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Transfusion and Apheresis Science j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / t r a n s c i
Review
Extracorporeal photopheresis in prevention and treatment of acute GVHD Carrie L. Kitko *, John E. Levine Blood and Marrow Transplant Program, Division of Pediatric Hematology/Oncology, University of Michigan, 1500 E. Medical Center Dr. MPB 4202, Ann Arbor, MI 48109-5718
A R T I C L E
I N F O
A B S T R A C T
Acute graft versus host disease (GVHD), a common complication after allogeneic hematopoietic cell transplantation (HCT), occurs in as many as 70% of recipients of this life saving treatment. Front line therapy for GVHD with corticosteroids will fail in up to 40% of patients, which leads to high morbidity and mortality. Traditional prevention and treatment strategies have focused on reducing alloreactivity, typically with therapy to reduce cytotoxic T-cell function. Emerging evidence exists that promotion of regularly T-cell function, through treatments such as extracorporeal photopheresis, is effective for GVHD treatment and has potential for prevention as well. This review will focus on literature reporting the success of ECP for steroid refractory acute GVHD and the potential for delivery of ECP in the early pre and post-transplant periods that shows promise as a less immunosuppressive strategy to reduce rates of acute GVHD. © 2015 Published by Elsevier Ltd.
Contents 1. 2. 3. 4. 5. 6. 7.
Introduction .............................................................................................................................................................................................................................. GVHD prevention with ECP: potential mechanism of action ..................................................................................................................................................................................................................................... Current prevention strategies ............................................................................................................................................................................................. Extracorporeal photopheresis for GVHD treatment .................................................................................................................................................... Extracorporeal photopheresis during HCT preparative regimens .......................................................................................................................... ECP for GVHD prevention ..................................................................................................................................................................................................... Conclusions ............................................................................................................................................................................................................................... References ..................................................................................................................................................................................................................................
1. Introduction Allogeneic hematopoietic cell transplantation (HCT) is widely used for a variety of illnesses including leukemia and lymphoma as well as bone marrow failure syndromes and
* Corresponding author. Blood and Marrow Transplant Program, Division of Pediatric Hematology/Oncology, University of Michigan, 1500 E. Medical Center Dr. MPB 4202, Ann Arbor, MI 48109-5718. Tel.: 734-764-7126; fax: 734-615-0464. E-mail address: [email protected] (C.L. Kitko).
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immunodeficiencies. Graft versus host disease (GVHD), the result of donor immune system cells treating normal host tissue as foreign, remains the most serious complication following HCT. Current GVHD prevention strategies target donor T cell alloreactivity with such techniques as in-vitro or in-vivo T-cell depletion or pharmacologic dampening of T cell function [1,2]. Commonly used GVHD prophylaxis strategies result in rates of GVHD of 40–60% depending on donor source and preparative regimen used, resulting in significant morbidity and mortality for transplant recipients. GVHD resistant to standard first-line treatment (high dose steroids) develops in approximately 25% of recipients
http://dx.doi.org/10.1016/j.transci.2015.02.001 1473-0502/© 2015 Published by Elsevier Ltd.
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and accounts for the majority of non-relapse mortality. To date, there is no consensus on standard second-line therapy but current approaches focus on intensification of immunosuppression [3]. Novel prevention and treatment strategies that target other pathways involved in the development of GVHD are needed. One such approach is extracorporeal photopheresis (ECP), which has been shown to impact at least one key component of the GVHD pathway, regulatory T-cells (Tregs). 2. GVHD prevention with ECP: potential mechanism of action There has been extensive research using both murine models and clinical studies to help improve our understanding of GVHD pathophysiology [4–6]. The GVHD cycle is initiated by the conditioning regimen delivered prior to HCT infusion, which leads to tissue damage, and resultant increases in inflammatory cytokines. This enhanced inflammatory background primes the second phase during which presentation of MHC antigens by host dendritic cells (DCs) to donor T-cells occurs, leading to donor T-cell activation and further increases in inflammatory cytokines. In the final phase, the effector immune cells cause direct cytotoxicity of host tissue, which is amplified further by inflammatory mediators such as LPS, TNF-α and IL-1 (Fig. 1A). There are four essential factors necessary for this process to proceed, which include (1) Triggers such as HLA-mismatch and if conditioning induced tissue damage, (2) Sensors, primarily antigen presenting cells such as DCs, (3) Mediators, which include donor T-cell subsets such as naive CD4+ and CD8+ T-cells as well as Tregs, and (4) Effectors of GVHD primarily effector T-cells and inflammatory cytokines. Most GVHD prevention strategies target the T-cell effectors of the GVHD process. There is emerging evidence however, that it is also possible to target the mediators of GVHD, such as Treg, to amelioriate or prevent GVHD. Experimental GVHD data from mouse models, as well as results from patients treated with ECP, lend support to the hypothesis that ECP can prevent GVHD by affecting both the DC (sensor) and Treg (mediator) populations. 3. Current prevention strategies Historically, GVHD prophylactic treatments focused on the use of alkylators and antimetabolities following HCT. The first widely adopted treatment was methotrexate (MTX), a folate antagonist, which was shown to be effective at reducing GVHD severity and prolonging survival, first in canine
models [7] and later in clinical trials [8]. Unfortunately, this regimen still resulted in unacceptably high rates of severe GVHD [9], leading to the introduction of additional agents to MTX for improved GVHD prevention. Calcineurin inhibitors, which block IL-2 mediated T-cell expansion and cytotoxicity, were added to MTX and proved to be beneficial at both reducing the rates of acute GVHD and improving overall survival in patients [10–15]. These studies led to widespread adoption of calcineurin inhibitors, such as cyclosporine or tacrolimus plus methotrexate as standard GVHD prophylaxis. Despite these improvements, toxicities associated with MTX containing regimens, such as delayed engraftment and increased oral mucositis, led to the development of protocols to potentially replace MTX. One such approach has been to substitute MTX with sirolimus, also known as rapamycin, which inhibits the mammalian target of rapamycin (mTOR), blocking IL-2 signaling and causing effector T-cells to become unresponsive and eventually apoptotic [16]. Another attractive effect of sirolimus is the inhibition of dendritic cell maturation resulting in decreased antigen presentation to donor T-cells and relative sparing of the function of regulatory T-cells [17]. Single institution experience with tacrolimus and sirolimus without MTX for both related and unrelated donors was excellent, with only 5% TRM by day 100, and cumulative incidence of grade II–IV and grade III– IV GVHD of 21% and 5% respectively [18]. A large multicenter randomized trial compared tacrolimus/sirolimus versus tacrolimus/MTX in 304 related donor HCT patients and found similar rates of acute GVHD (24% versus 34%, p = 0.48), indicating that tacrolimus/sirolimus is as effective as tacrolimus/MTX [19]. Recipients of tacrolimus/ sirolimus did experience significantly faster engraftment and less severe mucositis. Unfortunately, there were different toxicities observed with this combination of prophylactic agents based on the preparative regimen used [20], which limits broad applicability of this strategy [21]. The role of regulatory T cells (Tregs), which inhibit cytotoxic T cell activity, as potential mediators of GVHD has been explored. Preclinical data from murine models showed that lethal GVHD could be prevented by co-infusion of Tregs [22,23]. In a clinical study, the frequency of Tregs was almost 50% lower at the time of GVHD onset compared to matched non-GVHD controls and patients with the lowest frequency of Tregs at GVHD onset were significantly more likely to experience treatment failure and die [24]. These data suggest that Tregs are protective against GVHD, a finding that opens up a novel therapeutic avenue for GVHD prevention and treatment.
Fig. 1. A. Pathophysiology of GVHD. This involves three phases, including (1) damage induced by the HCT preparative regimen which leads to increased inflammatory cytokine secretion which is sensed by the host APCs, leading to their activation. (2) Activated host APCs then interact with donor T-cells, mediators of GVHD, leading to their activation, proliferation and differentiation. Treatments that promote increases in Treg can suppress this reaction. And finally, if the process is left unchecked, the increased activated alloreactive cells cause tissue damage and the release of more inflammatory cytokines that are also harmful to host tissues. B. ECP for GVHD prevention. (1) Patients undergo a leukopheresis during ECP treatment, and these white blood cells are exposed to 8-methoxypsoralen (8-MOP) and ultraviolet A radiation. (2) Treated cells are reinfused to the patient, and all will undergo apoptosis within 24–48 hours of treatment. (3) APCs are able to engulf these apoptotic cells. Early post-HCT these APCs will be of host-origin, but at later time points, donor derived APCs will also participate in this process. After apoptotic cell uptake, DCs and macrophages promote tolerance through the secretion of antiinflammatory cytokines such as TGF-β and IL-10. (4) These tolerogeneic DCs are unable to stimulate the differentiation of donor T-cells into cytotoxic lymphocytes, but will promote increased number and function of Tregs. Thus ECP for prophylaxis can potentially modulate the traditional GVHD pathway by changing the DC phenotype to promote tolerance rather than alloreactivity through the generation of increased numbers of Treg. (Hildegard T. Greinix, Robert Knobler (Eds.) Extracorporeal Photopheresis Cellular Photoimmunotherapy.)
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Given these findings, another potential strategy for GVHD prevention is infusion of Tregs, and clinical studies investigating the potential benefit of post-HCT infusion of exvivo expanded Tregs have demonstrated safety, and potentially some benefit, toward reducing rates of GVHD [25,26]. A major limitation to widespread adoption of these strategies is obtaining the large number of Tregs needed, which can be time consuming, labor intensive and limited to institutions with expertise in this area. ECP may allow an in vivo treatment approach that might enhance Treg populations in post-HCT recipients. 4. Extracorporeal photopheresis for GVHD treatment ECP has been studied as a treatment for steroid refractory acute GVHD in twelve publications that reported results in a rigorous and comparable manner (Table 1) [27–38]. Overall response rates were variable, but ranged from 65 to 100%. Of the total of 249 patients with reported results for individual organs, complete responses (CR) were observed in 85% (176/208) of skin, 57% (54/95) of liver and 62% (66/106) of gastrointestinal GVHD cases. The number and frequency of ECP treatments required to achieve response are not yet established, but generally, patients receiving intensive initial therapy (2–3 times/wk) until response was achieved resulted in the best outcomes. ECP appears to be effective for both adult and pediatric patients. Given these encouraging results for acute GVHD treatment with ECP, ECP has also been explored for GVHD prevention. 5. Extracorporeal photopheresis during HCT preparative regimens Addition of ECP to HCT preparative regimens was initially attempted to help overcome graft failure following nonmyeloablative conditioning (NMA). Because ECP treatment has been shown to induce tolerogenic DCs [39–44], treatment with ECP prior to HCT may result in less rejection of donor hematopoietic elements by residual host DCs. Miller et al. explored a strategy in NMA HCT recipients that combined ECP, pentostatin and low-dose total body irradiation (TBI) in order to decrease DC function and therefore
promote donor chimerism. A total of 55 NMA HCT recipients received ECP (given on two consecutive days), followed by 48 hours of continuous infusion pentostatin (4 mg/m2/ day × 2 days), and TBI 200 cGy × 3 doses (600 cGy total) [45]. All patients also received cyclosporine, MTX and MMF as GVHD prophylaxis, and the majority (80%) received sibling donor HCT. High rates of donor chimerism (98%) and low rates (11%) of non-relapse mortality (NRM) at 100 days post HCT were observed. In addition, patients treated with this regimen had lower than expected rates of both acute and chronic GVHD (9% and 43% respectively). The 2-year event free survival (EFS) was 47%. Further studies to better elucidate the impact of pre-HCT ECP in facilitating engraftment following NMA HCT have not yet been published. Based on these results, a phase II multi-institutional study evaluated the role of ECP pre-HCT using a myeloablative preparative regimen [46]. All 62 patients received a cyclophosphamide (60 mg/kg/day × 2 day) and TBI (10– 13.5 Gy over 3–4 days) preparative regimen. In addition, all patients were treated with 2 days of ECP within 4 days of starting the preparative regimen. Standard GVHD prophylaxis included cyclosporine and MTX. Half of the study participants received a sibling donor HCT. The 100 day cumulative incidence (CI) of acute GVHD grades II–IV was 35%, and the 1 year CI of chronic GVHD was 38%, with a 1 year DFS of 69%. Data from the Center for International Blood and Marrow Transplant Research (CIBMTR) formed a historic control. Compared to 347 matched historical controls, the ECP treated group had a lower rate of grade II–IV GVHD (relative risk 0.61; 95% CI, 0.38–0.97; p = 0.04). Recently, Bethge et al. attempted to replicate these findings using a canine model (n = 9), and found no benefit to ECP and pentostatin for GVHD prevention [47]. While far from definitive, these findings support further investigation into ECP as a GVHD prevention strategy. 6. ECP for GVHD prevention A recently completed clinical trial at the University of Michigan tested an approach that augmented standard GVHD prophylaxis following high risk HCT using unrelated and mismatched donors with a combination of TNF-α inhibition and ECP for Treg induction. The standard GVHD prevention
Table 1 Results of studies of the use of ECP in patients with steroid resistant acute GVHD. Study type
No. of patients
Overall response (%)
Overall survival (%)
CR skin no (%)
CR liver no (%)
Phase I/II Retrospective Prospective* Retrospective Retrospective* Retrospective Retrospective* Retrospective* Retrospective* Pilot Prospective* Phase I/II*
59 57 50 34 33 23 21 15 15 12 12 9
70% 66% 68% 65% 75% 52% (CR) 90% 100% 66% 75% 83% 77%
47% 60% 44% 51% 55% 48% 43% 87% 63% 42% 75% 67%
47/57 (82%)
14/23 (61%)
39/47 (83%) 34 27/33 (82%) 15/23 (65%) 81% 12/13 (93%) 13/14 (93%) 8/12 (67%) 9/10 (90%) 6/9 (67%)
16/24 (67%) 9 9/15 (60%) 3/11 (27%) 67% 1/1 (100%) 5/7 (71%) 0/2 (0%) 5/9 (56%) 1/3 (33%)
CR gut no (%) 9/15 (60%) 8/11 (73%) 13 15/20 (75%) 8/20 (40%) 55% 10/14 (71%) 6/10 (60%) 2/5 (40%) 5/6 (83%) 3/5 (60%)
Reference [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38]
Abbreviations: no = number, CR = complete response. * Indicates an exclusively pediatric publication.
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backbone of the trial was tacrolimus and mycophenolate mofetil. Etanercept (TNF-α inhibitor) was given early postHCT (D0 – D56) to block cytokine mediated GVHD pathways pre-engraftment when ECP cannot be delivered. ECP was started at D28, since patients were anticipated to be postengraftment, and continued on a tapering schedule through day 180. Given the tight relationship between GVHD and graft-versus-leukemia effect, the goal of this study was to attenuate GVHD to a more treatment responsive phenotype. Preliminary results, not yet published, suggest this may have occurred as 1 year overall survival (73%) was better than expected. There are several factors that are important to consider when designing a clinical trial that will incorporate ECP for GVHD prevention. One of the most critical is the time to engraftment. Until the white blood count is reliably greater than 1000, it is not possible to deliver effective ECP treatments. Therefore, in order to have an impact on very early GVHD prevention, it will likely be necessary to utilize a highly effective regimen for the first 2–4 weeks post-HCT. A potential approach may be to add complementary treatments to enhance Treg induction such as sirolimus [48] or low dose IL-2 [49], as both have been shown to increase the numbers of Tregs. More work is also needed to better understand the impact of cell dose and the effectiveness of ECP therapy. Recent work has demonstrated that there is a linear relationship between the peripheral blood lymphocyte count and that observed in the buffy coat collected during apheresis, as well as increased efficiency of lymphocyte collection using the CELLEX machine compared to the older UVAR XTS device [50], and based on these results, future studies could assess the impact of lymphocytes treated. 7. Conclusions Despite many improvements in prevention strategies, GVHD remains the main cause of morbidity and mortality following allogeneic HCT. Future strategies that focus on promoting immune tolerance through expansion of Tregs in vivo may reduce rates of GVHD and promote improved immune recovery. There is expanding evidence to support that ECP may have a significant impact on these essential mediators of the GVHD pathway that would result in less alloreactivity, and therefore, less graft versus host disease (Fig. 1B). Importantly, since ECP is felt to be immunomodulating, rather than immunosuppressive, this potential decreased GVHD will not come at the expense of higher infectious complications. Future investigations should focus on overcoming the challenges of delivering ECP earlier and in the most effective manner. References [1] Ferrara JL, Levine JE, Reddy P, Holler E. Graft-versus-host disease. Lancet 2009;373(9674):1550–61. [2] Ram R, Gafter-Gvili A, Yeshurun M, Paul M, Raanani P, Shpilberg O. Prophylaxis regimens for GVHD: systematic review and meta-analysis. Bone Marrow Transplant 2009;43(8):643–53. [3] Martin PJ, Rizzo JD, Wingard JR, Ballen K, Curtin PT, Cutler C, et al. First- and second-line systemic treatment of acute graft-versus-host disease: recommendations of the American Society of Blood and Marrow Transplantation. Biol Blood Marrow Transplant 2012;18(8):1150–63.
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Contents lists available at ScienceDirect
Transfusion and Apheresis Science j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / t r a n s c i
Review
Extracorporeal photopheresis in prevention and treatment of acute GVHD Carrie L. Kitko *, John E. Levine Blood and Marrow Transplant Program, Division of Pediatric Hematology/Oncology, University of Michigan, 1500 E. Medical Center Dr. MPB 4202, Ann Arbor, MI 48109-5718
A R T I C L E
I N F O
A B S T R A C T
Acute graft versus host disease (GVHD), a common complication after allogeneic hematopoietic cell transplantation (HCT), occurs in as many as 70% of recipients of this life saving treatment. Front line therapy for GVHD with corticosteroids will fail in up to 40% of patients, which leads to high morbidity and mortality. Traditional prevention and treatment strategies have focused on reducing alloreactivity, typically with therapy to reduce cytotoxic T-cell function. Emerging evidence exists that promotion of regularly T-cell function, through treatments such as extracorporeal photopheresis, is effective for GVHD treatment and has potential for prevention as well. This review will focus on literature reporting the success of ECP for steroid refractory acute GVHD and the potential for delivery of ECP in the early pre and post-transplant periods that shows promise as a less immunosuppressive strategy to reduce rates of acute GVHD. © 2015 Published by Elsevier Ltd.
Contents 1. 2. 3. 4. 5. 6. 7.
Introduction .............................................................................................................................................................................................................................. GVHD prevention with ECP: potential mechanism of action ..................................................................................................................................................................................................................................... Current prevention strategies ............................................................................................................................................................................................. Extracorporeal photopheresis for GVHD treatment .................................................................................................................................................... Extracorporeal photopheresis during HCT preparative regimens .......................................................................................................................... ECP for GVHD prevention ..................................................................................................................................................................................................... Conclusions ............................................................................................................................................................................................................................... References ..................................................................................................................................................................................................................................
1. Introduction Allogeneic hematopoietic cell transplantation (HCT) is widely used for a variety of illnesses including leukemia and lymphoma as well as bone marrow failure syndromes and
* Corresponding author. Blood and Marrow Transplant Program, Division of Pediatric Hematology/Oncology, University of Michigan, 1500 E. Medical Center Dr. MPB 4202, Ann Arbor, MI 48109-5718. Tel.: 734-764-7126; fax: 734-615-0464. E-mail address: [email protected] (C.L. Kitko).
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immunodeficiencies. Graft versus host disease (GVHD), the result of donor immune system cells treating normal host tissue as foreign, remains the most serious complication following HCT. Current GVHD prevention strategies target donor T cell alloreactivity with such techniques as in-vitro or in-vivo T-cell depletion or pharmacologic dampening of T cell function [1,2]. Commonly used GVHD prophylaxis strategies result in rates of GVHD of 40–60% depending on donor source and preparative regimen used, resulting in significant morbidity and mortality for transplant recipients. GVHD resistant to standard first-line treatment (high dose steroids) develops in approximately 25% of recipients
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and accounts for the majority of non-relapse mortality. To date, there is no consensus on standard second-line therapy but current approaches focus on intensification of immunosuppression [3]. Novel prevention and treatment strategies that target other pathways involved in the development of GVHD are needed. One such approach is extracorporeal photopheresis (ECP), which has been shown to impact at least one key component of the GVHD pathway, regulatory T-cells (Tregs). 2. GVHD prevention with ECP: potential mechanism of action There has been extensive research using both murine models and clinical studies to help improve our understanding of GVHD pathophysiology [4–6]. The GVHD cycle is initiated by the conditioning regimen delivered prior to HCT infusion, which leads to tissue damage, and resultant increases in inflammatory cytokines. This enhanced inflammatory background primes the second phase during which presentation of MHC antigens by host dendritic cells (DCs) to donor T-cells occurs, leading to donor T-cell activation and further increases in inflammatory cytokines. In the final phase, the effector immune cells cause direct cytotoxicity of host tissue, which is amplified further by inflammatory mediators such as LPS, TNF-α and IL-1 (Fig. 1A). There are four essential factors necessary for this process to proceed, which include (1) Triggers such as HLA-mismatch and if conditioning induced tissue damage, (2) Sensors, primarily antigen presenting cells such as DCs, (3) Mediators, which include donor T-cell subsets such as naive CD4+ and CD8+ T-cells as well as Tregs, and (4) Effectors of GVHD primarily effector T-cells and inflammatory cytokines. Most GVHD prevention strategies target the T-cell effectors of the GVHD process. There is emerging evidence however, that it is also possible to target the mediators of GVHD, such as Treg, to amelioriate or prevent GVHD. Experimental GVHD data from mouse models, as well as results from patients treated with ECP, lend support to the hypothesis that ECP can prevent GVHD by affecting both the DC (sensor) and Treg (mediator) populations. 3. Current prevention strategies Historically, GVHD prophylactic treatments focused on the use of alkylators and antimetabolities following HCT. The first widely adopted treatment was methotrexate (MTX), a folate antagonist, which was shown to be effective at reducing GVHD severity and prolonging survival, first in canine
models [7] and later in clinical trials [8]. Unfortunately, this regimen still resulted in unacceptably high rates of severe GVHD [9], leading to the introduction of additional agents to MTX for improved GVHD prevention. Calcineurin inhibitors, which block IL-2 mediated T-cell expansion and cytotoxicity, were added to MTX and proved to be beneficial at both reducing the rates of acute GVHD and improving overall survival in patients [10–15]. These studies led to widespread adoption of calcineurin inhibitors, such as cyclosporine or tacrolimus plus methotrexate as standard GVHD prophylaxis. Despite these improvements, toxicities associated with MTX containing regimens, such as delayed engraftment and increased oral mucositis, led to the development of protocols to potentially replace MTX. One such approach has been to substitute MTX with sirolimus, also known as rapamycin, which inhibits the mammalian target of rapamycin (mTOR), blocking IL-2 signaling and causing effector T-cells to become unresponsive and eventually apoptotic [16]. Another attractive effect of sirolimus is the inhibition of dendritic cell maturation resulting in decreased antigen presentation to donor T-cells and relative sparing of the function of regulatory T-cells [17]. Single institution experience with tacrolimus and sirolimus without MTX for both related and unrelated donors was excellent, with only 5% TRM by day 100, and cumulative incidence of grade II–IV and grade III– IV GVHD of 21% and 5% respectively [18]. A large multicenter randomized trial compared tacrolimus/sirolimus versus tacrolimus/MTX in 304 related donor HCT patients and found similar rates of acute GVHD (24% versus 34%, p = 0.48), indicating that tacrolimus/sirolimus is as effective as tacrolimus/MTX [19]. Recipients of tacrolimus/ sirolimus did experience significantly faster engraftment and less severe mucositis. Unfortunately, there were different toxicities observed with this combination of prophylactic agents based on the preparative regimen used [20], which limits broad applicability of this strategy [21]. The role of regulatory T cells (Tregs), which inhibit cytotoxic T cell activity, as potential mediators of GVHD has been explored. Preclinical data from murine models showed that lethal GVHD could be prevented by co-infusion of Tregs [22,23]. In a clinical study, the frequency of Tregs was almost 50% lower at the time of GVHD onset compared to matched non-GVHD controls and patients with the lowest frequency of Tregs at GVHD onset were significantly more likely to experience treatment failure and die [24]. These data suggest that Tregs are protective against GVHD, a finding that opens up a novel therapeutic avenue for GVHD prevention and treatment.
Fig. 1. A. Pathophysiology of GVHD. This involves three phases, including (1) damage induced by the HCT preparative regimen which leads to increased inflammatory cytokine secretion which is sensed by the host APCs, leading to their activation. (2) Activated host APCs then interact with donor T-cells, mediators of GVHD, leading to their activation, proliferation and differentiation. Treatments that promote increases in Treg can suppress this reaction. And finally, if the process is left unchecked, the increased activated alloreactive cells cause tissue damage and the release of more inflammatory cytokines that are also harmful to host tissues. B. ECP for GVHD prevention. (1) Patients undergo a leukopheresis during ECP treatment, and these white blood cells are exposed to 8-methoxypsoralen (8-MOP) and ultraviolet A radiation. (2) Treated cells are reinfused to the patient, and all will undergo apoptosis within 24–48 hours of treatment. (3) APCs are able to engulf these apoptotic cells. Early post-HCT these APCs will be of host-origin, but at later time points, donor derived APCs will also participate in this process. After apoptotic cell uptake, DCs and macrophages promote tolerance through the secretion of antiinflammatory cytokines such as TGF-β and IL-10. (4) These tolerogeneic DCs are unable to stimulate the differentiation of donor T-cells into cytotoxic lymphocytes, but will promote increased number and function of Tregs. Thus ECP for prophylaxis can potentially modulate the traditional GVHD pathway by changing the DC phenotype to promote tolerance rather than alloreactivity through the generation of increased numbers of Treg. (Hildegard T. Greinix, Robert Knobler (Eds.) Extracorporeal Photopheresis Cellular Photoimmunotherapy.)
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Given these findings, another potential strategy for GVHD prevention is infusion of Tregs, and clinical studies investigating the potential benefit of post-HCT infusion of exvivo expanded Tregs have demonstrated safety, and potentially some benefit, toward reducing rates of GVHD [25,26]. A major limitation to widespread adoption of these strategies is obtaining the large number of Tregs needed, which can be time consuming, labor intensive and limited to institutions with expertise in this area. ECP may allow an in vivo treatment approach that might enhance Treg populations in post-HCT recipients. 4. Extracorporeal photopheresis for GVHD treatment ECP has been studied as a treatment for steroid refractory acute GVHD in twelve publications that reported results in a rigorous and comparable manner (Table 1) [27–38]. Overall response rates were variable, but ranged from 65 to 100%. Of the total of 249 patients with reported results for individual organs, complete responses (CR) were observed in 85% (176/208) of skin, 57% (54/95) of liver and 62% (66/106) of gastrointestinal GVHD cases. The number and frequency of ECP treatments required to achieve response are not yet established, but generally, patients receiving intensive initial therapy (2–3 times/wk) until response was achieved resulted in the best outcomes. ECP appears to be effective for both adult and pediatric patients. Given these encouraging results for acute GVHD treatment with ECP, ECP has also been explored for GVHD prevention. 5. Extracorporeal photopheresis during HCT preparative regimens Addition of ECP to HCT preparative regimens was initially attempted to help overcome graft failure following nonmyeloablative conditioning (NMA). Because ECP treatment has been shown to induce tolerogenic DCs [39–44], treatment with ECP prior to HCT may result in less rejection of donor hematopoietic elements by residual host DCs. Miller et al. explored a strategy in NMA HCT recipients that combined ECP, pentostatin and low-dose total body irradiation (TBI) in order to decrease DC function and therefore
promote donor chimerism. A total of 55 NMA HCT recipients received ECP (given on two consecutive days), followed by 48 hours of continuous infusion pentostatin (4 mg/m2/ day × 2 days), and TBI 200 cGy × 3 doses (600 cGy total) [45]. All patients also received cyclosporine, MTX and MMF as GVHD prophylaxis, and the majority (80%) received sibling donor HCT. High rates of donor chimerism (98%) and low rates (11%) of non-relapse mortality (NRM) at 100 days post HCT were observed. In addition, patients treated with this regimen had lower than expected rates of both acute and chronic GVHD (9% and 43% respectively). The 2-year event free survival (EFS) was 47%. Further studies to better elucidate the impact of pre-HCT ECP in facilitating engraftment following NMA HCT have not yet been published. Based on these results, a phase II multi-institutional study evaluated the role of ECP pre-HCT using a myeloablative preparative regimen [46]. All 62 patients received a cyclophosphamide (60 mg/kg/day × 2 day) and TBI (10– 13.5 Gy over 3–4 days) preparative regimen. In addition, all patients were treated with 2 days of ECP within 4 days of starting the preparative regimen. Standard GVHD prophylaxis included cyclosporine and MTX. Half of the study participants received a sibling donor HCT. The 100 day cumulative incidence (CI) of acute GVHD grades II–IV was 35%, and the 1 year CI of chronic GVHD was 38%, with a 1 year DFS of 69%. Data from the Center for International Blood and Marrow Transplant Research (CIBMTR) formed a historic control. Compared to 347 matched historical controls, the ECP treated group had a lower rate of grade II–IV GVHD (relative risk 0.61; 95% CI, 0.38–0.97; p = 0.04). Recently, Bethge et al. attempted to replicate these findings using a canine model (n = 9), and found no benefit to ECP and pentostatin for GVHD prevention [47]. While far from definitive, these findings support further investigation into ECP as a GVHD prevention strategy. 6. ECP for GVHD prevention A recently completed clinical trial at the University of Michigan tested an approach that augmented standard GVHD prophylaxis following high risk HCT using unrelated and mismatched donors with a combination of TNF-α inhibition and ECP for Treg induction. The standard GVHD prevention
Table 1 Results of studies of the use of ECP in patients with steroid resistant acute GVHD. Study type
No. of patients
Overall response (%)
Overall survival (%)
CR skin no (%)
CR liver no (%)
Phase I/II Retrospective Prospective* Retrospective Retrospective* Retrospective Retrospective* Retrospective* Retrospective* Pilot Prospective* Phase I/II*
59 57 50 34 33 23 21 15 15 12 12 9
70% 66% 68% 65% 75% 52% (CR) 90% 100% 66% 75% 83% 77%
47% 60% 44% 51% 55% 48% 43% 87% 63% 42% 75% 67%
47/57 (82%)
14/23 (61%)
39/47 (83%) 34 27/33 (82%) 15/23 (65%) 81% 12/13 (93%) 13/14 (93%) 8/12 (67%) 9/10 (90%) 6/9 (67%)
16/24 (67%) 9 9/15 (60%) 3/11 (27%) 67% 1/1 (100%) 5/7 (71%) 0/2 (0%) 5/9 (56%) 1/3 (33%)
CR gut no (%) 9/15 (60%) 8/11 (73%) 13 15/20 (75%) 8/20 (40%) 55% 10/14 (71%) 6/10 (60%) 2/5 (40%) 5/6 (83%) 3/5 (60%)
Reference [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38]
Abbreviations: no = number, CR = complete response. * Indicates an exclusively pediatric publication.
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backbone of the trial was tacrolimus and mycophenolate mofetil. Etanercept (TNF-α inhibitor) was given early postHCT (D0 – D56) to block cytokine mediated GVHD pathways pre-engraftment when ECP cannot be delivered. ECP was started at D28, since patients were anticipated to be postengraftment, and continued on a tapering schedule through day 180. Given the tight relationship between GVHD and graft-versus-leukemia effect, the goal of this study was to attenuate GVHD to a more treatment responsive phenotype. Preliminary results, not yet published, suggest this may have occurred as 1 year overall survival (73%) was better than expected. There are several factors that are important to consider when designing a clinical trial that will incorporate ECP for GVHD prevention. One of the most critical is the time to engraftment. Until the white blood count is reliably greater than 1000, it is not possible to deliver effective ECP treatments. Therefore, in order to have an impact on very early GVHD prevention, it will likely be necessary to utilize a highly effective regimen for the first 2–4 weeks post-HCT. A potential approach may be to add complementary treatments to enhance Treg induction such as sirolimus [48] or low dose IL-2 [49], as both have been shown to increase the numbers of Tregs. More work is also needed to better understand the impact of cell dose and the effectiveness of ECP therapy. Recent work has demonstrated that there is a linear relationship between the peripheral blood lymphocyte count and that observed in the buffy coat collected during apheresis, as well as increased efficiency of lymphocyte collection using the CELLEX machine compared to the older UVAR XTS device [50], and based on these results, future studies could assess the impact of lymphocytes treated. 7. Conclusions Despite many improvements in prevention strategies, GVHD remains the main cause of morbidity and mortality following allogeneic HCT. Future strategies that focus on promoting immune tolerance through expansion of Tregs in vivo may reduce rates of GVHD and promote improved immune recovery. There is expanding evidence to support that ECP may have a significant impact on these essential mediators of the GVHD pathway that would result in less alloreactivity, and therefore, less graft versus host disease (Fig. 1B). Importantly, since ECP is felt to be immunomodulating, rather than immunosuppressive, this potential decreased GVHD will not come at the expense of higher infectious complications. Future investigations should focus on overcoming the challenges of delivering ECP earlier and in the most effective manner. References [1] Ferrara JL, Levine JE, Reddy P, Holler E. Graft-versus-host disease. Lancet 2009;373(9674):1550–61. [2] Ram R, Gafter-Gvili A, Yeshurun M, Paul M, Raanani P, Shpilberg O. Prophylaxis regimens for GVHD: systematic review and meta-analysis. Bone Marrow Transplant 2009;43(8):643–53. [3] Martin PJ, Rizzo JD, Wingard JR, Ballen K, Curtin PT, Cutler C, et al. First- and second-line systemic treatment of acute graft-versus-host disease: recommendations of the American Society of Blood and Marrow Transplantation. Biol Blood Marrow Transplant 2012;18(8):1150–63.
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Please cite this article in press as: Carrie L. Kitko, John E. Levine, Extracorporeal photopheresis in prevention and treatment of acute GVHD, Transfusion and Apheresis Science (2015), doi: 10.1016/j.transci.2015.02.001
