Abstract
Question
Is there a benefit associated with the use of extracorporeal photopheresis (ecp) compared with other treatment options for patients who have received allogeneic stem-cell transplantation (sct) and are experiencing graft-versus-host disease (gvhd), if response rate, survival, or improvement in symptoms are the outcomes of interest?
Perspectives
After allogeneic sct, gvhd is a common complication historically categorized as either acute (agvhd: onset ≤100 days post-transplantation) or chronic (cgvhd: >100 days post-transplantation). Graft-versus-host disease occurs when the donor’s immune cells recognize the host patient’s tissues and organs as foreign and attack them, causing a multitude of problems, often in liver, gastrointestinal system, and skin.
Photopheresis is one therapy that has emerged since the early 2000s for the management of steroid-refractory gvhd because of its steroid-sparing ability, low associated toxicity, and efficacy in some clinical settings.
The present recommendation report summarizes the available data about photopheresis for the treatment of gvhd and provides recommendations on its use.
Methodology
The medline (Ovid) database was systematically searched for January 1995 to August 2013, and the best available evidence was used to draft recommendations relevant to adult and pediatric patients in Ontario who have received allogeneic sct and are experiencing gvhd. Draft recommendations were first reviewed by clinical and methodology experts before undergoing internal review. Final approval of this practice guideline report was obtained from both the Stem Cell Transplant Steering Committee and the Report Approval Panel of the Program in Evidence-Based Care.
Recommendations
These recommendations apply to adult and pediatric patients who have received an allogeneic sct and are experiencing gvhd:
ecp is an acceptable therapy for the treatment of steroid-dependent or refractory agvhd in adult and pediatric patients.
ecp is an effective therapy for the treatment of steroid-dependent or refractory cgvhd in adult and pediatric patients.
Qualifying Statement
In Ontario, ecp is currently a covered therapy for patients with steroid-refractory gvhd who meet certain eligibility criteria.
Keywords: Stem-cell transplantation, bone marrow, peripheral blood, graft-versus-host disease, photopheresis
1. RATIONALE
Graft-versus-host disease (gvhd) is a common complication after allogeneic stem-cell transplantation (sct) occurring either acutely (agvhd: onset ≤100 days post-transplantation) or chronically (cgvhd: >100 days post-transplantation)1–3. More than half of all patients undergoing allogeneic sct experience gvhd. In the simplest terms, gvhd is a complication in which the infused donor’s immune cells recognize the host patient’s tissues and organs as foreign and begin causing tissue damage. The result is significant morbidity and, for many patients, mortality—either directly or indirectly.
Primary therapy for agvhd has remained unchanged for 30 years and consists primarily of a calcineurin inhibitor in combination with corticosteroids. Approximately half the affected patients will experience complete resolution of their agvhd with this approach. Patients failing first-line therapy have a poor prognosis, with a 1-year survival of less than 50%. Second-line therapies are varied and are supported mostly by small single-arm trials or cohort studies4,5. Many randomized trials of promising therapies for gvhd have been negative or were stopped early because of toxicity or futility. It is well recognized that there is no defined standard second-line therapy for agvhd. Photopheresis in the setting of steroid-dependent and refractory agvhd has demonstrated steroid-sparing effects and clinical responses in limited studies6–11.
As already indicated, cgvhd is one of the main morbidities and causes of mortality in patients surviving the first few months after allogeneic sct. Like agvhd, cgvhd is treated in the first line with corticosteroids with or without a calcineurin inhibitor12,13. Patients with cgvhd have compromised quality of life and lesser survival and a very poor prognosis when front-line therapy for cgvhd fails. As for agvhd, there is no standard second-line therapy for cgvhd. In practice, a variety of therapies for steroid-refractory cgvhd are applied in a trial-and-error approach14,15. In addition to having limited efficacy, each of these therapies is either expensive, associated with the potential of moderate-to-severe toxicities, or both. Although research continues on the biology and treatment of cgvhd, no novel therapy currently in trials offers a foreseeable and significant advance over the current state of the art. Photopheresis is a therapy that emerged in the early 2000s for the management of steroid-refractory gvhd because of its steroid-sparing ability, low associated toxicity, and efficacy in some clinical settings6,16–19.
Photopheresis is currently covered by the Ontario Ministry of Health and Long-Term Care for patients with steroid-refractory gvhd, but the therapy requires patients to travel to Toronto for therapy at the Princess Margaret Cancer Centre, which results in limited access for patients from other regions of the province because of travel and cost. More importantly, this patient population is medically complex, often with compromised functioning, and the travel requirement can be medically unsafe.
The present recommendation report summarizes the available data about photopheresis for the treatment of gvhd and provides recommendations on its use.
2. METHODS
2.1. Recommendation Development
This recommendation report, produced by the Program in Evidence-Based Care (pebc) and the Stem Cell Transplantation Steering Committee of Cancer Care Ontario was developed through systematic review of the available evidence and interpretation of that evidence by clinical experts. Members of the Committee formed a working group to develop the report. The working group members disclosed any potential conflicts of interest. The pebc is editorially independent of the Ontario Ministry of Health and Long-Term Care.
This report was developed as part of the mandate of the Stem Cell Transplantation Steering Committee to provide advice to the Ontario Ministry of Health and Long-Term Care with respect to stem-cell transplantation and associated technologies and supportive care interventions. It will be assessed for currency and updated in the future at the request of the Committee.
2.2. Literature Search Strategy
The medline (Ovid) database (1995 through July Week 1, 2012) was searched on July 17, 2012, and the search was updated on August 14, 2013. The search used logic combination of terms: [graft-versus-host disease] AND [stem cell transplantation, OR bone marrow transplantation, OR peripheral blood cell transplantation] AND [photopheresis].
Relevant articles and abstracts were selected and reviewed by two reviewers (CB, RBR), and the reference lists in those sources were searched for additional trials. Personal files were also searched.
3. RESULTS
3.1. Literature Search
The eighteen papers retained6–11,16–27 included, for adults, one consensus report based on a systematic review22, one randomized controlled trial (rct)18, one crossover rct19, one prospective cohort study9, three retrospective cohort studies8,16,17, one case series with historical controls11, and four case series6,21,24,27; and for pediatric patients, one clinical practice guideline23 (which also contained case-series data), one nonrandomized controlled trial10, one prospective cohort study26, and four case series7,20,23,25 (including the series from the practice guideline). Of those eighteen papers, fourteen were identified using the medline (Ovid) database, three were submitted from the files of the lead author (CB), and one was identified from the reference list in one of the papers located in the search (Figure 1).
FIGURE 1.
Selection of studies investigating extracorporeal photopheresis in the management of graft-versus-host disease in patients who underwent allogeneic blood or bone marrow transplantation.
3.2. Adult Patients
In the twelve papers on the use of photopheresis in adult patients with gvhd after sct6,8,9,11,16–19,21,22,24,27, the number of patients reported ranged from 9 (in the case series reported by Lucid et al.24) to 82 (in the case series reported by Dignan et al.21). The patient diagnoses varied, but the typical population comprised patients with gvhd in whom either steroid treatment6,9,21 or immunosuppressive therapy24,27 had failed. Where an ecp device was reported, the only one described was either the uvar or uvar xts system by Therakos (Raritan, NJ, U.S.A.)6,9,16–18,21,27. The duration for which patients received ecp treatment varied greatly, from a low of 2 weeks (median not reported) in the prospective cohort study by Greinix et al.9 to a high of 528 weeks (median: 68 weeks) in the retrospective cohort study by Bisaccia et al.17. The most commonly reported outcome was the response rate, followed by survival, treatment-related mortality (trm), safety, quality of life, and the effect of ecp on various measures of gvhd by affected site (Table i).
TABLE I.
Study and patient characteristics, adult patients
| Reference | Study years | Patients (n) | Diagnosis |
Extracorporeal photopheresis (ecp)
|
Outcomes reported | |
|---|---|---|---|---|---|---|
| Details (device) | Treatment weeks [range (median)] | |||||
| Consensus recommendations and evidence review | ||||||
| Hildebrandt et al., 201122 | 8 Studies of ecp in cgvhd | boop/cop/obstructive lung involvement | Varies | Varies | Response | |
| Randomized controlled trial | ||||||
| Flowers et al., 200818 | 2002–2005 |
ecp: 48 Control: 47 |
Histologically confirmed cgvhd with cutaneous symptoms at 100 days or more after transplantation | Week 1: 3 times Weeks 2–12: 2 times per week on consecutive days; responsive patients could continue with 2 treatments every 4 weeks until week 24 (uvar xtsa) |
12–24 | Skin response, steroid-sparing effects, extracutaneous response, quality of life, safety, mortality |
| Crossover randomized controlled trial | ||||||
| Greinix et al., 201119 | 2003–2006 | 25 | Same as Flowers et al., 2008 | Same as Flowers et al., 2008 | 12–24 | Skin response, steroid-sparing effects, extracutaneous response, safety |
| Prospective cohort study | ||||||
| Greinix et al., 20069 | 1996–1999 | 59 | Grade ii–iv agvhd after first-line treatment with steroids | Patients were treated on 2 consecutive days (1 cycle) at 1- to 2-week intervals until improvement and then every 2–4 weeks until maximal response; treatment was reduced over 25 months (uvar xtsa) | nr | Response, treatment-related mortality, survival, long-term outcome |
| Retrospective cohort studies | ||||||
| Apisarnthanarax et al., 200316 | 1998–2001 | 32 | Patients had cutaneous symptoms of cgvhd after day 100 post-transplantation |
ecp sessions—Total: 34 (median), 12–98 (range) Per month: 6 (median) 2–17 (range) (uvar or uvar xtsa) |
4–121 (23) | Response, survival |
| Bisaccia et al., 200617 | 2000–2005 | 14 (of 20) | Patients had cgvhd after bmt or pbsct, but were in complete remission of primary disease and had adequate hemodynamic and cardiac status | Three times per week on alternating days, but could be decreased to twice per week, once per week, or once on alternating weeks, depending on patient response (uvar xtsa) | 13–191 (74) | Response, time to response, survival |
| Couriel et al., 20068 | 1998–2002 | 63 | Patients had steroid-resistant cgvhd and 3 or fewer lines of immunosuppressant treatment | Patients were started on 2- to 3-weekly ecp treatment, then decreased to 1 or 2, according to clinical response and the discretion of the managing physician | nr | Response, survival |
| Case series with historical controls | ||||||
| Perfetti et al., 200811 | 1996–2006 | 23 | Steroid-refractory patients with grade ii–iv agvhd | Two treatments on 2 consecutive days every week for the first month, a cycle every 2 weeks for the following 2 months, and a cycle every month until gvhd was resolved or stabilized | 0–144 (30) | Average gvhd score, average steroid dose, overall response, overall survival |
| Case series | ||||||
| Greinix et al., 19986 | 1993–1998 | 21 | Patients with chronic extensive gvhd or with agvhd resistant to steroid treatment | Patients treated on 2 consecutive days at 2-week intervals for the first 3 months and then every 4 weeks until resolution of gvhd (uvara) | 17–135 | Response by site affected: skin, liver, joints, mouth, ocular, thrombopenia |
| Seaton et al., 200327 | 1994–2001 | 28 | Patients with cgvhd refractory to immunosuppressive treatment | Given on 2 consecutive days once every 2 weeks for the first 4 months, and then on 2 consecutive days once per month; continuing ecp treatment was reassessed every 6 months (uvar and uvar xtsa) | 4–252 (26) | Skin score, hepatic score, pulmonary score, mucosal score, neuromuscular score, treatment-related mortality |
| Lucid et al., 201124 | 2008–2009 | 9 | Patients with bronchiolitis obliterans refractory to immunosuppressive treatment | Two sessions per week for 3–4 weeks and then 2 sessions every 2–3 weeks, with the goal of bringing patients to a once-every-4-weeks treatment schedule | NR | Response |
| Dignan et al., 201221 | 2005–2010 | 82 | Patients were steroid-refractory, steroid-dependent, or steroid-intolerant with mucocutaneous cgvhd | Two consecutive days every 2 weeks until a partial response was reported, then treatment was reduced to 1 cycle per month (uvar xtsa) | 6–141 (47) | Response, reduction in immunosuppressive treatment, reduction in steroid treatment, overall survival |
Johnson and Johnson, West Chester, PA, U.S.A.
gvhd = graft-versus-host disease (cgvhd: chronic gvhd; agvhd = acute gvhd); boop = bronchiolitis obliterans organizing pneumonia; cop = cryptogenic organizing pneumonia; nr = not reported; bmt = bone marrow transplantation; pbsct = peripheral blood stem-cell transplantation.
Quality was assessed according to the criteria described in Section 2, “Methods.” See Table i for details of patient selection criteria, ecp treatment given, and outcomes reported. Because the recommendations in the consensus statement22 are only indirectly related to photopheresis, and because the data on which the recommendations were based are not fully described, the working group decided that adapting the statement was not feasible, and a formal assessment of quality using the agree 2 instrument was therefore not performed.
The rct reported by Flowers et al.18 did not explicitly describe the method of randomization, but noted that a block method was used in a 1:1 ratio. The trial was reported as being single-blind, but no description of the power and sample size calculation, nor of the length of follow-up, was provided. The statistical analyses used were well described, with continuous variables summarized as medians and ranges, and categorical variables, as totals and percentages. The primary endpoint of total skin score was analyzed using a Wilcoxon rank-sum test, and cumulative response rates [complete (cr) and partial (pr)] were compared using the log-rank test. Withdrawals were well described for both arms, and no losses to follow-up were reported. Therakos provided funding for the trial.
The crossover study reported by Greinix et al.19 included patients from the rct reported by Flowers et al.18 that crossed over from the non-ecp arm to the ecp arm, and the resulting sample was well described, as was the intervention that each patient received. All relevant outcomes were reported, including response rates, total skin scores, and change in steroid use. Therakos provided funding for the study.
The prospective cohort study reported by Greinix et al.9 selected patients based on nonresponse to steroid treatment in a well-described population. The ecp treatment was well described, as were the outcomes of response and survival. A European Commission grant (QLK3-CT-2002-01936 TransEurope) provided funding for the study.
All three of the retrospective cohort studies8,16,17 located for this review had well-described patient samples representative of a typical patient population. The study by Couriel et al.8 did not report details of the ecp methods. The study by Apisarnthanarax et al.16 reported on a series of patients in whom various ecp regimens were used, and those authors therefore did not report the details. By contrast, the study by Bisaccia et al.17 fully described the single ecp protocol used for all patients. All three studies reported response rates, two reported survival16,17, and one also reported median time to response17. Therakos supported the study by Apisarnthanarax et al.16. The other two studies did not report any source of funding.
The case-series study with historical controls reported by Perfetti et al.11 had a well-described series of patients, which were representative of the population under study. The ecp regimen was also well reported. Outcomes reported were response rates and survival. This study reported non-industry funding (Association Italiana Ricerca contro il Cancro, carige, Fondazione Ricerca per Trapianto Midollo Osseo).
The four case-series studies located for this review6,21,24,27 had well-defined groups of patients who were representative of the population of interest; however, Lucid et al.24 included only patients with bronchiolitis obliterans, and Dignan et al.21 included only patients with mucocutaneous symptoms of gvhd. All four of the studies included detailed descriptions of the ecp intervention, and all patients received the same regimen. Lucid et al.24 reported response rates, and Dignan et al.21 reported response rates, survival, and reductions in the dose of immunosuppressant drugs or in use of steroids. Seaton et al.27 and Greinix et al.6 both reported on the change in various scores associated with the sites affected by gvhd. No study reported the source of funding.
In summary, the quality assessment found that all studies of ecp in the treatment of gvhd in adult patients were of acceptable quality given the nature of their study designs. Table ii presents results for all adult patients.
TABLE II.
Results, adult patients
| Reference | Study years | Patients (n) | Response (%) | Treatment-related mortality (%) | Overall survival (%) | Quality of life (%) |
|---|---|---|---|---|---|---|
| Randomized controlled trial | ||||||
| Flowers et al., 200818 | 2002–2005 |
ecp: 48 Cnvl: 47 |
cr, 40; pr, 10 p=0.002 |
ecp, 98; Cnvl, 94 p=nr |
nr |
ecp, 19; Cnvl, 2.5 p=0.01 |
| Crossover randomized controlled trial | ||||||
| Greinix et al., 201119 | 2003–2006 | 25 | At 12 weeks: epc, 26; Cnvl, 8 p=0.04 At 24 weeks: epc, 31a |
nr | nr | nr |
| Prospective cohort study | ||||||
| Greinix et al., 20069 | 1996–1999 | 59 | Cutaneous, 82; liver, 61; gut, 61 p=nr |
nr | 4-Year: 47 With cr: 47 Without cr: 11 p<0.0001 |
nr |
| Retrospective cohort studies | ||||||
| Bisaccia et al., 200617 | 2000–2005 | 14 | Cutaneous, 50; cr only, 21 p=nr |
nr | 85 | nr |
| Couriel et al., 20068 | 1998–2002 | 63 | Overall, 59; cr only, 21 p=nr |
nr | 5-Year: 41 Primary causes of death: gvhd, 68%; relapse, 26%; infection, 3% |
nr |
| Apisarnthanarax et al., 200316 | 1998–2001 | 32 | Overall, 56; cr only, 22 p=nr |
nr | 66 (Of all deaths under study, 100% were related to cgvhd) | nr |
| Case series with historical controls | ||||||
| Perfetti et al., 200811 | 1996–2006 |
ecp: 23 Ctrl: 307 |
cr, 52 | nr | 48 ecp, 45; Ctrl, 44 p=ns |
nr |
| Case series | ||||||
| Greinix et al., 19986 | 1993–1998 | 21 | agvhd (n=6) Skin (n=6): cr, 67; pr, 33 Liver (n=2): cr, 100; pr, — cgvhd (n=15) Skin (n=15): cr, 80; pr, 20 Joints (n=4): cr, —; pr, 100 Mouth (n=11): cr, 100; pr, — Liver (n=10): cr, 70; pr, 20; nc: 10 Ocular (n=6): cr, 17; pr, 67; nc, 17 Thrombopenia (n=3): cr, 67; pr, —; nc, 33 |
nr | nr | nr |
| Seaton et al., 200327 | 1994–2001 | 28 | nr | 14 | nr | nr |
| Lucid et al., 201124 | 2008–2009 | 9 | 67 | nr | nr | nr |
| Dignan et al., 201221 | 2005–2010 | 82 | 79; at 6 months, 94 | nr | 3-Year: 69 | nr |
No data reported for the non-ecp arm at 24 weeks because of the large number of patients in that arm who discontinued the study.
ecp = extracorporeal photopheresis; Cnvl = conventional treatment; cr = complete response; pr = partial response; nr = not reported; gvhd = graft-versus-host disease (cgvhd: chronic gvhd; agvhd = acute gvhd); Ctrl = control group; nc = no change.
3.3. Pediatric Patients
Among the six papers on the use of photopheresis in pediatric patients with gvhd after sct7,10,20,23,25,26, the clinical practice guideline by Kanold et al.23 also reported case-series data (described in Tables iii and iv). The number of patients included in the studies ranged from 9 in the prospective cohort study reported by Salvaneschi et al.26 to 77 in the nonrandomized controlled trial reported by Messina et al.10. As in the adult patients, the diagnoses in the pediatric patients varied, but the typical population comprised patients with gvhd for whom either steroid treatment20,25,26 or immunosuppressive therapy10 had failed. The two studies that reported specifics of the ecp system both used the uvar system by Therakos10,20. The reported outcomes varied, but response rate was the most common, followed by survival, trm, reductions in the use of steroids or immunosuppression, infection rates, mycosis, and changes in skin scores (Table iii).
TABLE III.
Study and patient characteristics, pediatric patients
| Reference | Study years | Patients (n) | Diagnosis |
Extracorporeal photopheresis (ecp)
|
Outcomes reported | |
|---|---|---|---|---|---|---|
| Details (device) | Treatment weeks [range (median)] | |||||
| Clinical practice guideline | ||||||
| Kanold et al., 200723 | 1996–2006 | 27 | agvhd or cgvhd | Patients treated 3 times weekly (with a 1-day rest between 2 sessions) for the first 3 weeks, and then gradually reduced for patients who stabilized or showed improvement | nr | ecp should be considered first-line therapy in grade iv agvhd (in association with conventional pharmacologic approaches) and in limited cgvhd; ecp should be considered second-line therapy in steroid-resistant grades ii–iii agvhd and extensive cgvhd |
| Nonrandomized controlled trial | ||||||
| Messina et al., 200310 | 1992–2000 | 77 | Patients refractory to immunosuppressive therapy with agvhd or cgvhd | Patients were treated on 2 consecutive days at 1-week intervals for the 1st month, and then every 2 weeks for the 2nd and 3rd months, and then monthly for at least 3 months (uvara) | 1–66 (10.5) | Response, survival |
| Prospective cohort study | ||||||
| Salvaneschi et al., 200126 | 1998–nr | 9 | Patients with steroid-resistant, grade ii–iv agvhd and cgvhd, all of whom had been refractory to at least 1 line of treatment | agvhd: 3 times weekly on alternate days until improvement, and then on 2 consecutive days at 2-week intervals for 3 months until discontinued; cgvhd: 2 consecutive days at 2-week intervals for 3 months; if improvements were shown, then ecp was given on 2 consecutive days at 3-week intervals for another 3 months; discontinuation depended on individual assessment of response |
nr | Response, survival, reduction in immunosuppressive therapy |
| Case series | ||||||
| Berger et al., 200720 | 2001–2005 | 25 | Steroid-refractory patients with agvhd or cgvhd | 2 Consecutive days at weekly intervals for the 1st month, 2 consecutive days every other week for the 2nd and 3rd months, and then 2 consecutive days once monthly for 3 months (uvara) | nr | Response, survival, treatment-related mortality |
| Kanold et al., 200723 | 1996–2006 | 27 | agvhd or cgvhd | Treatments 3 times weekly (with a 1-day rest between 2 sessions) for the first 3 weeks, and then gradually reduced for patients who stabilized or showed improvement | NR | Response, survival, change in skin scores |
| Calore et al., 20087 | 1999–2005 | 31 | Patients with grades ii–iv agvhd | 2 Consecutive days weekly for the 1st month, then every 2 weeks for the 2nd and 3rd months, then monthly for another 3 months (6 months’ total treatment); immunosuppressive treatment was maintained and then reduced or discontinued, depending on clinical response | 5–44 (24) | Response, survival, progression-free survival, treatment-related mortality, infection, mycosis |
| Perotti et al., 201025 | nr | 73 | Steroid-refractory patients with agvhd or cgvhd | agvhd: 2 or 3 treatments per week (on alternate days) until clinical improvement; cgvhd: 2 procedures weekly 2 times, 2 procedures every other week 3 times, then 2 procedures monthly until clinical improvement or reduction in immunosuppressive therapy (or both) |
nr | Response, survival |
Johnson and Johnson, West Chester, PA, U.S.A.
gvhd = graft-versus-host disease (cgvhd: chronic gvhd; agvhd = acute gvhd); nr = not reported.
TABLE IV.
Results, pediatric patients
| Reference | Study years | Patients (n) | Response (%) | Treatment-related mortality (%) | Overall survival (%) | Quality of life (%) |
|---|---|---|---|---|---|---|
| Nonrandomized controlled trial | ||||||
| Messina et al., 200310 | 1992–2000 | 77 agvhd: 33 cgvhd: 44 |
agvhd (n=33): cr, 54; pr, 21; no response, 24 cgvhd (n=34 survived treatment): cr, 44; pr, 29; no response, 26 |
nr | 5-Year, agvhd: responders, 69; non-responders, 12 p=0.001 5-Year, cgvhd: responders, 96; non-responders, 58 p=0.04 |
nr |
| Prospective cohort study | ||||||
| Salvaneschi et al., 200126 | 1998–nr | 23 agvhd: 9 cgvhd: 14 |
agvhd (n=9): response rate, 78; cr, 71; pr, 29 (both evolving into cgvhd) cgvhd (n=14): response rate, 64; cr, 44; pr, 56; no response, 36 (2 with stable disease, 3 worsening) |
nr | agvhd (n=9): 78 cgvhd (n=14): 79 (of the 3 nonresponders, all died) |
nr |
| Case series | ||||||
| Berger et al., 200720 | 2001–2005 | 25 |
cr: agvhd
ii (n=7), 100; agvhd
iii (n=4), 50 pr: agvhd iii, 25 No response: agvhd iii, 25; agvhd iv (n=4), 100 cr: limited (n=3) vs. extensive (n=7) cgvhd, 100 vs. 14 pr: extensive cgvhd, 14 Nonresponse: extensive cgvhd, 71 |
agvhd: ii, 0; iii/iv, 42 p=0.05 cgvhd: ecp responder, 0; ecp nonresponder, 50 p=0.022 |
agvhd: ii, 100; iii/iv, 30 p=0.006 cgvhd: Limited, 100; extensive, 28 p=0.03 |
|
| Kanold et al., 200723 | 1996–2006 | 27 agvhd 12 cgvhd 15 |
agvhd (n=12): cr, 58; pr, 25 cgvhd (n=15): cr, 27; pr, 47 |
nr | agvhd (n=12): 75 cgvhd (n=15): 67 |
nr |
| Calore et al., 20087 | 1999–2005 |
ecp: 15 gr: 16 |
ecp (n=15): cr, 73; pr, 27 gr (n=16): cr, 56; pr, 44 |
ecp, 0 gr, 6 |
2-Year: ecp, 85; gr, 57 | nr |
| Perotti et al., 201025 | nr | 73 agvhd: 50 cgvhd: 23 |
agvhd (n=50): overall response, 68; cr, 32 cgvhd (n=23): overall response, 69.5; cr, 21.7 |
nr | agvhd (n=50): 44; responders, 62 (21 of 34); nonresponders, 6.3 (1 of 16) cgvhd (n=23): 78.3; responders, 87.5 (14 of 16); nonresponders, 57 (4 of 7) |
nr |
gvhd = graft-versus-host disease (cgvhd: chronic gvhd; agvhd = acute gvhd); cr = complete response; pr = partial response); nr = not reported; ecp = extracorporeal photopheresis; gr = good response to steroid-based treatment.
Quality was assessed according to the criteria described in Section 2, “Methods.” See Table iii for details of patient selection criteria, ecp treatment given, and outcomes reported.
One clinical practice guideline, reported by Kanold et al.23, was obtained. However, this guideline located no supporting evidence, and its recommendations are based solely on expert opinion and a single case series reported by the same authors. Our working group therefore decided that a direct review of the evidence and development of new recommendations would be more appropriate than an attempt to adapt the guideline, and so a formal assessment of quality using the agree 2 instrument was not performed.
In the nonrandomized controlled study reported by Messina et al.10, the patient selection criteria were well described, and the resulting cohort was representative of the population of interest, as was the ecp regimen. The reported outcomes were response, survival, and adverse effects. This study was funded by non-industry sources (grants from the Associazione Italiana Ricerca sul Cancro, the Consiglio Nazionale delle Ricerche, the Ministero dell’Universita e della Ricerca Scientifica e Tecnologica, and the Istituto di Ricovero e Cura a Carattere Scientifico).
In the prospective cohort study26 that was located, the patients were well described and were representative of the population of interest, as was the ecp regimen. The reported outcomes were response and survival. This study was funded through non-industry sources (grants from the Associazione Italiana Ricerca sul Cancro, the Consiglio Nazionale delle Ricerche, the Ministero dell’Universita e della Ricerca Scientifica e Tecnologica, and the Istituto di Ricovero e Cura a Carattere Scientifico).
Of the four case series7,20,23,25 located, three7,20,25 included full descriptions of the patients included and the ecp regimen used; the study by Kanold et al.23 had no description at all of the patients included or the ecp regimen. Outcomes reported in these studies were response rate7,20,23,25, survival7,20,25, trm7,20, progression-free survival7, infection7, and mycosis7. Two studies reported non-industry funding: the study by Perotti et al.25 reported hospital funding, and the study by Calore et al.7 reported funding from the Fondazione Citta della Speranza, Associazione Italiana Leucemie e Linfomi.
In summary, the quality assessment found that all the studies of ecp in the treatment of gvhd in pediatric patients were of acceptable quality given the nature of the study designs.
4. OUTCOMES
4.1. Adult Population
4.1.1. Response
The rct by Flowers et al.18 detected a statistically significant difference in response rate in favour of ecp over conventional corticosteroid treatment (40% vs. 10%, p = 0.002). Comparing ecp with conventional treatment, the crossover rct reported a similarly significant increase in the overall response rate (26% vs. 8%, p = 0.04)19. None of the other comparative studies reported a difference between groups8,9,16,17. Noncomparative studies reported response rates ranging from 50%11,17 to 100% (in liver manifesting agvhd only)6. The rct reported by Flowers et al.18, which detected a benefit in favour of ecp, remains the best evidence because of the study design.
4.1.2. Treatment-Related Mortality
Only the rct by Flowers et al.18 reported on trm, with no difference being detected.
4.1.3. Overall Survival
Only one study, the case series with historical controls reported by Perfetti et al.11, compared overall survival between ecp and a control group, with no difference being detected (45% for ecp vs. 44% for control). In the remaining studies, survival ranged from a low of 41% in the study reported by Couriel et al.8 to a high of 85% in the study reported by Bisaccia et al.17 (both retrospective cohort studies).
4.1.4. Quality of Life
Only the rct by Flowers et al.18 reported on quality-of- life outcomes, with a significant benefit being detected for ecp treatment compared with conventional treatment (19% for ecp vs. 2.5% for control, p = 0.01).
4.1.5. Other Outcomes
The rct by Flowers et al.18 reported total skin scores; eye, oral, and joint changes associated with gvhd; and adverse events. Significant differences were detected only in eye gvhd, which showed improvement more often with ecp than with conventional treatment (30% for ecp vs. 7% for control, p = 0.04).
The case series by Seaton et al.27 reported on change from baseline scores after 6 months for cutaneous, hepatic, pulmonary, mucosal, and neuromuscular cgvhd; significant improvements were detected only for cutaneous cgvhd scores [89% at baseline (skin median score: 131) vs. 52% at 6 months (skin median score: 61), p = 0.003].
4.2. Pediatric Population
4.2.1. Response
Only one of the pediatric studies, the case series by Calore et al.7, reported response outcomes that were comparable for ecp and another treatment option. That study reported response rates for patients who received ecp and patients who remained on steroid treatment. The cr rate was higher in the ecp group (73% vs. 56%, p value not reported), but the pr rate was higher in the group that received steroid treatment (44% vs. 27%, p value not reported).
In the remaining studies, cr rates ranged from a low of 32%25 to a high of 100% (grade ii only)20, and pr rates ranged from a low of 21%10 to a high of 29%10,26 in patients with agvhd. For patients with cgvhd, cr rates ranged from a low of 21.7%25 to highs of 44%10,26, and pr rates ranged from a low of 29%10 to a high of 56%26.
4.2.2. Treatment-Related Mortality
Two of the studies, the case series by Calore et al.7 and by Berger et al.20, reported trm outcomes. Calore et al. found a trm of 6% in the group that had a good response to steroid treatment; mortality was zero in the ecp group (p value not reported). Berger et al. found an increase in trm as agvhd symptoms worsened (0% in grade ii disease vs. 42% in grade iii–iv disease, p = 0.05); they also found an increase in nonresponders to both treatments (0% in ecp responders vs. 50% in nonresponders to both treatments, p = 0.022).
4.2.3. Overall Survival
Six of the studies reported overall survival outcomes7,10,20,23,25,26. Only the study by Calore et al.7 reported comparable survival rates for ecp and another treatment, with patients who received ecp having a survival rate of 85% and patients who received steroid-based treatment having a survival rate of 57% (p = 0.2).
For agvhd, the study by Messina et al.10 detected a significant survival benefit in ecp responders compared with nonresponders at a median follow-up of 5 years (69% vs. 12%, p = 0.001). Perotti et al.25 reported a 62% survival rate in ecp responders compared with 6.3% in nonresponders at a median follow-up of 23.7 months (p value not reported). Berger et al.20 reported a 100% survival rate in patients with grade ii acute disease; the rate was 30% in patients with grade iii or iv disease at a median follow-up of 1.6 years (p = 0.006).
In patients with cgvhd, Messina et al.10 reported a survival rate of 96% in ecp responders compared with 58% in nonresponders (median follow-up: 5 years; p = 0.04), and Salvaneschi et al.26 reported a survival rate of 79% in ecp responders compared with zero in nonresponders (median follow-up: 36 months; p value not reported). The study by Berger et al.20 reported a survival rate of 100% in patients with limited symptoms, but the rate fell to 28% in patients with extensive symptoms (median follow-up: 2.6 years; p = 0.03).
4.2.4. Quality of Life
None of the studies reported quality of life.
4.2.5. Other Outcomes
In their case series, Calore et al.7 presented 2-year progression-free survival, but no difference between the groups was reported (87% for ecp vs. 67% for steroid responders, p value not reported).
5. REVIEW PROCESS
The clinical lead author wrote the initial recommendations and qualifying statement pertaining to the benefit associated with the use of ecp for patients experiencing gvhd. This report was circulated to the members of the Stem Cell Transplantation working group and discussed during a teleconference. The draft recommendations were then generated. The ensuing recommendation report was presented to the entire Stem Cell Transplantation Steering Committee to ensure the clinical relevance and utility of the recommendations, the absence of obvious defects in the evidence base, and the reasonableness of the recommendations derived through expert opinion. Refined recommendations and a summary of the key evidence were first reviewed by the pebc’s Report Approval Panel (Scientific Director and the pebc Assistant Director) to ensure that the guideline development was methodologically rigorous and that the evidence-based recommendations are indeed supported by the evidence in a transparent way. Upon completion of preliminary review and feedback provided by the pebc Assistant Director, the recommendation report was presented to the pebc Scientific Director for final review.
Practice guidelines and recommendation reports developed by the pebc are reviewed and updated as needed. Please visit the Cancer Care Ontario Web site (http://www.cancercare.on.ca) for the full report and subsequent updates.
6. PRACTICE GUIDELINE
Evidence from a systematic search of the primary literature, consensus of expert opinion, feedback obtained through the review process, and a final approval given by the Stem Cell Transplant Steering Committee and the pebc’s Report Approval Panel collectively form the basis of this recommendation report, completed in August 2013.
6.1. Target Population
The following recommendations apply to adult and pediatric patients who have received allogeneic transplantation and are experiencing gvhd.
6.2. Recommendations
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Extracorporeal photopheresis is an acceptable therapy for the treatment of steroid-dependent or refractory agvhd in adult and pediatric patients.
This recommendation is based on results of three non-comparative studies in adult patients (one prospective single cohort23 and two case series6,11) and six studies in pediatric patients (one clinical trial10, one prospective cohort26, and four case series7,20,23,25) that reported response rates ranging from 32% to 100% in favour of ecp. Only one of the pediatric studies reported comparable response rates for patients who received ecp and patients who remained on conventional treatment7.
In the opinion of the Expert Panel, although the quality of the data for steroid-refractory agvhd is limited, patients with refractory skin gvhd primarily should be considered for ecp treatment.
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Extracorporeal photopheresis is an effective therapy for the treatment of steroid-dependent or refractory cgvhd in adult and pediatric patients.
This recommendation is supported by the evidence obtained from two studies (an rct18 and a crossover rct19) because, in both studies, a significant increase in the response rate favours ecp over conventional corticosteroid treatment. Five additional comparative studies8,10,16,17,26 and six noncomparative studies6,20,21,23–25 reported response rates ranging from 50% to 80%.
6.3. Key Evidence
Although the proof for efficacy of ecp is of mixed quality, the weight of the evidence supports that ecp works in certain patients and that, when it works, it can provide clinical improvement. The best data, as summarized earlier, support the use of ecp for steroid-refractory cgvhd that is affecting primarily skin or subcutaneous tissue, lung, and liver3,8,9,18,19,21,22,24. The data for steroid-refractory agvhd are more limited, but patients with refractory skin gvhd primarily should also be considered8,9,23. Additional factors that favour the use of photopheresis include its steroid-sparing effect and its lack of toxicity. Steroid-sparing is of particular importance, because many patients with cgvhd are older individuals who tolerate corticosteroids poorly. Definitive randomized trial data defining second-line therapy for either agvhd or cgvhd is, for a variety of reasons, many years away (no good candidates, complexity of trials, cost to conduct trials, limited peer funding for such trials, a small market discouraging industry pursuit of the indication). In the interim, the transplant community has, based on practice patterns, identified photopheresis as a valuable component of gvhd management for some patients in whom front-line therapy fails4,5,8,15. Appropriate application of photopheresis combined with data collection and reporting will enable ongoing evaluation of this therapy compared with other emerging options for gvhd patients in Ontario.
6.4. Qualifying Statement
In Ontario, ecp is currently a covered therapy for patients with steroid-refractory gvhd who meet certain eligibility criteria.
7. ACKNOWLEDGMENTS
The Stem Cell Transplant Steering Committee, the Advisory Panel on Bone Marrow and Stem Cell Transplantation, and the working group thank the following individuals for their assistance in developing this report: Melissa Brouwers, Sheila McNair, and Hans Messersmith for providing feedback on draft versions; Mark Gichuru for conducting a data audit; and Bruce Histed for copyediting.
Cancer Care Ontario’s pebc is sponsored by the Ministry of Health and Long-Term Care through Cancer Care Ontario. The full recommendation report is available on the Cancer Care Ontario Web site, at the pebc Collaborative Projects page: https://www.cancercare.on.ca/toolbox/qualityguidelines/other-reports/collaborative-pr-ebs/.
8. CONFLICT OF INTEREST DISCLOSURES
The authors of this recommendation report disclosed potential conflicts of interest relating to the topic. The lead author (CB) reported a potential conflict, because if photopheresis were to become a widely funded procedure, his income could potentially increase by more than $10,000. The remaining authors (RBR, NPV, JK, CTK) reported no conflicts of interest.
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