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`|
`EXPERT
`| REVIEWS
`
`Current and future approaches
`for control of graft-versus-
`host disease
`
`Expert Rev, Hematol. 1(1), 111-128 (2008)
`
`John Koreth’ and
`Joseph H Antin
`‘Author for correspondence
`Division of Hematologic
`Malignancies, Dana Farber
`Cancer Institue, 44 Binney
`Street, Boston, MA 02115, USA
`Tel. +1 617 632 3470
`Fax: +7 617 632 5168
`john_koreth@dfci. harvard.edu
`
`Graft-versus-host disease (GVHD), both acute and chronic, remains one of the major barriers
`to improving outcomesafterallogeneic stem cell transplantation. The pathophysiology of GVHD
`is complex and incompletely understood. GVHD is believed to arise from the interaction of:
`tissue damage and proinflammatory cytokines causing activation of antigen-presenting cells
`(APCs, donor T-cell activation by APCs and cytokines and host tissue injury by effector
`T lymphocytes and proinflammatory cytokines. There is also a role for additional lymphocyte
`subtypes (naive and memoryT cells, regulatory T cells, naturalkiller T cells and B cells) in GVHD
`pathogenesis, Strategies to improve donor-recipient HLA match, and to minimize conditioning
`toxicity, cytokine release and APC and effector T-lymphocyte activation, will likely improve
`prophylaxis of acute (and possibly chronic) GVHD. Therapy of established acute and chronic
`GVHD isstill heavily dependent on corticosteroids, despite their limited efficacy and considerable
`toxicity. Novel agents (and/or combinations of agents) comprising pharmacologic, biologic and
`cellular therapies targeting specific steps or subsets involved in immune activation will
`likely
`comprise future advances in GVHD control. This article reviews the current state of knowledge
`regarding the prevention and treatment of acute and chronic GVHD. Novel approaches currently
`undergoing evaluation are also highlighted.
`
`Keyworops: allogeneic stem cell transplantation © graft-versus-host disease
`
`Allogeneic stem cell transplantation (alloSCT) is
`often the only curative option for patients with
`various hematologic and/or immune disorders,
`particularly those with aggressive or advanced
`hematologic malignancies. However, the toxic-
`ity of alloSCT remains a significant barrier to
`its wider utilization. Graft-versus-host disease
`(GVHD)remainsthe most frequent complication
`after alloSCT.
`Clinically, GVHD was categorized as ‘acute’
`and‘chronic’ based on time of presentation, Any
`GVHD before day 100 was knownas ‘acute’,
`and after day 100 it was known as ‘chronic’. The
`severity of GVHD was graded: acute GVHD
`was categorized as grade I-IV by modified
`Glucksberg criteria (A—D by the International
`Bone Marrow Transplant Registry index) (Tarte 1)
`1,2]; chronic GVHD was commonlycategorized
`as limited or extensive [3]. Based on these criteria,
`grade [I-IV acute GVHD is thought to occur
`in approximately 35%of recipients of matched,
`related donor transplants, and in up to 50%of
`unrelated or alternative donor transplantrecipi-
`ents. Chronic GVHD can affect up to 60%of
`
`recipients who survive beyond 100 days after
`matched donor alloSCT.
`While the simplicity of the day 100 definition
`is appealing, it is irrelevant biologically and clini-
`cally, For instance, in patients receiving reduced
`intensity conditioning (RIC) alloSCT,or after
`donor lymphocyte infusion (DLN),clinical acute
`GVHD may develop months after the proce-
`dure [4]. Hence, there is a current attempt by the
`National Institutes of Health chronic GVHD
`consensus project working group to reclassify
`acute GVHD into classic acute and late-onset
`acute; and chronic GHVDinto classic chronic
`and overlap syndrome[5], Classic acute GVHD
`is characterized by a maculopapular erythematous
`skin rash, gastrointestinal symptomsorcholestatic
`hepatic abnormalities occurring within 100 days
`ofalloSCT or DLI, while late acute GVHD pres-
`ents similarly beyond 100 days after alloSCT or
`DLI, Classic chronic GVHD consists solely of
`manifestations ascribable to chronic GVHD
`(without acute GVHD features) (Tanz 2), while
`overlap syndromehas clinical features of both
`acute and chronic GVHD occurring together.
`
`www.expert-reviews.com
`
`10.1586/17474086.1.1.111
`
`© 2008 Expert Reviews Lrd
`
`ISSN 1747-4086
`
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`Gut Organ stage Skin*
`
`oe
`
`Table 1. Modified Glucksberg criteria for acute graft-versus-host disease grading.
`aici
`
`1
`
`Rash < 25%
`
`Rash 25-50%
`
`Rash > 50%
`
`4
`
`Generalized erythroderma with
`bullae
`
`Overall grade
`I
`ll
`
`Stage 1 or 2
`Stage 3 or
`
`-
`I
`Stage 4 or
`Iv
`“Use ‘rule of nines’ to determine body surface area
`Data from [I].
`
`Risk factors for GVHD
`Therisk factors for GVHD include:
`
`* Donor-recipient match at the major histocompatibility com-
`plex (MHC) loci, for instance, HLA class I (HLA-A, -B and
`-C) and class Il (HLA-DR, -DP and -DQ). Mismatches at
`HLA-A,-B, -C or -DRB1 (and possibly also -DQ and -DP)
`increase the risk of GVHD (nonpermissive donor—recipient
`HLA mismatches may particularly influence GVHD severity)
`and negatively impact survival [6-10];
`Donor stem cell source: compared with bone marrow stem
`cells, peripheral blood stem cells (PBSCs) have a higher GVHD
`risk, while umbilical cord blood cells appear to have a lower
`risk [11-14];
`
`T-cell dose: compared with T-cell replete grafts, 2-3 log deple-
`tion of CD3* T lymphocytes ofthe graft can effectively reduce
`acute GVHD incidence (although the effect on chronic GVHD
`is less clear), while less-intensive log reductions of T cells have
`no significant impact [15.16]. However, the benefit of T-cell
`depletion is counteracted by increased risks of graft failure,
`opportunistic infection and disease relapse such that pan-T-cell
`depletion strategies are not currently favored [17];
`* Additional risk factors include donor and recipient age,
`donor-recipient sex mismatch (female donorto malerecipient),
`donorparity and allosensitization, disease stage and intensity
`ofconditioning (for acute GVHD). Acute GVHD isa powerful
`predictor of chronic GVHD risk [18].
`Measures to reduce GVHD risk would therefore include
`improvements in donorselection, improved HLA matching, as
`well as reduced intensity conditioning where possible. However,
`other trends, such as the increased use ofdonor PBSCsas a source
`of stem cells, extending alloSCT to older/sicker patients and the
`use of alternative donors (haploidentical and HLA-mismatched
`donors), suggest that GVHD control will remain a significant
`issue for the foreseeable future.
`
`112
`
`Bilirubin 2-2.9 mg/dl
`
`Diarrhea 500-1000cc/d or biopsy-proven upper GI
`involvement
`
`Bilirubin 3-6 mg/dl
`
`Bilirubin 6.1-15 mg/dl
`
`Bilirubin > 15 mg/dl
`
`None
`Stage 1 or
`
`Stage 2 or 3 or
`Stage 4
`
`Diarrhea 1000-1500cc/d
`
`Diarrhea 1500-2000cc/d
`
`Diarrhea > 2000 cc/d or severe abdominal pain with or
`without ileus
`
`None
`
`Stage 1
`
`Stage 2-4
`
`Etiopathogenesis of GVHD
`The etiology of GVHD is complex, but Billingham’s criteria
`still apply [19]. First, the graft must contain immunologically
`competent cells (T lymphocytes and possibly B lymphocytes).
`Second, the recipient must be incapable of rejecting the trans-
`plantedcells (achieved by conditioning chemotherapyorradia-
`tion). Third, the recipient must express tissue antigens that are
`not present in the donor (major or minor histocompatibility
`mismatch).
`Ourcurrent understanding ofacute GVHD,although incom-
`plete, is better than that of chronic GVHD.In part, this is due to
`the better availability of mouse models of acute GVHD.Broadly
`however, both forms of GVHD are believed to be caused by
`similar alloimmune responses that also underlie the beneficial
`graft-versus-leukemia (GVL) effect. Maintaining control of
`GVHD,while enabling the curative GVL response remains the
`holy grail of allorransplantation.
`The development of acute GVHD is frequently divided into
`three phases (Ficurr 1):
`
`* Tissue damage, owing to underlying disease, infections and
`conditioning regimentoxicity, resulting in leakage ofbacterial
`lipopolysaccharides across the damaged gut epithelium and a
`‘cytokine storm’ with the production of inflammatorycytok-
`ines, such as TNF-a, and IL-1 by injured cells, resulting in
`secondary changes in expression of adhesion molecules, MHC
`antigens and chemokines, which can act as danger signals
`and activate residual host and donor antigen-presenting cells
`{APCs) [20-24]. APC activation can occur via both Toll-like
`receptor (TLR) and non-TLR (e.g., nucleotide-binding
`oligomerization domain [NOD]) pathways(25.26);
`
`Donor T-cell activation, cytokine release, proliferation and
`tissue localization occurs in the context of the proinflamma-
`tory post-transplant milieu and after alloantigen presentation
`and costimulation by APCs (donor or host) [27-30];
`
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`|
`
`Current &future approachesforcontrolof graft-versus-hostdisease
`
` Table 2. Definite and probable manifestations of chronic graft-versus-host disease.
`
`Skin
`
`Mucous membranes
`
`GI tract
`
`Liver
`
`Scleroderma (superficial or fasciitis), lichen planus,
`vitiligo, scarring alopecia, hyperkeratosis pilaris,
`contractures from skin immobility, nail bed dysplasia
`
`Lichen planus, noninfectious ulcers, corneal erosions/
`noninfectious conjunctivitis
`
`Esophageal strictures, steatorrhea
`
`None
`
`GU tract
`Musculoskeletal/serosa
`
`Vaginal stricture,lichen planus
`
`Nonseptic arthritis, myositis, myasthenia, polyserositis,
`contractures from joint immobilization
`
`Hematologic
`
`None
`
`Lung
`
`Bronchiolitis obliterans
`
`GI: Gastrointestinal; GU: Genitourinary; GVHD: Graft-versus-host disease.
`
`* The effector phase of GVHD target organ damageinvolves a
`complex interaction of cytokine and cellular effectors, Cyto-
`toxic T lymphocytes (CTLs), both CD4" and CD8’, are the
`major cellular effectors of GVHD and cause cell death by a
`variety of pathways, such as Fas—Fas ligand (FasL), TNF recep-
`tor (TNFR)-like death receptors (e.g., TRAIL and TWEAK)
`and perforin—granzyme[31-36]. Inflammatory cytokines, such
`as TNF-a and IL-l, synergize with CTLs and can also act
`directly to promote tissue injury and inflammation in GVHD
`target organs [37-40].
`
`Eczematoid rash, dry skin, maculopapular rash, hair
`loss, hyperpigmentation
`
`Xerostomia, keratoconjunctivitis sicca
`
`Anorexia, malabsorption, weight loss, diarrhea,
`abdominal pain
`
`Elevation of alkaline phosphatase, transaminitis,
`cholangitis, hyperbilirubinemia
`
`Noninfectious vaginitis, vaginal atrophy
`Arthralgia
`
`Thrombocytopenia, eosinophilia, autoimmune
`cytopenias
`
`Bronchiolitis obliterans with organizing pneumonia,
`interstitial pneumonitis
`
`after alloSCT [59-1]. Similarly, polymorphisms in the non-TLR
`(NOD) pathway of adaptive immuneactivation can impact
`GVHD risk [62]. Genes inyolved in drug metabolism have also
`been linked to toxicity and GVHD after alloSCT [e3,64]. Finally,
`genes with onlyindirect associations with immuneactivity have
`also been linked to GVHD (és-67]. Both donor and recipient
`polymorphismsare often relevant with regards to GVHD risk,
`as in the case of IL-10 [eg].
`There is increasing awareness ofthe role of additional cellular
`subsets in GVHD:
`
`¢ Naive and memoryT cells: naive (CD62L") T cells, but not
`memory (CD62L))T cells, are often considered to have allore-
`active potential that can result in acute GVHD [69,70]. However,
`contrasting recentdataalso suggest a role for alloreactive mem-
`otyT cells and their precursor stem cells in the development of
`GVHD [71,72];
`
`Based on their cytokine expression pattern, there are at least
`two types of T helper (Th) effector cells involved in GVHD:
`Thl and Th2 cells. Th cells generate IL-2, TNF-a and IFN-¥,
`while Th2 cells produce IL-4 and IL-10. While the ‘cytokine
`storm’ phase of GVHD, which is amplified by Th1 cytokines,
`correlates with the development of acute GVHD, cytokines
`that polarize donor T cells to Th2 (e.g., granulocyte colony-
`stimulating factor [G-CSF], IL-4 and IL-18) can reduce acute
`GVHD [ai-44], However, this model may be an oversimplifica-
`tion, as Thl and Th2 subsets can each cause injury to distinct
`GVHD target organs in some mouse models of acute GVHD [as].
`Additional complexities involve possible roles for newly identi-
`fied Th17 cells in GVHD and the interaction between Th17
`effector cells and peripheral regulatory T cells (Tregs), given
`their alternate developmentalfates from commonnaive precursor
`T cells [46-48].
`Additionally, genetic polymorphismsthar lead to altered
`cytokine expressionlevels (e.g., IL-6, IL-10 and TNF-a) have
`also been linked to differences in acute and chronic GVHD
`incidence [49-58]. Furthermore, polymorphismsinvolving natural
`* NKTcells: host NKT cells also have immune suppressive
`killer (NK) cell receptor/ligand complex, collectively termed
`effects that can control GVHD in an IL-4-dependentfashion
`the killer immunoglobulin-like receptor family (KIR), have
`[30,81]. Human clinical data suggest that enhancing recipient
`been linked to differences in both GVHD and relapse rates
`
`* Tregs: CD4'CD25' FoxP3' Tregs from the donor have been
`shown to suppress the expansion of alloreactive donor T cells
`and the development of GVHD, without abrogating GVL in
`this MHC-mismatched murine model [73]. IL-2, initially iden-
`tified as a lymphocyte growth factor and thoughtprimarily to
`promote effector T-cell responses in vivo, is now identified as
`acytokinecritical for the development, expansion and activity
`of ‘regs [74,75]. In humans, FoxP3 mRNAlevels (considered a
`relatively specific marker for Tregs) wassignificantlydecreased
`in patients with GVHD [76,77]. The expression ofthe cell sur-
`face marker CD62L wasalso found to becritical for the ability
`of donor Tregs to control GVHD [73,79];
`
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`
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`

`Koreth & Antin
`
`(I) Recipient conditioning
`tissue imaging
`
`|
`
`Small
`intestine
`
`aN ees
`IL-1
`
`Target cell
`apoptosis
`
`(II) Donor T-cell=\
`
`IL-2
`
`Prophylaxis of GVHD
`Pilot studies omitting GVHD prophylaxis
`indicated an acute GVHD incidence of
`nearly 100% [s9]. Studies using methotrex-
`ate as a single agent for GVHD prophylaxis
`via inhibition of rapidly dividing alloreac-
`tive T cells, indicated an acute grade II-IV
`GVHD rate of over 50%, even in the set-
`ting of HLA-matched sibling donors [90].
`The introduction of a calcineurin inhibi-
`tor, cyclosporine (and subsequently tac-
`rolimus), represented the next advance in
`the prevention of GVHD, with improved
`efficacy in GVHD control compared with
`methotrexate [91-93]. Cyclosporine and tac-
`rolimus bound to cyclophilin or FK-binding
`protein 12 (FKBP12), respectively, inhibit
`calcineurin (a protein phosphatase that is
`calcium- and calmodulin-dependent) and
`prevent the dephosphorylation and nuclear
`translocation of the transcription factor
`nuclear factor of activated T cells (NFAT).
`By blocking NFAT,one of the most impor-
`tant regulators of cytokine gene transcrip-
`tion following T-cell activation, calcineu-
`rin inhibitors block T-cell activation and
`proliferation (94,95). The combination of
`calcineurin inhibitor (cyclosporine) and
`methotrexate was moreeffective than either
`agentalone, with grade I-IV acure GVHD
`rates of 20-56% after HLA-matched sib-
`ling alloSCT (96,97), Compared with
`cyclosporine, tacrolimus has an improved
`toxicity profile and, more importantly,
`randomized data indicate improved acute
`GVHD prophylaxis in both HLA-matched siblings and unrelated
`donor allotransplants [93,99]. The length of immunosuppressive
`therapy appears to have no role in improving control of chronic
`GVHD. Patients with acute GV HD orbiopsy evidence of subclini-
`cal acute GVHD were randomly assignedto 6 versus 24 months of
`cyclosporine therapy. Therates ofclinical extensive chronic GVHD
`were 39 and 51%, respectively, a nonsignificant difference [100].
`Similarly, the presence or absence ofday 11 methotrexate does not
`likely impact chronic GVHD rates[101.102].
`Corticosteroids, the mainstay of therapy for established acute
`GVHD,do not have a significant role in GVHD prophylaxis.
`Various trials compared prednisone and cyclosporine to the three-
`drug combination ofmethotrexate, cyclosporine and prednisone.
`In one large trial, the acute GVHD rate in the cyclosporine
`and prednisone control arm was 23%, compared with only 9%
`in the three-drug arm of methotrexate, cyclosporine and pred-
`nisone [103]. However, subsequenttrials could not demonstrate
`similarly improved GVHD control, or improved long-term out-
`comes with the three-drug combination, and, currently, steroids
`are not routinely used in GVHD prophylaxis [104].
`
`activation
`
`~S IFN-y
`
`~ NK
`
`Tw sictetol
`
`elea uture Science GroupLtd (2008)
`
`Figure 1, Etiopathogenesis of acute graft-versus-host disease,
`Modified with permission from [245].
`
`NKTcells by total lymphoid irradiation (TLD in conjunction
`with anti-thymocyte globulin-based conditioning similarly
`promoted Th2 polarization and significantly reduced GVHD
`[82]. However, it is important to note that NKTcells are
`heterogeneous and their roles in GVHD are incompletely
`understood;
`
`B cells: traditionally, a major role for B cells and humoral
`immunityin the development of GVHD has not been con-
`sidered. However, recent work suggests that, in the context
`of matched sibling PBSC allotransplantation, the concentra-
`tion of CD20" B cells in the apheresis product may predict
`the development of acure GVHD [33]. Additionally, auto- and
`alloantibodies have been described in chronic GVHD, some
`of which may play a direct role in disease progression (e.g.,
`activating PDGF receptor antibodies) [84-37]. High circulat-
`ing levels of B-cell activation factor at 6-months post-trans-
`plant were a predictor of subsequent chronic GVHD, further
`supporting a role for B-cell dysfunction in chronic GVHD
`[38]. The role of humoral immunity in GVHD remains an
`area of controversy and further investigation.
`
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` Current &future approachesforcontrol of graft-versus-hostdisease|§\=))=) |
`
`Cyclophosphamide has been used post-transplant since the
`1980s for GVHD prevention and act via inhibition of rapidly
`dividing T cells (in a manner similar to methotrexate) [195].
`Stem cells contain high levels of aldehyde dehydrogenase that
`converts the active metabolite 4-hydroxycyclophosphamide to
`an inactive nonalkylating metabolite, thus protecting the stem
`cell from the antiproliferative activity of the agent. Similarly, the
`gutepithelium has high levels of aldehyde dehydrogenasethatis
`protective against excess mucosal toxicity despite prior intensive
`conditioning, Used as a single agent after myeloablative condi-
`tioning in related and unrelated allotransplants, the grade [I-IV
`acute GVHD rate was 41%, with few late infections, attributed
`to the brief duration of immune suppressive therapy [100]. It is
`also currently being evaluated for alternative donor transplants
`(haploidentical donor) [107].
`Mycophenolate mofetil (MMF)isa potent, selective, noncom-
`petitive reversible inhibitor of inosine monophosphate dehydro-
`genase that inhibits the de move pathway ofguanosine nucleotide
`synthesis. It has potent cytostatic effects on lymphocytes (both
`T and B) whose proliferation is dependent on de novo purine
`synthesis. With good oral bioavailability, the optimal dosing
`interval remains uncertain, usually two- to three-times daily.
`It has been used for GVHD prophylaxis in various combina-
`tions (usually with a calcineurin inhibitor + methotrexate), The
`incidence of grade II-IV acute GVHD has ranged between 38
`and 62% [108,109]. In a single-center randomized study, the com-
`bination of cyclosporine plus MMF was associated with faster
`engraftment and reduced mucositis incidence, but with similar
`incidence of acute and chronic GVHD andsurvival comparable
`to cyclosporine plus methotrexate, possibly affected by limited
`sample size and follow-up duration for these secondary end
`points[110], Longer-term use of cyclosporine in combination with
`MMF after RIC alloSCT with matched related donors did not
`impact the rates of acute grade II-IV or chronic GVHD [u1).
`Sirolimus (also called rapamycin) binds uniquely to FKBP12
`and forms a complex with mammalian target of rapamycin
`(mTOR) that interacts with various upstream pathways includ-
`ing PTEN/PI3 kinase/Akt pathway and the Janus kinase path-
`way [112.113]. The sirolimus-mTOR complex inhibits several
`biochemical pathways, resulting in reduction of DNAtranscrip-
`tion/translation, protein synthesis and cell cycle progression,
`whichresults in T-cell immunosuppression [114.115]. Interestingly,
`there is apparentdifferential inhibition ofT-cell subsets, possibly
`involving selective inhibition of Thl cell responses, and sparing
`of Th2 and ‘Treg activity [116-120]. Despite theoretical concerns
`for competition for FKBP binding with calcineurin inhibitors,
`these agents appear to work synergistically, and sirolimus does
`not interact with calcineurin or its downstream effectors [112].
`In contrast to calcineurin inhibitors, sirolimus may also exert
`its immunosuppressive effects through suppression of APC
`activity via a reduction in antigen uptake, cellular processing,
`intracellular signaling and induction of apoptosis [121-123]. The
`combination ofsirolimus and tacrolimus appears more effective
`thansirolimus plus cyclosporine in reducingalloreactive memory
`T-cell production, abrogation of effector CTL induction and
`
`WWW.expert-reviews.com
`
`apoptosis induction [124]. Single-institution clinical studies of
`sirolimus and tacrolimus with and without low-dose methotrex-
`ate for GVHD prophylaxis after myeloablative conditioning with
`cyclophosphamide/total-body irradiation (TBI) indicate excel-
`lent efficacy and acceptable toxicity in the matched related and
`unrelated donor context, with grade [I-IV acute GVHD rates
`of 19 and 23%, respectively[125]. The rates of chronic GVHD,
`however, were not significantly impacted. Similar efficacy in
`acute GVHD control was noted despite omitting low-dose meth-
`otrexate, and toxicity was further reduced (126). Similar low-acute
`GVHD rates were also noted in the context of RIC. Other recent
`single-institution reports indicate concordant as well as variant
`estimates ofsirolimus efficacy for GVHD prophylaxis in the
`myeloablative alloSCT context [127.123]. Sirolimus plus tacroli-
`musis currently being evaluated in a Phase II multi-institution
`context in comparison to methotrexate plus tacrolimus.
`Biologic agents have also been evaluated for GVHD prophy-
`laxis. Jn vivo T-cell depletion with horse- or rabbit-derived poly-
`clonal antithymocyte globulin (ATG) has been evaluated for
`prevention of GVHD,as initially proposed by Ramseyet al. [129].
`Such agents administered pre- and peritransplant can simultane-
`ously target host and donor T cells to control both graft rejection
`and GVHD [130-132]. However, additional cellular components,
`such as B cells, NK cells and APCs, can also be affected by
`polyspecific antibodies. Their use does appear to reduce the inci-
`dence of chronic GVHD and chronic lung dysfunction, with
`improved late transplant-related mortality [133]. Whether the
`reduction in chronic GVHD is also associated with increased
`disease relapse remainsto be determined. Higher doses of rabbit
`ATG (thymoglobulin) are associated with increased infections
`that can abrogate its positive impact on GVHD [134]. TLI in
`conjunction with ATG-based conditioning also significantly
`reduced GVHD [2].
`Monoclonal antibodies, such as alemtuzumab (Campath-1H;
`anti-CD52), are widely used for i# vivo GVHD prophylaxis.
`It has been found to reduce GVHD and nonrelapse mortality
`after related and unrelated transplants, and can also facilitate
`engraftment [135]. Monoclonal antibodies targeting the IL-2
`receptor (CD25) may also show benefit [136]. However, IL-2
`is also critical for Treg development, expansion and activity,
`hence IL-2 targeting in GVHD may have the unintended
`consequence of impairing Tregs that are important to control
`GVHD [74,75]. Low-dose IL-2 is currently being evaluated for
`GVHD prophylaxis. Some biologic agents that may have activ-
`ity in established active GVHD,such as IL-1 antagonists and
`ricin-conjugated CD5 antibody, do not show benefit in the
`prophylactic setting (137-141). Interestingly, rituximab, a mono-
`clonal CD20 antibodythat depletes B cells, may independently
`decrease acute GVHD risk [142]. It is also being evaluated for
`the prophylaxis of chronic GVHD.
`in vitro T-cell depletion (TCD) has also been attempted to
`control GVHD,with some success in controlling acute (and pos-
`sibly chronic) GVHD. However, in a randomized study compar-
`ing GVHD prophylaxis with approximately 1-log TCD (with
`monoclonal antibody T10B9 targeting the T-cell receptor) plus
`
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` oe
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`cyclosporine versus methotrexate and cyclosporine, improved
`acute GVHD control did not lead to improvement in long-term
`survival, and disease relapse and infection risk was significantly
`increased after T-cell depletion [16,143]. In an attempt to circum-
`vent problems associated with global TCD,selective depletion
`strategies focused on [T-cell subsets (e.g., CD4*, CD6* and CD8*
`T cells) have been utilized, with limited success [144-146]. Orher
`studies have combined TCD and scheduled DLI post-alloSCT,
`to improve relapse rates and outcomes after TCD, with mixed
`results (147,148). In an alternative strategy to induce anergy to donor
`alloantigens, a smalltrial utilized costimulation blockade of HLA
`haploidentical donorT cells by ex vive incubation with CTLA4
`antibody and donor APCs with some reported success [149].
`Proteasomeinhibition may have a role in GVHD control. The
`transcription factor NF-«B plays an importantrole in cytokine
`signaling and the generation of cell-mediated immuneresponses.
`In addition, the proteasome has been shown to play a critical role
`in T-cell activation, proliferation and apoptosis, largely through
`NF-«B activation [150-152]. In addition to direct cytotoxic effects,
`the proteasome inhibitor bortezomib demonstrates immuno-
`modulatory effects through NF-«B [153]. It can attenuate TLR4-
`mediated APC activation, with reduced cytokine production and
`immunostimulatoryactivity [154]. Additionally, in the allogeneic
`setting, bortezomib preferentially and specifically depletes allore-
`active T lymphocytes [155]. In murine models of GVHD,bort-
`ezomibearly after stem cell infusion protected against GVHD
`without impairing engraftment[156,157]. Phase I and II trials for
`prevention and treatment of acute GVHD are ongoing, with
`interesting preliminary results [158].
`Additional agents that haye efficacy in the treatment of estab-
`lished acute GVHD are also being evaluated for primary GVHD
`prophylaxis. Examples include pentostatin and etanercept (dis-
`cussed later). Novel approaches include blocking lymphocyte
`migration to GVHD target organs using chemokine blockade
`(although there is significant redundancy in this system, com-
`plicating targeting efforts) and the use of extracorporeal photo-
`pheresis, which mayalter host antigen presentation and enhance
`Tregs for GVHD control[159-162], Ursediol, utilized for control
`of hepatotoxicity and treatment-related mortality (TRM) peri-
`transplant, was reported to also control severe acute GVHD [163].
`However, a meta-analysis confirmed the hepatotoxic and TRM
`benefit of ursodiol, but did not note improved GVHD control
`[164], Thalidomide was evaluated for chronic GVHD prophylaxis
`ina Phase III trial, with negative impact on mortality and chronic
`GVHD incidence [165]. Revlimid® or newer congeners may be
`more useful. Attempts to prevent thymic atrophy and associated
`chronic GVHD with thymic tissue implants, thymic epithelial
`cells or thymic hormones have not hadpositive results [166,167].
`
`Treatment of established GVHD
`In patients with established acute GVHD,the goal of therapy is
`to achieve rapid control, since the probability of survival depends
`upon theinitial stage of GVHD atpresentation and response to
`therapy [168-170], Long-term survival of patients with grade 0—-I
`acute GVHD is 50%, while long-term survival of those with
`
`116
`
`grade IV acute GVHD is as low as 11%[168]. Response to therapy
`is a key predictor of outcome, as mortality in acute grade J-IV
`GVHD is lowest in those with a complete response to initial
`therapy [169,171,172]. Corticosteroids are lympholytic and inhibit
`inflammatory cytokine cascades. Other agents have been uti-
`lized as first-line therapy, however none have proven superior to
`corticosteroids [169,173]. Corticosteroids also remain the primary
`front-line therapy for chronic GVHD,often in combination with
`a calcineurin inhibitor, as discussed later.
`
`First-line therapy of GVHD
`Corticosteroids (typically prednisone or methylprednisolone)
`dosed at approximately 2 mg/kg/day are the standard therapy
`for acute grade I-IV GVHD [174.175]. After single-agent steroid
`therapy, response rates were approximately 50% [169,171]. Higher
`doses have not been associated with improvedresponserates. Ina
`prospective randomized study comparing methylprednisolone at 2
`versus 10 mg/kg/day in patients with acute grade I-IV GVHD,
`response rates, TRM, GVHD progression and overall survival
`were similar [176]. TRM andlong-term survival were significantly
`improved in patients with early acute GVHD response that per-
`mitted steroid taper by day 5 of therapy [172]. In order to reduce
`the toxicities of prolonged systemic steroids, adjuvant topical ster-
`oids have been evaluated. In one randomized study, prednisone
`with and without oral nonabsorbable steroids (enteric-coated
`beclomethasone) were evaluated for therapy of gastrointestinal
`acute GVHD.Prednisone taper wasinitiated on day 10 if clinical
`response occurred. Durable responses and day 200 mortality were
`improved in the beclomethasone plus prednisone arm [177].
`The limited response to systemic steroids alone has prompted
`evaluation ofadditional immunosuppressive agents in the initial
`therapy of GVHD, This strategy has had only limited success,
`given the increased risks of infection and TRM. ATGis the most
`widely studied in this setting. Initial studies of upfront therapy
`with ATG plus steroids reported impressive response rates of
`67-80% [178.179], However, in a randomized study,initial therapy
`of acute grade I-IV GVHD with prednisone with and without
`ATG failed to demonstrate an improvementin response rates or
`survival in the ATG arm.Infectious complications were more
`commonin the combination ATG arm [iso].
`Otherbiologic agents have been evaluated in combination with
`steroids for initial therapy of acute GVHD.One randomized study
`evaluated systemic steroids with and without the monoclonal anti-
`body daclizumab that targets CD25 (the IL-2 receptor a-chain)
`present on activated T cells, dosed at 1 mg/kg on days | and 4 and
`weekly thereafter. Overall response rates were similar in the two
`groups, but survival at 100 days and 1 year wasinferiorin the dacli-
`zumab plus steroid group [11]. Similar lack of benefit was noted
`in a randomized study evaluating prednisone and cyclosporine
`with and without another monoclonalantibodytargeting the IL-2
`receptor (BT'563) [182]. CD5, found on the majority ofT cells, acts
`as a costimulation molecule to regulate signaling via the T-cell
`receptor. A randomized trial utilizing a CD5-specific immuno-
`toxin or placebo in combination with methylprednisolone found
`improved early response of acute GV HD in the immunoconjugate
`
`Expert Rew, Hematol. 1(1), (2008)
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`Current &future approachesforcontrol of graft-versus-hostdisease|§\=))=) |
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`arm, but comparable long-term outcomes [140]. The TNF-a. inhibi-
`tor etanercept in combination with corticosteroids plus tacrolimus
`demonstrated superior acute GVHD control in comparison to a
`historical cohort treated with steroids alone, in a small study that
`was recently updated (133,134).
`Currently, none of these agents have displaced corticosteroids
`as upfront therapy for acute GVHD,butthere is significant
`interest in finding better therapies for initial treatment of acute
`GVHD.Adjunctive agents that are currently being evaluated in
`an ongoing randomized trial by the Bone Marrow Transplant
`Clinical Trials Network include etanercept, denileukin diftitox,
`mycophenolate mofetil and pentostatin, each in combination
`with corticosteroids.
`Corticosteroids are also the mainstay of therapy for chronic
`GVHD. Other single agents are associated with a low response
`rate, Currently, there is no standard second-line therapy for
`chronic GVHD and therapy typically consists of prolonged
`administration of a corticosteroid combined with other immu-
`
`nosuppressive medications, such as calcineurin inhibitors
`(cyclosporine or tacrolimus). In a randomized trial compari