Transfusion and Apheresis Science xxx (2014) xxx–xxx

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Review

Extracorporeal photopheresis in acute and chronic graft-versus-host disease Hildegard T. Greinix a,⇑, Nina Worel b, Ulrike Just c, Robert Knobler c a

Medical University of Vienna, Department of Internal Medicine, I, Bone Marrow Transplantation, Austria Medical University of Vienna, Department of Blood Group, Serology and Transfusion Medicine, Austria c Medical University of Vienna, Department of Dermatology, Austria b

a r t i c l e

i n f o

Article history: Available online xxxx Keywords: Extracorporeal photopheresis Graft-versus-host disease

a b s t r a c t Graft-versus-host disease (GvHD) is a serious complication of allogeneic hematopoietic cell transplantation causing significant morbidity and mortality. Corticosteroids are the established first-line treatment of GvHD. Patients not responding to corticosteroids have a dismal prognosis. Extracorporeal photopheresis (ECP) has objective activity in the treatment of both acute and chronic corticosteroid-refractory GvHD patients, has an excellent safety profile and is internationally well-established. ECP has been recommended by a significant number of renowned scientific organizations as an efficient treatment option for patients with GvHD. ECP has a proven corticosteroid-sparing effect and favourably impacts on survival and quality of life of responding patients. Ó 2014 Published by Elsevier Ltd.

Contents 1. 2. 3. 4. 5. 6. 7.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Extracorporeal photopheresis in acute graft-versus-host disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Recommendations on the use of extracorporeal photopheresis in acute graft-versus-host disease . . Extracorporeal photopheresis in chronic graft-versus-host disease . . . . . . . . . . . . . . . . . . . . . . . . . . . Biomarkers for prediction and monitoring of response to ECP in chronic GvHD . . . . . . . . . . . . . . . . . Recommendations on the use of extracorporeal photopheresis in chronic graft-versus-host disease Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Allogeneic hematopoietic cell transplantation (HCT) is a curative therapy for many malignant and non-malignant hematological diseases. Graft-versus-host disease (GvHD) ⇑ Corresponding author. Address: Medical University of Vienna, Klinik fuer Innere Medizin I, Knochenmarktransplantation, Waehringer Guertel 18-20, A-1090 Vienna, Austria. Tel.: +43 140400 4457; fax: +43 140400 2511. E-mail address: [email protected] (H.T. Greinix).

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is one of the most important complications of allogeneic HCT [1]. It is an immune-mediated, potentially life-threatening syndrome in which host tissues are attacked by donor immune cells including T cells, natural killer cells and macrophages [1]. GvHD can occur in 30–50% of patients transplanted with either an HLA-identical related or unrelated donor and incidence rates are substantially higher in recipients of HLA-mismatched stem cell grafts. Clinically, GvHD is divided into acute and chronic forms with different pathophysiologic mechanisms involved [1].

http://dx.doi.org/10.1016/j.transci.2014.04.005 1473-0502/Ó 2014 Published by Elsevier Ltd.

Please cite this article in press as: Greinix HT et al. Extracorporeal photopheresis in acute and chronic graft-versus-host disease. Transf Apheres Sci (2014), http://dx.doi.org/10.1016/j.transci.2014.04.005

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H.T. Greinix et al. / Transfusion and Apheresis Science xxx (2014) xxx–xxx

Severe manifestations of GvHD have been associated with significant morbidity and mortality mainly due to serious opportunistic infections during immunodeficiency [1]. In patients developing GvHD a decreased rate of relapse of their malignant disease has been observed [2,3]. On the other hand, hematopoietic cell grafts depleted of T cells reduce the risk of GvHD but are associated with increased rates of relapse in hematologic malignancies [4,5]. Therefore, mild acute or chronic GvHD may be beneficial and enable an immune-mediated graft-versus-leukemia/ tumour (GvL) effect aiding in the eradication of residual malignant cells. This GvL effect remains the most potent form of cellular immune therapy for hematological malignancies and some solid tumours, contributing to the curative potential of allogeneic HCT for malignancies refractory to all other treatments. Thus, there is a fine balance between detrimental GvHD and a beneficial GvL effect. The ability to predict severe GvHD would enable clinicians to tailor therapy on an individual basis to improve outcome, avoid irreversible organ damage and improve quality of life of patients afflicted. At the present time, unfortunately, no validated biomarkers for prediction of GvHD and its prognosis are available to the HCT community. Current GvHD prevention strategies focus on eliminating or attenuating donor T cell alloreactivity using in vitro or in vivo T cell depletion or pharmacological targeting of T cell function [1,6]. Calcineurin inhibitors (CNI) in combination with either methotrexate (MTX) or mycophenolate mofetil (MMF) are most frequently administered for GvHD prophylaxis. Recently, MTX has been substituted with sirolimus, which inhibits the mammalian target of rapamycin (m-TOR) [7]. Considering the substantial rates of GvHD currently observed despite applied GvHD prophylaxis, novel prevention strategies that target other pathways involved in the development of GvHD are highly warranted. One such approach is extracorporeal photopheresis (ECP) which has been shown to impact on dendritic cells (DCs) and regulatory T cells (Tregs) [8]. In a multicenter phase II study Shaughnessy and colleagues administered two ECP treatments to 62 patients during myeloablative conditioning consisting of cyclophosphamide and total body irradiation (TBI) combined with GvHD prophylaxis with cyclosporine A (CSA) and MTX [9]. They reported 100 day cumulative incidence (CI) of acute GvHD grades II–IV of 35% and one year CI of chronic GvHD of 38%. Compared to 347 matched historical controls from the Center for International Blood and Marrow Transplant Research (CIBMTR), the ECP treated cohort had a lower rate of grades II–IV acute GvHD. These promising results support further investigation into the role of ECP for prevention of GvHD. Despite major advances in the understanding of the pathophysiology of acute GvHD and the development of more targeted immunosuppressive treatments, corticosteroids remain the standard first-line therapy for patients who failed prevention and developed GvHD [1]. Since only up to 40% of patients respond completely to first-line treatment, many still require additional salvage therapy for corticosteroid-refractory GvHD and have a dismal prognosis. Many new immunosuppressive agents currently in use for salvage treatment are not able to control GvHD activity

in a satisfying way since no improvement in long-term survival has been achieved during the last years in the vast majority of patients afflicted. ECP is the first FDA approved cellular photoimmunotherapy for cancer, namely cutaneous T cell lymphoma, and has demonstrated efficacy in various T cell mediated diseases including prevention and treatment of acute and chronic GvHD, organ transplant rejection, selected autoimmune diseases and Sezary syndrome [8,10]. During ECP, patient’s blood mononuclear cells are collected, exposed to ultraviolet A light in the presence of extracorporally administered liquid 8-methoxypsoralen and reinfused into the patient. Besides its considerable efficacy ECP has an excellent safety profile, does not cause generalized immunosuppression and thus, does not increase risk of infectious complications and relapse of malignant disease [8,10]. In the following chapters results on the use of ECP in corticosteroid-refractory acute as well as chronic GvHD will be presented.

2. Extracorporeal photopheresis in acute graft-versushost disease Despite prophylactic treatment with immunosuppressive agents, 20–80% of patients develop acute GvHD after allogeneic HCT [1]. The incidence of acute GVHD is higher after HCT from an unrelated or HLA-nonidentical donor compared with HLA-identical sibling donors or a female donor graft given to a male recipient [1]. The pathophysiology of acute GvHD involves a complex cascade of cellular and humoral interactions between donor and recipient cells and it is thought to consist of three sequential phases [11]. First, patients’ conditioning causes damage and the activation of host tissues with predominance of those in the intestinal tract. Innate immune cells activated by microbial products then secrete proinflammatory cytokines, which enhance the recognition of host antigens by mature donor T cells contained in the stem cell graft through their effects on antigen-presenting, co-stimulatory and adhesion molecules. The second phase involves the activation and proliferation of donor T cells leading to cell death in target tissues during the effector phase. Established first-line treatment of acute GVHD grades II–IV consists of corticosteroids with doses ranging from 1 to 2.5 mg/kg body weight (bw) achieving a complete response (CR) rate of around 50% [1,12]. While first-line treatment of acute GvHD is based on prospective randomized trials, decisions on second-line therapy are derived solely from uncontrolled phase II trials or retrospective analyses and consecutively, no accepted treatment algorithm for second-line treatment of corticosteroidrefractory acute GvHD does exist [12,13]. Results of larger clinical studies on the use of ECP in corticosteroid-refractory acute GvHD patients are shown in Table 1. The Medical University of Vienna reported on the so far largest patient cohort treated with ECP as second-line therapy within a prospective phase II study [17,18]. Intensification of ECP therapy to 2–3 treatments per week on a weekly basis resulted in significantly

Please cite this article in press as: Greinix HT et al. Extracorporeal photopheresis in acute and chronic graft-versus-host disease. Transf Apheres Sci (2014), http://dx.doi.org/10.1016/j.transci.2014.04.005

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H.T. Greinix et al. / Transfusion and Apheresis Science xxx (2014) xxx–xxx Table 1 Results of second-line treatment of acute GvHD using extracorporeal photopheresis. Author

No of pts

CR skin No (%)

CR liver No (%)

CR gut No (%)

OS (%)

Salvaneschi et al. [14] Dall’Amico and Messina [15] Messina et al. [16] Greinix et al. [17,18] Garban et al. [19] Kanold et al. [20] Calore et al. [21] Perfetti et al. [22] Gonzalez-Vicent et al. [23] Perotti et al. [24]

9 14 33 59 12 12 15 23 8 50

6/9 (67) 10/14 (71) 25/33 (76) 47/57 (82) 8/12 (67) 9/10 (90) 12/13 (92) 15/23 (65) 8/8 (100) 39/47 (83)*

1/3 (33) 4/7 (57) 9/15 (60) 14/23 (61) 0/2 (0) 5/9 (55.5) 14/14 (100) 3/11 (27) 2/2 (100) 16/24 (67)*

3/5 (60) 6/10 (60) 15/20 (75) 9/15 (60) 2/5 (40) 5/6 (83) 85 at 5 yrs 8/20 (40) 4/7 (57%) 8/11 (73)*

67 57 69 at 5 yrs 47 at 5 yrs 42 75 at 8.5 mo 48 at 37 mo 37.5 64 at 1 yr

Abbreviations: No = number, pts = patients, CR = complete resolution, OS = overall survival, yrs = years, mo = months. Results were provided as complete and partial resolution.

*

improved CR rates in patients with gastrointestinal (GI) involvement (73% versus 25%) and patients with grade IV acute GvHD (60% versus 12%) [17,18,25], respectively. Overall CR rates were 82%, 61% and 60% in patients with cutaneous, hepatic and GI manifestations of acute GvHD. The CI of transplant-related mortality (TRM) at 4 years was 36% (95% confidence interval, 10–31%) and significantly lower for patients achieving a CR to ECP (14% versus 73%). Corticosteroid dose below 1 mg/kg bw at 4 weeks and below 0.5 mg/kg bw at 8 weeks after initiation of ECP were significantly associated with lower TRM confirming the importance of the corticosteroid-sparing effect of ECP. Overall survival at 4 years was significantly better in patients completely responding to ECP compared to those not achieving a CR (59% versus 11%, p < 0.0001). Of note, a higher grade of acute GvHD both at start of first-line as well as at start of ECP treatment, a higher corticosteroid dose and more organs afflicted by acute GvHD at initiation of ECP and failure to achieve a CR to ECP at 3 months were significantly associated with worse survival. Recently, Jagasia and colleagues compared ECP to anticytokine therapy consisting of inolimumab or etanercept as second-line treatment for corticosteroid-refractory acute GvHD patients [26]. ECP administered at the Vanderbilt University, University of Nottingham and Medical University of Vienna to a total of 57 patients compared favourably to anticytokine treatment given to 41 patients at the Saint Louis Hospital in Paris. Rate of CR was significantly higher in the ECP cohort compared to the anticytokine therapy one (54% versus 20%, p = 0.001), respectively. In multivariable analyses, ECP, adjusted for corticosteroid dose and grade of acute GvHD, was an independent predictor of response and was associated with superior survival (hazard ratio, HR 4.6, p = 0.016) in patients with corticosteroid-refractory acute GvHD grade II.

3. Recommendations on the use of extracorporeal photopheresis in acute graft-versus-host disease In recently published recommendations of the American Society of Blood and Marrow Transplantation (ASBMT) based on high quality prospective and retrospective studies

besides horse antithymocyte globulin (ATG) ECP was the second most frequently reported second-line treatment of patients with corticosteroid-refractory acute GvHD [12]. In 67 reports summarizing results of second-line treatment, data on CR and partial response (PR) of acute GvHD and 6-month survival did not support the choice of any specific agent for second-line therapy. Amongst the 5 studies with outliers in 6-month survival, Messina and colleagues’ study on ECP was cited with a higher survival rate [16]. In view of the fact that only children were treated with ECP, Martin and colleagues concluded that these outliers could reflect age differences between patient cohorts since the benchmark study investigating horse ATG included a patient cohort with a median age of 27 years. In the ASBMT’s comparison of second-line treatments ECP was rated favourably with limited toxicity, no increased risk for infections and no concerns for increased viral reactivations during ECP treatment. As typical ECP schedule 3 times per week during the first week followed by twice per week on a weekly basis was recommended. The joint working group established by the HaematoOncology Subgroup of the British Committee for Standards in Haematology (BCSH) and the British Society for Bone Marrow Transplantation (BSBMT) recently recommended ECP for use in second-line treatment of corticosteroidrefractory acute GvHD based on the review of the available literature [27]. Furthermore, the excellent safety profile of ECP was acknowledged by these scientific organizations. However, access to ECP for acute GvHD in the UK reportedly is limited to those centers where ECP is available on site since patients with corticosteroid-refractory acute GvHD are usually in no clinical condition to travel longer distances to receive efficient treatment. Recently, the Italian Society of Hemapheresis and Cell Manipulation (SIdEM) and the Italian Group for Bone Marrow Transplantation (GITMO) published a consensus process on the use of ECP for treatment of acute and chronic GvHD patients [28]. There, ECP is recommended as valuable option for second-line therapy of patients with acute GvHD not responding to corticosteroids and CNIs. An early start of ECP treatment was recommended particularly in children and patients given either a haploidentical or unrelated donor HCT. The consensus group stated that

Please cite this article in press as: Greinix HT et al. Extracorporeal photopheresis in acute and chronic graft-versus-host disease. Transf Apheres Sci (2014), http://dx.doi.org/10.1016/j.transci.2014.04.005

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ECP represents a promising therapeutic approach for patients with acute GvHD for whom due to viral reactivation or other infectious complications further immunosuppressive treatment is contraindicated. As schedule 2 ECP sessions per week on a weekly basis were recommended and clinical response should be assessed weekly in patients with acute GvHD. In recently approved guidelines the European Academy of Dermatology and Venereology (EADV), the European Dermatology Forum (EDF) and the European Association of Medical Societies recommended the use of ECP in patients with corticosteroid-refractory acute GvHD [29].

4. Extracorporeal photopheresis in chronic graft-versushost disease Chronic GvHD remains a major cause of late morbidity and mortality after allogeneic HCT with reported incidences varying between 6% and 80% [1]. Use of unrelated donors, HLA-disparity between patient and donor, use of peripheral blood stem cells (PBSC) as stem cell source, older patient or donor age and use of female donors for male recipients significantly increase the risk of chronic GvHD [1,30]. The pathophysiology of chronic GvHD is poorly understood [31]. Since chronic GvHD only occurs in allogeneic HCT recipients and can be prevented by T cell depletion from the donor graft, donor T cells responding to allogeneic antigens in the patient are of critical importance for the development of chronic GvHD. Besides the presence of autoantibodies abnormalities of B cell function seen as distortion of B cell homeostasis and excess of production of B cell activation factor (BAFF) characterize chronic GvHD [32]. Involvement of thymus-dependent T cell pathways in chronic GvHD development have been reported that begin with thymic injury from chemotherapy and/or irradiation and/or occurrence of acute GvHD leading to survival of autoreactive T cells that escaped negative selection in the thymus [31,33]. Disruption of programmed cell death and failure to eliminate the majority of autoreactive lymphocytes may then lead to impairment of lymphocyte homeostasis and self-tolerance [33]. Expansion and effector functions of autoreactive T cells will promote development of autoimmunity. Of note, the clinical signs of chronic GvHD can resemble those seen in autoimmune disorders such as systemic lupus erythematosus, Sjogren syndrome, scleroderma and rheumatoid arthritis [1,34]. Chronic GvHD is a multiorgan alloimmune and autoimmune disorder characterized by immune dysregulation, immune deficiency, impaired end-organ function and decreased survival [1,34]. Affected patients present unique clinical features, including lichenoid and sclerodermatous skin lesions, keratoconjunctivitis sicca, lichenoid mucositis and bronchiolitis obliterans syndrome (BOS) which have recently been reclassified within the National Institutes of Health (NIH) consensus development project [34]. Most frequently the skin, oral mucosa, eyes and liver are involved by chronic GvHD [1,3]. Based on the NIH definitions classic chronic GvHD without features of acute GvHD and overlap syndrome with synchronous clinical features of acute and chronic GvHD can be distinguished [34].

Besides individual organ severity scoring into grades 0–3, global chronic GvHD stage distinguishing mild, moderate and severe forms account for patients symptoms, impairment of their quality of life and need of topical or systemic immunosuppressive treatment. Of note, chronic GvHD is closely related to GvL effect and thus, significantly reduces patients’ risk of relapse of malignant disease [1–3]. Established first-line treatment of moderate to severe chronic GvHD consists of corticosteroids at 1 mg/kg bw/ day with or without a CNI [35]. The median duration of treatment for chronic GvHD is approximately 2 years in patients who had HCT with marrow cells and approximately 3.5 years in those given PBSC [36]. Evidence for first-line treatment options is based on controlled trials using the old classification of chronic GvHD and so far, no other immunosuppressive agent has been able to replace corticosteroids in first-line therapy. Approximately half of all patients reportedly respond to primary treatment of chronic GvHD [35] and thus, a substantial number of patients is in need of more efficient treatment strategies. Indications for second-line therapy include worsening manifestations in a previously affected organ, development of manifestations in a previously unaffected organ, absence of improvement after 1 month of treatment or inability to decrease the dose of corticosteroids below 1 mg/kg/day within 2 months [37]. To date, no consensus has been reached regarding the optimal choice of agents for second-line therapy of corticosteroid-refractory chronic GvHD and clinical management is generally approached through empirical trial and error [37]. ECP represents a frequently used therapeutic approach for the treatment of chronic corticosteroid-dependent or corticosteroid-refractory GvHD [37]. Recently, Martin and colleagues performing a comprehensive review of both retrospective and prospective studies on therapy of chronic GvHD reported on 60 studies evaluating 17 different agents [38]. Interestingly, ECP was the most frequently studied agent (n = 17) in this review. Results of larger clinical studies on the use of ECP in corticosteroid-refractory chronic GvHD patients are shown in Table 2. Most of the clinical experience in ECP treatment of corticosteroidrefractory chronic GvHD patients is based on retrospective analyses with limited number of patients [8,10,14– 16,37,39–47] with consistently high complete responses in up to 80% of patients with cutaneous manifestations and significant improvement in sclerodermatous skin involvement [39,41,42,45,46]. Couriel and colleagues treated 71 patients with corticosteroid-refractory severe chronic GvHD with ECP achieving a response rate of 61%, with an inferior outcome in patients with thrombocytopenia and a trend toward a higher response rate in de novo chronic GvHD [46]. Dignan and colleagues reported on 82 corticosteroid-refractory chronic GvHD patients including 91% of patients with NIH-defined severe disease given initially a bimonthly regimen of 2 ECP treatments on consecutive days [50]. After 6 months of ECP treatment, 65/82 (79%) patients had a complete or partial improvement in symptoms and signs of chronic GvHD. Among those receiving immunosuppressive drugs at the start of ECP treatment, 77% had a dose reduction after 6 months of therapy and 80% had reduced their corticosteroid dose.

Please cite this article in press as: Greinix HT et al. Extracorporeal photopheresis in acute and chronic graft-versus-host disease. Transf Apheres Sci (2014), http://dx.doi.org/10.1016/j.transci.2014.04.005

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H.T. Greinix et al. / Transfusion and Apheresis Science xxx (2014) xxx–xxx Table 2 Results of second-line treatment of chronic GvHD using extracorporeal photopheresis. Author

Patients

CR/PR skin (%)

CR/PR liver (%)

CR/PR oral (%)

ORR (%)

Corticosteroid-sparing

OS n (%)

Greinix et al. [39] Child et al. [40] Salvaneschi et al. [14] Seaton et al. [41] Apisarnthanarax et al. [42] Messina et al. [16] Foss et al. [43] Rubegni et al. [44] Garban et al. [19] Bisaccia et al. [45] Greinix 06 [8] Couriel et al. [46] Kanold 07 [20] Perseghin et al. [47] Flowers et al. [48] Jagasia et al. [49] Perotti et al. [24] Dignan et al. [50] Greinix et al. [51] Del Fante et al. [52] Hautmann et al. [53]

15 11 14 28 32 44 25 32 15 14 47 71 15 25 48 43 23 69 29 88 32

100 100 83 48 59 57 64 81 100 50 93 57 75 80 40 NA 83 92 31 NA 59

90 17 67 32 NA 60 0 77 33 60 84 71 82 67 29 NA 100 NA 50 NA 100

100 75 67 21 NA NA 46 92 NA 43 95 78 86 78 53 NA 80 91 70 NA 60

93 NA 64 36 56 59 64 69 87 NA 83 61 73 80

Yes Yes Yes No Yes Yes Yes NA NA Yes Yes Yes No NA Yes Yes Yes Yes Yes NA No

14/15 (93) 9/11 (82) 11/14 (79) 24/28 (86) 19/32 (59) 34/44 (77) 15/25 (60) NA NA 10/14 (71) 42/47 (89) 13/71 (18) 10/15 (67) 19/25 (76) 47/48 (98) NA 18/23 (78) 50/69 (72) 29/29 (100) NA 21/32 (66)

65 69.5 79 31 NA 44

Abbreviations: CR = complete resolution; PR = partial resolution; ORR = overall response rate; OS = overall survival; n = number; NA = not applicable.

Besides indwelling line infections in 4 patients and an increase in red cell transfusion requirements in 3 patients no other side effects during the course of ECP treatment were observed. Improvement in visceral and lung manifestations of chronic GvHD to ECP has been less consistent [8,14,16,19,20,24,39–41,43–47,53]. Two studies demonstrated that initiation of ECP within less than 1 year of diagnosis revealed better response rates in skin, liver and mucosal chronic GvHD [16,40]. These findings, however, were not confirmed by Foss and colleagues [43] and Apisarnthanarax and collegues [42]. In 2008 Flowers and colleagues reported results of a prospective randomized phase II study in 95 patients with corticosteroid-refractory/dependent/intolerant chronic GvHD given ECP for 12–24 weeks in combination with conventional immunosuppressive medication [48]. Although no significant difference in improvement of total skin score (TSS) at week 12 was observed, a significantly higher rate of CR and PR of cutaneous chronic GvHD as assessed by the clinicians was reported in the ECP cohort compared to the control arm. Furthermore, by week 12 significantly more patients in the ECP arm had at least a 50% reduction of corticosteroid dose and at least a 25% decrease of TSS. A corticosteroid sparing effect of ECP treatment has also been reported by other investigators as shown in Table 2 [8,14,16,24,39,40,42,43,45,46,49,50]. In a following clinical study 29 patients initially treated prospectively with conventional immunosuppressive medication and not responding crossed over to receive ECP treatment [51]. Significantly higher responses in the skin, oral mucosa and ocular involvement were observed at 12 weeks after crossing over to ECP treatment compared to the same previous period when these patients were receiving conventional therapy alone. Overall, responses in extracutaneous manifestations of chronic GvHD including oral mucosa, eyes, liver and lung by week 24 were 70%, 47%, 50% and 50%, respectively.

Experience is limited with ECP in other manifestations of chronic GvHD, such as lung involvement with 100 patients reported achieving a response rate of 51% including 14 CR, 20 PR and 17 improvements [15,16,40,46,48,51,54]. In view of the dismal prognosis of BOS and the limited therapeutic options for these patients, results of ECP in pulmonary chronic GvHD are encouraging. Nonetheless, the efficacy of ECP in lung manifestations of chronic GvHD needs to be determined in prospective studies with a larger patient number. Considering its excellent safety profile ECP should be administered earlier in the course of chronic GvHD to avoid irreversible tissue damage and patient mortality due to infections during immunodeficiency. Of note, ECP reportedly does not cause generalized immunosuppression [55] and no increase in infectious complications has been reported during ECP therapy [8,25,39,48]. Furthermore, significantly improved survival rates and improvements in quality of life have been reported in ECP-responders [16,39,46]. So far, no treatment schedule (weekly versus two-weekly) has reportedly revealed superior response rates. Due to the variety of ECP schedules applied, however, the impact of dose intensity and length of treatment cannot be assessed accurately based on the currently available literature and prospective well-designed clinical studies are highly warranted to improve our knowledge in this area. So far, published evidence on the use of ECP for treatment of chronic GvHD almost exclusively consists of patients with corticosteroid-refractory or corticosteroiddependent chronic GvHD. Based on the excellent safety profile of ECP and frequently reported evidence that the GvL effect seems to be not impaired by ECP, leading experts in the field of allogeneic HCT recommend the use of ECP earlier in the course of chronic GvHD [8,10,56]. Currently, a prospective multicenter phase II study supported by Therakos Inc. is ongoing recruiting patients with newly diagnosed NIH-defined moderate or severe chronic GvHD to investigate the safety and efficacy of adjunct ECP treatment in

Please cite this article in press as: Greinix HT et al. Extracorporeal photopheresis in acute and chronic graft-versus-host disease. Transf Apheres Sci (2014), http://dx.doi.org/10.1016/j.transci.2014.04.005

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comparison with conventional immunosuppressive therapy with CNI and corticosteroids (NCT01380535). In view of the poor prognosis of patients with corticosteroid-refractory chronic GvHD and the promising results obtained with ECP as well as the excellent safety profile of ECP treatment, it is tempting to consider ECP in first-line therapy of chronic GvHD to improve patients’ outcome. However, data on prospective controlled trials are currently lacking and thus, international cooperations and all our combined efforts are warranted to perform and complete prospective studies on the use of ECP in first-line therapy of chronic GvHD.

5. Biomarkers for prediction and monitoring of response to ECP in chronic GvHD In view of the logistical challenges associated with intensified ECP schedules and the rising demands for efficient use of limited resources in costly areas such as allogeneic HCT, biomarkers predicting response to ECP treatment are highly warranted. Furthermore, some patients with chronic GvHD including sclerodermatous cutaneous manifestations are in need of ECP treatment for prolonged periods of time to achieve meaningful clinical response and improvement in the patients’ quality of life [39]. Our group at the Medical University of Vienna investigated CD19+CD21 B lymphocytes in peripheral blood (PB) of patients with chronic GvHD before start of ECP and up to 21 months thereafter [57]. CR and PR to ECP were observed in 25 of 34 patients (74%) after 12 months. Patients not responding to 6 months of ECP treatment had a significantly (p = 0.02) higher percentage of CD19+CD21 B lymphocytes (mean 22%) in PB prior to start of ECP compared with patients achieving a CR (mean 8%) and PR (mean 16%). Furthermore, the CD21 /CD27+ B cell ratio was significantly higher (p = 0.03) in patients not responding to ECP (mean 17.4) compared with CR patients (mean 1.6), respectively. During ECP treatment chronic GvHD patients achieving a CR–ECP had significantly lower percentages of CD19+CD21 B lymphocytes in PB 6 (mean 5% versus 25%, p < 0.001), 12 (mean 6% versus 24%, p < 0.001) and 21 (mean 6% versus 26%, p < 0.001) months after start of ECP compared with ECP non-responders. In addition, the CD21 /CD27+ B cell ratio was significantly lower at 6 (mean 2.2 versus 9.6, p = 0.001), 12 (mean 2.7 versus 6, p = 0.006) and 21 (mean 2 versus 17, p = 0.001) months in ECP responders compared with patients not responding to ECP. Thus, relative amounts of CD19+CD21 B cells represent the first reported cellular biomarkers predicting response to ECP. They can also serve as a novel biomarker for measuring activity of chronic GvHD objectively and should be investigated in further prospective clinical trials. The tumour necrosis factor family member BAFF is a crucial survival factor for peripheral B cells and is a key regulator of normal B cell homeostasis [58]. High BAFF levels have been reported in patients with a variety of autoimmune disorders including active chronic GvHD [32,59,60]. Whittle and Taylor measured serum BAFF levels in 46 patients with chronic GvHD prior to and during ECP and reported that BAFF level at 1 month of ECP predicted

cutaneous response at 3 and 6 months [61]. Serum BAFF level below 4 ng/mL at 1 month of ECP treatment was associated with significant improvement of skin involvement seen as reduction of TSS from a median of 47 prior to ECP to 4.5 after 3 months of ECP treatment. Lower BAFF level at 1 month of ECP treatment was also associated with continuing improvement after 6 months of ECP treatment and CR of cutaneous manifestations in 11 of 20 (55%) patients. Patients with BAFF levels below 4 ng/mL at 1 month of ECP therapy were more likely to achieve at least a 50% reduction of corticosteroid dose between 1 and 6 months of ECP compared to patients with high BAFF levels (70% versus 46%). Thus, relative amounts of CD19+CD21 B cells and serum BAFF levels can serve as novel biomarkers for prediction of response to ECP. Whether these findings are ECP-specific is currently unknown since no other treatment cohorts were analyzed and the mechanisms of action of ECP are still subject to further research. Whereas CD19+CD21 B cells significantly correlated with activity of chronic GvHD and thus, can be used for objective monitoring of disease at various time points during ECP treatment, serum BAFF level is known to be influenced by corticosteroid dose and therefore, could be limited in its clinical usefulness for monitoring disease activity in the treatment course. An imbalance of regulatory and effector T cells is thought to underpin the development of GvHD [62]. In animal models of contact hypersensitivity and acute GvHD the infusion of ECP-treated PB cells induced regulatory T cells supporting the promoting of immune tolerance by ECP [63,64]. Biagi and colleagues observed a rapid increase of circulating CD4+CD25+FOXP3+CD62L+ regulatory T cells in both acute and chronic GvHD patients given ECP and these cells were capable of inhibiting alloreactive responses in a contact-dependent manner [65]. In a further research project, this group demonstrated in a cohort of 18 patients with chronic GvHD that ECP response is associated with increased levels of regulatory T cells that maintained STAT-5 pathway activity and that higher levels of regulatory T cells in ECP-responding patients correlated with a decreased frequency of circulating Th-17 cells that reportedly are involved in the pathogenesis of GvHD [66]. Well-designed prospective studies with larger patient numbers are needed to better allow evaluation of the predictive and diagnostic value of these very promising novel biomarkers.

6. Recommendations on the use of extracorporeal photopheresis in chronic graft-versus-host disease Recently, recommendations of a joint working group of BCSH and BSBMT have been published based on the review of the available literature [67]. There, ECP is strongly recommended (Grade 1B) as second-line therapy for skin, oral and liver manifestations of chronic GvHD with a schedule of fortnightly-paired treatments for a minimum assessment period of 3 months. Grade 1 recommendation means that there is confidence about the benefits of ECP and no other immunosuppressive therapeutic modality

Please cite this article in press as: Greinix HT et al. Extracorporeal photopheresis in acute and chronic graft-versus-host disease. Transf Apheres Sci (2014), http://dx.doi.org/10.1016/j.transci.2014.04.005

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was recommended stronger for second-line therapy of chronic GvHD. Furthermore, ECP was recommended as third-line treatment option in chronic GvHD involving other organs (Grade 2C). The German/Austrian/Swiss consensus conference on second-line treatment of chronic GvHD in daily clinical practice recommended ECP with a strength of recommendation of C–I, meaning use in second-line treatment is justified, based on grade II evidence [37]. Of note, ECP was considered to be superior to other novel immunosuppressive agents due to its excellent safety profile and steroidsparing effect. These recommendations were based on the fact that numerous investigators had reported not only high response rates in skin, liver and oral manifestations of corticosteroid-refractory chronic GvHD but also improved survival rates both in children as well as in adults. In the recently published consensus-based recommendations of the SIdEM and GITMO ECP treatment was recommended in both adult and pediatric patients with corticosteroid-refractory as well as corticosteroid-dependent chronic GvHD irrespective of disease extent and severity [28]. Furthermore, the corticosteroid-sparing potential of ECP and its positive effect on patients’ quality of life were emphasized. In the absence of controlled clinical trials a schedule of 2 ECP sessions per week on a weekly basis until maximum response followed by tapering of ECP treatments according to clinical response were recommended. Clinical response assessment should be performed every 8–12 weeks. Furthermore, the EADV, the EDF and the European Association of Medical Societies recommended the use of ECP in patients with corticosteroid-refractory and corticosteroiddependent chronic GvHD [29].

7. Conclusions Despite many improvements in GvHD prevention and treatment strategies, this HCT complication remains one of the main contributors to morbidity and mortality following allogeneic HCT. Current evidence shows that ECP is a reasonable first choice for treatment of corticosteroid-refractory acute and chronic GvHD patients. For acute GvHD an intensified schedule with weekly treatments until CR of GvHD is of tremendous importance for optimal response especially of patients with higher grades of acute GvHD and gastrointestinal involvement by acute GvHD. For corticosteroid-refractory cutaneous chronic GvHD at least 24 weeks of ECP treatment are necessary to achieve adequate response and patients with deep sclerosis due to chronic GvHD may benefit from longer ECP treatment duration. ECP has also demonstrated promising efficacy in extracutaneous manifestations and patients with long duration of chronic GvHD. Advantages of ECP include no increased risk of infection compared to other therapies and an excellent safety profile. Since ECP is felt to be immunomodulating, rather than immunosuppressive, response of GvHD to ECP will not come at the expense of higher relapse rates and no diminution of the GvL effect after ECP has been reported. Limitation of ECP includes the need for specialized service

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and adequate venous access to deliver the treatment. Of note, use of a central venous line is known to be associated with increased risk for infections and venous thrombosis and thus, should be avoided if possible. Due to the favorable risk–benefit profile of ECP in adults and children and an increasing number of clinical trial results available to the scientific community, many clinical investigators as well as scientific organizations have agreed to recommend the use of ECP earlier in the course of acute and chronic GvHD. Nevertheless, well-designed prospective, multicenter clinical studies with suitable patient numbers and acceptable therapeutic control groups as well as clinically meaningful endpoints are highly warranted to better define the potential of ECP in prevention and treatment of acute and chronic GvHD including its use as first-line therapy. Furthermore, prospective clinical studies should be performed to characterize the optimal schedule and duration of ECP and to investigate novel soluble and cellular biomarkers for prediction and monitoring of response to ECP treatment.

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Please cite this article in press as: Greinix HT et al. Extracorporeal photopheresis in acute and chronic graft-versus-host disease. Transf Apheres Sci (2014), http://dx.doi.org/10.1016/j.transci.2014.04.005