bjh
`
`guideline
`
`Diagnosis and management of chronic graft-versus-host
`disease
`
`Fiona L. Dignan,1,2 Persis Amrolia,3 Andrew Clark,4 Jacqueline Cornish,5 Graham Jackson,6 Prem Mahendra,7
`Julia J. Scarisbrick,8 Peter C. Taylor,9 Bronwen E. Shaw1,10 and Michael N. Potter1 on behalf of the Haemato-oncology Task
`Force of the British Committee for Standards in Haematology and the British Society for Blood and Marrow
`Transplantation
`
`1Section of Haemato-oncology, The Royal Marsden NHS Foundation Trust, London, 2St John’s Institute of Dermatology, St Thomas’
`Hospital, London, 3Department of Bone Marrow Transplantation, Great Ormond Street Hospital, London, 4Bone Marrow Transplant
`Unit, Beatson Oncology Centre, Gartnavel Hospital, Glasgow, 5Department of Haematology, Bristol Royal Hospital for Children, Bris-
`tol, 6Department of Haematology, Freeman Road Hospital, Newcastle, 7Department of Haematology, University Hospital Birmingham,
`Birmingham, 8Department of Dermatology, University Hospital Birmingham, Birmingham, 9Department of Haematology, Rotherham
`General Hospital, Rotherham, and 10Anthony Nolan, London, UK
`
`Summary
`
`A joint working group established by the Haemato-oncology
`subgroup of the British Committee for Standards in Haema-
`tology (BCSH) and the British Society for Bone Marrow
`Transplantation (BSBMT) has reviewed the available litera-
`ture and made recommendations for the diagnosis and man-
`agement of chronic graft-versus-host disease (GvHD). This
`guideline includes recommendations for the diagnosis and
`staging of chronic GvHD as well as primary treatment and
`options for patients with steroid-refractory disease. The goal
`of treatment should be the effective control of GvHD while
`minimizing the risk of toxicity and relapse.
`
`graft-versus-host disease,
`Keywords: Chronic,
`management, diagnosis.
`
`transplant,
`
`Summary of recommendations
`
`1 Chronic graft-versus-host disease (GvHD) and overlap
`syndrome should be diagnosed primarily using clinical
`criteria, supported by biopsy when possible. (1B)
`2 Chronic GvHD should be graded as mild, moderate or
`severe according to National Institutes of Health (NIH)
`consensus criteria (Filipovich et al, 2005). (1A)
`All patients with signs or
`symptoms
`suggestive of
`chronic GvHD in one organ should be assessed for
`involvement of other organs. (1A)
`
`3
`
`Correspondence: BCSH Secretary, British Society for Haematology,
`
`100 White Lion Street, London, N1 9PF, UK.
`
`E-mail: bcsh@b-s-h.org.uk
`
`First published online 26 April 2012
`doi: 10.1111/j.1365-2141.2012.09128.x
`
`b'h
`~ British Journal of Haematology
`
`5
`
`7
`
`8
`
`10
`
`11
`
`12
`
`4 Corticosteroids are recommended in the first line treat-
`ment of chronic GvHD. (1A)
`An initial starting dose of 1 mg/kg prednisolone is rec-
`ommended. (1B)
`in the initial
`6 Calcineurin inhibitors may be helpful
`treatment of GvHD as a steroid-sparer. (2C)
`Extracorporeal photopheresis (ECP) may be considered
`as a second line treatment in skin, oral or liver chronic
`GvHD. (1B)
`ECP schedule should be fortnightly-paired treatments
`for a minimum assessment period of 3 months. (1C)
`9 Mammalian target of rapamycin (mTOR) inhibitors are
`suggested as a second line treatment option in refrac-
`tory chronic GvHD. (2C)
`Pentostatin is suggested as a second line treatment
`option in refractory chronic GvHD. (2B)
`Rituximab is
`suggested as a second line treatment
`option in refractory cutaneous or musculoskeletal
`chronic GvHD. (2B)
`Imatinib is suggested as a second line treatment option
`in refractory pulmonary or sclerodermatous chronic
`GvHD. (2C)
`ECP,
`imatinib and rituximab may be considered as
`third line treatment options in chronic GvHD involving
`other organs. (2C)
`The following agents are suggested as third line treat-
`ment options in refractory chronic GvHD: mycopheno-
`late mofetil, methotrexate, pulsed corticosteroids. (2C)
`There is insufficient evidence, at present, to support
`recommendations
`to use
`the
`following agents
`in
`the management of chronic GvHD: cyclophospha-
`mide, mesenchymal stem cells, thalidomide, retinoids,
`alemtuzumab, infliximab, etanercept, clofazimine, alefa-
`cept, daclizumab,
`basiliximab, hydroxychloroquine,
`thoraco-abdominal irradiation. (1C)
`
`13
`
`14
`
`15
`
`ª 2012 Blackwell Publishing Ltd
`British Journal of Haematology, 2012, 158, 46–61
`
`

`

`16
`
`Azathioprine is not recommended in the management of
`chronic GvHD due to the risk of oral malignancy. (1C)
`
`Introduction
`
`Chronic graft-versus-host disease (cGvHD) remains a major
`complication of allogeneic stem cell transplantation and is
`the leading cause of late non-relapse death (Lee et al, 2002).
`The prevalence varies from 25–80% in long-term survivors
`(Baird & Pavletic, 2006). A clear diagnostic and manage-
`ment strategy for cGvHD has been difficult to achieve due
`to the polymorphic nature of the disorder and the paucity
`of evidence for the majority of
`treatment options. The
`National Institutes of Health (NIH) consensus development
`project has tried to address this issue by developing criteria
`for clinical trials in cGvHD (Filipovich et al, 2005; Couriel
`et al, 2006a; Martin et al, 2006; Pavletic et al, 2006; Schultz
`et al, 2006; Shulman et al, 2006). Similarly, the German-
`Austrian-Swiss working party on bone marrow and blood
`stem cell
`transplantation held a consensus conference to
`define clinical management of cGvHD in 2009 and have
`recently published several papers,
`including a summary of
`first- and second-line management of cGvHD (Wolff et al,
`2010, 2011).
`At present there are no UK guidelines on the diagnosis
`and management of cGvHD. T-cell depletion is used widely
`in the UK and this practice may have an impact on the fre-
`quency and pattern of cGvHD and, therefore, management
`guidelines from other countries may be less applicable in this
`setting. This document attempts to provide a summary of an
`evidence-based approach to the diagnosis, staging and man-
`agement of cGvHD in clinical practice. The diagnosis and
`management of acute GvHD is discussed in a separate docu-
`ment (Dignan et al, 2012a) and the organ-specific manage-
`ment and supportive care of patients with GvHD is also
`discussed in a separate document (Dignan et al, 2012b).
`These guidelines are designed to be used together and to
`complement each other in order to provide an evidence-
`based approach to managing this complex disorder.
`
`Methodology
`
`The production of these guidelines involved the following steps:
`
`• Establishment of a working group comprising experts in
`the field of allogeneic transplantation followed by literature
`review to 17th June 2011 including Medline,
`internet
`searches and major conference reports.
`• Development of key recommendations based on random-
`ized, controlled trial evidence. Due to the paucity of
`randomized studies some recommendations are based on
`literature review and a consensus of expert opinion.
`• The GRADE nomenclature was used to evaluate levels of
`evidence and to assess the strength of recommendations.
`
`ª 2012 Blackwell Publishing Ltd
`British Journal of Haematology, 2012, 158, 46–61
`
`Guideline
`
`The GRADE criteria are specified in the British Committee
`for Standards in Haematology (BCSH) guideline pack and
`the GRADE working group website. See Appendix I. Fur-
`ther information is available from the following websites:
`
`o http://www.bcshguidelines.com/4_HAEMATOLOGY_
`GUIDELINES.html
`o http://www.gradeworkinggroup.org/index.htm
`
`• Review by the BCSH committees, British Society of Blood
`and Marrow Transplantation (BSBMT) executive commit-
`tee, the UK Photopheresis Society and the UK Paediatric
`Bone Marrow Transplant Group
`• Review by sounding board of
`the British Society for
`Haematology (BSH) and allogeneic transplant centres in
`the UK.
`
`Diagnosis
`
`Historically, cGvHD was defined as occurring more than
`100 d after transplant. The NIH consensus conference pro-
`posed two subcategories for cGvHD, classic and overlap syn-
`drome, based on clinical features rather than time of onset.
`This proposal recognized that classical features of cGvHD
`could occur within 100 d of transplant and that features of
`acute and cGvHD could occur together (Filipovich et al,
`2005). Futhermore, there is now evidence that this classifica-
`tion has clinical validity (Jagasia et al, 2009).
`The consensus conference also identified ‘diagnostic’ and
`‘distinctive’ features of cGvHD. Diagnostic signs are clinical
`features that establish the diagnosis of cGvHD without the
`need for further investigations. Diagnostic manifestations
`include poikiloderma and lichen planus-like features of the
`skin,
`lichen planus in the mouth or genitals, fasciitis and
`joint contractures. Distinctive signs are clinical features not
`associated with acute GvHD but which would be insufficient
`to make the diagnosis of cGvHD unless supported by posi-
`tive biopsy or
`laboratory findings. Distinctive findings
`include skin depigmentation, nail dystrophy, alopecia, xero-
`stomia, mucoceles, ulceration of the mouth, keratoconjuncti-
`vitis
`sicca and myositis. A full
`list of diagnostic and
`distinctive findings is detailed in the first report of the NIH
`consensus conference (Filipovich et al, 2005). Additional
`investigations are helpful
`in confirming the diagnosis of
`cGvHD in patients with distinctive features and excluding
`other conditions, e.g. infection or drug toxicities. The role of
`additional
`investigations is discussed in the organ-specific
`management document of
`these guidelines (Dignan et al,
`2012b).
`The new diagnostic definitions were designed for use in
`clinical trials and have yet to be fully validated in clinical
`practice. A recent report from a German, Austrian and Swiss
`consensus conference reported a high rate of acceptance of
`the new cGvHD subcategories and diagnostic classification
`(Greinix et al, 2011).
`
`47
`
`

`

`Guideline
`
`Recommendation
`
`• Chronic GvHD and overlap syndrome should be diag-
`nosed primarily using clinical criteria, supported by
`biopsy when possible (1B).
`
`Grading
`
`Chronic GvHD was originally staged as limited or extensive dis-
`ease based on the observations in 20 patients in a retrospective
`review (Shulman et al, 1980). The NIH consensus development
`project on criteria for clinical trials in cGvHD has reviewed
`staging of cGvHD (Filipovich et al, 2005). This document pro-
`posed a new clinical scoring system on a four point scale (0–3)
`with 0 representing no involvement, 1 mild involvement (no
`significant impairment of daily living), 2 moderate involvement
`(significant impairment of daily living) and 3 representing
`severe impairment (major disability). Chronic GvHD may then
`be classified as mild, moderate or severe. Patients with involve-
`ment of one or two organs with a score of 1 and no pulmonary
`GvHD are classified as having mild cGvHD. Moderate cGvHD
`is defined as involvement of three organs with a score of 1, at
`least one organ with a score of 2 or pulmonary GvHD with a
`score of 1. Patients who have major disability resulting in a
`score of 3 in any organ or site or patients who have pulmonary
`GvHD scoring 2 or 3 would be classified as having severe
`cGvHD. This classification is discussed in detail in Filipovich
`et al (2005) and has been reviewed by Devergie (2008). It is rec-
`ommended that all patients are scored using the NIH criteria
`(Filipovich et al, 2005) at 3 months following transplant. In
`patients diagnosed with GvHD, restaging using NIH criteria is
`recommended every 3 months.
`
`Prognostic factors
`
`The John Hopkins group showed in multivariate analysis
`that extensive (>50%) skin involvement, a platelet count of
`<100 9 109/l and progressive onset from acute GvHD were
`associated with poor prognosis (Akpek et al, 2001a). More
`recently, Arora et al (2011) reported a cGvHD risk score.
`Ten variables were identified as being significant in terms of
`overall survival and non-relapse mortality: age, prior acute
`GvHD, time from transplantation to cGvHD, donor type,
`disease status at transplantation, GvHD prophylaxis, gender
`mismatch,
`serum bilirubin, Karnofsky score and platelet
`count (Arora et al, 2011).
`
`Recommendation
`
`• Chronic GvHD should be graded as mild, moderate or
`severe according to NIH consensus criteria (Filipovich
`et al, 2005) (1A).
`• All patients with signs or
`suggestive of
`symptoms
`chronic GvHD in one organ should be assessed for
`involvement of other organs (1A).
`
`48
`
`Principles of cGvHD treatment
`
`A multi-disciplinary approach is mandatory. Patients may
`require joint care with specialist teams including the derma-
`tology, ophthalmology, gastroenterology, gynaecology and
`rheumatology teams as well as intensive input from physio-
`therapists and occupational
`therapists. Topical
`treatments
`and supportive agents also have an important role in effec-
`tive management of cGvHD and may be sufficient in those
`patients with mild disease. Detailed organ-specific manage-
`ment including diagnosis, topical treatment and supportive
`care are discussed in a separate document entitled ‘Organ
`specific management and supportive care in GvHD’ (Dignan
`et al, 2012b).
`
`First line systemic treatment for cGvHD
`
`Corticosteroids
`
`The NIH consensus conference recommended systemic treat-
`ment for moderate or severe GvHD (Filipovich et al, 2005).
`Corticosteroids have been used as first
`line treatment
`in
`cGvHD since the 1980s. Their effect is likely to be due to
`lympholytic effects and anti-inflammatory properties (Deeg,
`2007). The standard dose used has been 1 mg/kg in studies
`of steroids alone or in combination with other agents (Sulli-
`van et al, 1988a; Koc et al, 2002). There are no randomized
`studies comparing this dose to higher or lower steroid doses.
`Topical steroids may be used in conjunction with systemic
`steroids and may allow dose reduction in those patients with
`GvHD limited to the skin.
`At present, there is no consistent tapering protocol for ste-
`roid reduction in the UK. The Seattle group have reported
`on an alternate day dosing regimen for tapering steroids.
`This regimen involved using a daily dose of 1 mg/kg for two
`weeks and subsequently tapering to 1 mg/kg on alternate
`days over 4 weeks if cGvHD is stable or improving. The
`initial report (Sullivan et al, 1988a) used this schedule in com-
`bination with ciclosporin. In a recent review, Lee & Flowers
`suggested a similar initial schedule of 1 mg/kg for 2 weeks and
`then reducing the dose by 25% each week, aiming for a dose of
`1 mg/kg on alternate days after 6–8 weeks. In severe GvHD,
`this dose may be maintained for 2–3 months and then tapered
`by 10–20% per month for a total duration of 9 months. An
`alternative regimen is to miss out the period of stable dosing of
`2–3 months and to taper the dose by 10–20% per month until
`a dose of 0·5 mg/kg is reached. A slower steroid taper is
`advised thereafter depending on clinical response (reviewed by
`Lee & Flowers, 2008). Although there are no randomized
`studies comparing an alternate day approach to daily adminis-
`tration of corticosteroids in this setting, it is likely from studies
`undertaken in other patient groups that this approach may
`reduce side effects while maintaining efficacy (Dumler et al,
`1982; Jabs et al, 1996).
`
`ª 2012 Blackwell Publishing Ltd
`British Journal of Haematology, 2012, 158, 46–61
`
`

`

`In patients who are receiving other immunosuppressive
`agents it
`is recommended that steroids are tapered first.
`Other immunosuppressive agents can be tapered one at a
`time over a 3–9 month period with dose reductions every 2–
`4 weeks depending on clinical response (Lee & Flowers,
`2008). The median duration of immunosuppressive therapy
`is 2–3 years (Lee & Flowers, 2008).
`
`Calcineurin inhibitors
`
`Ciclosporin is commonly used in the prophylaxis of GvHD.
`Ciclosporin binds to cyclophilin and prevents generation of
`nuclear factor of activated T cells (NF-AT), which is a
`nuclear factor for initiating gene transcription for lympho-
`kines including interleukin 2 and interferon gamma. This
`action leads
`to suppression of cytokine production and
`subsequent inhibition of T-cell activation (reviewed in Grei-
`nix, 2008). Early reports suggested a possible benefit of ci-
`closporin in the primary treatment of cGvHD (Sullivan
`et al, 1988a). One randomized trial has been performed
`comparing the use of ciclosporin and daily 1 mg/kg pred-
`nisolone to prednisolone alone in the initial management
`of cGvHD. This study included 287 evaluable patients who
`
`Table I. Summary of the major toxicities of cGvHD treatments.
`
`Guideline
`
`had platelet counts >100 9 109/l at the start of treatment.
`The cumulative incidence of transplantation-related mortal-
`ity at 5 years was 17% in the combination arm compared
`to 13% in those patients who received prednisolone alone.
`There was no difference in efficacy as assessed by the need
`for secondary therapy at 5 years (11% vs. 17%) or the
`median interval to discontinuation of
`immunosuppression
`(1·6 vs. 2·2 years). A combination regimen of ciclosporin
`and prednisolone may have a steroid-sparing effect and
`reduce the incidence of
`steroid-associated complications:
`22% of patients in the prednisolone arm developed avascu-
`lar necrosis compared to 13% in the combination arm
`(Koc et al, 2002). These results may not be applicable to
`all types of transplant as this study group had received my-
`eloablative conditioning regimens and had all received bone
`marrow.
`There are limited data on the role of calcineurin inhibitors
`in the treatment of patients with refractory cGvHD. A pro-
`spective study of 17 patients with refractory disease reported
`a response to tacrolimus in six patients (Tzakis et al, 1991).
`In a larger Phase 2 study including 26 evaluable patients with
`cGvHD, a response to tacrolimus was observed in 12 patients
`(Kanamaru et al, 1995). In a single arm, open-label Phase 2
`
`Treatment
`
`Corticosteroids
`
`Calcineurin Inhibitors
`Mycophenolate mofetil
`
`Sirolimus
`
`Thalidomide
`Azathioprine
`Pentostatin
`Methotrexate
`
`Major toxicities
`
`Infection, hypertension, poor glycaemic control, mood swings,
`osteoporosis, weight gain, growth impairment
`Infection, renal impairment, thrombotic microangiopathy, hypertension
`Infection, deranged liver function tests, gastrointestinal disturbance,
`haematotoxicity, relapse
`Thrombotic microangiopathy, hyperlipidaemia, haematotoxicity
`
`Teratogenecity, peripheral neuropathy, constipation, thrombosis, fatigue
`Oral malignancies, pancytopenia
`Infection, pancytopenia
`Deranged liver function tests, cytopenias
`
`Hydroxychloroquine
`Clofazimine
`
`Gastrointestinal, ocular toxicity, rashes
`Skin pigmentation, gastrointestinal, methaemoglobinaemia
`
`Cyclophosphamide
`Extracorporeal photopheresis
`
`Alefacept
`Imatinib
`Rituximab
`Alemtuzumab
`
`Infliximab
`Etanercept
`
`Haematological, infection, urothelial toxicity
`Patients with poor vascular access require indwelling catheter,
`vaso-vagal episodes
`Infection
`Dyspnoea, fluid retention, pancytopenia, deranged liver function
`Infusional reactions/infection, progressive multifocal leucoencepthalopathy
`Infusional reactions/infections especially opportunistic e.g. cytomegalovirus
`
`Infusional reactions/ infection
`Infection
`
`Basiliximab
`Thoraco-abdominal irradiation
`Retinoids
`
`Infection/infusional reactions
`Haematotoxicty
`Teratogenicity, hyperlipidaemia, deranged liver function
`
`ª 2012 Blackwell Publishing Ltd
`British Journal of Haematology, 2012, 158, 46–61
`
`Reference
`
`Joint Formulary
`Committee (2011)
`Koc et al (2002)
`Martin et al (2009)
`Onishi et al (2010)
`Jurado et al (2007)
`Johnston et al (2005)
`Koc et al (2000)
`Curtis et al (2005)
`Pidala et al (2010)
`Inagaki et al (2008)
`Huang et al (2005)
`Gilman et al (2000)
`Lee et al (1997)
`Moreira et al (1998)
`Mayer et al (2005)
`Scarisbrick (2009)
`
`Shapira et al (2009)
`Stadler et al (2009)
`Kharfan-Dabaja et al (2009)
`Park et al (2009)
`Peleg et al (2007)
`Sleight et al (2007)
`Chiang et al (2002)
`Busca et al (2007)
`Willenbacher et al (2001)
`Robin et al (2005)
`Marcellus et al (1999)
`
`49
`
`

`

`Guideline
`
`study, 8/39 patients achieved a benefit of switching from
`ciclosporin to tacrolimus for refractory cGvHD (Carnevale-
`Schianca et al, 2000). Regular monitoring of
`levels
`is
`required when using calcineurin inhibitors to avoid toxicity.
`
`Recommendations
`
`• Corticosteroids are recommended in the first line treat-
`ment of chronic GvHD (1A).
`• An initial starting dose of 1 mg/kg prednisolone is rec-
`ommended (1B).
`• Calcineurin inhibitors may be helpful in the initial treat-
`ment of GvHD as a steroid sparer (2C).
`
`Second-line systemic treatment in cGvHD
`
`A number of agents have been used as second- and third-line
`therapy for cGvHD. The role of these therapies in the sys-
`temic management of cGvHD will be discussed in the follow-
`ing sections. The authors acknowledge that it is difficult to
`conduct randomized controlled trials in cGvHD and that the
`management suggestions made in this guideline are based on
`the interpretation of limited data available at time of review
`and widespread expert opinion. Many of these agents have
`significant toxicities, which are summarized in Table I.
`These agents may be helpful in the management of ste-
`roid-refractory disease or as steroid-sparing agents in patients
`who are steroid-dependent or intolerant to steroids. The def-
`inition of steroid-refractory disease varies between studies
`but may include progression on prednisolone at 1 mg/kg per
`day for two weeks, stable disease on  0·5 mg/kg per day of
`prednisolone for 4–8 weeks and inability to taper predniso-
`lone below 0·5 mg/kg per day (Martin et al, 2006; Wolff
`et al, 2011).
`Ideally, patients with steroid-refractory cGVHD should be
`entered in to clinical trials. Where this is not possible, the
`choice of agent is likely to depend on the toxicity profile,
`organ involvement, patient preference and availability. Some
`agents may be used in combination or sequentially depend-
`ing on clinical judgement. As there are no established predic-
`tors of response, second line therapy should, where possible
`avoid the changing of more than one agent at a time, with
`assessment at 8–12 weeks. Where there is progression within
`a 4-week period alternative therapies can be considered,
`although patients with sclerotic skin disease are likely to take
`longer to demonstrate response.
`
`Extracorporeal photopheresis
`
`Extracorporeal photopheresis (ECP) has been widely used as
`a second line therapy for the treatment of mucocutaneous
`cGvHD, with consistently high complete response rates of up
`to 80% with cutaneous manifestations, and significant
`improvement in sclerodermatous skin involvement (Couriel
`
`50
`
`et al, 2006b; Dignan et al, 2011). Flowers et al (2008) pub-
`lished the first multicentre, randomized controlled, prospec-
`tive Phase II trial of ECP in the treatment of patients with
`cGHVD. This study included patients who were steroid-
`dependent, steroid-refractory and those who were intolerant
`of steroids. Ninety-five patients were randomized to receive
`either ECP and standard therapy (corticosteroids plus other
`immunosuppressive agents including ciclosporin, tacrolimus
`or mycophenolate mofetil) or standard therapy alone. The
`study used percentage improvement in total skin scores after
`12 weeks of ECP treatment as the primary endpoint. The
`percentage reduction in total skin score from baseline was
`greater in the ECP arm compared to the non-ECP arm but
`this did not achieve statistical significance (P = 0·48). The
`proportion of patients who had at least a 50% reduction in
`steroid dose and at least a 25% decrease in total skin score
`was 8·3% in the ECP arm at week 12 and 0% in the control
`arm (P = 0·04) (Flowers et al, 2008). A major limitation of
`this study is that the study arm assignment was known to
`physicians who were controlling the prednisolone dose. This
`study has several other limitations due to the methodological
`challenges of conducting clinical
`trials
`in patients with
`cGvHD. These include the short duration of treatment, only
`using skin as the primary endpoint to assess response, the
`limited time allowed for reduction in steroids (6 weeks) and
`the large variation in immunosuppressive regimens used.
`The response reported in patients with visceral GvHD, e.g.
`liver, is more variable. Greinix et al (2006) reported a complete
`response rate of 68% for liver cGvHD (17/25 patients). Similarly,
`Couriel et al (2006b) reported a partial response rate of 15/21
`(71%) for liver cGvHD. These results have not been reflected
`in all studies (Seaton et al, 2003; Foss et al, 2005). Lung and
`gut involvement have demonstrated less consistent responses
`(Greinix et al, 1998; Child et al, 1999; Couriel et al, 2006b).
`There are mixed reports of the benefits of earlier (<12 months)
`versus delayed treatment with ECP (Child et al, 1999; Apisarn-
`thanarax et al, 2003; Messina et al, 2003; Foss et al, 2005).
`Response to ECP has been associated with increased survival and
`reduction in the use of corticosteroids (Foss et al, 2005).
`A UK consensus statement on the use of ECP in cGvHD
`suggested that patients with cutaneous, mucous membrane
`and hepatic manifestations of GvHD should be given priority
`for treatment as it is particularly efficacious in this setting
`(Scarisbrick et al, 2008). This consensus group recommended
`a treatment schedule of two ECP treatments on two consecu-
`tive days every 2 weeks with less frequent monthly treatment
`in those who respond (Scarisbrick et al, 2008). No benefit
`has
`been demonstrated for more
`regular
`treatments
`(reviewed in Scarisbrick et al, 2008; Foss et al, 2005). The
`median number of ECP cycles in a recent UK study was 15
`(30 treatments) and the median duration of treatment was
`330 d (Dignan et al, 2011).
`Although a number of biomarkers have been reported to
`predict response to ECP, none have been clinically validated.
`
`ª 2012 Blackwell Publishing Ltd
`British Journal of Haematology, 2012, 158, 46–61
`
`

`

`
`The proportions of immature CD19+ CD21
`B lymphocytes
`may predict the response to ECP in cGvHD (Kuzmina &
`Greinix, 2009). There is some evidence that the ECP-treated
`cell dose may correlate with ECP effect (Perseghin et al,
`2007; Whittle et al, 2011). Abnormalities of B-cell homeosta-
`sis with increased B-cell activating factor (BAFF) have been
`noted in cGvHD, with evidence of normalization in ECP
`responders (Whittle & Taylor, 2011). The use of ECP is asso-
`ciated with improved outcomes
`in classic and overlap
`cGvHD (Jagasia et al, 2009).
`ECP requires venous access, which is not always possible
`using peripheral veins. Central
`lines may be required with
`the attendant complications of infection and blockage (Scar-
`isbrick, 2009). Systemic infections requiring either oral or
`intravenous antibiotics are at least halved in patients receiv-
`ing ECP for 12 months (personal observations, PCT). Other
`side effects are minimal and include vasovagal episodes and
`fatigue.
`ECP facilities should be quality assured. ECP requires
`well-maintained and validated machines, specifically trained
`staff, as well as skilful overall management to ensure effective
`use of resources, a safe patient care pathway and achievement
`of desirable outcomes. Clinical standards for such a service
`should be identified and adhered to through a quality assur-
`ance programme.
`It is suggested that ECP may be helpful as a second line
`treatment in steroid-refractory cGvHD involving the skin,
`mouth or liver. There is less data supporting the use of ECP
`in cGvHD involving other organs but it may have a role as a
`third line option. The authors acknowledge that this special-
`ized form of therapy may not currently be uniformly avail-
`able in the UK.
`
`Mammalian target of rapamycin (mTOR) inhibitors
`
`Sirolimus is a macrolide antibiotic that exerts its immuno-
`suppressive effect by inhibiting cytokine-driven signalling
`pathways of the T cell via mTOR blockade and specifically
`inhibiting the progression of cells from the G1 phase to the
`S phase. Sirolimus has been used in combination with other
`immunosuppressive agents in the management of refractory
`cGvHD. A Phase 2 study reported an overall response rate of
`63% [6/35 complete response, 16/35 partial response (defined
`as > 50% improvement
`in clinical manifestations)]
`in
`patients with steroid-resistant cGvHD when sirolimus was
`used in combination with tacrolimus and corticosteroids
`(Couriel et al, 2005). Four patients developed thrombotic
`microangiopathy and 77% had infectious complications. The
`median survival was 15 months. A similar Phase 2 study
`enrolled 19 patients (Johnston et al, 2005). Only 16 were
`evaluable for response because three had discontinued the
`sirolimus after less than one month’s treatment due to toxic-
`ity. A partial response was defined as any improvement in
`symptoms. This study reported an initial clinical response in
`15/16 evaluable patients. Adverse events
`included renal
`
`ª 2012 Blackwell Publishing Ltd
`British Journal of Haematology, 2012, 158, 46–61
`
`Guideline
`
`impairment in four patients and haemolytic-uraemic syn-
`drome in two patients and relapse in one patient, leading to
`discontinuation of sirolimus in six patients (Johnston et al,
`2005). Sirolimus levels were not checked in all patients. Sirol-
`imus was used in a retrospective study in patients with
`refractory disease in combination with either calcineurin
`inhibitors, MMF or prednisolone in 47 patients (Jurado et al,
`2007). Clinical
`responses were seen in 81% (38/47) of
`patients. Eighteen had a complete response and 20 had a
`partial response (defined as improvement in 1 organ without
`evidence of progression in another). Survival was 54·7% at
`3 years. Four patients developed thrombotic microangiop-
`athy (Jurado et al, 2007).
`In an
`Everolimus
`is an alternative mTOR inhibitor.
`abstract of a single centre retrospective analysis including 29
`patients with steroid-resistant disease, responses were seen in
`69% of patients (two complete responses) treated with ever-
`olimus without an additional calcineurin inhibitor. No
`patients developed thrombotic microangiopathy (Klink et al,
`2008).
`mTOR inhibitors are suggested for use as a second line
`treatment option in refractory cGvHD. They should be used
`with caution in combination with calcineurin inhibitors in
`view of the risk of thrombotic microangiopathy and trough
`levels should be monitored. Patients should also be moni-
`tored for hyperlipidaemia. Care should be taken to avoid
`toxicity due to interactions with other medications, particu-
`larly azoles (Wolff et al, 2011).
`
`Pentostatin
`
`Pentostatin is a nucleoside analogue and is a potent inhibitor
`of adenosine deaminase. Cell death occurs as a result of
`accumulation of 2-deoxyadenosine 5-triphosphate particu-
`larly in T cells and Natural Killer cells. The drug also causes
`prolonged lymphopenia although it is not significantly myel-
`osuppressive (Margolis & Vogelsang, 2000). A Phase 2 study
`administered pentostatin fortnightly
`for 12 doses
`and
`reported a response rate of 55% in 58 heavily pre-treated
`patients with refractory cGvHD (Jacobsohn et al, 2007). A
`clearly defined scoring system was used to assess patients at
`3-monthly intervals and 31 patients were considered to have
`a major response according to the study criteria. Survival
`was 70% at 2 years and 11 infectious episodes were possibly
`related to pentostatin. The same investigators reported a 53%
`response rate in a Phase 2 study of 51 children with refrac-
`tory cGvHD (Jacobsohn et al, 2009). Similarly, a clearly
`defined scoring system was used to assess response at 3-
`monthly intervals and seven patients had a complete res-
`ponse and 20 had a partial response. Overall survival at one
`year was 84%. There were 27 episodes of infection occurring
`in 15 patients. A dose of 4 mg/m2 was administered intrave-
`nously every 2 weeks in these reports and the main toxicities
`were infection and haematotoxicity. In a retrospective series,
`10/18 patients with refractory cGvHD obtained a complete
`
`51
`
`

`

`Guideline
`
`or partial response to pentostatin treatment (Pidala et al,
`2010). As infections are frequent, it has been recommended
`that pentostatin is not used in the context of acute infection
`or in pulmonary cGvHD (Wolff et al, 2011).
`
`Rituximab
`
`Rituximab is an anti-CD20 monoclonal antibody used widely
`in the management of B-cell malignancies. Ratanatharathorn
`et al (2000) reported the first case of patient with cGvHD
`and immune thrombocytopenia having a complete response
`to four doses of 375 mg/m2 of rituximab. Cutler et al (2006)
`reported the results of a Phase 1/2 study that included 21
`patients with steroid-refractory cGvHD treated with 375 mg/
`m2 weekly of
`rituximab. A response rate of 70% was
`observed although many responses were partial and limited
`to cutaneous and musculoskeletal disease. In addition, many
`patients had relatively mild GvHD. Responses were durable
`for one year (Cutler et al, 2006). A further Phase 2 study of
`37 patients reported 8 complete and 24 partial responses
`with higher responses in skin, oral cavity and musculoskeletal
`systems (Kim et al, 2010). Similar results ha