Pathogenesis and
`Management of
`Graft-versus-Host
`Disease
`
`Sung W. Choi, MDa,*, John E. Levine, MDb,
`James L.M. Ferrara, MD, DScc
`
`KEYWORDS
` Acute graft-versus-host disease
` Chronic graft-versus-host disease
` Hematopoietic cell transplantation  GVHD
`
`Allogeneic hematopoietic cell transplantation (HCT) is an important therapeutic option
`for various malignant and nonmalignant conditions.1 The indication for its use has
`expanded, especially among older patients, in recent years through novel strategies
`using donor leukocyte infusions, nonmyeloablative conditioning and umbilical cord
`blood (UCB) transplantation.2 As allogeneic HCT continues to increase, with more
`than 20,000 allogeneic transplantations performed annually worldwide, greater
`attention is given to improvements in supportive care, infectious prophylaxis, immuno-
`suppressive medications, and DNA-based tissue typing. Despite advances, graft-
`versus-host disease (GVHD) remains the most frequent and serious complication
`following allogeneic HCT and limits the broader application of this important therapy.3
`GVHD can be considered an exaggerated manifestation of a normal inflammatory
`mechanism in which donor lymphocytes encounter foreign antigens in a milieu that
`fosters inflammation. In the context of hematological malignancies, a delicate balance
`exists between the harmful consequences of GVHD and the beneficial effects incurred
`
`Dr Choi is a St Baldrick’s Career Development Scholar.
`Dr Ferrara is an American Cancer Society Clinical Research Professor.
`a Department of Pediatrics, Blood and Marrow Transplant Program, University of Michigan
`Medical School, 1500 E. Medical Center Drive, 6303 Comprehensive Cancer Center, Ann Arbor,
`MI 48109-5942, USA
`b Department of Internal Medicine and Pediatrics, Blood and Marrow Transplant Program,
`University of Michigan Medical School, 1500 E. Medical Center Drive, 5303 Comprehensive
`Cancer Center, Ann Arbor, MI 48109-5941, USA
`c Department of Internal Medicine and Pediatrics, Blood and Marrow Transplant Program,
`University of Michigan Medical School, 1500 E. Medical Center Drive, 6303 Comprehensive
`Cancer Center, Ann Arbor, MI 48109-5942, USA
`* Corresponding author.
`E-mail address: sungchoi@med.umich.edu (S.W. Choi).
`
`Immunol Allergy Clin N Am 30 (2010) 75–101
`doi:10.1016/j.iac.2009.10.001
`immunology.theclinics.com
`0889-8561/10/$ – see front matter ª 2010 Elsevier Inc. All rights reserved.
`
`

`

`76
`
`Choi et al
`
`when donor lymphocytes attack recipient malignant cells, a process referred to as the
`graft-versus-leukemia/tumor (GVL) effect. Given the increasing number of transplant
`recipients, there will be an increasing population of patients with GVHD. Recent
`advances in the understanding of the pathogenesis of GVHD have led to new
`approaches to its management, including using it to preserve the GVL effect following
`allogeneic transplant. This article reviews the important elements in the complex
`immunologic interactions involving cytokine networks, chemokine gradients, and
`the direct mediators of cellular cytotoxicity that cause clinical GVHD, and discusses
`the risk factors and strategies for management of GVHD.
`
`ACUTE GVHD
`Epidemiology and Risk Factors
`
`In 1966, Billingham4 formulated three requirements for the development of GVHD:
`the graft must contain immunologically competent cells; the recipient must express
`tissue antigens that are not present in the transplant donor; and the recipient must be
`incapable of mounting an effective response to eliminate the transplanted cells. It is
`now known that T cells are the immunologically competent cells, and when tissues
`containing T cells (blood products, bone marrow [BM], and solid organs) are trans-
`ferred from one person to another who is unable to eliminate those cells, GVHD
`can develop.5,6
`Allogeneic HCT is the most common setting for the development of GVHD, in which
`recipients receive immunoablative chemotherapy or radiation before hematopoietic
`cell infusion containing donor T cells. GVHD ultimately develops when donor T cells
`respond to recipient tissue antigens secondary to mismatches between major or
`minor histocompatibility antigens between the donor and recipient. The major histo-
`compatibility complex (MHC) contains the genes that encode tissue antigens. In hu-
`mans, the MHC region lies on the short arm of chromosome 6 and is called the
`human leukocyte antigen (HLA) region.7 Class I HLA (A, B, and C) proteins are ex-
`pressed on almost all nucleated cells of the body at varying densities. Class II (DR,
`DQ, and DP) proteins are primarily expressed on hematopoietic cells (B cells, dendritic
`cells, monocytes, and activated T cells), but their expression can be induced on many
`other cell types following inflammation or injury. High-resolution DNA typing of HLA
`genes with polymerase chain reaction (PCR)-based techniques has now largely
`replaced earlier methods. The incidence of GVHD is directly related to HLA disparity8,9
`and with more HLA mismatches, the likelihood of developing GVHD increases.10,11
`Recent data from the National Marrow Donor Program (NMDP) suggest that high-
`resolution matching for HLA-A, -B, -C, and -DRBI (8/8 match) maximizes post trans-
`plant survival.12,13
`Despite HLA identity between a patient and donor, the incidence of acute GVHD
`ranges from 26% to 32% in recipients of sibling donor grafts, and 42% to 52% in
`recipients of unrelated donor grafts (Center for International Blood and Marrow Trans-
`plant Research [CIBMTR] Progress Report January–December 2008). The incidence is
`likely related to genetic differences that lie outside the HLA loci, or ‘‘minor’’ histocom-
`patibility antigens (HA), which are immunogenic peptides derived from polymorphic
`proteins presented on the cell surface by MHC molecules.14 Some minor HAs, such
`as HY and HA-3, are expressed on all tissues and are targets for GVHD and GVL,
`whereas other minor HAs, such as HA-1 and HA-2, are expressed abundantly on
`hematopoietic cells (including leukemic cells) and may induce a greater GVL effect
`with less GVHD.14,15 However, the precise elucidation of most human minor antigens
`remains to be accomplished.14,16
`
`

`

`Management of Graft-versus-Host Disease
`
`77
`
`The impact of donor and recipient polymorphisms in cytokine genes with critical
`roles in the classic ‘‘cytokine storm’’ of GVHD has been examined as a risk factor
`for GVHD.17 Various polymorphic genes, including tumor necrosis factor a (TNF-a),
`interleukin 10 (IL-10), and interferon-g (IFN-g) variants, have been associated with
`GVHD, although not always.18–20 There is no unequivocal evidence that polymorphic
`genes for cytokines or other proteins involved in innate immunity 21–24 sufficiently influ-
`ence GVHD and transplant outcome to change clinical practice. Nonetheless, future
`strategies to identify the best possible transplant donor will likely incorporate HLA
`and non-HLA genetic factors.
`In addition to genetic factors, other risk factors which have been associated with the
`development of GVHD include older donor and recipient age,25–28 multiparous female
`donor,28,29 advanced malignant condition at transplantation,9,29 donor type,28 and
`donor hematopoeitic cell source.30–32 In the last decade, there has been a shift in
`clinical practice from the use of intraoperative harvested BM to granulocyte colony-
`stimulating factor mobilized peripheral blood stem cells (PBSC) as the donor hemato-
`poietic cell source. However, definitive data demonstrating long-term advantages of
`PBSC rather than BM are lacking. One meta-analysis found that acute and chronic
`GVHD are more common following peripheral blood stem cell transplant (PBSCT)
`compared with bone marrow transplant (BMT) and indicated a trend toward decreased
`relapse rate following PBSCT.31 The relative risk (RR) for acute GVHD after PBSCT was
`1.16 (95% confidence interval [CI], 1.04–1.28) compared with BMT; the RR for chronic
`GVHD after PBSCT was 1.53 (95% CI, 1.25–2.05); and the RR for relapse after PBSCT
`was 0.81 (95% CI, 0.62–1.05). Thus, the survival benefit of PBSC versus BM remains in
`question. A large prospective, randomized, multicenter clinical trial of PBSC versus BM
`in unrelated donor transplantation conducted through the Blood and Marrow Trans-
`plant Clinical Trials Network (BMT CTN) has recently finished accrual.
`For individuals without a suitable HLA-matched donor, UCB has become an alter-
`native to BM or PBSC.33–36 The incidence and severity of acute GVHD seem to be
`lower following UCB transplant than after HLA-matched marrow unrelated donor
`transplant, despite HLA disparities between the donor and recipient.37,38 In an effort
`to meet the minimum cell dose required to ensure reliable engraftment, the simulta-
`neous transplantation of 2 partially HLA-matched UCB units has been studied.39 A
`recent report comparing transplantation with 2 partially HLA-matched UCB units
`versus a single unit demonstrated an increased incidence and earlier presentation
`of acute GVHD associated with the double UCB graft.40
`
`Prevention
`
`Prevention of acute GVHD is an integral component to the management of patients
`undergoing allogeneic HCT. The primary strategy employed is in the use of pharma-
`cologic GVHD prophylaxis. The most widely used GVHD prophylaxis following full
`intensity conditioning includes a combination of a calcineurin inhibitor (eg, cyclo-
`sporine, tacrolimus) with methotrexate (MTX). This standard regimen was initially
`described in 198641 and since then several clinical trials have shown the superiority
`of this combination in reducing the incidence of GVHD and improving survival
`compared with either agent alone.42–45 The calcineurin inhibitors cyclosporine and ta-
`crolimus impede the function of the cytoplasmic enzyme calcineurin, which is critical
`to the activation of T cells. The most common side effects include hypomagnesemia,
`hyperkalemia, hypertension, and nephrotoxicity.46 Large randomized studies
`comparing tacrolimus-MTX with cyclosporine-MTX have demonstrated a reduced
`incidence of grade II to IV acute GVHD with tacrolimus, but no overall survival
`advantage.43,46
`
`

`

`78
`
`Choi et al
`
`Recently, sirolimus, a widely used immunosuppressant in solid organ transplanta-
`tion,47 has become attractive as a GVHD prophylactic agent because of the nonover-
`lapping toxicities with calcineurin inhibitors and the different mechanism of action.
`Sirolimus binds uniquely to FK binding protein 12 (FKBP12) and then complexes
`with mammalian Target of Rapamycin (mTOR).48 Several studies have shown that
`the combination of sirolimus and tacrolimus has resulted in rapid engraftment, low
`incidence of acute GVHD,
`reduced transplant-related toxicity, and improved
`survival.49 A prospective, randomized, multicenter trial is being conducted through
`the BMT CTN (protocol 0402) comparing sirolimus-tacrolimus versus tacrolimus-
`MTX following HLA-matched, related donor PBSCT.
`A commonly used GVHD prophylaxis following reduced-intensity conditioning
`includes a combination of a calcineurin inhibitor (eg, cyclosporine, tacrolimus) with
`mycophenolate mofetil (MMF) instead of MTX. MMF, the prodrug of mycophenolic
`acid, selectively inhibits inosine monophosphate dehydrogenase, an enzyme critical
`to the de novo synthesis of guanosine nucleotide, which is needed for proliferation
`of T cells. In a prospective randomized trial, patients who received MMF as part of
`GVHD prophylaxis experienced significantly less severe mucositis and more rapid
`neutrophil engraftment than those who received MTX.50 Although the optimal prophy-
`laxis regimen following reduced-intensity HCT is not well established, MMF has been
`shown to be safe in this context.51–55 MMF is also often preferred to MTX in UCB trans-
`plants because of its advantageous toxicity profile with respect to neutropenia and
`mucositis.
`Many centers have previously attempted to decrease the risk of GVHD by ex vivo
`T cell depletion. Despite significant reductions in the incidence and severity of
`GVHD, T cell depletion has not achieved wide acceptance because of high rates of
`graft rejection, life-threatening infections, and leukemia relapse.56–58 In vivo T cell
`depletion has also been widely studied using alemtuzumab, a monoclonal antibody
`specific for CD52 antigen expressed abundantly on the surface of normal and malig-
`nant lymphocytes,59,60 or antithymocyte globulin (ATG), a polyclonal antibody mixture
`of either horse or rabbit origin directed against multiple epitopes of human T cells.61
`These approaches are associated with significant reduction in acute GVHD, but at
`the cost of impaired immune reconstitution and increased risk of leukemia relapse.
`Thus, the focus of most prevention strategies remains pharmacologic manipulation
`of T cells following transplant.
`
`Pathophysiology
`
`Acute GVHD is mediated by donor lymphocytes infused into the recipient, in whom
`they encounter profoundly damaged tissues from the effects of the underlying
`disease, prior infections, and the transplant conditioning regimen. The allogeneic
`donor cells encounter a foreign environment that has been altered to promote the acti-
`vation and proliferation of inflammatory cells. Thus, acute GVHD reflects an exagger-
`ated response of the normal inflammatory mechanisms that involves donor T cells and
`multiple innate and adaptive cells and mediators. Three sequential phases can be
`conceptualized to illustrate the complex cellular interactions and inflammatory
`cascades that ultimately evolve to acute GVHD: (1) activation of antigen-presenting
`cells (APCs); (2) donor T cell activation, proliferation, differentiation and migration;
`and (3) target tissue destruction.62
`
`Phase 1: activation of APCs
`In the first phase, APCs are activated by the underlying disease and the HCT
`conditioning regimen.63 Animal models 63,64 and clinical HCT 65 have supported the
`
`

`

`Management of Graft-versus-Host Disease
`
`79
`
`observation that increased risk of GVHD is associated with intensive conditioning
`regimens that contribute to extensive tissue injury and subsequent release of inflam-
`matory cytokines. Damage to host tissues leads to the secretion of proinflammatory
`cytokines, such as TNF-a and IL-1, and chemokines, such as CCL2-5 and CXCL9-
`11, thereby producing increased expression of adhesion molecules, MHC antigens
`and costimulatory molecules on host APCs. For example,
`increase of plasma
`TNF-a receptor 1 levels, a surrogate marker for TNF-a, at 1 week after HCT strongly
`correlates with the later development of GVHD.66 Systemic translocation of immunos-
`timulatory microbial products, such as lipopolysaccharide (LPS), as a result of damage
`to the gastrointestinal (GI) tract induced by the conditioning regimen, enhances the
`activation of host APCs.67,68 The initial site of interaction between activated APCs
`and donor T cells is likely the secondary lymphoid tissue in the GI tract.69 Different
`distinct subsets of APCs, including host and donor type APCs,68,70,71 dendritic
`cells,72,73 Langerhans cells,74 and monocytes/macrophages,75 have been implicated
`in this phase. However, the relative contributions of these various APCs remain to be
`elucidated. The intensity of the conditioning regimen and the degree of tissue injury
`seem to be associated with the risk of GVHD. Reduced intensity conditioning
`regimens have thus become more widely employed in an effort to reduce acute
`GVHD by decreasing the damage to host tissues.65,76
`
`Phase 2: donor T cell activation
`Donor T cell activation, proliferation, differentiation, and migration in response to
`primed APCs occur during the second phase of acute GVHD. The T cell receptors
`(TCR) of donor T cells recognize alloantigens on host and donor type APCs that are
`present in secondary lymphoid organs.77,78 During direct presentation, donor T cells
`recognize either the peptide bound to host MHC molecules, or the foreign MHC mole-
`cules themselves.79 During indirect presentation, donor T cells respond to the
`peptides generated by degradation of the host MHC molecules that are presented
`on donor-derived MHC.80
`Following antigen recognition, signaling through the TCR induces a conformational
`change in adhesion molecules, resulting in high affinity binding to the APC.81 The
`complex interaction between T cell costimulatory molecules and their ligands on
`APCs facilitates full T cell activation. Many T cell costimulatory molecules display unique
`and overlapping functions.82 Receptors of the B7 family and the TNF family play espe-
`cially critical roles in GVHD, and are known to deliver positive and negative signals to T
`cells.83 Blockade of costimulatory and inhibitory pathways can reduce acute GVHD in
`murine models, but this approach has not yet been tested in clinical trials.2
`Murine studies have shown that control of alloreactive responses responsible for
`GVHD depends at least in part on CD41 CD251 regulatory T cells. Studies in mice
`suggest that regulatory T cells added to donor grafts can prevent or delay GVHD.84
`However, the role of regulatory T cells in clinical allogeneic HCT has not been well
`established, in part because of the lack of clear identification of human regulatory T
`cell phenotype. In contrast to murine studies, more severe acute GVHD developed
`clinically when donor grafts contained larger numbers of donor CD41 CD251 T
`cells.85 One recent study found that HCT recipients with higher absolute numbers of
`FOXP31 CD41 T cells were associated with a reduced risk of developing GVHD.86
`However, FOXP3 expression in humans is not specific for regulatory T cell pheno-
`type,87 and improved techniques to identify and expand regulatory T cells are required
`for its wider application in clinical BMT.
`Several intracellular biochemical pathways are rapidly amplified following T cell acti-
`vation. Activated T cells secrete cytokines that are generally classified as Th1 (IFN-g,
`
`

`

`80
`
`Choi et al
`
`IL-2 and TNF-a) or Th2 (IL-4, IL-5, IL-10, and IL-13) and Th17. Although Th1 cytokines
`induce GVHD efficiently, the balance of Th1 and Th2 cytokines is important in the im-
`munopathogenesis of GVHD, but remains incompletely understood.88 TNF-a, already
`discussed as an inducer of APC activation in phase I,
`functions to amplify
`T cell activation and proliferation in this second phase of GVHD. IL-2 production is
`also integral in this early development of acute GVHD,89 and remains the principal
`target of many current clinical therapeutic and prophylactic approaches to GVHD,
`such as cyclosporine, tacrolimus, and monoclonal antibodies against IL-2 and its
`receptor.44 However, recent data suggest that regulatory T cell function is dependent
`on the presence of calcineurin-dependent IL-2, and that interference with IL-2 may
`possibly antagonize the induction of tolerance.90
`IFN-g is a cytokine with diverse effects in vivo that can amplify and suppress acute
`GVHD. With regards to amplification, IFN-g increases the expression of molecules
`such as chemokine receptors, MHC proteins, and adhesion molecules. IFN-g also
`sensitizes monocytes and macrophages to stimuli such as LPS, thereby accelerating
`intracellular cascades in response to these stimuli.88 IFN-g may also amplify GVHD by
`directly damaging target cells in the GI tract and in the skin while conversely inducing
`nitric oxide-mediated immunosuppression.91 IFN-g itself can prevent experimental
`GVHD by hastening the apoptosis of activated donor T cells.92 Thus, this complexity
`makes it a challenging target with respect to therapeutic intervention.
`IL-10 can suppress the expression of proinflammatory cytokines, chemokines, and
`adhesion molecules, and antigen-presenting and costimulatory molecules in mono-
`cytes/macrophages, neutrophils, and T cells.93 Recent clinical data suggest that
`genetic polymorphism in the IL-10 promoter region of the recipient has a significant
`impact on the risk of developing acute GVHD.94 Increased IL-10 production by recip-
`ient cells stimulated ex vivo has been associated with a reduced risk of acute GVHD.95
`Experimental data have also demonstrated that transforming growth factor b (TGF-b),
`another suppressive cytokine, attenuates acute GVHD, but may lead to chronic
`GVHD.96 Thus multiple cytokines are important in GVHD pathogenesis and regulation.
`Furthermore, the timing and duration of cytokine expression may be a critical factor
`determining the induction of the GVH reaction, and cytokine dysregulation could
`potentially contribute to the severity of acute GVHD.62
`
`Phase 3: cellular and inflammatory effector phase
`A complex cascade of cellular and inflammatory mediators occurs during the effector
`phase of acute GVHD. These mediators synergize to amplify local tissue injury and
`damage target tissues. As such, the effector phase of GVHD involves aspects of the
`innate and adaptive immune response and interactions with the proinflammatory cells
`and cytokines generated during phase 1 and 2.
`
`Cellular effectors Cytotoxic T cells are the major cellular effectors of acute GVHD and
`lyse target cells using principally the Fas/Fas ligand (FasL) and the perforin/granzyme
`pathways.97 The Fas-FasL pathway seems to predominate in hepatic GVHD whereas
`the perforin/granzyme pathways are more important in the GI tract and skin.2 The
`‘‘danger’’ signals generated in phase 1, augmented by the expression of costimulatory
`molecules in phase 2, induce the production of chemokines. The migration of donor
`T cells from lymphoid tissues to the target organs in which damage occurs is directed
`by these chemokine gradients and adhesion molecules such as L-selectin and aLb2
`integrin. The upregulation of chemokines, such as CCL2, CCL3, CCL4, CCL5,
`CXCL9, CXCL10, and CXCL11 in GVHD target organs (skin, liver, and gut), play
`primary roles in this homing process.98 Furthermore, integrin receptors, which are
`
`

`

`Management of Graft-versus-Host Disease
`
`81
`
`regulated by chemokines, mediate many adhesive interactions that are critical for
`successful T cell migration.99
`
`Inflammatory effectors The secretion of inflammatory cytokines, such as TNF-a or IL-1
`also results in GVHD target organ injury. The secretion signal may be provided through
`toll-like receptors (TLRs) by LPS and other microbial products that have leaked through
`damaged intestinal mucosa by the conditioning regimen in phase 1.100 TNF-a is
`produced by donor and host cells and is a critical component of GVHD pathophysi-
`ology. TNF-a can (1) activate APCs and enhance alloantigen presentation, (2) recruit
`effector cells to target organs through the induction of inflammatory chemokines, and
`(3) directly cause tissue damage via apoptosis and necrosis. IL-1 is also involved in
`the pathogenesis of acute GVHD.17 Its secretion occurs predominantly in the spleen
`and skin during the effector phase of experimental GVHD.101 Increased expression of
`mononuclear IL-1 mRNA has been associated with the development of GVHD.102
`However, the blockade of IL-1 using recombinant human IL-1 receptor antagonist in
`patients undergoing HCT did not reduce the risk of GVHD.103
`
`Clinical Features
`
`The three main organs involved in acute GVHD are the skin, liver, or GI tract. GVHD
`presents clinically in an acute or chronic form. Historically, the acute and chronic forms
`were arbitrarily defined based on the timeframe post transplant (less than or more than
`100 days, respectively).104 However, current consensus is that clinical manifestations
`guide whether the signs and symptoms of GVHD are acute, chronic, or an overlap
`syndrome (wherein diagnostic or distinctive features of acute and chronic GVHD
`appear together).105
`The extent (stage) of involvement of the three principal target organs determines the
`overall severity (grade) of acute GVHD (Table 1).106 The overall grades are classified as
`I (mild), II (moderate), III (severe), and IV (very severe). A poor prognosis is associated
`with severe grade III or IV GVHD, with 25% and 5% overall survival, respectively.107
`Skin is generally the first and most commonly affected organ.104 The presentation of
`skin involvement generally coincides with donor cell engraftment and is characterized
`by an erythematous, maculopapular rash that is often pruritic. In severe cases the skin
`may blister and ulcerate.108 The pathognomonic histopathologic finding is apoptosis
`at the base of epidermal rete ridges. Other features include dyskeratosis, exocytosis
`of lymphocytes, satellite lymphocytes adjacent to dyskeratotic epidermal keratino-
`cytes, and a perivascular lymphocytic infiltration in the dermis.1,109
`Liver GVHD can be a challenging diagnosis. The initial feature typically includes the
`development of jaundice or an increase in the alkaline phosphatase and bilirubin;
`hepatomegaly may be noted. However, it is often difficult to distinguish from other
`causes of liver dysfunction following allogeneic HCT, such as drug toxicity, venoocclu-
`sive disease, opportunistic (bacterial, viral, and fungal) infections, total parenteral
`nutrition, acalculous cholecystitis, and iron overload, because of the overlapping
`patterns of clinical history, physical examination, and laboratory and imaging data.
`Thus, a biopsy is often required to confirm the diagnosis of liver GVHD.110 The histo-
`logic features are endothelialitis, lymphocytic infiltration of the portal areas, pericho-
`langitis, and bile duct destruction.111 However, the increased risk of bleeding
`associated with thrombocytopenia in the immediate post transplant period can
`preclude obtaining a biopsy. As such, the diagnosis of liver GVHD is often a clinical
`diagnosis of exclusion.
`GI tract involvement of acute GVHD may present as nausea, vomiting, anorexia,
`diarrhea, or abdominal pain. It is a panintestinal process with focal lesions of varying
`
`

`

`82
`
`Choi et al
`
`Table 1
`Acute GVHD grading criteria
`
`Stage
`
`Skin
`
`Liver (Bilirubin)
`
`GI Tract (Stool Output/d)
`
`0
`
`1
`
`2
`
`3
`
`4
`
`No GVHD rash
`
`<2 mg/dL
`
`Maculopapular rash
`<25% BSA
`
`2–3 mg/dL
`
`Maculopapular rash
`25%–50% BSA
`
`Maculopapular rash
`>50% BSA
`
`Generalized erythroderma
`with bullous formation
`
`3.1–6 mg/dL
`
`6.1–15 mg/dL
`
`>15 mg/dL
`
`Adult: <500 mL/d
`Child: <10 mL kg/d
`
`Adult: 500–999 mL/d
`Child: 10–19.9 mL/kg/d or
`persistent nausea,
`vomiting, or anorexia,
`with a positive upper GI
`biopsy
`
`Adult: 1000–1500 mL/d
`Child: 20–30 mL/kg/d
`
`Adult: >1500 mL/d
`Child: >30 mL/kg/d
`
`Severe abdominal pain
`with or without ileus
`
`Overall clinical grade: grade 0, no stage 1–4 of any organ; 1, stage 1–2 skin rash and no liver or GI
`involvement; 2, stage 3 skin rash, or stage 1 liver involvement, or stage 1 GI involvement; 3, stage
`0–3 skin rash, with stage 2–3 liver involvement, or stage 2–3 GI involvement; 4, stage 4 skin rash,
`liver, or GI involvement.
`The standard GVHD grading criteria were developed by Glucksberg in 1974. (Data from
`Glucksberg H, Storb R, Fefer A, et al. Clinical manifestations of graft-versus-host disease in human
`recipients of marrow from HL-A-matched sibling donors. Transplantation 1974;18(4):295–304) and
`then revised at the 1994 Consensus Conference in Keystone. (Data from Pzrepiorka D, Weisdorf D,
`Martin P, et al. Consensus conference on acute GVHD grading. Bone Marrow Transpl 1995;15:825–8.)
`The grading system did not initially take into consideration the staging of the GI tract for pediatric
`patients. However, most pediatric centers have adopted the modified Glucksberg grading scale and
`adjusted the staging of the GI tract to be based on volume per kg of body weight.
`Abbreviation: BSA, body surface area.
`
`is not always
`intensity. Gastric involvement causes postprandial vomiting that
`preceded by nausea. The diarrhea of GVHD is secretory and may be accompanied
`by significant GI bleeding as a result of mucosal ulceration, which is a prognostic
`factor for poor outcome.112 In advanced disease, diffuse, severe abdominal pain
`and distension are accompanied by voluminous diarrhea. The histologic features
`include patchy ulcerations, apoptotic bodies in the base of crypts, crypt abscesses,
`and loss and flattening of the epithelium surface.113
`
`Diagnostic Approach
`
`The diagnosis of acute GVHD is based entirely on clinical criteria that can be
`confirmed by biopsy of one of the three target organs. Laboratory data or imaging
`studies are also useful tests in the diagnostic approach to GVHD. However, a major
`challenge with the diagnosis is the absence of laboratory tests that can reliably predict
`or screen for the condition before its onset: that can establish a diagnosis in real time;
`that can distinguish it from other conditions that present with similar symptoms, such
`as infection; or that can stratify patients according to response to therapy. Thus,
`experimental blood tests with predictive value for GVHD such as a 4-biomarker
`panel114,115 may ultimately be useful to further identify high-risk groups and their
`outcomes (Fig. 1). These biomarkers could result in immunosuppressive treatment
`schemas tailored to patients in several risk groups.
`
`

`

`Management of Graft-versus-Host Disease
`
`83
`
`GVHD+
`
`•
`
`-■
`•
`
`■
`
`■ -
`
`I I. I -I •
`- ■- ■I .. • ■
`■ -- • •
`L ••
`'I ■ -•
`
`LJ
`
`.J
`
`•
`
`■
`■
`Fold-change from the mean
`
`1/4
`
`1/2
`
`2
`
`4
`
`Composite
`
`- .,
`
`I I
`
`L
`
`•
`
`0.017
`0.018
`0.035
`0.07
`0.12
`0.13
`
`• 0.17
`•
`-r 0.37
`
`0.24
`0.27
`
`0.38
`0.80
`
`•
`• 0.0002
`• • 0.007
`
`0.0003
`0.0004
`
`Fold•
`change
`P-value
`from T-test GVHD +/.
`1.4E-07
`2.82
`5.9E-06
`5.44
`2.1 E-05
`4.45
`7.9E-05
`1.69
`2.33
`1.58
`2.53
`2.79
`1.42
`2.73
`1.34
`2.14
`1.30
`1.38
`0.76
`1.28
`1.38
`0.83
`1.20
`0.94
`
`A
`Protein
`IL-2Rn
`CRP
`IL-8
`ICAM-1
`TIMP-1
`TNFR1
`HGF
`CA19.9
`VEGF-O
`IL-12p70
`VCAM-1
`IL-10
`Anglostatin
`EotaXin
`IGF-1
`FGF-basic
`MMP-2
`Anglopoietin-2
`TGF-JI
`FasL
`
`B
`
`Q)
`
`..... cu
`
`0
`T"""
`
`<X)
`0
`
`(0
`0
`
`N
`0
`
`0::
`Q)
`>
`~ ·u5
`0 V
`a..
`0
`Q)
`=-i
`'-I-
`
`. : . . I
`~
`
`.
`
`r· -
`'
`
`I
`
`_.;
`
`HGF
`
`IL-2Ra_ . . <·?•~·
`.~·· · ""
`.·x'
`X
`
`_:_;
`,, ; ,
`
`IL-8
`
`TNFR1
`
`.: ,
`(
`r ···
`
`0
`0
`
`,·
`0.0
`
`0.2
`
`0.8
`
`1.0
`
`0.6
`0.4
`False Positive Rate
`Fig. 1. From discovery to validation of plasma biomarkers of acute GVHD. (A) The heatmap
`of proteins levels measured sequential enzyme-linked immunosorbent assay in the discovery
`set samples. Samples from 21 GVHD patients (left) and 21 GVHD1 patients (right) are rep-
`resented. Eleven proteins gave a P value for differences between GVHD1 and GVHD
`patient plasma <0.05. (B) The receiver-operating characteristic (ROC) curves of 4 individual
`discriminator proteins and the composite panel in the training set. Individual ROC curves
`for IL-2Ra, TNFR1, human growth factor, and IL-8 and the composite panel. (From Paczesny
`S, Krijanovski OI, Braun TM, et al. A biomarker panel for acute graft-versus-host disease.
`Blood 2009;113(2):273–8; with permission.)
`
`Treatment
`
`Despite routine treatment with calcineurin-based prophylaxis, GVHD remains a major
`complication of allogeneic HCT. The most important predictor of long-term survival in
`patients with acute GVHD is the primary response to the first line of treatment.116 Many
`centers treat mild skin GVHD (grade I) with topical corticosteroids alone, but for more
`severe skin GVHD or visceral GVHD involvement (grade II or greater), systemic
`
`

`

`84
`
`Choi et al
`
`corticosteroids are the mainstay of therapy, typically starting at 1 to 2 mg/kg/d.
`Durable responses occur in less than half of patients with grade II to IV GVHD,117
`and with increasing severity of the disease, the likelihood of response decreases.104
`Treatment with high-dose steroids often continues for 7 days or more, with a gradual
`dose reduction depending on the clinical response. In a recent retrospective analysis,
`low-dose (1 mg/kg/d) versus high-dose (2 mg/kg/d) prednisone was compared for
`initial treatment of acute GVHD. In patients with grades I to II GVHD, the nonrelapse
`mortality and overall survival were similar between regimens, with a reduced risk of
`invasive fungal
`infections and shorter hospitalizations in the low-dose prednisone
`group. The number of patients with grades III to IV at onset was too few to draw
`any significant conclusions.
`In addition to topical corticosteroid therapy for skin GVHD, nonabsorbed steroid
`therapy is commonly used in GI GVHD. Oral budesonide in combination with systemic
`corticosteroids in patients with grade II or higher acute GI GVHD has shown complete
`responses in 77% of patients compared with 32% of historical controls.118 In a more
`recent randomized, placebo-controlled trial of oral beclomethasone for GI GVHD, oral
`beclomethasone dipropionate (BDP) reduced GVHD flares following a prednisone
`taper and resulted in superior survival at 1 year post transplant.119 Intraarterial admin-
`istration of steroids for GI and hepatic GVHD has also been attempted to deliver
`steroids directly to the target organ.120
`Prolonged therapy with steroids invariab