`
`For reprin t orders, piease contact reprin ts@expert—reviews.com
`
`EXPERT
`I REVIEWS
`
`Current and future approaches
`for control of graft—versus-
`host disease
`
`Expert Rev. Hematoi, 1(1). 111—128(2008)
`
`John KorethT and
`
`Joseph H Antin
`*Author for correspondence
`Division of Hemaroiogic
`Maiignancies, Dana Farber
`Cancer institue, 44 Binney
`Street, Boston, MA 0215, USA
`Tel: +i 63‘? 632 3470
`Fax: +1 61'? 632 53'68
`john_koreth@dfci.harvard,edu
`
`Graft-versus-host disease (GVHD), both acute and chronic, remains one of the major barriers
`to improving outcomes after allogeneic 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 memory T cells, regulatory T cells, natural killer 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 is still 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
`
`Kevwonos: allogeneic stem cell transplantation I 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) remains the most frequent complication
`after alloSCT.
`
`Clinically, GVHD was categorized as ‘acute’
`and ‘chronic’ based on time ofpresentation. Any
`GVHD before day 100 was known as ‘acute’,
`and after day 100 it was known as ‘chronic'. The
`severity of GVHD was graded: acute GVHD
`was categorized as grade I—[V by modified
`Glucksberg criteria (A—D by the International
`Bone Marmw Transplant Registry index) (Tm: 1}
`[1.2]; chronic GVl-ID was commonly categorized
`as limited or extensive [3]. Based on these criteria,
`grade II—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 transplant recipi—
`ents. Chronic GVHD can affect up to 60% of
`
`recipients who survive beyond 100 days after
`matched donor alloSCT.
`
`While the simplicity ofthe 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 (DLI), 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 GHVD into classic chronic
`
`and overlap syndrome [5]. Classic acute GVHD
`is characterized bya maculopapular erythematous
`skin rash, gaStrointestinal symptoms or cholestatic
`hepatic abnormalities occurring within 100 days
`of alloSCT or DLl,while late acute GVl-ID pres—
`ents similarly beyond 100 days after alloSCT 0r
`DLI. Classic chronic GVHD consists solely of
`manifestations ascribable to chronic GVHD
`(without acute GVHD features) (Tm: 2), while
`overlap syndrome has clinical features of both
`acute and chronic GVHD occurring together.
`
`www.9xpart-review3.com
`
`10.1586i17474086i1.1.111
`
`© 2008 Expert Reviews Ltd
`
`ISSN 1:47—40:55
`
`111
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`| Review
`
`Gut Organ stage Skin'
`
`Table 1. Modified Glucksberg criteria for acute graftrversusrhost disease grading.
`Liver
`
`1
`
`2
`
`3
`
`4
`
`Rash < 25%
`
`Bilirubin 2-2.9 mgfdl
`
`Diarrhea SUD-iooflccrd or biopsy-proven upper GI
`involvement
`
`Rash 25—50%
`
`Rash 3‘ 50%
`
`Generalized erythroderma with
`bullae
`
`Bilirubin 3-6 mgfdl
`
`Bilirubin 61—15 mg/dl
`
`Bilirubin > i5 mg/dl
`
`Diarrhea iODD—lSODcc/d
`
`Diarrhea lSOO—ZOOOCC/d
`
`Diarrhea > 2000 cc/d or severe abdominal pain with or
`without ileus
`
`Overall grade
`|
`N
`
`Stage 1 or 2
`Stage 3 or
`
`-
`III
`Stage 4 or
`IV
`'Use 'rule of nines' to determine body surface area
`Data from [I].
`
`Risk factors for GVHD
`The risk factors for GVHD include:
`
`None
`Stage 1 or
`
`Stage 2 or 3 or
`Stage 4
`
`None
`
`Stage 1
`
`Stage 2—4
`
`0 Donor—recipient match at the major histocompatibility com-
`plex (MHC) loci, for instance, HLA class I (HLA—A, —B and
`-C) and class II (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 [6710];
`
`0 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];
`
`0 T—cell dose: compared with T-ceil 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 [IT];
`
`0 Additional risk factors include donor and recipient age,
`donor—recipient sex mismatch (female donor to male recipient),
`donor parity and allosensitization, disease stage and intensity
`ofconditioning (for acute GVHD). Acute GVHD is a powerful
`predictor of chronic GVHD risk [18].
`Measures to reduce GVHD risk would therefore include
`
`improvements in donor selection, improved HLA matching, as
`well as reduced intensity conditioning where possible. However,
`other trends, such as the increased use ofdonor PBSCs as a source
`
`of stem cells, extending aiioSCT to older/sicker patients and the
`use of alternative donors (haploidentical and HLArmismatched
`donors), suggest that GVHD control will remain a significant
`issue for the foreseeable future.
`
`"2
`
`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-
`planted cells (achieved by conditioning chemOtherapy or radia—
`tion]. Third, the recipient must express tissue antigens that are
`not present in the donor (major or minor histocompatibility
`mismatch).
`
`Our current understanding ofacute GVHD, although incom-
`plete, is better than that ofch ronic GVH D. 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
`gtaft-vetsus-leukemia (GVL) effect. Maintaining control of
`GVH D, while enabling the curative GVL response remains the
`holy grail of allotransplantation.
`The development of acute GVHD is frequently divided into
`three phases {Flaunt 1):
`
`0 Tissue damage. owing to underlying disease, infec1ions and
`conditioning regimen toxicity, resulting in leakage of bacterial
`lipopolysaccharides across the damaged gut epithelium and a
`‘cytokine storm1 with the production of inflammatory cytok—
`ines, such as TNF—ot, and IL—1 by injured cells, resulting in
`secondary changes in expression ofad hesion 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 [NODD pathways [25.26];
`
`' Donor T—cell activation, cytokine release, proliferation and
`tissue localization occurs in the context of the proinflamma-
`torypost—rransplant milieu and after alloantigen presentation
`and costimulation by APCs (donor or host) [27730];
`
`Expert Rat). Hemamt'. 1(1). (EUOS)
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`
`Current & luture approaches for control or grott-versus-hosl disease
`
` Table 2. Definite and probable manifestations of chronic grafteversusehost disease.
`
`Skin
`
`Mucous membranes
`
`GI tract
`
`Liver
`
`Scleroderma (superficial or iasciitis), 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
`
`Eczematoid rash, dry skin, maculopapular rash, hair
`loss, hyperpigmentation
`
`Xerostomia, keratoconjunctivitis sicca
`
`Anorexia. malabsorption. weight loss. diarrhea.
`abdominal pain
`
`Elevation of alkaiine phosphatase, transaminitis,
`cholangitis, hyperbilirubinemia
`
`Noninfectious vaginitis, vaginal atrophy
`Arthralgia
`
`Thrombocytopenia, eosinophilia, autoimmune
`cytopenias
`
`Bronchiolitis obliterans with organizing pneumonia,
`interstitial pneumonitis
`
`Lung
`
`Bronchiolitis obliterans
`
`GI: Gastrointestinal; GU: Genitourinary; GVHD: Grait-versus-hostdisease,
`
`' The effector phase of GVHD target organ damage involves 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 ofpathways, 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-Ot and lL-l, synergize with CTLs and can also act
`directly to promote tissue injury and inflammation in GVHD
`target organs [37—40].
`
`Based on their cytokine expression Pattern, there are at least
`two types ofT helper (Th) effector cells involved in GVHD:
`Th1 and Th2 cells. Th] cells generate IL-2, TNF-Gt and lFN-‘y,
`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 [41—44]. However, this model may be an oversimplifica-
`tion, as Th1 and Th2 subsets can each cause injury to distinct
`GVHD target organs in some mouse models ofacute GVHD [45].
`Additional complexities involve possible roles for newly identi—
`fied Th17 cells in GVHD and the interaction between Thl7
`
`effector cells and peripheral regulatory T cells (Tregs), given
`their alternate developmental fates from common naive precursor
`T cells [46-43].
`
`Additionally, genetic polymorphisms that lead to altered
`cytokine expression levels (e.g., IL-6, IL-10 and TNF-ot) have
`also been linked to differences in acute and chronic GVHD
`
`incidence [49-53]. Furthermore, polymorphisms involving natural
`killer (NK) cell receptorlligand complex, collectively termed
`the killer immunoglobulin-like receptor family (KIR), have
`been linked to differences in both GVHD and relapse rates
`
`after alloSCT [39—61]. Similarly, polymorphisms in the non‘TLR
`(NOD) pathway of adaptive immune activation can impact
`GVHD risk [62]. Genes involved in drug metabolism have also
`been linked to terxicityand GVHD after alloSCT [63,64]. Finally,
`genes with only indirect associations with immune activity have
`also been linked to GVHD [65-67]. Both doneir and recipient
`polymorphisms are often relevant with regards to GVHD risk,
`as in the case of IL-10 [63].
`There is increasing awareness of the role of additional cellular
`subsets in GVHD:
`
`' Naive and memory T cells: naive (CD62L‘) T cells, but not
`memory (CD62L‘) T cells, are often considered to have allore—
`active porentia] that can result in acute GVHD [69,70]. However,
`contrasting recent data also suggest a role for alloreactive mem—
`oryT cells and their precursor stem cells in the development of
`GVHD [71,72];
`
`' 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-Z, initially iden-
`tified as a lymphocyte growth factor and thought primarily to
`promOte effector T—cell responses in viva, is now identified as
`a cytokine critical for the development, expansion and activity
`of Tregs [74,75]. In humans, Fox P3 mRNA levels (considered a
`relatively specific marker for Tregs) was significantly decreased
`in patients with GVHD [76,77]. The expression of the cell sur—
`face marker CD62L was also found to be critical for the ability
`of donor Tregs to control GVHD [73.79];
`
`' NK T cells: host NKT cells also have immune suppressive
`effects that can control GVHD in an IL-4‘dependent fashion
`[80.81]. Human clinical data suggest that enhancing recipient
`
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`Koreth 8: Antin
`
`Host
`iissues
`
`(I) Recipient conditioning
`tissue imaging
`
`
`
`intestine
`
`TNF-tt
`IL-1
`
`Target ceii
`apoptosis
`
`{Ill} Dono' T—cell
`activation
`
`x... lFN—r
`ILA2
`
`q. NK
`
`(Iii) Eifeciot
`
`Export Rot: .' tori:-
`
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`l
`
`Prophylaxis of GVHD
`Pilot studies omitting GVHD prophylaxis
`indicated an acute GVHD incidence of
`
`nearly 100% [39]. Studies using methonex—
`ate as a single agent for GVHD prophylaxis
`via inhibition of rapidly dividing alloreac-
`tive T cells, indicated an acute grade [l—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 (FKBPlZ), 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 (N FAT).
`By blocking NEAT, one of the most impor-
`tant regulators ofcytoltine gene transcrip—
`tion following T—cell activation, calcineu—
`tin inhibitors block T~cell activation and
`
`proliferation mass]. The combination of
`calcineurin inhibitor (cyclosporine) and
`methot rexate was more effective than either
`
`agent alone, with grade ll—lV acute GVHD
`rates of20-56% after HI.A-matched sib-
`
`Figure 1. Etiopathogenesis of acute graft-versus-host disease.
`Modified with permission from [215].
`
`N KT cells by total lymphoid irradiation {TLl} in conjunction
`with anti—thymocyte globulin—based conditioning similarly
`promored Th2 polarization and significantly reduced GVHD
`[32]. However, it is important to note that NKT cells are
`heterogeneous and their roles in GVHD are incompletely
`understood;
`
`0 B cells: traditionally, a major role for B cells and humoral
`immunity in the development of GVHD has nor been con-
`sidered. HOwever, recent work suggests that, in the context
`ofmatched sibling PBSC allottansplantation, the concentra-
`tion of CD20+ B cells in the apheresis product may predict
`the development ofacute GVHD [33]. Additionally, auto— and
`alloantibodies have been described in chronic GVH D, some
`of which may play a direct role in disease progression (e.g.,
`activating PDGF receptor antibodies) [Sit—3?]. High circulat-
`ing levels of B-cell activation factor at 6-months post-trans:
`plant were a predictor ofsubsequent 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.
`
`"4
`
`ling alloSCT [96.97]. Compared with
`cyclosporine, tacrnlimus has an improved
`toxicity profile and, more importantly,
`randomized data indicate improved acute
`GVHD prophylaxis in both Hl.A-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 GVHD or biopsy evidence of subclini-
`cal acute GVHD were randomly assigned to 6 versus 24 months of
`cyclosporine therapy. The rates of clinical extensive chronic GVH D
`were 39 and 51%, respectively, a nonsignificant difference [100].
`Similarly, the presence or absence ofday 1] methotrexate does not
`likely impact chronic GVHD rates [101.102].
`CUFIiCOSIerOidS, 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, subsequent trials could not demonstrate
`similarly improved GVHD control, or improved long-term out-
`comes with the th tee-drug combination, and, currently, steroids
`are not routinely used in GVHD prophylaxis [10a].
`
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` Current&1u1ure approaches torcontrol otgrofl-versus-hosldlsease Review I
`
`Cyclophosphamide has been used post—transplant since the
`19805 for GVHD prevention and act via inhibition of rapidly
`dividing T cells (in a manner similar to methotrexate) [105].
`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 ofthe agent. Similarly, the
`gut epithelium has high levels of aldehyde dehyd rogenase that is
`protective against excess mucosa] toxicity despite prior intensive
`conditioning. Used as a single agent after myeloablative condi—
`tioning in related and unrelated allonansplants, the grade II—IV
`acute GVHD rate was 41%, with few late infections, attributed
`to the brief duration of immune suppressive therapy [106]. It is
`also currently being evaluated for alternative donor transplants
`(haploidentical donor) [107].
`Mycophenolate mofetil (MMF) is a potent, selective, noncom—
`petitive reversible inhibitor of inosine monophosphate dehydro-
`genase that inhibits the dc mum pathway ofguanosine nucleotide
`synthesis. It has potent cytostatic effects on lymphocytes (both
`T and B) whose proliferation is dependent on de nova 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 1 methotrexate). The
`incidence of grade II—IV acute GVHD has ranged between 38
`and 62% [105,109]. 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 GVH D and survival comparable
`to cyclosporine plus methouexate, 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 [111].
`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 [111113]. The sirolimus—mTOR complex inhibits several
`biochemical pathways, resulting in reduction of DNA transcrip-
`tionftranslation, protein synthesis and cell cycle progression,
`which results in T—cell immunosuppression [114,115]. Interestingly,
`there is apparent differential inhibition ofT—cell subsets, possibly
`involving selective inhibition of Th1 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 of sirolimus and tacrolimus appears more effective
`than sirolimus plus cyclosporine in reducing alloreactive memory
`T‘cell production, abrogation of effector CTL induction and
`
`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
`cyclophosphamidehowl—body irradiation (TBI) indicate excel—
`lent efficacy and acceptable toxicity in the matched related and
`unrelated donor context, with grade II—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 ofRIC. Other recent
`
`single—institution reports indicate concordant as well as variant
`estimates of sirolimus efficacy for GVHD prophylaxis in the
`myeloablative alloSCT context [127,123]. Sirolimus plus tacroli-
`mus is currently being evaluated in a Phase III multi-institution
`context in comparison to methotrexate plus tacrolimus.
`Biologic agents have also been evaluated for GVHD prophy-
`laxis. In vim T— cell depletion with horse— or rabbit—derived poly—
`clonal antithymocyte globulin [ATCD has been evaluated for
`prevention ofGVHD, as initially proposed by Ramsey and. [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 remains to 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 [32].
`Monoclonal antibodies, such as alemtuzumab (Campath-IH;
`anti-CD52), are widely used for in viva 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 lL-1 antagonists and
`ricin-conjugated CD5 antibody, do not show benefit in the
`prophylactic setting [137—141]. IntereStingly, rituximab, a mono—
`clonal CDZO antibody that depletes B cells, may independently
`decrease acute GVHD risk [142]. It is also being evaluated for
`the prophylaxis of chronic GVHD.
`In vim: T—cell depletion (TCD) has also been attempted to
`control GVH D, with some success in controlling acute (and pos—
`sibiy chronic) GVHD. However, in a randomized study comparr
`ing GVHD prophylaxis with approximately 1-log TCD (with
`monoclonal antibody T10B9 targeting the T-cell receptor) plus
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` | Review
`
`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., CD42 CD6+ and CD 8‘
`T cells]I have been utilized, with limited success [144—146]. Other
`studies have combined TCD and scheduled DLI post—alloSCT,
`to improve relapse rates and outcomes after TCD, with mixed
`results [147,143]. In an alternative strategy to induce anergy to donor
`alloantigens, a small trial utilized costimulation blockade of HLA
`haploidentical donor T cells by ex m’w incubation with CTLA4
`antibody and donor APCs with some reported success [149].
`Proteasome inhibition may have a role in GVHD control. The
`transcription factor NF—KB plays an important role in cytokine
`signaling and the generation ofcell—mediated immune responses.
`In addition, the proteasome has been shown to play a critical role
`in T—cell activation, proliferation and apoptosis, largely through
`NF-KB activation [1507152]. In addition to direct cytotoxic effects,
`the proteasome inhibitor bortezomib demonstrates immuno-
`modulatory effects through NF-KB [153]. It can attenuate TLR4-
`mediated APC activation, with reduced cytokine production and
`immunostimulatory activity [15a]. Additionally, in the allogeneic
`setting, bortezomib preferentially and specifically depletes allore-
`active T lymphocytes [155]. In murine models of GVHD, bort—
`ezomib early 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 [155].
`Additional agents that have 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 may alter host antigen presentation and enhance
`Tregs for GVHD control [159—162]. Ursodiol, 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
`[16:1]. Thalidomide was evaluated for chronic GVHD prophylaxis
`in a Phase III trial, with negative impact on mortality and chronic
`GVI—ID 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 had positive 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 the initial stage of GVHD at presentation and response to
`therapy [163—170]. Long—term survival of patients with grade D—I
`acute GVHD is 50%. while long-term survival of those with
`
`”6
`
`grade IV acute GVHD is as low as 11% [168]. Response to therapy
`is a key predictor ofoutcome, as mortality in acute grade II—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 GVH D, often in combination with
`a calcineurin inhibitor, as discussed later.
`
`First-line therapy of GVHD
`Corticosteroids (typically prednisone or methylprednisolone)
`dosed at approximately 2 mgfkgfday are the standard therapy
`for acute grade IlilV GVHD [174.13]. After single-agent steroid
`therapy, response rates were approximately 50% [16mm]. Higher
`doses have not been associated with improved response rates. In a
`prospective randomized study comparing methylprednisolone at 2
`versus 10 mga'kga'day in patients with acute grade II—IV GVHD,
`response rates, TRM, GVHD progression and overall survival
`were similar [176]. TRM and long-term survival were significantly
`improved in patients with early acute GVHD response that per-
`mitted steroid taper by day 5 of therapy [17-2]. In order to reduce
`the toxicities ofprolonged systemic steroids, adj uvant 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 was initiated on day 10 if clinical
`response occurred. Durable responses and day 200 mortality were
`improved in the beclomethasone plus prednisone arm [17?].
`The limited response to systemic steroids alone has prompted
`evaluation of additional immunosuppressive agents in the initial
`therapy of GVHD. This strategy has had only limited success,
`given the increased risks of infection and TRM. ATG is the most
`widely studied in this setting. Initial studies of upfront therapy
`with ATG plus steroids reported impressive response rates of
`67—80% [1?3,1?9]. However, in a randomized study, initial therapy
`of acute grade II—IV GVHD with prednisone with and without
`ATG failed to demonstrate an improvement in response rates or
`survival in the ATG arm. Infectious complications were more
`common in the combination ATG arm [130].
`Other biologic 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 {it—chain)
`present on activated T cells, dosed at 1 mg}kg on days I and 4 and
`weekly thereafter. Overall response rates were similar in the two
`groups, but survival at 100 days and 1 year was inferior in the dacli-
`zumab plus steroid group [131]. Similar lack of benefit was noted
`in a randomized study evaluating prednisone and cyclosporine
`with and without another monoclonal antibody targeting the IL-2
`receptor {BT563} [132]. CD5, found on the majority of T cells, acts
`as a costimulation molecule to regulate signaling via the T-cell
`receptor. A randomized trial utilizing a CD‘S—specific immuno—
`toxin or placebo in combination with methylprednisolone found
`improved early response of acute GVHD in the immunoconjugate
`
`Expert Rat). Hemdmr'. 1(1). (EUOS)
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`Currenmlurure approaches torcontrol or grott-versus-hosl disease Review I
`
`arm. but comparable long—term outcomes [140]. The TNF—o. inhibi—
`tor etanercept in combination with corticosteroids plus tacrolimus
`demonstrated superior acute GVHD control in comparison to a
`hist0rical 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, but there is significant
`interest in finding better therapies for initial treatment of acute
`GVI—ID. 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 pentosratin, 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 t