Bone Marrow Transplantation (2014) 49, 704–708 & 2014 Macmillan Publishers Limited All rights reserved 0268-3369/14 www.nature.com/bmt
ORIGINAL ARTICLE
Impact of extracorporeal photopheresis on skin scores and quality of life in patients with steroid-refractory chronic GVHD FL Dignan1,2,3, S Aguilar1, JJ Scarisbrick4, BE Shaw2,3, MN Potter2, J Cavenagh5, JF Apperley6, AK Fielding7, A Pagliuca8, K Raj8, DI Marks9, A Peniket10, C Crawley11, MB Koh12 and FJ Child1 There are few prospective studies evaluating the role of extracorporeal photopheresis (ECP) in chronic GVHD (cGVHD) and only occasional reports of the effect of ECP on patients’ quality of life (QoL). We report a single-centre prospective study of patients undergoing fortnightly ECP for moderate or severe cGVHD. Response was assessed after 6 months of treatment using NIH scoring criteria and reduction in immunosuppression. QoL assessments were undertaken at baseline and at 6 months using the chronic GVHD symptom scale (cGVHD SS) and dermatology life quality index (DLQI). An intention-to-treat analysis showed that 19/38 (50%) of patients had a complete or partial response. Twenty-seven out of 38 patients completed 6 months of ECP treatment and 70% (19/27) had a complete or partial response. Eighty per cent of patients who completed 6 months of ECP treatment had a reduction in immunosuppression dose. A subset of patients completed QoL questionnaires. Seventeen out of 18 patients (94%) showed an improvement in scores. The mean cGVHD SS and mean DLQI score were both significantly lower after 6 months of ECP (22 compared with 36, P ¼ 0.012 and 3.4 compared with 6.9, P ¼ 0.009, respectively). This study confirms that ECP can lead to objective clinical responses and, in addition, may lead to an improvement in QoL in cGVHD. Bone Marrow Transplantation (2014) 49, 704–708; doi:10.1038/bmt.2014.21; published online 24 February 2014 Keywords: GVHD; extracorporeal photopheresis; quality of life
INTRODUCTION Extracorporeal photopheresis (ECP) is a cell-based immunemodulatory therapy, which was first reported by Edelson et al.1 for the treatment of erythrodermic cutaneous T-cell lymphoma. Our group and others have previously reported the efficacy of ECP in the management of cGVHD in retrospective studies.2–5 To date, there are only a few prospective studies of ECP for this condition6–9 and one randomised prospective trial.10 In addition, there are few data on the effect of ECP on quality of life (QoL) in patients with cGVHD. In a retrospective study, we have previously shown that a fortnightly regimen of ECP improved the clinical signs and symptoms of cGVHD.2 The aim of the current report was to prospectively assess the effect of a fortnightly schedule of ECP on the clinical signs and symptoms of cGVHD. The secondary aims were to assess the effect of ECP on health-related QoL and to assess response in terms of change in immunosuppression dose at 6 months. SUBJECTS AND METHODS Patient population From 1 October 2010 to 1 December 2011, a total of 52 consecutive patients commenced ECP treatment for GVHD at St John’s Institute of Dermatology, St Thomas’ Hospital in London, UK. Six patients were excluded from the study, as they were 18 years of age, did not give written informed consent or completed less than one cycle of treatment. Four
patients were excluded, as they had received ECP for acute GVHD elsewhere prior to referral and, at the time of initial clinic assessment, had no clinical signs of cGVHD. Four patients with isolated hepatic or gastrointestinal GVHD were excluded, as they had persistent acute GVHD and did not fulfil the National Institutes of Health (NIH) diagnostic criteria for cGVHD. Thirty-eight patients were eligible for the study. Referrals were made to the ECP unit at the discretion of the transplant physicians from centres in southern England, and the decision to offer treatment was made by the ECP unit. Patients had steroid-refractory or steroid-dependent disease or were intolerant of corticosteroids. All patients gave written informed consent to data collection and study participation. The study was approved by the Kent Research Ethics Committee (10/H1101/021). The clinical assessment of the symptoms and signs of cGVHD was based on the NIH consensus development project on criteria for clinical trials in cGVHD.11 The extent of cutaneous involvement was measured by the percentage of body surface area involved. This measurement was subdivided to include the percentage of erythema and the percentage of movable and non-movable sclerosis. The percentage of oral mucosa involved with lichenoid change or erythema was documented, and the number of ulcers or mucoceles in the mouth was also recorded. These findings were used to assign an oral score between 0 and 12. Patients were also asked to give an oral pain score between 0 and 10 and an ocular pain score between 0 and 10.
Response criteria Response was assessed after 6 months of ECP treatment using NIH criteria.11 Response was primarily assessed by one dermatologist to avoid inter-observer variation. A complete overall response was defined as a complete resolution of all symptoms and signs of cGVHD. A partial overall
1 St John’s Institute of Dermatology, St Thomas’ Hospital, London, UK; 2Section of Haemato-oncology, The Royal Marsden Hospital, Sutton, UK; 3University College London, Cancer Institute, London, UK; 4Department of Dermatology, Queen Elizabeth Hospital, Birmingham, UK; 5Department of Haematology, St Bartholomew’s Hospital, London, UK; 6Centre for Haematology, Imperial College, London, UK; 7Department of Haematology, University College London, London, UK; 8Department of Haematological Medicine, King’s College London Denmark Hill Campus, London, UK; 9Department of Haematology, University Hospitals Bristol NHS Foundation Trust, Bristol, UK; 10Department of Haematology, The Churchill Hospital, Oxford, UK; 11Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK and 12Department of Haematology, St George’s Hospital, London, UK. Correspondence: Dr FL Dignan, Manchester Royal Infirmary, Oxford Road, Manchester SM2 5PT, UK. E-mail: fl[email protected] Received 31 October 2013; revised 2 January 2014; accepted 6 January 2014; published online 24 February 2014
Photopheresis in GVHD FL Dignan et al
705 clinical response was defined as a 50–99% improvement in one organ when compared with baseline and no evidence of cGVHD progression in other organs. In addition, a minimal response was defined as a 25–49% response in one organ compared with baseline and no evidence of cGVHD progression in other organs. A mixed response was defined as a complete or partial response in one organ but progression of disease in another, and stable disease was defined as o25% improvement or o25% deterioration in cGVHD organ score. Progressive disease was defined as X25% deterioration in cGVHD organ score. Specifically, a partial response in cutaneous GVHD was defined as a 50–99% reduction in the body surface area involved. A partial response in oral GVHD was defined as a 50–99% reduction in oral score. Oral pain score was documented but was not used to determine response. A partial response in ocular GVHD was defined as a 50–99% reduction in ocular pain score. A partial response in joint GVHD was defined as a 50–99% improvement in range of movement. Many patients had multi-organ involvement, and the ability to reduce immunosuppression after 6 months of treatment was used as a global measure of response to ECP.
Table 1.
Characteristic Male Female Median age (range) years Diagnosis Acute leukaemia/myelodysplastic syndrome Lymphoma Chronic leukaemia Othera
QoL assessment Patients were asked to complete two questionnaires to assess healthrelated QoL at the start of treatment and at 3-monthly intervals thereafter. The first questionnaire was the Lee chronic GVHD symptom scale (cGVHD SS).1 A change of 6–7 points in cGVHD SS was considered to be a clinically significant change.11,12 The second was the dermatology QoL index (DLQI).13 A change of 3.2 points in the DLQI score was considered clinically significant. (http://www.dermatology.org.uk/quality/dlqi/quality-dlqi-faqs.html).
Extracorporeal photopheresis ECP treatment was administered on 2 consecutive days every 2 weeks until a partial clinical response was achieved and was then reduced to a monthly schedule as per the UK consensus statement.14 ECP was performed using the UVAR XTS or CELLEX photopheresis systems (Therakos, Ascot, UK). The technique has been described previously.2
Blood parameters Full blood count, urea and electrolytes and liver function tests were measured at the start of treatment and on the first day of each cycle of ECP treatment.
Statistical analysis Descriptive data were summarised using median values, ranges and percentages. The comparison of QoL scores at baseline and after 6 months of treatment was undertaken using the Student’s t-test. A P-value of o0.05 was considered significant.
RESULTS Demographics Patient characteristics are summarised in Table 1. The median time from transplant to commencing ECP was 1.7 years (3 months to 7 years and 9 months). In all, 30/38 patients had classic cGVHD, 5/38 had overlap syndrome and 3/38 had developed GVHD following DLI. Using the NIH global scoring system for cGVHD, 11/38 patients with cGVHD had severe disease and 27/38 had moderate disease.15 Twenty-two patients (58%) had a history of previous acute GVHD. Thirty-two patients had cutaneous disease. Twelve patients had sclerodermoid disease and 15 had lichenoid disease. Five patients had features of both sclerodermoid and lichenoid disease. Seventeen patients had oral disease. Other organs involved included liver (8), eyes (14), gut (7), lung (3) and muscles/joints (6). At the start of ECP, 36/38 patients were receiving immunosuppressive drugs. The remaining two patients had a previous history of steroid intolerance or steroid-refractory disease. The median dose of prednisolone at the start of treatment was 17.5 mg (2.5–140 mg). The median dose of cyclosporin was 200 mg daily (20–150 mg twice daily). The median dose of mycophenolate mofetil was 2 g per day (1–5 g). The number of immunosuppressive agents that each patient was receiving is detailed in Table 1. & 2014 Macmillan Publishers Limited
Patient characteristics (n ¼ 38) No. of patients, n (%) 19 (50) 19 (50) 47.2 (18.1–72.6) 27 (71) 4 (11) 5 (13) 2 (5)
Donor type Unrelated donor Sibling/related donor
24 (63) 14 (37)
Donor sex Male Female Unknown
22 (58) 11 (29) 5 (13)
Stem cell source Peripheral blood
38 (100)
Conditioning Full intensity Reduced intensity T-cell depletion
11 (29) 27 (71) 18 (47)
Number of GVHD treatments None One Two Three
2 9 20 7
(5) (24) (53) (18)
a
Plasma cell leukaemia, Waldenstrom’s macroglobulinaemia.
Duration of ECP treatment Eleven patients (11/38, 29%) were no longer receiving ECP at the time of analysis. Twenty-seven patients (27/38, 71%) were receiving ongoing treatment but had received at least 6 months of ECP. One patient had reduced the frequency of ECP to monthly after 3 months of ECP and the others all received fortnightly therapy. Response Clinical assessment of overall response. Twenty-seven out of 38 patients were evaluable for response following 6 months of ECP treatment. Two patients had died of infectious complications of the transplant and nine patients had completed less than 6 months of treatment because of relapse of underlying malignant disease (3), lack of efficacy of ECP (1), lost to follow-up as patient left UK (1), catheter-related infection (1), line thrombosis (1) and being too unwell to travel for treatment because of GVHD symptoms or related infections (2). This group included five patients with severe cGVHD and six with moderate cGVHD. An intention-to-treat analysis showed that 19/38 (50%) of patients had a complete or partial improvement in symptoms and signs of GVHD. Nineteen out of 27 (70%) patients who completed 6 months of ECP showed an overall complete or partial response. Two patients had a complete improvement and seventeen had a partial improvement. Three patients had progressive disease, two had a minimal response and three had a mixed response (complete response in one organ and progressive disease or new disease in another organ). Three patients developed signs of oral GVHD while on ECP treatment. Table 2 shows the response in each organ and the overall response. Bone Marrow Transplantation (2014) 704 – 708
Photopheresis in GVHD FL Dignan et al
706 Table 2.
GVHD subtype, response in each organ and overall response to ECP in patients who completed 6 months of treatment
Patient no.
GVHD subtype
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27
Classic Classic Classic Classic Classic Classic Classic Classic Classic Overlap Classic Classic Classic Classic Classic Classic Classic Classic Classic Overlap Classic Classic Classic Classic Classic Classic Overlap
Skin response
Oral response
PD SD PD PD CR MR CR PR PR SD
New
CR PR CR CR MR CR CR CR PR
Ocular response
Other (specify)
Other response
Gut Gut
CR CR
MS
SD
Gut
CR
MS Gut
SD CR
MS
PR
MS þ lung gut gynae
PR CR SD
lung MS
SD PR
Overall response Mixed Partial Progressive Progressive Complete Minimal Partial Partial Partial Partial Partial Partial Partial Partial Complete Minimal Partial Partial Partial Mixed Partial Partial Partial Mixed Progressive Partial Partial
MR PD CR
SD SD
SD CR SD PR New
CR PR CR PR SD MR PR CR SD
SD CR PR PD
New
PR
CR
SD MR
Abbreviations: CR ¼ complete response; MR ¼ minimal response; MS ¼ musculoskeletal; New ¼ new onset of disease while receiving ECP; PR = partial response; SD = stable disease.
40
100
% BSA baseline
35
80
% BSA baseline
60
% BSA 6 months
40 20 0 1
2
3
4
5
6
7
8
9 10 11 12 13
Patients
Figure 1. Skin scores in patients with lichenoid GVHD at baseline and after 6 months of ECP.
Clinical assessment of response in each organ. The skin scores for lichenoid and non-movable sclerodermoid disease are shown in Figures 1 and 2; the oral clinical and pain scores in Figure 3. In the 14 patients with lichenoid disease who completed 6 months of ECP treatment, 7 (50%) patients had a CR, 3 (22%) had a PR, 2 (14%) had stable disease and 2 (14%) had PD. In the 10 patients with non-movable sclerodermoid disease who completed 6 months of ECP treatment, 5 (50%) patients had a CR, 3 (30%) had a PR (including those where non-movable sclerosis had become movable), 1 (10%) had a minimal response and 1 (10%) had stable disease. In the 11 patients with oral disease who had completed 6 months of ECP treatment, 3 (27%) patients had a CR, 1 (9%) a PR, 1 (9%) had a minimal response, 5 (46%) had stable disease and 1 (9%) had progressive disease. Table 2 shows the response in each organ and the overall response. Change in immunosuppressive dose. Thirty-six patients were receiving immunosuppressive drugs at the start of ECP treatment. Twenty-five were reassessed at 6 months. The remaining 11 patients had either died (2) or completed less than 6 months of treatment (9). Assuming that the patients who died or did not complete 6 months of ECP did not respond to treatment, 20/36 Bone Marrow Transplantation (2014) 704 – 708
% BSA involved
% BSA involved
120
% BSA 6 months
30 25 20 15 10 5 0 1
2
3
4
5
6
7
8
9
10
Patient number
Figure 2. Skin scores in patients with non-movable sclerosis at baseline and after 6 months of ECP.
(55%) had a reduction in immunosuppression. Twenty out of 25 (80%) patients who completed 6 months of ECP had a reduction in immunosuppressive dose. Twenty-eight patients were receiving steroids at the start of ECP treatment. Nineteen patients were evaluable for assessment at 6 months. Seventeen patients (89%) had a dose reduction (5 stopped completely, 4X75% reduction, 4X50% reduction and 4o50% reduction). Two patients’ doses were stable and one patient had started steroids. The median dose was 10 mg (2–21.25 mg). Figure 4 is a flow chart showing change in dose in patients who were on steroids at the start of ECP treatment. Six out of 27 patients who were evaluable for assessment at 6 months were not receiving steroids at the start of ECP but were receiving an alternative immunosuppressive medication. Three patients remained on the same dose of cyclosporin, & 2014 Macmillan Publishers Limited
Photopheresis in GVHD FL Dignan et al
cGvHD score baseline
60 Oral exam score baseline Oral exam score 6 months Oral pain score baseline Oral pain score 6 months
cGvHD score
Oral scores
707 70
9 8 7 6 5 4 3 2 1 0
cGvHD score 6 months
50 40 30 20 10
1
2
3
4
5
6
7
8
0
9 10 11
1
Patient number
Total : 38 patients
Completed 6 months ECP: 27 patients
Steroids at start: 19 patients
Dose stable: 2 patients
Dose Increase: 0 patients
Stopped: 5 patients
≥ 75% dose reduction: 4 patients
≥ 50% dose reduction: 4 patients
< 50% dose reduction: 4 patients
Figure 4. A flow chart to show change in steroid dose after 6 months of ECP treatment.
mycophenolate mofetil and imatinib, respectively. Two patients had a 50% dose reduction in the dose of mycophenolate mofetil and one patient had a 75% dose reduction in ciclosporin. Two patients were not receiving immunosuppression at the start of ECP. One of these patients commenced steroids and the other did not start any additional agents during ECP treatment. QoL assessment. Eighteen patients completed the cGVHD SS at baseline and after 6 months of ECP treatment. The remaining patients did not return questionnaires. Baseline scores ranged from 8/120 to 64/120 with a median score of 38/120. Seventeen & 2014 Macmillan Publishers Limited
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18
Patient number
Figure 3. Oral examination and pain scores at baseline and after 6 months of ECP.
Dose Reduction: 17 patients
2
Figure 5. cGVHD symptom scores at baseline and after 6 months treatment.
out of 18 (94%) showed an improvement in scores and in 13/18 (72%) this was a clinically significant improvement. In the patients who had completed 6 months of ECP treatment and questionnaires at both time points (n ¼ 18), the mean cGVHD SS was significantly lower after 6 months of ECP (22 compared with 36, P ¼ 0.012). Figure 5 shows cGVHD SS scores at baseline and after 6 months of ECP. Sixteen patients completed the DLQI score at baseline and after 6 months of ECP treatment. Baseline scores ranged from 0/30 to 15/30 with a median score of 7/30. Thirteen out of 16 (81%) patients showed an improvement in scores and in 6/16 (38%) this was a clinically significant improvement. In the patients who had completed 6 months of ECP treatment and questionnaires at both time points (n ¼ 16), the mean DLQI score was significantly lower after 6 months of ECP treatment (3.4 compared with 6.9, P ¼ 0.009). Thirteen out of these 18 patients (72%) had a PR, one patient had a CR, two patients had a mixed response, one a minimal response and one patient had progressive disease. All the patients who had a CR or PR had an improvement in both scores except for one. The patients who had a minimal or mixed response had a clinically significant change in cGVHD scores but not in DLQI. The patient with progressive disease did not have a clinically significant change on cGVHD SS but did have on the DLQI. All the three patients with overlap syndrome achieved a clinically significant improvement on cGVHD SS but not on the DLQI. Toxicity. Low numbers of toxicities were found. Five patients developed indwelling catheter-related infections during the course of ECP treatment. One patient had a catheter-related thrombosis. One patient had an increase in red cell transfusion requirements, which was felt to be due to ECP alone. Five patients reported fatigue following treatment. DISCUSSION This paper reports a prospective evaluation of patients treated with fortnightly ECP for cGVHD. There are very few previous prospective studies of ECP in cGVHD because of the rarity of the disease, complexity of the treatment and absence of a standardised regimen. Previous reports have used a variety of schedules and have not reported the effect on QoL using validated questionnaires.6–10 This is the first prospective study to investigate the effect of a fortnightly schedule of ECP on clinical response and QoL in cGVHD using two validated questionnaires. This report benefits from a standardised regimen of ECP, prospective data accrual, lack of inter-observer variation and stringent use of NIH criteria. The results are remarkably consistent with the retrospective study we have reported previously.2 The earlier study showed that 77% of patients who completed 6 months of ECP treatment had a reduction in immunosuppression, and the prospective study showed that 80% of patients who completed 6 months of ECP had a reduction in immunosuppression. Bone Marrow Transplantation (2014) 704 – 708
Photopheresis in GVHD FL Dignan et al
708 One limitation of this study was the number of patients who did not complete 6 months of treatment (11/38, 29% of patients). This figure reflects the high morbidity and mortality rate in patients with steroid-refractory cGVHD.16 In addition, the ECP facility is an out-patient unit, so patients had to be well enough to attend treatment. Another limitation is that only a minority of patients who completed 6 months of treatment had visceral localisation of GVHD. This study population may represent a favourable cohort of patients who may be more likely to respond to ECP. A number of previous reports have reported an adverse impact of cGVHD on QoL following HSCT.17–22 To date, very few studies have investigated the impact of ECP on QoL. In the only randomized controlled trial to date, Flowers et al.10 used a Targeted Symptoms Assessment questionnaire, which included 12 questions to assess the effect of cutaneous, ocular and oral GVHD on various aspects of patients’ QoL. In this study, baseline scores were similar between the two arms, and after 12 weeks of ECP there was a significant difference between the median improvement in TSA scores in the ECP arm compared with the control arm (19% vs 2.5%, P ¼ 0.01). Other studies have used performance status as a surrogate marker of response.23,24 The current report used two validated questionnaires, the organ-specific DLQI13 and the cGVHD SS,12 to assess QoL at baseline and after 6 months of ECP treatment. This study showed a significant improvement in both cGVHD SS and DLQI scores in patients who completed 6 months of ECP, which is in keeping with previous reports of improvement in TSA and performance status. It is interesting to note that even the four patients who did not achieve a PR or CR in symptoms or signs of GVHD in this study obtained an improvement in either the cGVHD of DLQI QoL assessments. This finding may be due partly to the ‘placebo effect’ of regular medical and nursing assessments and the opportunity during ECP treatment to talk to other patients with similar problems. Another limitation is possible selection bias because of the fact that the patients who chose to complete the questionnaires may have been the ones who had noticed an improvement in QoL. In conclusion, this paper reports on a prospective study of the role of fortnightly ECP in managing patients with cGVHD. The findings suggest that our previously reported data from a retrospective analysis are reproducible in a prospective cohort of patients, with 80% of patients who completed 6 months of ECP having a reduction in immunosuppression. In addition, it adds to the current literature by suggesting that ECP may help to improve QoL as assessed by two validated questionnaires. Further randomised studies are required to assess the optimal regimen of ECP and the effect of the treatment on patients’ QoL and should aim to include a longer follow-up period. CONFLICT OF INTEREST FLD has received research funding, honoraria and speakers’ fees from Therakos, a Johnson and Johnson company. BES, JFA and JJS have received honoraria and speakers’ fees from Therakos, a Johnson and Johnson company. FJC and KR have received honoraria from Therakos, a Johnson and Johnson company.
ACKNOWLEDGEMENTS We wish to thank Stephanie Lee and Andrew Finlay for their permission to use the cGVHD SS and DLQI questionnaires. JFA is grateful for the support from the NIHR Biomedical Research Centre funding scheme.
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Bone Marrow Transplantation (2014) 704 – 708
3 Child FJ, Ratnavel R, Watkins P, Samson D, Apperley J, Ball J et al. Extracorporeal photopheresis (ECP) in the treatment of chronic graft-versus-host disease (GVHD). Bone Marrow Transplant 1999; 23: 881–887. 4 Couriel DR, Hosing C, Saliba R, Shpall EJ, Anderlini P, Rhodes B et al. Extracorporeal photochemotherapy for the treatment of steroid-resistant chronic GVHD. Blood 2006; 107: 3074–3080. 5 Jagasia MH, Savani BN, Stricklin G, Engelhardt B, Kassim A, Dixon S et al. Classic and overlap chronic graft-versus-host disease (cGVHD) is associated with superior outcome after extracorporeal photopheresis (ECP). Biol Blood Marrow Transplant 2009; 15: 1288–1295. 6 Foss FM, DiVenuti GM, Chin K, Sprague K, Grodman H, Klein A et al. Prospective study of extracorporeal photopheresis in steroid-refractory or steroid-resistant extensive chronic graft-versus-host disease: analysis of response and survival incorporating prognostic factors. 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A multicenter prospective phase 2 randomized study of extracorporeal photopheresis for treatment of chronic graft-versus-host disease. Blood 2008; 112: 2667–2674. 11 Pavletic SZ, Martin P, Lee SJ, Mitchell S, Jacobsohn D, Cowen EW et al. Response Criteria Working Group. Measuring therapeutic response in chronic graft-versushost disease: National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IV. Response Criteria Working Group report. Biol Blood Marrow Transplant 2006; 12: 252–266. 12 Lee S, Cook EF, Soiffer R, Antin JH. Development and validation of a scale to measure symptoms of chronic graft-versus-host disease. Biol Blood Marrow Transplant 2002; 8: 444–452. 13 Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI)--a simple practical measure for routine clinical use. Clin Exp Dermatol 1994; 19: 210–216. 14 Scarisbrick JJ, Taylor P, Holtick U, Makar Y, Douglas K, Berlin G et al. Photopheresis Expert Group. 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& 2014 Macmillan Publishers Limited
ORIGINAL ARTICLE
Impact of extracorporeal photopheresis on skin scores and quality of life in patients with steroid-refractory chronic GVHD FL Dignan1,2,3, S Aguilar1, JJ Scarisbrick4, BE Shaw2,3, MN Potter2, J Cavenagh5, JF Apperley6, AK Fielding7, A Pagliuca8, K Raj8, DI Marks9, A Peniket10, C Crawley11, MB Koh12 and FJ Child1 There are few prospective studies evaluating the role of extracorporeal photopheresis (ECP) in chronic GVHD (cGVHD) and only occasional reports of the effect of ECP on patients’ quality of life (QoL). We report a single-centre prospective study of patients undergoing fortnightly ECP for moderate or severe cGVHD. Response was assessed after 6 months of treatment using NIH scoring criteria and reduction in immunosuppression. QoL assessments were undertaken at baseline and at 6 months using the chronic GVHD symptom scale (cGVHD SS) and dermatology life quality index (DLQI). An intention-to-treat analysis showed that 19/38 (50%) of patients had a complete or partial response. Twenty-seven out of 38 patients completed 6 months of ECP treatment and 70% (19/27) had a complete or partial response. Eighty per cent of patients who completed 6 months of ECP treatment had a reduction in immunosuppression dose. A subset of patients completed QoL questionnaires. Seventeen out of 18 patients (94%) showed an improvement in scores. The mean cGVHD SS and mean DLQI score were both significantly lower after 6 months of ECP (22 compared with 36, P ¼ 0.012 and 3.4 compared with 6.9, P ¼ 0.009, respectively). This study confirms that ECP can lead to objective clinical responses and, in addition, may lead to an improvement in QoL in cGVHD. Bone Marrow Transplantation (2014) 49, 704–708; doi:10.1038/bmt.2014.21; published online 24 February 2014 Keywords: GVHD; extracorporeal photopheresis; quality of life
INTRODUCTION Extracorporeal photopheresis (ECP) is a cell-based immunemodulatory therapy, which was first reported by Edelson et al.1 for the treatment of erythrodermic cutaneous T-cell lymphoma. Our group and others have previously reported the efficacy of ECP in the management of cGVHD in retrospective studies.2–5 To date, there are only a few prospective studies of ECP for this condition6–9 and one randomised prospective trial.10 In addition, there are few data on the effect of ECP on quality of life (QoL) in patients with cGVHD. In a retrospective study, we have previously shown that a fortnightly regimen of ECP improved the clinical signs and symptoms of cGVHD.2 The aim of the current report was to prospectively assess the effect of a fortnightly schedule of ECP on the clinical signs and symptoms of cGVHD. The secondary aims were to assess the effect of ECP on health-related QoL and to assess response in terms of change in immunosuppression dose at 6 months. SUBJECTS AND METHODS Patient population From 1 October 2010 to 1 December 2011, a total of 52 consecutive patients commenced ECP treatment for GVHD at St John’s Institute of Dermatology, St Thomas’ Hospital in London, UK. Six patients were excluded from the study, as they were 18 years of age, did not give written informed consent or completed less than one cycle of treatment. Four
patients were excluded, as they had received ECP for acute GVHD elsewhere prior to referral and, at the time of initial clinic assessment, had no clinical signs of cGVHD. Four patients with isolated hepatic or gastrointestinal GVHD were excluded, as they had persistent acute GVHD and did not fulfil the National Institutes of Health (NIH) diagnostic criteria for cGVHD. Thirty-eight patients were eligible for the study. Referrals were made to the ECP unit at the discretion of the transplant physicians from centres in southern England, and the decision to offer treatment was made by the ECP unit. Patients had steroid-refractory or steroid-dependent disease or were intolerant of corticosteroids. All patients gave written informed consent to data collection and study participation. The study was approved by the Kent Research Ethics Committee (10/H1101/021). The clinical assessment of the symptoms and signs of cGVHD was based on the NIH consensus development project on criteria for clinical trials in cGVHD.11 The extent of cutaneous involvement was measured by the percentage of body surface area involved. This measurement was subdivided to include the percentage of erythema and the percentage of movable and non-movable sclerosis. The percentage of oral mucosa involved with lichenoid change or erythema was documented, and the number of ulcers or mucoceles in the mouth was also recorded. These findings were used to assign an oral score between 0 and 12. Patients were also asked to give an oral pain score between 0 and 10 and an ocular pain score between 0 and 10.
Response criteria Response was assessed after 6 months of ECP treatment using NIH criteria.11 Response was primarily assessed by one dermatologist to avoid inter-observer variation. A complete overall response was defined as a complete resolution of all symptoms and signs of cGVHD. A partial overall
1 St John’s Institute of Dermatology, St Thomas’ Hospital, London, UK; 2Section of Haemato-oncology, The Royal Marsden Hospital, Sutton, UK; 3University College London, Cancer Institute, London, UK; 4Department of Dermatology, Queen Elizabeth Hospital, Birmingham, UK; 5Department of Haematology, St Bartholomew’s Hospital, London, UK; 6Centre for Haematology, Imperial College, London, UK; 7Department of Haematology, University College London, London, UK; 8Department of Haematological Medicine, King’s College London Denmark Hill Campus, London, UK; 9Department of Haematology, University Hospitals Bristol NHS Foundation Trust, Bristol, UK; 10Department of Haematology, The Churchill Hospital, Oxford, UK; 11Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK and 12Department of Haematology, St George’s Hospital, London, UK. Correspondence: Dr FL Dignan, Manchester Royal Infirmary, Oxford Road, Manchester SM2 5PT, UK. E-mail: fl[email protected] Received 31 October 2013; revised 2 January 2014; accepted 6 January 2014; published online 24 February 2014
Photopheresis in GVHD FL Dignan et al
705 clinical response was defined as a 50–99% improvement in one organ when compared with baseline and no evidence of cGVHD progression in other organs. In addition, a minimal response was defined as a 25–49% response in one organ compared with baseline and no evidence of cGVHD progression in other organs. A mixed response was defined as a complete or partial response in one organ but progression of disease in another, and stable disease was defined as o25% improvement or o25% deterioration in cGVHD organ score. Progressive disease was defined as X25% deterioration in cGVHD organ score. Specifically, a partial response in cutaneous GVHD was defined as a 50–99% reduction in the body surface area involved. A partial response in oral GVHD was defined as a 50–99% reduction in oral score. Oral pain score was documented but was not used to determine response. A partial response in ocular GVHD was defined as a 50–99% reduction in ocular pain score. A partial response in joint GVHD was defined as a 50–99% improvement in range of movement. Many patients had multi-organ involvement, and the ability to reduce immunosuppression after 6 months of treatment was used as a global measure of response to ECP.
Table 1.
Characteristic Male Female Median age (range) years Diagnosis Acute leukaemia/myelodysplastic syndrome Lymphoma Chronic leukaemia Othera
QoL assessment Patients were asked to complete two questionnaires to assess healthrelated QoL at the start of treatment and at 3-monthly intervals thereafter. The first questionnaire was the Lee chronic GVHD symptom scale (cGVHD SS).1 A change of 6–7 points in cGVHD SS was considered to be a clinically significant change.11,12 The second was the dermatology QoL index (DLQI).13 A change of 3.2 points in the DLQI score was considered clinically significant. (http://www.dermatology.org.uk/quality/dlqi/quality-dlqi-faqs.html).
Extracorporeal photopheresis ECP treatment was administered on 2 consecutive days every 2 weeks until a partial clinical response was achieved and was then reduced to a monthly schedule as per the UK consensus statement.14 ECP was performed using the UVAR XTS or CELLEX photopheresis systems (Therakos, Ascot, UK). The technique has been described previously.2
Blood parameters Full blood count, urea and electrolytes and liver function tests were measured at the start of treatment and on the first day of each cycle of ECP treatment.
Statistical analysis Descriptive data were summarised using median values, ranges and percentages. The comparison of QoL scores at baseline and after 6 months of treatment was undertaken using the Student’s t-test. A P-value of o0.05 was considered significant.
RESULTS Demographics Patient characteristics are summarised in Table 1. The median time from transplant to commencing ECP was 1.7 years (3 months to 7 years and 9 months). In all, 30/38 patients had classic cGVHD, 5/38 had overlap syndrome and 3/38 had developed GVHD following DLI. Using the NIH global scoring system for cGVHD, 11/38 patients with cGVHD had severe disease and 27/38 had moderate disease.15 Twenty-two patients (58%) had a history of previous acute GVHD. Thirty-two patients had cutaneous disease. Twelve patients had sclerodermoid disease and 15 had lichenoid disease. Five patients had features of both sclerodermoid and lichenoid disease. Seventeen patients had oral disease. Other organs involved included liver (8), eyes (14), gut (7), lung (3) and muscles/joints (6). At the start of ECP, 36/38 patients were receiving immunosuppressive drugs. The remaining two patients had a previous history of steroid intolerance or steroid-refractory disease. The median dose of prednisolone at the start of treatment was 17.5 mg (2.5–140 mg). The median dose of cyclosporin was 200 mg daily (20–150 mg twice daily). The median dose of mycophenolate mofetil was 2 g per day (1–5 g). The number of immunosuppressive agents that each patient was receiving is detailed in Table 1. & 2014 Macmillan Publishers Limited
Patient characteristics (n ¼ 38) No. of patients, n (%) 19 (50) 19 (50) 47.2 (18.1–72.6) 27 (71) 4 (11) 5 (13) 2 (5)
Donor type Unrelated donor Sibling/related donor
24 (63) 14 (37)
Donor sex Male Female Unknown
22 (58) 11 (29) 5 (13)
Stem cell source Peripheral blood
38 (100)
Conditioning Full intensity Reduced intensity T-cell depletion
11 (29) 27 (71) 18 (47)
Number of GVHD treatments None One Two Three
2 9 20 7
(5) (24) (53) (18)
a
Plasma cell leukaemia, Waldenstrom’s macroglobulinaemia.
Duration of ECP treatment Eleven patients (11/38, 29%) were no longer receiving ECP at the time of analysis. Twenty-seven patients (27/38, 71%) were receiving ongoing treatment but had received at least 6 months of ECP. One patient had reduced the frequency of ECP to monthly after 3 months of ECP and the others all received fortnightly therapy. Response Clinical assessment of overall response. Twenty-seven out of 38 patients were evaluable for response following 6 months of ECP treatment. Two patients had died of infectious complications of the transplant and nine patients had completed less than 6 months of treatment because of relapse of underlying malignant disease (3), lack of efficacy of ECP (1), lost to follow-up as patient left UK (1), catheter-related infection (1), line thrombosis (1) and being too unwell to travel for treatment because of GVHD symptoms or related infections (2). This group included five patients with severe cGVHD and six with moderate cGVHD. An intention-to-treat analysis showed that 19/38 (50%) of patients had a complete or partial improvement in symptoms and signs of GVHD. Nineteen out of 27 (70%) patients who completed 6 months of ECP showed an overall complete or partial response. Two patients had a complete improvement and seventeen had a partial improvement. Three patients had progressive disease, two had a minimal response and three had a mixed response (complete response in one organ and progressive disease or new disease in another organ). Three patients developed signs of oral GVHD while on ECP treatment. Table 2 shows the response in each organ and the overall response. Bone Marrow Transplantation (2014) 704 – 708
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706 Table 2.
GVHD subtype, response in each organ and overall response to ECP in patients who completed 6 months of treatment
Patient no.
GVHD subtype
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27
Classic Classic Classic Classic Classic Classic Classic Classic Classic Overlap Classic Classic Classic Classic Classic Classic Classic Classic Classic Overlap Classic Classic Classic Classic Classic Classic Overlap
Skin response
Oral response
PD SD PD PD CR MR CR PR PR SD
New
CR PR CR CR MR CR CR CR PR
Ocular response
Other (specify)
Other response
Gut Gut
CR CR
MS
SD
Gut
CR
MS Gut
SD CR
MS
PR
MS þ lung gut gynae
PR CR SD
lung MS
SD PR
Overall response Mixed Partial Progressive Progressive Complete Minimal Partial Partial Partial Partial Partial Partial Partial Partial Complete Minimal Partial Partial Partial Mixed Partial Partial Partial Mixed Progressive Partial Partial
MR PD CR
SD SD
SD CR SD PR New
CR PR CR PR SD MR PR CR SD
SD CR PR PD
New
PR
CR
SD MR
Abbreviations: CR ¼ complete response; MR ¼ minimal response; MS ¼ musculoskeletal; New ¼ new onset of disease while receiving ECP; PR = partial response; SD = stable disease.
40
100
% BSA baseline
35
80
% BSA baseline
60
% BSA 6 months
40 20 0 1
2
3
4
5
6
7
8
9 10 11 12 13
Patients
Figure 1. Skin scores in patients with lichenoid GVHD at baseline and after 6 months of ECP.
Clinical assessment of response in each organ. The skin scores for lichenoid and non-movable sclerodermoid disease are shown in Figures 1 and 2; the oral clinical and pain scores in Figure 3. In the 14 patients with lichenoid disease who completed 6 months of ECP treatment, 7 (50%) patients had a CR, 3 (22%) had a PR, 2 (14%) had stable disease and 2 (14%) had PD. In the 10 patients with non-movable sclerodermoid disease who completed 6 months of ECP treatment, 5 (50%) patients had a CR, 3 (30%) had a PR (including those where non-movable sclerosis had become movable), 1 (10%) had a minimal response and 1 (10%) had stable disease. In the 11 patients with oral disease who had completed 6 months of ECP treatment, 3 (27%) patients had a CR, 1 (9%) a PR, 1 (9%) had a minimal response, 5 (46%) had stable disease and 1 (9%) had progressive disease. Table 2 shows the response in each organ and the overall response. Change in immunosuppressive dose. Thirty-six patients were receiving immunosuppressive drugs at the start of ECP treatment. Twenty-five were reassessed at 6 months. The remaining 11 patients had either died (2) or completed less than 6 months of treatment (9). Assuming that the patients who died or did not complete 6 months of ECP did not respond to treatment, 20/36 Bone Marrow Transplantation (2014) 704 – 708
% BSA involved
% BSA involved
120
% BSA 6 months
30 25 20 15 10 5 0 1
2
3
4
5
6
7
8
9
10
Patient number
Figure 2. Skin scores in patients with non-movable sclerosis at baseline and after 6 months of ECP.
(55%) had a reduction in immunosuppression. Twenty out of 25 (80%) patients who completed 6 months of ECP had a reduction in immunosuppressive dose. Twenty-eight patients were receiving steroids at the start of ECP treatment. Nineteen patients were evaluable for assessment at 6 months. Seventeen patients (89%) had a dose reduction (5 stopped completely, 4X75% reduction, 4X50% reduction and 4o50% reduction). Two patients’ doses were stable and one patient had started steroids. The median dose was 10 mg (2–21.25 mg). Figure 4 is a flow chart showing change in dose in patients who were on steroids at the start of ECP treatment. Six out of 27 patients who were evaluable for assessment at 6 months were not receiving steroids at the start of ECP but were receiving an alternative immunosuppressive medication. Three patients remained on the same dose of cyclosporin, & 2014 Macmillan Publishers Limited
Photopheresis in GVHD FL Dignan et al
cGvHD score baseline
60 Oral exam score baseline Oral exam score 6 months Oral pain score baseline Oral pain score 6 months
cGvHD score
Oral scores
707 70
9 8 7 6 5 4 3 2 1 0
cGvHD score 6 months
50 40 30 20 10
1
2
3
4
5
6
7
8
0
9 10 11
1
Patient number
Total : 38 patients
Completed 6 months ECP: 27 patients
Steroids at start: 19 patients
Dose stable: 2 patients
Dose Increase: 0 patients
Stopped: 5 patients
≥ 75% dose reduction: 4 patients
≥ 50% dose reduction: 4 patients
< 50% dose reduction: 4 patients
Figure 4. A flow chart to show change in steroid dose after 6 months of ECP treatment.
mycophenolate mofetil and imatinib, respectively. Two patients had a 50% dose reduction in the dose of mycophenolate mofetil and one patient had a 75% dose reduction in ciclosporin. Two patients were not receiving immunosuppression at the start of ECP. One of these patients commenced steroids and the other did not start any additional agents during ECP treatment. QoL assessment. Eighteen patients completed the cGVHD SS at baseline and after 6 months of ECP treatment. The remaining patients did not return questionnaires. Baseline scores ranged from 8/120 to 64/120 with a median score of 38/120. Seventeen & 2014 Macmillan Publishers Limited
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18
Patient number
Figure 3. Oral examination and pain scores at baseline and after 6 months of ECP.
Dose Reduction: 17 patients
2
Figure 5. cGVHD symptom scores at baseline and after 6 months treatment.
out of 18 (94%) showed an improvement in scores and in 13/18 (72%) this was a clinically significant improvement. In the patients who had completed 6 months of ECP treatment and questionnaires at both time points (n ¼ 18), the mean cGVHD SS was significantly lower after 6 months of ECP (22 compared with 36, P ¼ 0.012). Figure 5 shows cGVHD SS scores at baseline and after 6 months of ECP. Sixteen patients completed the DLQI score at baseline and after 6 months of ECP treatment. Baseline scores ranged from 0/30 to 15/30 with a median score of 7/30. Thirteen out of 16 (81%) patients showed an improvement in scores and in 6/16 (38%) this was a clinically significant improvement. In the patients who had completed 6 months of ECP treatment and questionnaires at both time points (n ¼ 16), the mean DLQI score was significantly lower after 6 months of ECP treatment (3.4 compared with 6.9, P ¼ 0.009). Thirteen out of these 18 patients (72%) had a PR, one patient had a CR, two patients had a mixed response, one a minimal response and one patient had progressive disease. All the patients who had a CR or PR had an improvement in both scores except for one. The patients who had a minimal or mixed response had a clinically significant change in cGVHD scores but not in DLQI. The patient with progressive disease did not have a clinically significant change on cGVHD SS but did have on the DLQI. All the three patients with overlap syndrome achieved a clinically significant improvement on cGVHD SS but not on the DLQI. Toxicity. Low numbers of toxicities were found. Five patients developed indwelling catheter-related infections during the course of ECP treatment. One patient had a catheter-related thrombosis. One patient had an increase in red cell transfusion requirements, which was felt to be due to ECP alone. Five patients reported fatigue following treatment. DISCUSSION This paper reports a prospective evaluation of patients treated with fortnightly ECP for cGVHD. There are very few previous prospective studies of ECP in cGVHD because of the rarity of the disease, complexity of the treatment and absence of a standardised regimen. Previous reports have used a variety of schedules and have not reported the effect on QoL using validated questionnaires.6–10 This is the first prospective study to investigate the effect of a fortnightly schedule of ECP on clinical response and QoL in cGVHD using two validated questionnaires. This report benefits from a standardised regimen of ECP, prospective data accrual, lack of inter-observer variation and stringent use of NIH criteria. The results are remarkably consistent with the retrospective study we have reported previously.2 The earlier study showed that 77% of patients who completed 6 months of ECP treatment had a reduction in immunosuppression, and the prospective study showed that 80% of patients who completed 6 months of ECP had a reduction in immunosuppression. Bone Marrow Transplantation (2014) 704 – 708
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708 One limitation of this study was the number of patients who did not complete 6 months of treatment (11/38, 29% of patients). This figure reflects the high morbidity and mortality rate in patients with steroid-refractory cGVHD.16 In addition, the ECP facility is an out-patient unit, so patients had to be well enough to attend treatment. Another limitation is that only a minority of patients who completed 6 months of treatment had visceral localisation of GVHD. This study population may represent a favourable cohort of patients who may be more likely to respond to ECP. A number of previous reports have reported an adverse impact of cGVHD on QoL following HSCT.17–22 To date, very few studies have investigated the impact of ECP on QoL. In the only randomized controlled trial to date, Flowers et al.10 used a Targeted Symptoms Assessment questionnaire, which included 12 questions to assess the effect of cutaneous, ocular and oral GVHD on various aspects of patients’ QoL. In this study, baseline scores were similar between the two arms, and after 12 weeks of ECP there was a significant difference between the median improvement in TSA scores in the ECP arm compared with the control arm (19% vs 2.5%, P ¼ 0.01). Other studies have used performance status as a surrogate marker of response.23,24 The current report used two validated questionnaires, the organ-specific DLQI13 and the cGVHD SS,12 to assess QoL at baseline and after 6 months of ECP treatment. This study showed a significant improvement in both cGVHD SS and DLQI scores in patients who completed 6 months of ECP, which is in keeping with previous reports of improvement in TSA and performance status. It is interesting to note that even the four patients who did not achieve a PR or CR in symptoms or signs of GVHD in this study obtained an improvement in either the cGVHD of DLQI QoL assessments. This finding may be due partly to the ‘placebo effect’ of regular medical and nursing assessments and the opportunity during ECP treatment to talk to other patients with similar problems. Another limitation is possible selection bias because of the fact that the patients who chose to complete the questionnaires may have been the ones who had noticed an improvement in QoL. In conclusion, this paper reports on a prospective study of the role of fortnightly ECP in managing patients with cGVHD. The findings suggest that our previously reported data from a retrospective analysis are reproducible in a prospective cohort of patients, with 80% of patients who completed 6 months of ECP having a reduction in immunosuppression. In addition, it adds to the current literature by suggesting that ECP may help to improve QoL as assessed by two validated questionnaires. Further randomised studies are required to assess the optimal regimen of ECP and the effect of the treatment on patients’ QoL and should aim to include a longer follow-up period. CONFLICT OF INTEREST FLD has received research funding, honoraria and speakers’ fees from Therakos, a Johnson and Johnson company. BES, JFA and JJS have received honoraria and speakers’ fees from Therakos, a Johnson and Johnson company. FJC and KR have received honoraria from Therakos, a Johnson and Johnson company.
ACKNOWLEDGEMENTS We wish to thank Stephanie Lee and Andrew Finlay for their permission to use the cGVHD SS and DLQI questionnaires. JFA is grateful for the support from the NIHR Biomedical Research Centre funding scheme.
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