cell rosetting. Recently, European centres performing TCD HSCT have used CD34 stem cell selection, most commonly the Miltenyi Clini-MACS system that uses an organic iron bead/anti-CD34 antibody conjugate to isolate purified CD34 stem cells through a magnetic column.11 However, this method also depletes grafts of beneficial stromal cells, so an alternative is to specifically deplete T-lymphocytes and B-lymphocytes while retaining CD34 cells together with engraftment-enhancing CD34− progenitors, natural killer, dendritic and graft-facilitating cells. γδ T cells normally represent 1–10% of blood lymphocytes. Although they can destroy intracellular and extracellular pathogens, they are not MHC-restricted and are therefore unlikely to cause GvHD. Depletion of T-cell α/β receptor (TCRαβ) and CD19 cells, with selection of TCRγδ T cells, is a new technique preserving the graft-versus-leukaemia effect with promising results in haploidentical HSCT.12 13 Dhir S, et al. Arch Dis Child 2014;0:1–8. doi:10.1136/archdischild-2013-304832
Box 1 shows first-line, second-line and third-line treatment options for acute GvHD. The modified Glucksberg clinical grades,14 which have been shown to correlate with overall survival in adults,15 are usually employed to stratify treatment for aGvHD. The components of first-line management have changed little over the last 30 years. Grade I aGVHD is managed by continuing the prophylactic CNI and adding topical steroids (and sometimes topical tacrolimus) to affected skin, while systemic immunosuppression with intravenous methylprednisolone 2 mg/kg/day is added for grades II–IV, although a recent adult trial suggested that 1 mg/kg/day is sufficient for grade II.16 Higher steroid doses offer no additional benefit and contribute to increased toxicity.17 In gastrointestinal aGvHD, the addition of nonabsorbable steroids (budesonide and beclomethasone) may facilitate reduction of systemic steroid doses.7 Unfortunately, a complete response to steroid treatment is seen in only about 70% of cases of aGvHD.17 However, newer treatments have been introduced for the treatment of steroid-refractory aGvHD, usually defined as failure to respond to 5 days of methylprednisolone and CNI, or deterioration after 3 days.7 9 18 It has been known for over 20 years that aGvHD refractory to initial treatment is associated with a survival rate of 50% of children with refractory cGvHD in a phase II trial, it causes a high incidence of serious infections.35 Recent small uncontrolled studies suggest that imatinib may improve sclerodermatous or pulmonary cGvHD,36 37 while rituximab may benefit skin and musculoskeletal cGvHD.38 Third-line treatments include MMF, high-dose steroid pulses and methotrexate. 6
RECENT DEVELOPMENTS Extracorporeal photopheresis ECP is an apheresis-based immunomodulatory therapy that has been used for over 20 years for the treatment of cutaneous T-cell lymphoma. It is now being used for a widening number of indications including solid organ allograft rejection, autoimmune-mediated disorders and GvHD. The patient’s blood is leukapheresed and centrifuged to separate out the leukocyte-enriched buffy coat, which is then injected with a photosensitising drug 8-methoxypsoralen and exposed to ultraviolet-A (UVA) irradiation. The photoactive buffy coat is then reinfused into the patient. Due to the large volume of extracorporeal blood required, until recently the procedure was limited to patients of over 40 kg. However, the Therakos Cellex device uses continuous flow separation technology with reduced extracorporeal blood volumes and shorter treatment times. With the addition of blood priming to the machine, patients weighing as little as 8 kg have been safely treated. Studies are ongoing to fully elucidate the mechanism of action against GvHD. Exposure to UVA light results in apoptosis of peripheral blood mononuclear cells, and it is thought that when these are reinfused, dendritic cells are involved in processing them, provoking anti-inflammatory cytokine responses and the generation of specific Tregs that suppress the effector T cells causing GvHD.39 Side effects are few and mainly related to central venous catheter infection and thrombosis. Care has to be taken to avoid hypotension particularly in young children and hypocalcaemia when citrate anticoagulation is used. A prospective randomised controlled trial demonstrated favourable results of a 12-week course of ECP in cGvHD, with further improvement when continued for 24 weeks.40 41 There is less published evidence for the treatment of aGvHD, but one trial in 59 patients with steroid-refractory aGvHD gave ECP on two consecutive days weekly until response and thereafter every 2–4 weeks until maximal response. In total, 82% with skin GvHD, 61% with liver and 61% with gut involvement had a complete response.42 Available evidence thus indicates that ECP is a valuable option for treatment of acute and chronic GvHD with proven safety in children.43 The main advantage is that it allows reduction in other immunosuppressive therapy that lessens the risk of immunosuppression-related morbidity and mortality.
Mesenchymal stromal cells MSCs are multipotent progenitors found in bone marrow, adipose tissue and also fetal membranes and umbilical cord blood (UCB). They have important immunoregulatory properties, including inhibition of T-cell proliferation, release of soluble factors and promotion of Tregs. They are hypoimmunogenic and do not need to be HLA-matched to the recipient. Their use as treatment for steroid-refractory aGvHD was pioneered by Le Blanc,44 and prospective studies demonstrated efficacy in paediatric and adult patients with aGvHD.45 Commercial preparations are now available. Most studies have used MSCs as second-line therapy in steroid-refractory aGvHD, but a phase II randomised multicentre study evaluated two different doses of MSCs given in combination with methylprednisolone for the initial therapy for aGvHD. Thirty-two adults with grade II–IV aGvHD were randomised to receive two doses of either two or eight million MSCs/kg each. The first MSCs infusion was given within the 48 h following diagnosis of grade II–IV aGvHD, and the second three days later. A total of 94% of patients achieved a complete (77%) or partial (16%) Dhir S, et al. Arch Dis Child 2014;0:1–8. doi:10.1136/archdischild-2013-304832
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Review response. Response rates were comparable in patients given two or eight million MSCs/kg.46 Further studies are needed to inform on the optimal timing and dose of MSCs to treat aGvHD. Efficacy is less convincing in patients with cGvHD.47 Cotransplantation of MSCs at the time of HSCT has been shown in some small studies to have a possible effect on reducing the incidence of aGvHD, suggesting a role in prevention as well as treatment of aGvHD.48
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Biomarkers The development of biomarkers that can potentially predict which patients are likely to develop GvHD or to respond to first-line treatment is an exciting advance that is likely to become increasingly available. A panel of four informative biomarkers (TNF receptor-1, IL-2 receptor, IL-8 and hepatocyte growth factor) was found to have diagnostic and prognostic value for aGvHD.49 In addition, GvHD target organ-specific biomarkers have been identified. Elafin is a specific marker for skin GvHD50 and regenerating islet-derived 3α for gut GvHD.51 When measured in serum samples obtained from the day of transplant (day 0), day 14 and day 28 of treatment, concentrations of these six GvHD biomarkers were predictive of the likelihood of treatment response and survival.52 There is increasing evidence for the role of genetic polymorphisms affecting the function of gene products. For example, two single-nucleotide polymorphisms in the heparanase gene associated with high recipient heparanase levels correlated with extensive cGvHD53 and polymorphisms in the PARP1 gene have been associated with a higher risk of cGvHD.54
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CONCLUSION Improved understanding of the pathobiology of acute and chronic GvHD should lead to the development of more refined preventive and therapeutic strategies. Measurement of biomarkers may enable prophylaxis and treatment to be tailored for individual patients, while increasing availability and use of ECP and MSCs may improve the currently poor outcomes of patients with steroid-resistant acute and chronic GvHD. Competing interests None. Provenance and peer review Commissioned; externally peer reviewed.
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Dhir S, et al. Arch Dis Child 2014;0:1–8. doi:10.1136/archdischild-2013-304832
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Recent advances in the management of graft-versus-host disease S Dhir, M Slatter and R Skinner Arch Dis Child published online July 12, 2014
doi: 10.1136/archdischild-2013-304832
Updated information and services can be found at: http://adc.bmj.com/content/early/2014/07/12/archdischild-2013-304832.full.html
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References
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