Bone Marrow Transplantation (2014) 49, 1251–1258 © 2014 Macmillan Publishers Limited All rights reserved 0268-3369/14 www.nature.com/bmt

REVIEW

Extracorporeal photopheresis for treatment of adults and children with acute GVHD: UK consensus statement and review of published literature E Das-Gupta1,9, F Dignan2,9, B Shaw3,9, K Raj4,9, R Malladi5,9, A Gennery6,9, D Bonney7,9, P Taylor8,10 and J Scarisbrick5,11 Extracorporeal photopheresis (ECP) has been used for over 20 years to treat acute GVHD (aGVHD) and chronic GVHD. Evidence on the efficacy of response in aGVHD has continued to accrue and data suggest that there is a good response and prolonged survival in both children and adults with grade II–IV aGVHD. Unlike chronic GVHD where treatment schedules are typically one or two times monthly for 12–18 months, patients with aGVHD respond rapidly to an intense weekly treatment schedule for 8 weeks, typically allowing steroids to be discontinued without flare-ups of aGVHD. Maintenance ECP therapy is generally not required. Many centres across Europe and United States treat aGVHD with ECP as second-line therapy and responses are excellent in a subset of patients. Unlike other second-line therapies, ECP is not immunosuppressive and has no reported drug interactions. Importantly, ECP does not have a negative impact on the graft-versus-malignancy effect of the transplant. This statement aims to select those patients most likely to respond to treatment and summarises treatment and monitoring schedules for the management of aGVHD in adult and paediatric patients to ensure the correct patients are treated with the optimal protocol for efficacy. Bone Marrow Transplantation (2014) 49, 1251–1258; doi:10.1038/bmt.2014.106; published online 2 June 2014

INTRODUCTION Extracorporeal photopheresis (ECP) is a cell-based immunomodulatory therapy involving the separation of leucocyte-rich plasma followed by ex vivo administration of a photosensitiser and UVA irradiation before reinfusion. The approach was first published by Edelson et al.1 in 1987 who reported the use of photopheresis in the treatment of erythrodermic cutaneous T-cell lymphoma in a multicentre trial. The UVAR system for ECP (Therakos, Exton, PA, USA) was granted approval by the Food and Drug Administration in the United States in 1988. Since this time, ECP has become an established treatment for cutaneous T-cell lymphoma and the technology has been used successfully to treat a variety of disorders associated with immune dysregulation, including acute and chronic GVHD (aGVHD and cGVHD). ECP is a safe form of immunotherapy with no increased risk of secondary infection, secondary malignancy or disease relapse. This is particularly valuable where alternative therapies are typically highly toxic, immunosuppressive and increase the likelihood of a second malignancy. While the licensed indication in the United States is currently restricted to treatment of cutaneous manifestations of cutaneous T-cell lymphoma, ECP has been used in a number of other indications, most widely in the treatment of cGVHD following haematopoietic SCT for which it is has been used for over two decades and is an accepted efficacious second-line therapy.2,3

aGVHD is a serious consequence of allogeneic haematopoietic SCT that causes significant morbidity and mortality through secondary infection and organ damage. Using standard GVHD prophylaxis with a calcineurin inhibitor and MTX, 20–40% of recipients of HLA-matched related donor transplants and as many as 50–80% of recipients of unrelated donor transplants develop grades II–IV aGVHD.4–6 OS has been consistently shown to correlate with the grade of aGvHD (Table 1), with grade II–IV aGVHD being associated with a worse outcome than grades 0 and I.7,8 The chronic leukaemia working party of the European Group for Blood and Marrow Transplantation reviewed 1294 patients who had received an allogeneic transplant for CML. The TRM for grades 0–IV aGvHD was 28%, 27%, 43%, 68% and 92%, respectively.7 Systemic corticosteroids remain the recommended first-line therapy of grade II–IV aGVHD, at a starting dose of 2 mg/kg.8 At this dose, CR rates of 25–50% can be expected.1 Failure to respond to corticosteroids is associated with an increased TRM.9,10 There is also evidence that an early response is indicative of improved long-term outcome.10 Second-line therapies for aGVHD are required for steroid nonresponders as well as for patients who have steroid-dependent aGVHD defined as recurrence of aGVHD (grade II or higher) during corticosteroid taper and before reaching 50% of initial starting dose of corticosteroids.3,8 Second-line therapies include immunosuppressive and immunomodulatory agents, which have recently

1 Centre for Clinical Haematology, Nottingham University Hospitals NSH Trust, Nottingham, UK; 2Central Manchester University Hospitals, Manchester, UK; 3Royal Marsden Hospital, London, UK; 4King’s College Hospital, London, UK; 5University Hospital Birmingham NHS Trust, Birmingham, UK; 6Great North Children’s Hospital, Newcastle-Upon-Tyne, UK; 7Royal Manchester Children’s Hospital, Manchester, UK and 8Rotherham Foundation NHS Trust, Rotherham, South Yorkshire, UK. Correspondence: Dr E Das-Gupta, Centre for Clinical Haematology, Nottingham University Hospitals, City Hospital Campus, Hucknall Road, Nottingham NG5 1PB, UK. E-mail: [email protected] 9 Member of Photopheresis Expert Group of the UK Photopheresis Society. 10 Chairperson. 11 Secretary. Received 22 October 2013; revised 15 March 2014; accepted 25 March 2014; published online 2 June 2014

Use of ECP in aGVHD E Das-Gupta et al

1252 Table 1.

aGVHD staging and grading based on modified Glucksberg criteria

Stage 1 2 3 4

Cutaneous rash

Hepatic (bilirubin)

Gut (diarrhoea/nausea)

o25% BSA 25–50% BSA Generalised erythroderma Generalised erythroderma with bullae and desquamation

34–50 mmol/L 51–102 mmol/L 103–255 mmol/L >255 mmol/L

>500 mL or nausea >1000 mL >1500 mL Pain/Ileus

Cutaneous

Hepatic

Gut

Stages 1 and 2 Stage 3 or Stage 4 or

0 Stage 1 or Stages 2–4 or

0 Stage 1 Stages 2–4

Functional grading I II III and IV

been reviewed in several publications.3,8 The lack of randomised controlled studies of second-line therapy means there is a paucity of comparative data relating to efficacy, safety, cost effectiveness or impact on quality of life for therapies. Current guidance does not make recommendations as to the order in which second-line therapies should be implemented.8 The British Committee for Standards in Haematology/British Society of Blood and Marrow Transplantation guidelines list ECP as one of five recommended second-line therapies for aGVHD; the other four agents being anti-TNF antibodies, sirolimus, mycophenolate mofetil and IL-2 receptor antibodies.8 This paper reviews the existing literature on ECP with particular emphasis on the guidelines for its use, efficacy in adults and children with aGVHD and safety profile. A consensus statement for the use of aGVHD has been produced by the UK Photopheresis Society to ensure that ECP is available to the patients who are likely to derive most benefit and to standardise care through the United Kingdom. MATERIALS AND METHODS Guidelines on the use of ECP in the management of aGVHD were identified through a literature and internet search of relevant medical databases (e.g. PUBMED, MEDLINE, CINAHL), as well as a targeted search of relevant professional bodies for guidelines (e.g. British Society for Blood and Marrow Transplantation, British Society for Haematology). Key words were searched to include ECP, treatment of aGVHD and guidelines of aGVHD. Guidelines were trawled along with targeted searches of bodies responsible for producing evidence-based guidelines (e.g. NICE, the Agency for Healthcare Research and Quality, the National Institutes of Health, American Society for Blood and Marrow Transplantation and the British Committee for Standards in Haematology). Searches were performed up until September 2013. The consensus statement was developed using evidence-based medicine and best medical practises of the UK Photopheresis Society on the appropriate use of ECP in aGVHD. Published data and experience was discussed during four meetings over the course of a 2-year period (2011–2013). The consensus statement builds on current guidelines for the provision of ECP, evidence-based reports and expert opinion on the appropriate use of ECP based on the ‘best medical practices’ of the group members. Each clinician provided protocols for the provision of ECP within their own centre. These protocols captured patient selection criteria, treatment schedule, monitoring protocol and patient assessment criteria. Where any differences in protocols were identified, the groups were asked to agree on an appropriate consensus position using evidence-based medicine. Differences between adult and paediatric care were recorded. A review of the safety and tolerability of ECP in aGVHD was also undertaken. Technical aspects are not discussed except in paediatric ECP as these are reported in Appendix 3, the UK Consensus Statement for ECP in cGVHD.2 The aim of this consensus document is to provide standardised eligibility, assessment and treatment strategies across the United Kingdom. This group is also piloting a national ECP treatment database. Prospective data collection will allow a more accurate comparison of treatment response between UK sites and provide the foundations for multicentre UK trials. Bone Marrow Transplantation (2014) 1251 – 1258

RESULTS Review of literature on the use of ECP in aGVHD Much of the early information on the use of ECP in aGVHD was recorded in case studies and series, and small studies from single centres (Table 2).11–24 The data on 76 patients (age range 5–55 years) from these early studies, all of whom were receiving ECP as second-line treatment for aGVHD, were collated and reviewed in 2002.17 Overall patient survival was 53%. ECP was associated with a CR of cutaneous manifestations of aGVHD in 67% of patients. Rates of CR for hepatic and gastrointestinal (GI) manifestations were 38% and 54%, respectively. Best response rates were seen in patients with grade II–III aGVHD; lower rates were observed for grade IV disease. The maximal response to ECP was seen after 6–8 weeks of treatment (2–5 cycles of ECP). ECP in adult patients with aGVHD. Greinix et al.18 have published a series consisting of 59 patients with either steroid-refractory or -dependent aGVHD. Overall, CR was shown in 82% of patients with cutaneous involvement, 61% with hepatic involvement and 61% with GI involvement. Results in the phase II study were better than those in the pilot study, particularly for patients with GI involvement and grade IV disease. This increase in efficacy was attributed to earlier initiation of ECP (with a median of 15 days of steroid therapy before ECP in the phase II study, compared with 21 days in the pilot study).19 The best response to ECP was observed after a median of 1.3 (range 0.5–6) months; therefore, patients generally required a short duration of treatment and did not experience flare-ups of aGVHD after ECP was stopped.19 In patients who responded to ECP, steroids could be discontinued at a median of 55 (range 17–284) days after the start of ECP. Univariate analysis of the response data showed that lower grades of aGVHD, fewer organs involved at the start of steroid therapy and at the initiation of ECP, and a lower cumulative steroid dose before the start of ECP all significantly increased the probability of a CR following ECP.18 Logistic regression analysis showed that only a lower grade of aGVHD at the start of ECP and later initiation of steroid therapy after transplant were associated with an increased probability of a CR following ECP.18 The overall cumulative incidence of TRM at 4 years was 36% (95% confidence interval (CI): 25–50%), but this was only 14% (95% CI: 10–31%) for those who achieved a CR following ECP, and was 73% (95% CI: 56–94%) for those who did not (P o0.0001).18 Corresponding data for OS at 4 years were 47% for all patients, 59% for those who experienced CR and 11% for those who did not. Univariate analysis showed that a shorter interval between transplant and ECP, a shorter duration of ECP and lower cumulative doses of steroids were all associated with a lower TRM. Two smaller studies support the results of this phase II trial.20,21 A more recent larger multicenter series documented the outcome of 139 patients treated with ECP as second-line therapy for steroid-refractory and -dependent GVHD.25 Grade III and IV © 2014 Macmillan Publishers Limited

Use of ECP in aGVHD E Das-Gupta et al

38/57 (66%) 15/23 (66%) 3/11 (27%) 8/20 (40%) 52%

57 16–67 34/23 45 8–99

47/57 (82%) 14/23 (61%) 9/15 (60%) 47%

23 18–66 17/6 14–148

© 2014 Macmillan Publishers Limited

100% (4 CR, 2 PR)

Abbreviations: ECP = extracorporeal photopheresis; F = female; M = male; NR = no response.

0% (6 NR)

4–24

2/4 (50%) 2/3 (67%) 3/3 (100%) 100% (4/4 all CR) 9–36 4/6 (67%) 2/2 (100%) 1/2 (50%) 1/11 (9%) 3/5 (60%)

50–134 30–70

9–36 13/21 (62%) 8/12 (67%) 0/4 (0%) 8/21 (38%) all CR

13–92

10/14 (71%) 4/7 (57%) 6/10 (60%) 57% (7 CR)

6 10/12 (83%) — 2/5 (40%) 42%

59 21–60 29/30 37 14–70 12 12–63 14

21 27–55 10/11 20–70 6 5–53

4 26–45 3/1 26–48 6 25–55

Greinix et al.11 Sniecinski et al.40

11

Patients (n) Age (years) Gender (M/F) BMT to ECP interval (days) ECP cycles (n) CR cutaneous (n) CR hepatic (n) CR gut (n) Overall response

Table 2.

Summary of results from studies of ECP in aGVHD

Miller et al.12

Smith et al.13

Greinix et al.15

Dall’Amico and Messina17

Garban et al.20 Greinix et al.18 Perfetti et al.21 Jagasia et al.26

1253 aGVHD was present at the onset of ECP in 39 patients (35%) with stages 3 and 4, cutaneous in 29 (21%), GI in 57 (41%) and hepatic in 25 (18%). The median number of ECP treatments was 11 (range 2–42); 77% patients responded to ECP. The median follow-up after ECP was 41.4 months, with a 2-year survival of 56%. In multivariate analyses, ECP response was an independent predictor of survival. Data have also been reported from a large, multicentre, retrospective comparison of ECP (86 patients) and anticytokine therapy (inolimomab or anti-TNF-α, 41 patients) for second-line treatment of adult patients with steroid-dependent and -refractory aGVHD.26 Patients received a median of 12 ECP treatments, over a median of 50 days. The aGVHD response was higher in the ECP group (73% vs 32%; P o 0.001) and was associated with a superior survival (not reached vs 4.9 months; P o 0.001). The cumulative incidence of 2-year non-relapse mortality was higher in the non-ECP group compared with the ECP group (82% vs 37%; P o 0.001). This international, multicentre study suggests that ECP is an effective second-line therapy for aGVHD and may be superior to non-ECP intervention. ECP in children with aGVHD. The efficacy of ECP as a treatment for aGVHD in adult patients has largely been replicated in paediatric patients (Table 3). An early multicentre, retrospective study involving 33 children with steroid-resistant aGVHD showed an overall CR rate of 54% (21% PR).27 Patients received a median of eight cycles of ECP and maximal response was seen after 8 weeks of treatment (weekly cycles for the first month, then every other week in months 2 and 3). CR rates in cutaneous, GI and hepatic GVHD were 76%, 75%, 60%, respectively. OS at 5 years was significantly better for ECP responders (69%) than non-responders (12%) (P = 0.001). In addition, as a result of ECP, it was possible to discontinue immunosuppressive therapy in eight patients (42%) and reduce the dose in seven patients (36%). Berger et al.28 reported a series of 15 paediatric patients with steroid-resistant aGVHD treated with ECP. Patients received a median of six cycles of ECP, starting at a median of 25 days after diagnosis of aGVHD. At the end of the scheduled ECP treatment, 62% of patients had a CR, including all patients with grade II disease at the start of ECP. Fifty percent of those with grade III disease experienced CR and 25% PR. For any grade of organ involvement, CR was seen for 8/12 patients with cutaneous (67%), 3/4 patients with hepatic (75%) and 5/7 patients with GI involvement (71%). The strongest predictor of treatment response was disease grade. Significant predictors of TRM were grade of aGVHD and response to ECP. Similarly, good results for individual organ systems were reported in a series of eight paediatric patients with steroidrefractory aGVHD.29 CR was shown in all eight patients with cutaneous, 2/2 patients with hepatic and 4/7 patients with GI involvement (3/7 experienced PR). Likewise, in a study of 12 patients with aGVHD, the overall response rate was 83% (10/12; 58% CR, 25% PR).30 Rates of CR for individual organ systems were 90% for cutaneous (9/10 patients), 56% for hepatic (5/9) and 83% for GI involvement (5/6). Overall, the steroid-sparing rate after 10 sessions of ECP was 63%, and corticosteroids could be stopped during ECP in six patients. ECP was extremely well tolerated in children with minimal side effects even with weight as low as 10 kg. The main difficulties were venous access and the psychological impact of treatment, but these were significantly reduced by treatment in a paediatric environment with an experienced team. They combined their experience treating children with ECP with available paediatric data to establish clinical practice guidelines. Calore et al.31 reported a comparison of ECP and steroid therapy in paediatric patients (15 and 16 patients, respectively) with grade II–IV aGVHD. The overall response rates were 73% CR and 27% PR for ECP, and 56% CR and 31% PR for steroid therapy. Response Bone Marrow Transplantation (2014) 1251 – 1258

Use of ECP in aGVHD E Das-Gupta et al

1254 Table 3.

Results of studies of the use of ECP in paediatric patients with aGVHD Patients (n)

Salvaneschi et al.16 Messina et al.27 Kanold et al.30 Berger et al.28 Calore et al.31 Gonzalez-Vicent et al.29 Perotti et al.32

9 33 12 15 15 8 50

CR cutaneous, n (%) 6/9 25/33 9/10 8/12 12/13 8/8 39/47

(67%) (76) (90) (67) (92) (100) (83)a

CR hepatic, n (%) 1/5 9/15 5/9 3/4

(20%) (60) (55.5) (75)

2/2 (100) 16/24 (67)a

CR gut, n (%) 3/5 15/20 5/6 5/7 14/14 4/7

(60%) (75) (83) (71) (100) (57) 8/11a

OS (%) 7/9 (78%) 69 at 5 yrs 75 at 8.5 mo — 85 at 5 yrs 64 at 1 yr

Abbreviations: CR = complete resolution; mo = months; yrs = years. Results were provided as complete and partial resolution. a

rates for individual organ involvement were also higher for ECP compared with steroid therapy: for cutaneous CR rates were 92% for ECP and 46% for steroids; for GI the rates were 71% and 57% and for hepatic 100% and 67%, respectively. At day 100, TRM was 6% for patients who had received steroid therapy and 0% for patients in the ECP group. In addition, at 2 years, OS rates were somewhat higher for ECP (85%) than steroid therapy (57%). A longitudinal study of 50 paediatric patients with aGVHD showed an overall response rate of 68% (32% CR, 36% PR).32 Overall response rates (CR+PR) for individual organ systems were: cutaneous 83%, hepatic 67% and GI system 73%. It was possible to stop steroid therapy in 16% of patients with aGVHD, and tapering of steroid dose after 30 days of ECP therapy was positively associated with survival of patients in this study. Non-response to ECP was significantly associated with risk of death. Review of guidelines on the use of ECP in aGVHD Martin et al.3 have recently published recommendations on the first- and second-line systemic treatment of aGVHD. While the first-line treatment with single-agent methylprednisolone or prednisolone is an accepted standard of therapy, there is no standard for second-line. This lack of an established treatment pathway for aGVHD is discussed. These guidelines consist of a comprehensive review of treatments available, interpretation of study data and a suggestion for future studies. They include ECP as a second-line option in the management of aGVHD. Other agents listed for consideration for second-line therapy include mycophenolate mofetil, denileukin diftitox, sirolimus, infliximab, etanercept, pentostatin, horse/rabbit anti-thymocyte globulin and alemtuzumab. There was no evidence that one second-line agent was superior to another and it is recommended that the choice of a second-line agent should be based on physician experience, availability and consideration of potential toxicities and interactions. ECP has the advantage over other treatments as it is the only treatment where the risk of viral reactivactivation is not increased. Toxicity is also low for ECP and may be a preferable therapy in at-risk patients. The disadvantages of ECP are the requirement for good venous access and the lack of convenience to the patient and cost. There is evidence that second-line therapy should be initiated earlier in severe aGVHD. It is recommended that second-line therapy should be considered after 3 days in patients with progressive aGVHD, after 1 week of persistent unimproving grade III/IV aGVHD or 2 weeks of persistent unimproving grade II aGVHD. A treatment schedule for ECP is suggested: three times a week for the first week, two times per week for weeks 2–12 and two times per month thereafter.3 A recent UK guideline for treatment of aGVHD published by the British Committee for Standards in Haematology/British Society of Blood and Marrow Transplantation advocates 1–2 mg/kg intravenous methylprednisolone as first-line treatment of grade II–IV aGVHD.8 This guideline also acknowledges the lack of standard second-line therapy. Second-line therapy is recommended in those patients with no improvement after 5 days of first-line Bone Marrow Transplantation (2014) 1251 – 1258

therapy and after 3 days in those with progressive disease. ECP is considered as a second-line treatment along with the following agents: anti-TNF-α antibodies, mammalian target of rapamycin inhibitors, mycophenolate mofetil and IL-2 receptor antibodies, whereas third-line treatment options include alemtuzumab, pentostatin, mesenchymal stem cells and MTX. The lack of randomised controlled trials has prevented these treatments being prioritised in terms of efficacy. Subsequently, second- and third-line therapies vary widely between centres. There is no standard schedule for ECP in aGVHD. They report a regimen of weekly ECP cycles for a minimum of 8 weeks and continued until maximal response or CR. The excellent safety profile of ECP is highlighted, and there have been no reports of increased infection or disease relapse. ECP in the United Kingdom is limited to those centres with machines on-site as patient or service transfer between sites is problematic. The American Society for Apheresis reviewed the data available on ECP in aGVHD from United States of America.33,34 They found that overall response rates for steroid-refractory aGVHD in paediatric and adult patients ranged from 52 to 100%, with responses in cutaneous (66–100%), GI tract (40–83%) and hepatic (27–71%). A high number of CRs were noted. However, ECP may offer less benefit to patients with severe aGVHD. ECP is recommended on two consecutive days (one cycle) per week until disease response and then tapered to alternate weeks before discontinuation. These European Dermatology Forum guidelines report on all indications for ECP.35 In aGVHD patients with disease unresponsive to corticosteroids (defined as progression at a minimum 3 days of 2 mg/kg per day or no response after 7 days) should receive adjunct ECP as second-line therapy. A schedule of treatments 2–3 times per week is recommended with rapid taper of corticosteroids, and ECP may be discontinued at CR. There is no evidence that maintenance of ECP is beneficial. It is recommended that activity of aGVHD should be assessed every 7 days with staging according to published criteria and assessments should relate to organ involvement. They conclude that ECP is well tolerated with an excellent safety profile in children and adults and is highly efficacious in aGVHD. Further prospective studies are warranted, including use of ECP in upfront therapeutic or prophylactic strategies. Quality of life data are important in this group with multiple morbidities. The British Photodermatology Group produced guidelines for ECP in 2006 reporting on a number of indications including aGVHD.36 This report noted that data on ECP in cGVHD has accumulated over past decades, whereas data on aGVHD is scarce. At this time, the data in aGVHD were primarily from a single centre (21 cases), suggesting a benefit in cutaneous and hepatic disease. However, there was conflicting data from smaller series relating the the efficacy of ECP in the treamtent of hepatic aGVHD. Kanold et al.30 produced guidelines for ECP in paediatric patients with GVHD. These guidelines consider ECP as a first-line therapy in grade IV aGVHD in conjunction with standard therapy and as a second-line therapy in grades II–III aGVHD steroid© 2014 Macmillan Publishers Limited

Use of ECP in aGVHD E Das-Gupta et al

1255 resistant (defined up to 2.5 mg/kg per day for 1 week without improvement), but to consider adding after 48 h in cases of insufficient efficacy. ECP should also be considered in steroidintolerant patients and patients who had been unsuccessfully treated with more than three lines of therapy. Recently, two Italian scientific societies, the Italian Society of Hemapheresis and Cell Manipulation (SidEM) and the Italian Group for Bone Marrow Transplantation (GITMO), joined to develop and disseminate recommendations on appropriate application of ECP in patients with GVHD.37 They concluded that ECP is a valuable option in the treatment of aGVHD in adults and children not responding to steroid and calcineurin inhibitors. They noted that better results are expected in patients with isolated cutaneous involvement, while the efficacy of the procedure in visceral GVHD is less well defined. They recommended ECP as a steroid-sparing agent in patients for whom further immunosuppression is contraindicated owing to viral reactivation or other infectious complications. They recommended that ECP be initiated at a schedule of two ECP treatments per week until maximum response, followed by tapering, tailored to the individual patient according to clinical response. They suggest that clinical response should be assessed weekly in aGVHD. These guidelines support ECP along with other second-line therapies in patients with grade II–IV aGVHD with steroidrefractory or -dependent disease or those subset of patients who are intolerant to systemic steroids. Corticosteroid refractory aGVHD is defined as worsening of aGVHD after 3 days of systemic corticosteroids (a minimum dose of 1 mg/kg), or no improvement after 7 days of systemic corticosteroids (a minimum dose of 1 mg/ kg). Corticosteroid-dependent aGVHD is defined as recurrence of aGVHD (grade II or higher) during corticosteroid taper and before reaching 50% of initial starting dose of corticosteroids. Administration of ECP for aGVHD The ECP circuit has a relatively small amount of the total fluid volume (approximately o 500 mL at a time) and is typically a very safe therapy, but as patients with grade III–IV aGVHD can be haemodynamically unstable, ECP may be best performed in an acute hospital setting, and where necessary, it can be safely performed within an intensive care unit. ECP can be delivered via ‘closed’ or ‘open’ system. Open ECP requires collection of a buffy coat (mononuclear cell layer) on a standard cell separator, separation of the buffy coat from the system and subsequent UVA irradiation in a separate device, before reinfusion to the patient. By contrast, the closed system incorporates an internal UVA source in the apheresis device with no separation of the buffy coat from the device, before being returned to the patient. While the open system has the potential advantages of wider availability of apheresis devices and increased cell dose, this is at the price of increased risk of microbial contamination. The buffy coat ‘product’ would need to meet regulatory requirements. The closed system device has an integrated mononuclear cell collection and 8-methoxypsoralen/UVA irradiation processing, and regulatory approval for treating patients. At the present time, the intravenous 8-MOP (methoxypsoralen; Uvadex) is only licensed for use with the Therakos closed system. Patients should be excluded from ECP therapy if they are photosensitive, have a sensitivity to psoralen compounds such as 8-MOP or suffer aphakia, because of the significantly increased risk of retinal damage owing to the absence of lenses. Weight o 40 kg is contraindicated in patients receiving ECP using the Therakos UVAR-XTS machine (Therakos, West Chester, PA, USA). This is largely due to patients with low body mass being unable to tolerate the shift in fluid volumes that occurs during treatment. The Therakos Cellex machine uses smaller volumes of fluid and blood prime regimens to allow the majority of paediatric patients to be treated. The limiting factor is tolerance of fluctuations in © 2014 Macmillan Publishers Limited

circulating volume up to 15%. It also has the benefit of a shorter treatment time. Both heparin or citrate may be safely used to prevent blood clotting as it passes through the ECP machine. Citrate may be the safer anticoagulant, as the small amounts required are cleared quickly and has been shown to be extremely safe for ECP procedures allowing treatment of patients with higher risk of bleeding and those with heparin contraindication.38,39 A platelet drop is not typically seen after ECP and reduction of 30–50% should alert the physician to the possibility of heparin-induced thrombocytopenia. Patients with thrombocytopenia (o 100 × 109/ L) can receive ECP, but platelet support may be required before the procedure. Citrate is the preferred method of anticoagulation in patients at risk of bleeding from any cause and may be of use in patients with aGVHD and acute bleeding risk owing to liver impairment or thrombocytopenia. A platelet count o20 × 109/L despite platelet transfusion support or o40 × 109/L with active bleeding is a contraindication to ECP.2 Treatment during pregnancy is not recommended. Review of the reported adverse reactions to ECP in aGVHD Several papers have reported on the safety profile of ECP in the treatment of both cutaneous T-cell lymphoma and GVHD in more than 500 000 treatments performed worldwide since 1987. The incidence of reported serious adverse events with ECP is o0.003%. The most common side effects are mild, such as nausea, fever or headache, and occur at a frequency of o1% of cycles. The side-effect profile in those patients with aGVHD is similar to other indications for ECP. In addition, there are challenges treating patients with aGVHD. Patients may have profound diarrhoea, electrolyte disturbances and hypoalbuminaemia with associated brittle haemodynamics requiring large volume fluid replacement and close observation of haemodynamics in patients. Children with aGVHD often have low body weight. Nevertheless, studies have shown good tolerability with body weight as low as 10 kg.27,28 Indeed, the tolerability of ECP in aGVHD allows treatment of patients with a low performance index.21 ECP does not appear to impact negatively on the graft-versus-tumour effect as there is no increase in relapse rates in steroid-refractory aGVHD patients treated with ECP.18 The constant feature in all publications is that ECP is noted to be an extremely safe form of therapy and significant reactions such as vasovagal syncope or infections secondary to indwelling catheters are infrequent. This is highly beneficial in a group of patients where alternative therapies are highly immunosuppressive. CONSENSUS STATEMENT ON THE USE OF ECP IN AGVHD Using evidence-based medicine and best medical practices discussed within this paper, the UK Expert Photopheresis Group have produced a consensus statement on the appropriate use of ECP in aGVHD. This includes: criteria for the selection of patients suitable for treatment with ECP; treatment schedule; monitoring protocol; and response criteria. The recommendations are formed from the current evidence base on ECP in aGVHD. It is recognised that data of ECP usage in aGVHD is further accumulating and revisions may be necessary in light of any new findings. Where the recommendations refer to a ‘cycle’ of treatment, this equates to two episodes of ECP treatment over consecutive days. Patient selection for ECP in aGVHD patients We recommend that only those patients with grade II–IV disease should be eligible for ECP because of the better prognosis of those with grade I disease. aGVHD should be staged for each organ Bone Marrow Transplantation (2014) 1251 – 1258

Use of ECP in aGVHD E Das-Gupta et al

1256 before a grade (I–IV) is determined. A clinical diagnosis of aGVHD is sufficient. Infective causes of diarrhoea should be excluded, although it must be recognised that aGVHD can occur concomitantly with infection, such as norovirus or Clostridium difficile, and positive results should be interpreted in light of the clinical features. Pre-existing gut infection may lead to isolated gut GVHD, and duodenal, terminal ileal and colonic biopsies should be performed to exclude dual pathology. ECP should be considered as second-line therapy with other agents for patients with aGVHD grades II–IV with one of the following: steroid refractory, steroid dependent or steroid intolerant as defined below. ECP preserves immune function and has an excellent safety profile. For these reasons, ECP may also be a valuable treatment in immunosuppressed patients unable to tolerate systemic steroids or other immunosuppressive secondline agents. Criteria ●

●

●

Corticosteroid-refractory aGVHD is defined as worsening of aGVHD after 3 days of systemic corticosteroids (minimum dose of 1 mg/kg) or no improvement after 7 days of systemic corticosteroids (minimum dose of 1 mg/kg). Corticosteroid-dependent aGVHD is defined as recurrence of aGVHD (grade II or higher) during corticosteroid taper and before reaching 50% of initial starting dose of corticosteroids. Steroid-intolerant aGVHD defined as patients with aGVHD who are unable to tolerate the side effects of adequate doses of systemic steroids.

Exclusion criteria ● ● ●

● ● ● ● ● ● ●

Patients exhibiting a known sensitivity to psoralen compounds such as 8-MOP. Patients with comorbidities that may result in photosensitivity. Patients with aphakia. UVADEX Sterile Solution is contraindicated in patients with aphakia, because of the significantly increased risk of retinal damage owing to the absence of lenses. Weight/circulating volume (defined by apheresis machine characteristics). Pregnancy. Uncontrolled infection. ANC o1.0 × 109/L despite GCSF support. Platelet count o20 × 109/L despite platelet transfusion support. Haemodynamically unstable from profuse diarrhoea. Recent history of bleeding.

>0.5 mg/kg in paediatric patients to continue with weekly cycles of ECP with weekly assessments and stop as soon as no further response. Patients receiving therapy for lower GI acute GVHD often take longer to respond. For those who show a response to ECP, a tapering schedule is advised, dropping to 2-weekly cycles after 8 weeks and then to monthly cycles according to response befoe discontinuing therapy. Patients without at least a PR after 8 weeks should be considered for alternative therapy. Steroid taper. In ECP-responsive patients who have steroiddependent acute GVHD, it is suggested that steroid taper should be commenced during the second week of ECP therapy and steroid dose reduced on a weekly basis with the aim of achieving a 50% reduction in first 4 weeks followed by a further 50% reduction in weeks 4–8. In steroid-refractory patients, where side effects outweigh benefits of high-dose steroids, we recommend commencing steroid taper early without waiting for a response to ECP. The starting dose of corticosteroid at the onset of second-line therapy may vary. Most centres use doses in the range of 1–2 mg/kg and continue that dose for 7–14 days, until there is evidence of response. Patients who respond can be tapered at a rate 5–10% of the dose per week. Attempts should be made to taper within 2 weeks for patients who are deemed corticosteroid refractory as continuation of corticosteroids at 2 mg/kg beyond 14 days are associated with increased risk of infectious complications. Lower doses at the onset of second-line therapy may be used if there are comorbidities that preclude higher doses (e.g. corticosteroid myopathy, active uncontrolled infections, uncontrolled diabetes,etc.). Monitoring protocol for aGVHD. All patients require weekly assessment and staging of cutaneous, hepatic and gut aGVHD8 to ensure ECP was given safely and to document a trend in organ involvement. The weekly patient assessment is aimed to highlight those with PR (defined below) to allow steroid tapering and to identify those with progressive disease for combination or alternative therapy. The aim is to treat all patients tolerating ECP without disease progression for a minimum of 8 weeks. Patient assessment criteria for aGVHD. Patient assessments should be used to determine a response to treatment. We have chosen to use patient responses similar to those used in the assessment of cGVHD.11 All responses should be determined according to organ involvement. Patient assessment of response to ECP

Treatment schedule for aGVHD Treatment schedule: Treatment initiation: One cycle of treatment (i.e. ECP on two consecutive days) should be initiated weekly for a minimum of eight cycles (8 weeks). Patients with grade III–IV aGVHD may benefit from three treatments per week for the first 4 weeks. Patients who have progressive aGVHD during this time may require a third-line therapy at the discretion of the treating physician. Assessment after 8 weeks of ECP therapy: Adult patients who have achieved a complete clinical response and are receiving a steroid dose of o20 mg per day methylprednisolone or 25 mg prednisolone or children on o 0.5 mg/kg may be able to stop ECP treatment after 8 weeks of therapy. In this circumstance, there is no need to taper the frequency of ECP before discontinuation of therapy. Patients who have achieved a partial clinical response at 8 weeks but are still requiring steroid doses of >20 mg per day methylprednisolone or 25 mg per day prednisolone in adults or Bone Marrow Transplantation (2014) 1251 – 1258

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Complete organ responses (CR) defined as resolution of organ involvement. Partial responses (PR) defined as a >50% response in organ involvement, but less than a CR. Stable disease (SD) defined as stable organ involvement, despite the tapering of other immunosuppressive agents by at least 50% of the dosage. Progressive disease (PD) as worsening of GVHD and the inability to taper other medications.

Adult patients with CR receiving a steroid dose of o20 mg per day methylprednisolone or 25 mg prednisolone should stop ECP treatment after 8 weeks of therapy. Patients without at least a PR after 8 weeks may be considered for alternative therapy. Patients who have achieved a partial clinical response but are still requiring steroid doses of >20 mg per day methylprednisolone or 25 mg prednisolone in adults or >0.5 mg/kg in paediatric patients © 2014 Macmillan Publishers Limited

Use of ECP in aGVHD E Das-Gupta et al

may benefit from the ongoing ECP therapy. Stable or progressive disease should be considered for additional or alternative therapy. Owing to the immunosuppressive nature of aGVHD and the ongoing treatments, prophylaxis against bacterial, viral, fungal and protozoal infections should be continued as per usual for patients on ECP therapy. CONCLUSION aGVHD remains a major cause of morbidity and mortality posttransplant. The disease and its therapies are typically highly toxic. Patients with aGVHD are universally treated with high-dose steroids. For patients who have steroid-refractory or steroiddependent aGVHD, there are a number of second-line agents, including ECP, with efficacy in aGVHD, but no algorithm exists for their usage. Decisions on which agent to use are made by the treatment centre and vary according to clinical experience, cost and treatment availability and are frequently decided on an individual patient basis. ECP has an excellent safety profile and is one of the least toxic second-line therapies for aGVHD. It is not immunosuppressive or nephrotoxic. Its use does not promote viral reactivation, and when used correctly, it is an effective steroidsparing agent for patients failing first-line therapy. From the extensive literature review and the current medical practices of our Expert Group, we were able to provide a consensus statement for patient selection for ECP treatment, a treatment schedule, monitoring protocol and patient assessment criteria for determining success or failure of treatment in aGVHD. This consensus statement aims to select those patients who are most likely to respond to ECP. Weekly assessments will allow nonresponders to be offered combination or alternative therapy and will ensure that treatment is delivered with maximum efficacy and discontinued at maximal response in responders. This consensus statement is a guideline for centres delivering ECP or setting up an aGVHD service. The standardisation of treatment across the UK and the introduction of a national ECP database will also allow treatment outcomes between centres to be compared. ECP should be considered with the other second-line agents for the treatment of steroid-refractory, steroid-dependent and steroid-intolerant patients with grades II–IV aGVHD DISCLAIMER While the advice and information in these guidelines is believed to be true and accurate at the time of going to press, neither the authors, the UK Photopheresis Group nor the publishers accept any legal responsibility for the content of these guidelines. CONFLICT OF INTEREST FLD, JJS and BES have received research funding, honoraria and speaker’s fees from Therakos. EDG has received honoraria and speaker’s fees from Therakos. PCT has received speaker fees from Therakos. KR has received sponsorship for attendance at conferences from Therakos. None of the other authors have declared any conflicts of interest.

ACKNOWLEDGEMENTS We are grateful to the members of UK Photopheresis Group in their support in preparing these guidelines.

AUTHOR CONTRIBUTIONS EDG (Y,A,B) and JJS (Y,A,B) reviewed the literature and wrote the initial draft of the manuscript. FD (A,B), BS (A,B), RM (A,B), DB (A,B), AG (A,B) and PT (A,B) reviewed the literature and revised the manuscript.

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REFERENCES 1 Edelson R, Berger C, Gasparro F, Jegasothy B, Heald P, Wintroub B et al. Treatment of cutaneous T-cell lymphoma by extracorporeal photochemotherapy. Preliminary results. New Engl J Med 1987; 316: 297–303. 2 Scarisbrick JJ, Taylor P, Holtick U, Makar Y, Douglas K, Berlin G et al. Photopheresis Expert Group UK. Consensus statement on the use of extracorporeal photopheresis for treatment of cutaneous T-cell lymphoma and chronic graft-versushost disease. Br J Dermatol 2008; 158: 659–678. 3 Martin PJ, Rizzo JD, Wingard JR, Ballen K, Curtin PT, Cutler C et al. First- and second-line systemic treatment of acute graft-versus-host disease: recommendations of the American Society of Blood and Marrow Transplantation. Biol. Blood Marrow Transplant 2012; 18: 1150–1163. 4 Jagasia M, Arora M, Flowers ME, Chao NJ, McCarthy PL, Cutler CS et al. Risk factors for acute GVHD and survival after hematopoietic cell transplantation. Blood 2012; 119: 296–307. 5 Couriel D, Saliba R, Hicks K, Ippoliti C, de Lima M, Hosing C et al. Tumor necrosis factor-alpha blockade for the treatment of aGvHD. Blood 2004; 104: 649–654. 6 Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE, Clift RA et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation 1974; 18: 295–304. 7 Gratwohl A, Hermans J, Apperley J, Arcese W, Bacigalupo A, Bandini G et al. Acute graft-versus-host disease: grade and outcome in patients with chronic myelogenous leukemia. Working Party Chronic Leukemia of the European Group for Blood and Marrow Transplantation. Blood 1995; 86: 813–818. 8 Dignan FL, Clark A, Amrolia P, Cornish J, Jackson G, Mahendra P et al. Diagnosis and management of acute graft-versus-host disease. Br J Haematol 2012; 158: 30–45. 9 MacMillan ML, Weisdorf DJ, Wagner JE, DeFor TE, Burns LJ, Ramsay NK et al. Response of 443 patients to steroids as primary therapy for acute graft-versushost disease: comparison of grading systems. Biol Blood Marrow Transplant 2002; 8: 387–394. 10 Van Lint MT, Uderzo C, Locasciulli A, Majolino I, Scimé R, Locatelli F et al. Early treatment of acute graft-versus-host disease with high- or low-dose 6-methylprednisolone: a multicenter randomized trial from the Italian Group for Bone Marrow Transplantation. Blood 1998; 92: 2288–2293. 11 Greinix HT, Volc-Platzer B, Rabitsch W, Gmeinhart B, Guevara-Pineda C, Kalhs P et al. Successful use of extracorporeal photochemotherapy in the treatment of severe acute and chronic graft-versus-host disease. Blood 1998; 92: 3098–3104. 12 Miller JL, Goodman SA, Stricklin GP, Lloyd EK. Extracorporeal Photochemotherapy in the Treatment of Graft-versus-Host Disease. IBMTR/ABMTR: Keystone, CO, USA, 1998. 13 Smith EP, Sniecinski I, Dagis AC, Parker PM, Snyder DS, Stein AS et al. Extracorporeal photochemotherapy for treatment of drug-resistant graft-vs-host disease. Biol Blood Marrow Transplant 1998; 4: 27–37. 14 Girardi M, McNiff JM, Heald PW. Extracorporeal photochemotherapy in human and murine graft-versus-host disease. J Dermatol Sci 1999; 19: 106–113. 15 Greinix HT, Volc-Platzer B, Kalhs P, Fischer G, Rosenmayr A, Keil F et al. Extracorporeal photochemotherapy in the treatment of severe steroid-refractory acute graft-versus-host disease: a pilot study. Blood 2000; 96: 2426–2431. 16 Salvaneschi L, Perotti C, Zecca M, Bernuzzi S, Viarengo G, Giorgiani G et al. Extracorporeal photochemotherapy for treatment of acute and chronic GVHD in childhood. Transfusion 2001; 41: 1299–1305. 17 Dall'Amico R, Messina C. Extracorporeal photochemotherapy for the treatment of graft-versus-host disease. Ther Apher 2002; 6: 296–304. 18 Greinix HT, Knobler RM, Worel N, Schneider B, Schneeberger A. The effect of intensified extracorporeal photochemotherapy on long-term survival in patients with severe acute graft-versus-host disease. Haematologica 2006; 91: 405–408. 19 Greinix HT, Worel N, Knobler R. Role of extracorporeal photopheresis (ECP) in treatment of steroid-refractory acute graft-versus-host disease. Biol Blood Marrow Transplant 2010; 16: 1747–1748; author reply 1749. 20 Garban F, Drillat P, Makowski C, Jacob MC, Richard MJ, Favrot M et al. Extracorporeal chemophototherapy for the treatment of graft-versus-host disease: hematologic consequences of short-term, intensive courses. Haematologica 2005; 90: 1096–1101. 21 Perfetti P, Carlier P, Strada P, Gualandi F, Occhini D, Van Lint MT et al. Extracorporeal photopheresis for the treatment of steroid refractory aGvHD. Bone Marrow Transplant 2008; 42: 609–617. 22 Besnier DP, Chabannes D, Mahé B, Mussini JM, Baranger TA, Muller JY et al. Treatment of graft-versus-host disease by extracorporeal photochemotherapy: a pilot study. Transplantation 1997; 64: 49–54. 23 Looks A, Fuchs D, Rulke D. Successful treatment of acute graft-versus-host disease after bone marrow transplantation in a 16-year-old girl with extracorporeal photopheresis. Onkologie 1997; 20: 340–342.

Bone Marrow Transplantation (2014) 1251 – 1258

Use of ECP in aGVHD E Das-Gupta et al

1258 24 Richter HI, Stege H, Ruzicka T, Soehngen D, Heyll A, Krutmann J. Extracorporeal photopheresis in the treatment of acute graft-versus-host disease. J Am Acad Dermatol 1997; 36: 787–789. 25 Das-Gupta E, Greinix, Jacobs R, Zhou L, Savani BN, Engelhard BG et al. Extracorporeal photopheresis as second-line treatment for acute graft-versus-host disease: Impact on six month freedom from treatment failure. (in press). 26 Jagasia M, Greinix H, Robin M, Das-Gupta E, Jacobs R, Savani BN et al. Extracorporeal photopheresis versus anticytokine therapy as a second-line treatment for steroid-refractory acute GVHD: a multicenter comparative analysis. Biol Blood Marrow Transplant 2013; 19: 1129–1133. 27 Messina C, Locatelli F, Lanino E, Uderzo C, Zacchello G, Cesaro S et al. Extracorporeal photochemotherapy for paediatric patients with graft-versus-host disease after haematopoietic stem cell transplantation. Br J Haematol 2003; 122: 118–127. 28 Berger M, Pessolano R, Albiani R, Asaftei S, Barat V, Carraro F et al. Extracorporeal photopheresis for steroid resistant graft versus host disease in pediatric patients: a pilot single institution report. J Pediatr Hematol Oncol 2007; 29: 678–687. 29 González Vicent M, Ramirez M, Sevilla J, Abad L, Díaz MA. Analysis of clinical outcome and survival in pediatric patients undergoing extracorporeal photopheresis for the treatment of steroid-refractory GVHD. J Pediatr Hematol Oncol 2010; 32: 589–593. 30 Kanold J, Merlin E, Halle P, Paillard C, Marabelle A, Rapatel C et al. Photopheresis in pediatric graft-versus-host disease after allogeneic marrow transplantation: clinical practice guidelines based on field experience and review of the literature. Transfusion 2007; 47: 2276–2289. 31 Calore E, Calò A, Tridello G, Cesaro S, Pillon M, Varotto S et al. Extracorporeal photochemotherapy may improve outcome in children with acute GVHD. Bone Marrow Transplant 2008; 42: 421–425. 32 Perotti C, Del Fante C, Tinelli C, Viarengo G, Scudeller L, Zecca M et al. Extracorporeal photochemotherapy in graft-versus-host disease: a longitudinal

Bone Marrow Transplantation (2014) 1251 – 1258

33

34

35

36

37

38

39

40

study on factors influencing the response and survival in pediatric patients. Transfusion 2010; 50: 1359–1369. Szczepiorkowski ZM, Winters JL, Bandarenko N, Kim HC, Linenberger ML, Marques MB et al. Guidelines on the use of therapeutic apheresis in clinical practice—evidence-based approach from the Apheresis Applications Committee of the American Society for Apheresis. J Clin Apher 2010; 25: 83–177. Szczepiorkowski ZM, Bandarenko N, Kim HC, Linenberger ML, Marques MB, Sarode R et al. Guidelines on the use of therapeutic apheresis in clinical practice: evidence-based approach from the Apheresis Applications Committee of the American Society for Apheresis. J Clin Apher 2007; 22: 106–175. Knobler R, Berlin G, Calzavara-Pinton P, Greinix H, Jaksch P, Laroche L et al. Guidelines on the use of extracorporeal photopheresis. J Eur Acad Dermatol Venereol 2014; 1: 1–37. McKenna KE, Whittaker S, Rhodes LE, Taylor P, Lloyd J, Ibbotson S et al. Evidence-based practice of photopheresis 1987–2001: a report of a workshop of the British Photodermatology Group and the U.K. Skin Lymphoma Group. Br J Dermatol 2006; 154: 7–20. Pierelli L, Perseghin P, Marchetti M, Messina C, Perotti C, Mazzoni A et al. Extracorporeal photopheresis for the treatment of acute and chronic graft-versushost disease in adults and children: best practice recommendations from an Italian Society of Hemapheresis and Cell Manipulation (SIdEM) and Italian Group for Bone Marrow Transplantation (GITMO) consensus process. Transfusion 2013; 53: 2340–2352. Apsner R, Uenver B, Sunder-Plassmann G, Knobler RM. Regional anticoagulation with acid citrate dextrose-A for extracorporeal photoimmunochemotherapy. Vox Sang 2002; 83: 222–226. Nedelcu E, Ziman A, Fernando LP, Cook K, Bumerts P, Schiller G. Exclusive use of acid citrate dextrose for anticoagulation during extracorporeal photopheresis in patients with contraindications to heparin: an effective protocol. J Clin Apher 2008; 23: 66–73. Sniecinski I, Smith B, Parker PM, Dagis A. Extracorporeal photochemotherapy for the treatment of graft-versus-host disease. J Clin Apher 1995; 10: 51.

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