Extracorporeal photopheresis for graft-versus-host disease

Transcription

1 Extracorporeal photopheresis for graft-versus-host disease Author: William Horsley March 2012

2 Summary Extracorporeal photopheresis is an intensive procedure which involves the removal and filtering of a proportion of a patient s blood, exposure to a light sensitive drug which will result in a reduced immune response from the white blood cells once they are returned to the patient. It is used for several indications including graft-versus-host disease. GvHD is a relatively common complication ranging in degrees of severity following a bone marrow transplant. It can be acute, chronic (occurring more than 100 days post-transplant) or both. ECP has been used in the management of GvHD, particularly chronic GvHD, for a relatively long time with the first documented reports emerging in the early 1990 s. There is a relatively large volume of evidence to support ECP in both acute and chronic GvHD in a range of patients. However, much of this evidence is of low quality, originating from often small non-comparative case series reports. Only one randomised comparative trial was identified, which measured outcomes in one dimension of GvHD and after a short follow-up of 12 weeks. The RCT did not demonstrate a significant benefit for ECP. The majority of the clinical evidence indicates patient improvement with ECP compared with baseline. Response rates are higher than expected in untreated patients. RCTs of ECP in acute and chronic GvHD are currently underway. ECP appears to present an acceptable adverse effect profile relative to the underlying condition. Treatment requires two day case appointments on consecutive days. Most NHS North East patients will need to travel to Rotherham for treatment and will therefore require an overnight stay. There is no definitive treatment regimen, with several variations evaluated in clinical studies. The standard regimen at the Rotherham centre is two-weekly for three months followed by monthly for three months, and then on an as required basis. ECP is a costly therapy, with maximum potential cost of 87,000 per patient for the first year. Actual costs will likely be less than this. The Rotherham centre estimates that the maximum likely cost is 45,000 per patient. Total patient volumes are likely to be small with indications that current referrals are of the order of about one patient per NHS North East PCT per annum. ECP may prove life-saving although this hasn t been demonstrated in a comparative study. North East Treatment Advisory Group, Mar

3 Introduction Graft-versus-host disease (GvHD) is an immunological disorder that affects many organ systems including the gastrointestinal tract, liver, skin and lungs. It is a common complication in patients who have had haematopoietic-cell transplantation (HCT), often referred to as a bone marrow transplant. HCT itself is an intensive treatment often used for high-risk blood cancers such as leukaemia. GvHD arises when the donor white blood cells begin attacking host cells. If left untreated GvHD can cause significant morbidity and mortality in affected patients. GvHD is usually distinguished between acute and chronic onset (agvhd and cgvhd respectively), with the boundary between the two terms set, somewhat arbitrarily, at 100-days post-transplant. agvhd is characterised by a generalised patchy skin rash, sickness, weight loss, loss of appetite, watery diarrhoea, severe abdominal pain, bloody diarrhoea, and jaundice. cgvhd may present with a wider range of symptoms and affected organs and includes symptoms such as alopecia (hair loss), skin thickening, nail loss, dry mouth and oral lesions, dry eyes, sore muscles and joints, raised liver enzymes, scarring of lung tissue with reduced lung function, pericarditis, and loss of blood cells (red, white, and platelets). Further details regarding the diagnosis of cgvhd are provided in appendix 1. GvHD, whether acute or chronic, is graded in severity from I (mild) through II (moderate), III (severe) to IV (very severe). The grade correlates to survival prognosis with 5-year survival of 25% for grade III and 5% for grade IV disease. The mainstay of treatment of GvHD is systemic steroid therapy, for example high-dose oral prednisolone. Sometimes intravenous steroids may be required. Topical steroids may be sufficient for less severe GvHD limited to the skin or mucosa. High doses of steroids may be required for prolonged periods of time, or cumulative doses from pulsed courses may be high, thus exposing patients to the known risks of steroid therapy, for example Cushing s syndrome, diabetes, weight gain, growth retardation, and osteoporosis. Steroid therapy is effective to varying degrees for a substantial proportion of patients. However some patients will not be able to tolerate high steroid doses for prolonged durations, or they become dependent on the steroids so that any tapering or withdrawal causes rebound GvHD, or the disease does not respond adequately. North East Treatment Advisory Group, Mar

4 Treatment options subsequent to steroid therapy are limited. Other immunosuppressant therapies may be tried, or newer biological therapies such as anti-tumour necrosis factor agents. Cyclosporin, or other calcineurin inhibitors, are usually prescribed prophylactically to prevent GvHD and in the event of disease emerging they are continued or increased. Extracorporeal photopheresis (ECP) is a relatively novel technique which involves the removal of a proportion of a patient s blood. The blood is then filtered and a proportion of white blood cells is removed in a total volume of about one pint (~550 ml). These are then incubated with a light-sensitive drug called 8-methoxypsoralen, exposed to ultraviolet light of a specific wavelength and then returned to the patient. The combination of the drug and light exposure will lead to the death of many of the white blood cells. The precise mode of action of ECP in GvHD is not known and appears to be complex. There are several different device and equipment manufacturers providing the equipment required for ECP. One of the leading companies in this field is Therakos and indeed the majority of published clinical experience appears to originate from use of the Therakos system. The NHS North East Treatment Advisory Group has been requested by a member commissioning organisation to conduct an appraisal of, and issue a recommendation for, the use of extracorporeal photopheresis in graft versus host disease. North East Treatment Advisory Group, Mar

5 Clinical evidence A substantial volume of evidence has been published on the use of ECP for several indications including chronic and acute GvHD. With respect to GvHD there is a greater volume with a longer history in chronic than in acute disease. However the evidence for both indications is limited with the majority of patients being included in non-randomised studies without a control group, thus amounting to a case series report, often performed retrospectively. Chronic GvHD A single prospective randomised controlled study was identified for ECP in cgvhd. 5 The study was described as a phase 2 randomised controlled trial and involved 48 patients treated with ECP plus standard therapy and 47 patients treated with standard therapy alone. Patients had skin symptoms of cgvhd which were inadequately controlled by steroid therapy. The primary outcome measure was the proportional (relative) change in total skin score of 10 body regions at week 12. The range of the total skin score was 0 to 50, with higher scores indicating worse disease. The score takes into account both the nature and extent of skin disruption. Patients received 25 sessions of ECP over 12 weeks (~ twice weekly on consecutive days). Rules were in place to permit cross-over if deemed clinically appropriate. After week 12, control patients could opt for up to 24 weeks of open-label ECP. 5 There were no obvious differences between patient groups following randomisation. Median age was about 42 years (range 13 to 67). The majority were white (91%) and male (59%). Over half of all patients were classified as steroid-dependent, 10 to 15% as steroid-refractory and about 30% as steroidintolerant. The median duration following transplant until diagnosis of cgvhd was 130 to 140 days (range 60 to 1,389 days). Over half of patients were diagnosed with progressive cgvhd, about 10% with quiescent and about ⅓ with de novo disease. Most (> 90%) had extensive disease. Median baseline total skin score was about 9.3 points (range 0.6 to 23.6). At baseline there was extensive use of immunosuppressive drugs, particularly mycophenolate and ciclosporin. Follow-up was good with 44 ECP and 41 control patients completing week 12. Thirty-six ECP patients completed week 24, and 25 out of 29 control patients completed ECP between weeks 12 and 36. North East Treatment Advisory Group, Mar

6 The median proportional change (reduction) in total skin score from baseline to week 12 was 14.5% with ECP and 8.5% with control (p = 0.48). At week 24, the reduction was 31.4% for ECP patients (not reported for control patients). The proportion of patients who reduced their steroid dose by more than 50% was 25% and 13% respectively (p = 0.13). The proportions of patients with an overall skin response to treatment at week 12 (i.e. complete or partial skin response) were 40% and 10% respectively (p = 0.002). 5 A comprehensive evidence review on the use of ECP for several indications was published in 2006 and included evidence up to With respect to cgvhd, the review does not appear to include any randomised controlled studies. Details of eight of the most recent reports are provided, and these include 68 patients (range 3 to 18 per report). Overall, 184 cases of cgvhd treated with ECP were identified in the literature. The most commonly involved organ was the skin which demonstrated a response rate of 75%, followed by liver (66%), lung (25%), gut (18%) and mucous membranes (68%). The review also states: 6 The majority of reports suggested that concurrent immunosuppression could be reduced during ECP therapy, and no increase in opportunistic infections was reported. Of the 21 deaths reported 18 were infection related and three were due to progressive liver GvHD; however, followup was variable and incomplete. In summary, there is fair evidence to support the use of ECP in cgvhd with cutaneous or mucosal involvement, but the evidence in hepatic disease is poor. There is fair evidence to support the rejection of ECP for gastrointestinal or pulmonary cgvhd. Other evidence on the efficacy and safety of ECP for cgvhd since 2001 is summarised in tables 1 and 3. A six-month randomised study of an intensive ECP regimen in moderate to severe cgvhd is currently underway and is not expected to be completed until February North East Treatment Advisory Group, Mar

7 Acute GvHD No published randomised studies in agvhd were identified. A comprehensive evidence review on the use of ECP for several indications was published in 2006 and included evidence up to With respect to agvhd, the review includes reports with a total of 32 cases. The only involved organs were (response rate) skin (58%) and liver (40%). The majority of the evidence originates from a single report and centre. The review concludes: 6 There is poor evidence to support the use of ECP for cutaneous or hepatic agvhd. The available evidence since 2001, consisting of case series reports, both prospective and retrospective, is summarised in table 2 and table 3. A multicentre international randomised study of ECP for agvhd in adults which included treatment centres in Rotherham, Newcastle and London was commenced in January 2006 but was terminated by June 2011 due to lack of recruitment. 8 A single-centre six-month randomised study of an intensive regimen of ECP for agvhd in patients with a body mass > 40 kg is currently underway. This is not expected to be completed until Safety The safety of ECP in GvHD is generally poorly reported in individual studies (see tables 1 to 3). In the randomised study in cutaneous cgvhd the most common adverse effects observed in the first 12 weeks were (ECP vs. control respectively); infection 53% and 44%, diarrhoea 20% in both groups, anaemia 25% and 6%, and nausea 18% and 12%. Serious adverse effects, mainly infections, occurred in 29% and 26% of patients respectively and none were considered related to ECP. Withdrawal during treatment occurred in seven and three patients respectively including one case of thrombocytopenia in an ECP patient. Four patients died during the first 12 weeks of the study, one in the ECP group and three in the control group. 5 In a review of ECP across multiple indications adverse effects are recorded at a rate typically < 1%, with nausea being the most common effect. No increase in the rate of cancer or infection has been observed. Mild transient treatmentrelated side effects include headache, fever, chills, and nausea. More severe adverse effects include hypotension, skin infections at site of venous access, septicaemia, anaemia, and clotting problems due to use of heparin flush. 3 North East Treatment Advisory Group, Mar

8 Table 1. Summary of clinical evidence for ECP in chronic GvHD (excluding randomised studies) Ref Study Patients Outcomes including safety 10 Case series. One cycle of ECP per 2 weeks. Mean duration of ECP: 8 months (range 2 to 25 months) 11 Case series. Mean 35 cycles per patient. 12 Retrospective case series. Two to four treatments per week, tapered to maintenance regimen of two treatments every two weeks. 13 Retrospective case series. ECP for at least 4 weeks; median of 36 sessions over a median of 5.3 months (range 1 to 28) 14 Prospective case series. One cycle of ECP per 2 weeks, or one cycle per week, for a median of 9 months (range 3 to 24). 15 Retrospective case series. Variable and decreasing intensity ECP regimen. Median duration of ECP was 17 months (range 3 to 44) 12 patients with cutaneous cgvhd despite prednisolone and other immunosuppressants. 32 patients with steroid-refractory cgvhd. 71 patients with steroid-dependent GvHD. 32 patients with steroid-dependent or refractory cutaneous cgvhd. 25 patients with steroid-refractory extensive cutaneous cgvhd 14 patients with extensive cutaneous cgvhd Mean daily dose of prednisolone reduced from 42 mg to 15 mg. Mean daily dose of cyclosporine (n = 3) reduced from 86 mg to 18 mg. Mean doses of other drugs not significantly reduced. 10 of 12 patients showed improvement in cutaneous symptoms; 7 of whom demonstrated a complete response. Overall positive outcome in 24 patients and overall negative outcome in 8 patients. ECP efficacy was determinant in 22% of case, good in 56% and ineffective in 22%. Overall response rate of 61%, complete response rate of 20%. Mortality rate 59% with median follow-up of 34 months (range 4 to 66) amongst survivors. Five-years after ECP overall survival was 19%. 18/28 patients on steroids achieved 50% dose reduction. 11/32 achieved a partial response. 7/32 achieved a complete response and 5 were sustained. 11/32 died after ECP. 8/32 surviving patients remain on ECP. 20/25 demonstrated improved cutaneous symptoms. 20/25 had steroid dose reduced or discontinued other immunosuppressant 0/25 had a complete response, 3/25 demonstrated no response, 6/25 had stable disease and 16/25 had a partial response. 3/14 had a complete cutaneous response. 4/14 had a partial cutaneous response. 7/14 had stable skin disease. Median response duration was 5 months (range 1 to 31). Longer-term follow-up: 7/14 continued with ECP; 3/14 lost to follow-up, 3/14 died; 1/14 discontinued due to complete response. Overall 5-year posttransplant survival was 77%. No attributable adverse effects. North East Treatment Advisory Group, Mar

9 Table 1. Continued from previous page. Ref Study Patients Outcomes including safety 16 Retrospective laboratory analyses; median follow-up 50 months (range 13 to 101), median number of ECP treatments was 26 (range 2 to 68). 17 Retrospective case series. One cycle of ECP every 2 to 4 weeks. Median follow-up 12 months and 16 cycles (range 12 to 36 cycles). 18 Combined review of evidence, all from case series reports. Variable ECP regimens utilised. Largest set (44/63) used mainly 1 cycle once weekly for 1 month, then once every 2 weeks for 2 months, and then monthly for at least 3 months. More intensive regimens were sometimes used. 19 Prospective case series. Six single courses during the first three weeks. If not complete response then continued with 1 course per week for six weeks. 20 Case series. ECP one cycle once every two weeks for three months. If response, then continued with one cycle every three weeks for three months, with tapering thereafter. 25 patients with cgvhd 14/25 had a good response to ECP. Two-year survival 88%. 11/25 had no response. Two-year survival 18%. 9/25 patients died; 2/14 responders and 7/11 non-responders. 8 patients with steroidrefractory extensive cgvhd 63 paediatric patients from five separate reports. 15 patients aged 14 to 62 with extensive, steroiddependent, immunosuppressantresisting cgvhd 14 patients, age 5 to 21 yrs, with cgvhd, 12 with extensive disease. 6/8 patients reported as experiencing a favourable outcome. No deaths. One patient developed severe thrombocytopenia. Response rate 63%, non-response rate 37%. Response rate by organ: Skin, 60%; liver, 73%; gut, 59%; lung, 47%; joint, 62%. 13/15 responded to treatment, 11/13 with complete response and 2/13 with a partial response. 12/12 patients with skin disease responded to treatment. Increase in haemoglobin levels and reduced need for blood transfusions. 4/14 patients had a complete response to ECP. 5/14 patients had a partial response to ECP. Maximal response occurred after a median of 6 months (range 3 to 26). 5/14 patients, all with extensive disease, did not respond to ECP, and three later died. North East Treatment Advisory Group, Mar

10 Table 1. Continued from previous page. Ref Study Patients Outcomes including safety 21 Prospective case series. One session weekly for three weeks and then gradually reduced for stabilised or responding patients. Follow-up range 5 to 108 months. 22 Case series. One cycle weekly for two weeks, then one cycle once every two weeks for six weeks, then monthly until response. Median 34 ECP sessions (range 16 to 43). Median follow-up: 59 months (range 8 to 145). 23 Case series. One cycle once every two weeks until response, possible to reduce to monthly cycles. Responses assessed after 6 months of treatment. 15 patients, age 5 to 18 yrs, with cgvhd. 12 with extensive disease. 23 paediatric patient, with cgvhd, mean age 11.8 yrs. 21 with extensive disease. 82 patients with mucocutaneous cgvhd, resistant, refractory or intolerant to steroids. 61% were male. Median age 45 years. Overall condition resolved for 4 patients, improved for 7, stabilised for 1, and worsened for 3. 5/15 patients died including 2 prior ECP-responders. 16/23 overall response. Overall response by organ: skin, 96%; liver,100%; gut, 75%; mucosae, 80%; eyes, 50%; joints, 50%; lung, 67%. 5/23 complete response, 11/23 partial response, 7/23 no response. 1 yr survival, 22/23. 5 yr survival, 19/23. 5 deaths by last follow-up. 69/82 patients were evaluable for response at 6 months. 6/82 had died and 7/82 had completed < 6 months of ECP. These 13 patients were counted as non-responders. 5/82 patients had a complete response, 60/82 had a partial response and 4/82 had stable disease. Over half of patients had a reduction in steroid dose. Four patients developed infusion-related infections, three patients required additional red cell transfusion, none developed iron deficiency anaemia and there were no other complications associated with ECP. Overall survival at 3 yrs post-ecp commencement was 69%. North East Treatment Advisory Group, Mar

11 Table 2. Summary of clinical evidence for ECP in acute GvHD Ref Study Patients Outcomes including safety 24 Prospective case series. One cycle every one or two weeks, then one cycle every two to four weeks. Duration of treatment; 0.5 to 25 months. 25 Retrospective comparative case series. One cycle once weekly for one month, then once every two weeks for two months, and then monthly for three months. 26 Retrospective case series. One cycle once weekly for one month, then once every two weeks for two months, and then monthly until response. 27 Combined review of evidence, all from case series reports. Variable ECP regimens utilised. Largest set (33/41) used mainly 1 cycle once weekly for 1 month, then once every 2 weeks for 2 months, and then monthly for at least 3 months. More intensive regimens were sometimes used. agvhd; median 8 cycles (range 2 to 20). 59 steroid-dependent and -refractory severe agvhd patients. 31 paediatric patients (age 1 to 18 yrs) with agvhd grade 2 to patients treated with ECP, 16 patients with good response to steroids maintained on standard therapy. 23 adult patients with steroid-refractory agvhd. 41 paediatric patients with agvhd from four separate reports. Complete response by affected organ: Skin 82%; liver 61%; gut 61%; Complete response by severity of disease: Grade 2, 86%; Grade 3, 55%; Grade 4, 30%. Transplant-related mortality at 4 yrs: 14% in non-responders; 73% in those with complete response to ECP for agvhd. Overall survival at 4 yrs: 11% in non-responders; 59% in those with complete response to ECP for agvhd. Complete response by day 100 post-transplant with standard therapy 56%, and 73% with ECP after 35 to 311 days on treatment. All other responses were partial responses in both groups (i.e. no nonresponders). Overall survival after 2 yrs was 57% with standard therapy and 85% with ECP. Infections occurred in 3/16 standard therapy patients and 4/15 ECP patients. Complete response rate was 12/23 (52%). Complete response by disease severity; Grade 2, 70%; Grade 3, 42%; Grade 4, 0%. Complete response by organ: Skin, 66%; gut, 40%; liver 27%. 10/23 patients died by day 92 post-ecp. One later death due to cgvhd. Response rate 73%, non-response rate 27%. Response rate by organ: Skin, 80%; liver, 59%; gut, 64%. North East Treatment Advisory Group, Mar

12 Table 2. Continued from previous page. Ref Study Patients Outcomes including safety 19 Prospective case series. Six single courses during the first three weeks. If not complete response then continued with 1 course per week for six weeks. 20 Case series. ECP three times weekly until clinical improvement. If response, then one cycle once every two weeks for three months with tapering thereafter. 21 Prospective case series. One session weekly for three weeks and then gradually reduced for stabilised or responding patients. Median follow-up 8.5 months (range 1 to 40). 22 Case series. Two to three sessions weekly until response. Median 18 ECP sessions (range 12 to 24). Median follow-up: 14 months (range 2 to 102). 12 patients aged 23 to 63 with steroidrefractory grade 2 to 4 agvhd. 9 patients, age 5 to 17 yrs, with steroidresistant grade 2 to 4 agvhd. 12 patients, age 4 to 18, with agvhd grade 2 to paediatric patients, mean age 9.9 yrs, with cgvhd grade 2 to 4. Response rate was 9/12. In total, up to six patients died within six months. 5/9 patients showed a complete response to EPC. 2/9 patients showed a partial response to EPC and progressed to cgvhd. 2/9 patients, both non-responders, died due to GvHD. 5/9 patients are alive and disease-free after median follow-up of 8 months post-transplant. Overall condition resolved for 7 patients, improved for 3 and worsened for 2. Response by organ: Skin, 9/10 complete and 1/10 partial; mucosal, no response 1/1; liver, complete 5/9, partial 1/9, no response 3/9; lung, complete 1/1; gut, complete 5/6, no response 1/6. 4/12 patients died. 34/50 overall response. Overall response by organ: skin, 83%; liver,67%; gut, 73%; mucosae, 88%; eyes, 50%; joints, 33%; lung, 0%. 16/50 complete response, 18/50 partial response, 16/50 no response. 1 yr survival, 32/50. 5 yr survival, 23/50. North East Treatment Advisory Group, Mar

13 Table 3. Summary of clinical evidence for ECP in mixed groups of acute and chronic GvHD patients Ref Study Patients Outcomes including safety 28 Case series. agvhd: One cycle weekly until response. cgvhd: One cycle once every two weeks until response. Follow-up: 2 to 43 months. Cycles: 2 to Scientific investigation. Mean number of ECP procedures was 20 (range 14 to 29). Median follow-up 24 months (range 20 to 28). 11 very low-weight paediatric patients; 7 with agvhd, 3 with cgvhd, 1 with a- & c- GvHD. 27 patients; 18 with cgvhd and 9 with agvhd. 5/11 patients died, three due to infection. Complete response rate by organ: Skin, 10/11; liver 3/4; gut, 5/8; lung, 0/6. All other responses were either partial or disease stable. Overall response rate: 19/27. Complete response rate: 15/27. Partial response rate: 4/27. North East Treatment Advisory Group, Mar

14 Guidelines and other recommendations No guidelines or protocols governing the use of photopheresis in GvHD for NHS North East patients are known to exist. Treatment access is usually secured via individual funding requests to a patient s PCT or directly to the NHS North East office of the North of England Specialised Commissioning Group. A UK-based team of clinicians published consensus guidelines on the use of ECP in cgvhd in These guidelines recommend ECP for patients with chronic extensive GvHD and who are refractory, dependent or intolerant of corticosteroids. The recommended ECP regimen is one cycle (two treatments on consecutive days) every two weeks. Therapy should be trialled for three months initially, and only those demonstrating improvement in GvHD or reduction in immunosuppression without flare-up of GvHD should continue. Patients achieving a partial response can be reduced to four-weekly intervals and continued until maximal response. Any progression of GvHD should result in withdrawal of ECP. Relapse of GvHD can be controlled with re-introduction of ECP, possibly using a more intensive regimen. The evidence review within this guideline included data published up until 2007 and therefore did not include the only randomised study by Flowers et al. 5,30 A policy from NORCOM, a collaborative commissioning group from five PCTs in South Yorkshire and North Derbyshire, was published in This policy recommended ECP for extensive steroid-refractory or intolerant mucosal, cutaneous or hepatic cgvhd. The current status of NORCOM or this specific policy is not clear. One of the four authors of the policy is the senior member within the ECP service at Rotherham General Hospital. 31 The NHS South Central Priorities Committee issued a policy statement in September 2009 indicating that ECP for cgvhd is a low priority. Specifically, the policy reports that the evidence for ECP in refractory cgvhd is weak and that no studies looking at the cost-effectiveness of ECP were identified. 32 The NHS West Midlands Strategic Commissioning Group published a policy on ECP for multiple indications including cgvhd in October This recommended ECP for cgvhd according to specific criteria; biopsy-proven, extensive, steroid-intolerant or refractory, cutaneous, mucosal, or hepatic disease following allogeneic or donor-lymphocyte infusion. This is essentially the same as the criteria developed in the 2004 NORCOM policy. The West Midlands policy stated that ECP for all other indications would not be routinely funded. Acute GvHD is not specifically named within the policy. 33 North East Treatment Advisory Group, Mar

15 Cost analysis There is no single defined regimen for ECP in GvHD. A commonly applied regimen in GvHD is two treatments, one each on consecutive days, constituting a single cycle, with each cycle repeated at two-weekly intervals initially for three to four months and then one cycle per month for at least another three months. The cycle interval can then be adjusted further according to response, or ECP can be discontinued. The number of cycles in the first three months is estimated at seven, followed by three further cycles in the following three months, constituting a minimum of 10 ECP cycles in the first six months of treatment. 34 ECP is not included within the NHS payment-by-results tariff. Department of Health guidance on NHS reference costs states that photopheresis is excluded as it is a highly specialist service. Only two providers are identified: Rotherham NHS Foundation Trust, and Guy s & St Thomas NHS Foundation Trust, London. 35 The nearest centre offering the treatment, and for which it is known that referrals are made for NHS North East patients, is at Rotherham General Hospital. 35,36 Detailed information, aimed equally at patients and clinicians, is available on a commercially registered website associated with the ECP service at Rotherham General Hospital. This provides information amongst other things relating to definitions of complete and partial responses, and criteria for continuing, tapering, and ceasing treatment. 34 A standard regimen is described which consists of two-weekly cycles for three months. Treatment for the following three months is determined by clinical response with frequency varying between twoweekly and monthly cycles. Treatment thereafter is determined by response varying from cessation, tapering, monthly or two-weekly cycles. It is therefore possible that a patient may remain on two-weekly cycles for a prolonged period of time or only receive treatment for six months. 34 The cost for the service with this provider is currently X,XXX per cycle. 36 Therefore the cost of an initial ten treatments spread over six months is XX,XXX. The cost for monthly cycles for three months is 10,008. The cost for two-weekly cycles for three months is 23,352. Depending on the clinical response observed at three, six or nine months, patients may remain on twoweekly cycles for a prolonged period, estimated at 87,000 per annum. The potential cost to commissioning organisations at the outset of treatment is therefore estimated to lie between 33,360 and 87,000 for the first year of treatment. North East Treatment Advisory Group, Mar

16 Rotherham NHS Foundation Trust has stated that the annual cost of treating a patient with photopheresis can be as much as 45,000 depending on the treatment schedule and response. There is no indication as to how this figure was derived. Many patients will not require on-going treatment although evidence to indicate the relative proportions of patients achieving specific responses at specific time points is not available. An average cost per patient has not been reliably estimated due to lack of data. Actual costs will vary widely depending on; patient response to treatment at specific time points, underlying health status, and adverse effects. 1-4,6 An approximation of the proportion of patients who will develop GvHD following an allogeneic bone marrow transplant is about 50%. However in practice this will vary depending on a number of factors such as histocompatibility between donor and recipient, recipient age, and haematological profile. 1-4,6 Accurate estimation is further confounded by some patients developing acute or chronic GvHD in isolation, and others developing acute leading to chronic GvHD. The number of NHS North East patients who might be eligible for ECP treatment is estimated at about 30 to 40 per annum, or about three per NHS North East PCT per annum. This is based on the number of allogeneic bone marrow transplants carried out for NHS North East patients between April 2010 and December 2011 (n = 122). 36 Annual incident allogeneic bone marrow transplant figures do not provide information concerning the size of the at-risk population (i.e. prevalence of GvHD is unknown). There will be some accumulation of annual patient cohorts which will, together, form the GvHD at risk population. cgvhd seldom occurs more than two-years post-transplant 2 therefore the maximum accumulation of at risk patients will extend to only two years, or up to about 80 patients. For some patients with GvHD the condition can be managed adequately with steroid therapy and they will not require subsequent treatments such as ECP. Again, there is little reliable evidence to indicate what proportion of patients will achieve adequate control of GvHD if they are treated with steroids. ECP is generally placed at a late stage in pathways for the treatment of GvHD. This will serve to reduce the number of patients who might require treatment. Due to the location of service providers substantial patient transport costs may be incurred in addition to the cost of treatment. It has not been possible to reliably estimate the potential patient transport costs. North East Treatment Advisory Group, Mar

17 Points to consider Photopheresis is an invasive therapy which has been used for many years in the management of GvHD, particularly chronic disease. Photopheresis must be delivered at a specialist centre, the nearest to NHS North East being at Rotherham General Hospital. This will impose certain constraints on patients. Overnight stays are provided in a local hotel which may not be a positive experience for all patients. Treatment is, initially at least, provided fortnightly and for three to four hours each in each session, 3 making further impositions on patients and their carers. There is a large volume of evidence for the use of ECP in both acute and chronic GvHD stretching back over many years. However the majority of this evidence is of low quality originating from case reports, and retrospective and prospective case series, many with limited follow-up and small numbers. Most of this evidence consistently demonstrates good overall response rates in patients following ECP. Overall, excluding the single published randomised study, there is low quality evidence that ECP is effective for the treatment of GvHD (tables 1-3). The patients in these studies were predominantly refractory to steroids and other immunosuppressive agents although these drugs were frequently continued concomitantly with ECP. Criteria for assessment of treatment response are variable although a partial response was often defined as 50% improvement from baseline and a complete response as the complete resolution of organ involvement. Follow-up was variable and often incomplete. ECP is not used in isolation of other therapies, and most patients will continue with steroid and immunosuppressant drugs. Many studies demonstrate that doses of concomitant drugs can be safely reduced with ECP. Only one randomised controlled trial of ECP has been published, in patients with cgvhd. This failed to demonstrate a significant difference between ECP and standard care after 12 weeks with respect to cutaneous symptoms or steroid doses. Most of the study outcomes were in favour of ECP. 5 ECP appears to present an acceptable adverse effect profile relative to the underlying condition although specific safety outcomes are poorly reported in most studies (tables 1-3). ECP is a costly therapy, estimated at a minimum of 33,500 for the first six months of therapy. The actual cost of therapy will depend on the intensity and duration of therapy, in turn determined largely by clinical response. Costs could, in theory, exceed 87,000 per patient per annum. Some patients could remain on treatment for prolonged periods although this is expected to be an exception. The total estimated annual patient volume has not been estimated due to absent, incomplete or unreliable data. Current referral volumes from NHS North East appear to be very low. North East Treatment Advisory Group, Mar

18 References 1. Ferrara JLM, Levine JE, Reddy P, Holler E. Graft-versus-host disease. Lancet 2009;373: BMJ Evidence Centre: Best Practice. Graft-versus-host disease. Updated October Scarisbrick J. Extracorporeal photopheresis: What is it and when should it be used? Clinical and Experimental Dermatology 2009;34: Penas PF, Zaman S. Many faces of graft-versus-host disease. Australasian Journal of Dermatology. 2010;51: Flowers MED, Apperley JF, van Beslen K et al. A multicenter prospective phase 2 randomized study of extracorporeal photopheresis for treatment of chronic graft-versus-host disease. Blood 2008;112(7): McKenna KE, Whittaker S, Rhodes LE et al. Evidence-based practice of photopheresis : a report of a workshop of the British Photodermatology Group and U.K. Skin Lymphoma Group. British Journal of Dermatology 2006;154(1): US National Institutes of Health. A safety and efficacy study of Uvadex and extracorporeal photopheresis (ECP) in chronic graft versus host disease US National Institutes of Health. Extracorporeal photoimmune therapy with UVADEX for the treatment of acute graft versus-host disease US National Institutes of Health. Photopheresis for the treatment of acute graft versus host disease Coyle TS et al. Steroid-sparing effect of extracorporeal photopheresis in the treatment of graft-vshost disease. Archives of dermatology 2004;140: Rubegni P et al. Role of extracorporeal photochemotherapy in patients with refractory chronic graft-versus-host disease. British Journal of Heamatology 2005;130: Couriel DR et al. Extracorporeal photochemotherapy for the treatment of steroid-resistant chronic GVHD. Blood 2006;107; Apisarnthanarax N et al. Extracorporeal photopheresis therapy in the management of steroidrefractory or steroid-dependent cutaneous chronic graft-versus-host disease after allogeneic stem cell transplantation: feasibility and results. Bone Marrow Transplantation 2003;31: Foss FM et al. Prospective study of extracorporeal photopheresis in steroid-refractory or steroidresistant extensive chronic graft-versus-host disease: analysis of response and survival incorporating prognostic factors. Bone Marrow Transplantation 2005;35: Bisaccia E et al. Treatment of extensive chronic graft-versus-host disease with extracorporeal photochemotherapy. Journal of Clinical Apheresis 2006;21: Perseghin P et al. Extracorporeal photochemotherapy for the treatment of chronic graft-versus-host disease: Trend for a possible cell dose-related effect? Therapeutic Apheresis and Dialysis 2007;11(2): Akhtari M et al. Receiver operating characteristic curve analysis of circulating blood dendritic cell precursors and T cells predicts response to extracorporeal photopheresis in patients with chronic graftversus-host disease. Transfusion 2010;50: Ilhan O et al. Extracorporeal photoimmunotherapy for the treatment of steroid refractory progressive chronic graft-versus-host disease. Transfusion and Apheresis Science 2004;30(3): Garban F et al. Extracorporeal chemophototherapy for the treatment of graft-versus-host disease: hematologic consequences of short-term, intensive courses. Haematologica 2005;90: Salvaneschi L et al. Extracorporeal photochemotherapy for treatment of acute and chronic GVHD in childhood. Transfusion 2001;41: North East Treatment Advisory Group, Mar

19 21. Kanold J 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: Perotti C et al. Extracorporeal photochemotherapy in graft-versus-host disease: a longitudinal study on factors influencing the response and survival in pediatric patients. Transfusion 2010;50: Dignan FL et al. Efficacy of bimonthly extracorporeal photopheresis in refractory chronic mucocutaneous GVHD. Bone Marrow Transplantation doi: /bmt Greinix HT et al. The effect of intensified extracorporeal photochemotherapy on long-term survival in patients with severe acute graft-versus-host disease. Haematologica 2006;91: Calore E et al. Extracorporeal photochemotherapy may improve outcome in children with acute GVHD. Bone Marrow Transplantation 2008;42: Perfetti P et al. Extracorporeal photopheresis for the treatment of steroid refractory acute GVHD. Bone Marrow Transplantation 2008;42: Kanold J et al. Update on extracorporeal photochemotherapy for graft-versus-host disease treatment. Bone Marrow Transplantation 2005;35:S Gonzalez-Vicent M et al. Extracorporeal photochemotherapy for steroid-refractory graft-versushost disease in low-weight pediatric patient: Immunomodulatory effects and clinical outcome. Haematologica 2008;93(8): Di Biaso I et al. Regulatory T cells and extracorporeal photochemotherapy: Correlation with clinical response and decreased frequency of proinflammatory T cells. Transplantation 2009;87: Scarisbrick JJ, Taylor P, Holtick U et al. U.K. consensus statement on the use of extracorporeal photopheresis for treatment of cutaneous T-cell lymphoma and chronic graft-versus-host disease. British Journal of Dermatology 2008;158: The ECP NORCOM Policy Development Group. A review of extracorporeal photopheresis for cancer and other diseases - version 3. July NHS South Central Priorities Committee. Policy statement number 158: Extra-corporeal photopheresis for the treatment of chronic graft versus host disease or cutaneous T cell lymphoma. September NHS West Midlands Strategic Commissioning Group. Commissioning policy (WM/21). Extracorporeal photopheresis (ECP) for erythrodermic cutaneous t cell lymphoma, sezary syndrome and graft versus host disease (GVHD). Version 1 October The Rotherham NHS Foundation Trust. Accessed February Department of Health. Reference costs guidance for 2011/12. January pdf 36. Data on file. North East Office; NHS North of England Specialised Commissioning Group. February Rotherham NHS Foundation Trust. Photopheresis. Information leaflet for NHS Commissioners. Date of preparation unknown. 38. Ferrara JLM, Deeg HJ. Mechanisms of disease: Graft-versus-host disease. New England Journal of Medicine 1991;324(10): Filipovich AH, Weisdorf D, Pavletic S et al. National Institute of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: 1. Diagnosis and staging working group report. Biology of Blood and Marrow Transplantation 2005;11: Author s declaration: The author has no relevant interests to declare. North East Treatment Advisory Group, Mar

20 Appendix 1. Clinical features of chronic graft versus host disease 38,39 Diagnostic (sufficient to establish cgvhd) Distinctive (seen in cgvhd but diagnostically insufficient alone) Other features Common to acute and chronic GvHD Skin Poikiloderma Lichen planus-like features Depigmentation Sweat impairment Ichythosis Erythema Maculopapular rash Morphea-like features Keratosis pilaris Pruririts Lichen sclerosus-like featues Hypo- or hyperpigmentation Nails Dystrophy Longitudinal ridging, splitting, or brittle nails Onycholysis Pterygium unguis Nail loss Scalp and body hair New onset of alopecia Scaling, papulosquamous lesions Thinning scalp hair with characteristic features Premature grey hair Mouth Lichen-type features Hyperkeratotic plaques Xerostomia Mucocele Gingivitis Mucositis Restriction of mouth opening from sclerosis Mucosal atrophy Pseudomembrances Erythema Pain Uclers Eyes Ulcers New onset dry, gritty, or painful eyes Cicatricial conjunctivitis Keratoconjunctivitis sicca Photophobia Periorbital hyperpigmentation Blepharitis Punctuate keratopathy Genitals Lichen planus-like features Vaginal scarring or stenosis Erosions Fissures Ulcers Gastrointestinal tract Oesophageal web Strictures or stenosis in the upper to mid third of the oesophagus Exocrine pancreatic insufficiency Anorexia Nausea Vomiting Weight loss Failure to three (infants and children) North East Treatment Advisory Group, Mar

21 Appendix 1. Continued from previous page Diagnostic (sufficient to establish cgvhd) Distinctive (seen in cgvhd but diagnostically insufficient alone) Other features Common to acute and chronic GvHD Liver Raised bilirubin or liver enzymes Lung Bronchitis obliterans diagnosed with biopsy Bronchiolitis obliterans diagnosed with function tests and radiology Bronchiolitis obliterans organising pneumonia Muscles and joints Fasciitis Joint stiffness or contractures secondary to sclerosis Myositis or polymyositis Oedema Muscle cramps Arthralgia or arthritis Blood and immune cells Thrombocytopenia Eosinophilia Lymphopenia Hypo- or hyper- gammaglobulinaemia Autoantibodies Other Pericardial or pleural effusions Ascites Peripheral neuropathy Nephrotic syndrome Myasthenia gravis Cardiac conduction abnormality or cardiomyopathy Limited cgvhd is described as disease with localised skin involvement, liver dysfunction, or both. Extensive cgvhd is described as disease with generalised skin involvement, or localised skin involvement or liver dysfunction plus any one of the following: aggressive hepatitis, bridging necrosis or cirrhosis; eye involvement, involvement of mucosalivary glands, mucosal involvement on lip biopsy, or involvement of other target organs. The diagnosis of cgvhd requires the following: 1. Distinction from agvhd. 2. Presence of at least one diagnostic clinical sign of cgvhd or presence of at least one distinctive manifestation confirmed by pertinent biopsy or other relevant tests. 3. Exclusion of other possible diagnoses. North East Treatment Advisory Group, Mar