The First International Symposium on Photopheresis in Hematopoietic Stem Cell Transplantation was held in Vienna, Austria with an educational grant from Therakos Inc. from 25 May to 27 May 2005. Three general issues were addressed: (1) pathophysiology of graft-versus-host disease (GvHD), (2) induction of immune tolerance and the immunology of phototherapy and (3) current standard treatment and prevention strategies of acute and chronic GvHD and the use of extracorporeal photopheresis (ECP). The objectives of the meeting were to open a dialogue among leading researchers in photobiology, immunology, and hematopoietic stem cell transplantation; foster discussions and suggestions for future studies of the mechanism of action of ECP in acute and chronic GvHD; and promote collaboration between basic scientists and clinicians. As can be seen from the summaries of the individual presentations, important advances have been made in our understanding of GvHD, including the use of photoimmunology interventions and the development of robust model systems. It is our expectation that data from photoimmunology studies can be used to generate hypotheses in animal models that can further define the mechanism of action of ECP and help translate the findings to clinical trials of ECP for the prophylaxis and treatment of both chronic and acute GvHD.
The First International Symposium on Photopheresis in Hematopoietic Stem Cell Transplantation was organized by the Medical University of Vienna, Austria with an educational grant from Therakos Inc. (Exton, PA, USA) and convened from 25 May to 27 May 2005 in Vienna, Austria. During this symposium, three general issues were addressed: (1) pathophysiology of graft-versus-host disease (GvHD), (2) induction of immune tolerance and the immunology of phototherapy and (3) current standard treatment and prevention strategies of acute and chronic GvHD, including use of extracorporeal photopheresis (ECP). The format of each of the three sessions was designed to allow for short presentations about the current state of knowledge in each topic area followed by extensive discussion among all participants. As can be seen from the summaries of the individual presentations that follow, important advances have been made in our understanding of GvHD, including the use of photoimmunology interventions and the development of robust model systems. Close collaboration between clinical specialists and basic science researchers is of utmost importance in acquiring critical information about hematopoietic stem cell transplant (HSCT) pathophysiology, which is a prerequisite for better treatment options. The organizers and authors of the conference proceedings would like to extend their gratitude to all participants for sharing their ideas, slide presentations and manuscripts and for making this event possible.
Phototherapy, tolerance induction and GvHD
The presentations in this session reviewed the role of photobiology in immune tolerance induction and described the proposed mechanism of action of ECP in the treatment of GvHD.
James LM Ferrara (Department of Pediatrics and Internal Medicine, University of Michigan Medical School, Ann Arbor, USA) discussed current concepts of GvHD pathophysiology,1 including the central role of host antigen-presenting cells (APCs) in acute GvHD, which was first demonstrated by Shlomchik et al.2 In an animal model with two different donor/recipient combinations, Ferrara et al. showed that older age significantly increased the risk of acute GvHD and involved enhanced gastrointestinal (GI) tract damage, elevated levels of tumor necrosis factor alpha (TNFα), and γ-interferon-producing CD4+ donor T cells.3, 4 The increased GvHD was seen in young animals engrafted with APCs from old mice (old host APCs) as compared with young animals engrafted with APCs from young mice (young host APCs). Therefore, he concluded that the increased age of host APCs enhanced allogeneic T-cell responses in vitro and in vivo and increased the risk of acute GvHD and not the age of target tissues. More recently, it was shown that the genotype (inflammatory or cytokine repertoire) of host APCs may predict the risk of GvHD, allowing improved donor selection in the near future.5 Less is known about the relationship between host APCs and donor T cells in chronic GvHD.
The intestine plays a critical role in the pathophysiology of GvHD. If the migration of CD8+ cytotoxic T cells (CTLs), which localize to Peyer's patches within 48 h of transplantation, is blocked by disrupting the gene encoding chemokine receptor CCR5 or by blocking integrin α4β7-MAdCAM-1 (mucosal vascular addressin) interactions, then lethal GvHD can be prevented.6
After this review, Ferrara provided his perspective on the role of ECP in GvHD. In contrast to other established treatments for GvHD, no removal of T cells or other cell fractions, including APCs, or suppression of T cells occurs during ECP but rather a regulation of cell function involved in GvHD, such as dendritic cells (DCs) and/or T cells, seems likely. Considerably more work needs to be done in animal models to validate these hypotheses.
Matthew L Albert (Department of Immunology, Institut Pasteur, Paris, France) reviewed concepts of APCs and immune tolerance, distinguishing the different roles of APCs in acute and chronic GvHD, and the important assumptions regarding the therapeutic induction of tolerance. Specifically, he discussed the role of DCs in capturing antigens in the periphery and trafficking to draining lymphatics, where DCs may engage T cells and induce deletional tolerance. Another mechanism for tolerance induction could be triggering or differentiation of regulatory cells (e.g., FOXP3-expressing CD4+ T cells) by DCs. As DCs are part of an innate immune system and are unable to distinguish between self- and donor-derived antigen, input from other cells, such as nonclassic T-cells or CD4+ helper cells, is required for the DC to ‘activate’ or ‘tolerize.’ Albert then reviewed published work that acute GvHD is mediated by host APCs priming alloreactive donor T-cells,1, 2 whereas in chronic GvHD, donor APCs cross-prime host antigens for the activation of alloreactive donor T-cells.7
Albert discussed some of the cellular and molecular requirements for distinguishing antigen cross-priming from cross-tolerance. The presence of antigen-specific CD4+ T cells allows for cognate interaction with DCs, and cross-priming results in proliferation of CD8+ T cells, production of γ-interferon, and acquisition of CTL effector function. In contrast, the absence of antigen-specific CD4+ cells results in deletional tolerance.
During ECP, when approximately 500 million apoptotic cells are being reinfused intravenously in patients, the role of apoptotic cells in tolerance induction is of significant interest. DCs are known to capture and cross-present antigens from apoptotic cells, leading to a skewing of the cytokine milieu, including an increase of transforming growth factor β (TGFβ) and a decrease of interleukin-12 (IL-12) release.8, 9 Although there is evidence in solid organ transplantation that TGFβ is critical to apoptotic cell induction of tolerance, there is no direct evidence linking TGFβ and apoptosis in GvHD. Therefore, ingestion of a dying cell may ‘reorient’ an inflammatory APC, converting a state of activation to a state of tolerization.8, 9, 10 Although the inflammatory mediators mature DCs in vitro, their effects on DCs in vivo are uncertain. In addition, there is no direct evidence for a relationship between cytokine secretion and tolerance induction.
Stephen Ullrich (University of Texas, MD Anderson Cancer Center, Houston, USA) provided an overview of the immunology of phototherapy. The link between ultraviolet (UV)-induced immunosuppression and skin carcinogenesis is well established in both humans and mice.11, 12 Rejection of transplanted UV-induced skin tumors, contact hypersensitivity (CHS), delayed-type hypersensitivity (DTH), and APC functions are all suppressed by UV radiation, whereas other immune reactions, including antibody production, CTL induction, macrophage activity and graft rejection are not. The effect of UV radiation on Langerhans cells (LCs) is critical to immunosuppression, resulting in a shift from immunogenic (TH1) to tolerogenic (TH2) response.13 This shift may be mediated by cytokine release and expression of costimulatory molecules.14, 15
Most of the literature describing the impact of UV radiation on the immune system involves studies that utilized UVB radiation (280–320 nm); by contrast, UVA radiation (320–400 nm) in combination with psoralens (PUVA) is administered for ECP. It is still unclear whether PUVA and UVB have similar immunologic effects, and thus extrapolations from the UVB literature to ECP may not be completely accurate. Both modalities cause antigen-specific immunosuppression and induce apoptosis by DNA damage. To date, the literature concerning the effects of UVA on the induction of immunity is inconsistent, although recent studies suggest that UVA can suppress secondary immune reactions.16, 17 Whether these effects are also involved in ECP remains to be elucidated.
Thomas Schwarz (Department of Dermatology and Allergology, University of Kiel, Germany) reviewed the evidence suggesting that the immunosuppressive effects of photopheresis are mediated by regulatory T cells (Tregs) that can be achieved by providing damaged APCs to the immune system. In an animal model using hapten (DFNB)-sensitized mice, APCs exposed to 8-methoxypsoralen (8-MOP) suppressed CHS responses in an antigen-specific fashion. This suppression can be adoptively transferred and occurred after exposure of APCs to the combination of 8-MOP and UVA, but not to 8-MOP or UVA alone.18 The exact mechanism of this type of PUVA-induced immunosuppression remains to be determined.
Schwarz et al.19 demonstrated that UVB damages, but does not kill, LCs that subsequently migrate into the lymph nodes, where they present antigens in a dysregulate fashion as a consequence of their damage. DNA damage in LCs appears to be critical to the induction of Tregs by UVB because prevention of DNA damage (e.g., by IL-12) alternates the generation of Tregs. Whether LCs behave similarly after PUVA exposure is currently unknown. Steroid treatment leads to depletion of LCs by steroid-induced apoptosis and prevents their emigration.20 Consequently, steroids do not induce Tregs. Induction of Tregs thus appears to be an active process that requires viable but damaged LCs in lymph nodes. Following ECP, PUVA-damaged APCs are reinfused into the patient, which allows their interaction with the immune system, and the possible induction of Tregs, shifting the balance toward tolerance and away from activation. The timing of cell death after ECP may be important given that damaged but viable cells are critical to the induction of tolerance following ECP. Although this animal model of CHS affords us a first glimpse into the potential mechanism of ECP and establishes hypotheses, it does not directly address the role of ECP in GvHD.
David Peritt (Therakos Inc., Exton, USA) reviewed the history and technical aspects of ECP. As the US Food and Drug Administration (FDA) approved ECP for the treatment of advanced refractory cutaneous T-cell lymphoma in 1988, ECP has become first-line treatment for patients with erythrodermic cutaneous T-cell lymphoma. ECP has also shown promise in treating GvHD, solid organ transplant rejection, and autoimmune diseases, including Crohn's disease and scleroderma.21 An international multicenter trial is underway to confirm the positive results of ECP in GvHD, Crohn's disease and rheumatoid arthritis.
The specific effects of ECP on the immune system are the focus of active research worldwide. ECP induces apoptosis in all leukocyte subsets within 24 to 48 h. Circulating apoptotic cells are phagocytosed by APCs, a process that is mediated by a highly conserved receptor system of apoptotic cell-associated membrane proteins (ACAMP) and ACAMP receptors on APCs. It is currently unclear whether the set of receptors used by phagocytes to engulf the dying cell have a direct impact on immune responses. In an experimental murine model of ECP, preapoptotic cells accumulated primarily in the spleen and liver; similar studies in humans are pending. An important unanswered question about the mechanism of action of ECP is whether any apoptotic body can induce tolerance or whether any antigen specificity is generated.
Potential mechanisms of ECP-induced immune tolerance include decreased stimulation or depletion of effector T-cells, increased production of anti-inflammatory or decreased production of pro-inflammatory cytokines, and generation of Tregs.22 Combining ECP with traditional immunosuppressive therapies to treat immune-related disorders, including GvHD, may allow for reduced doses of immunosuppression and may thus decrease the toxicity associated with such immunosuppression (particularly steroids). Adjunctive ECP therapy may also achieve synergistic effects on the immune system when combined with traditional immunosuppression.
Challenges and options in acute GvHD
Acute GvHD remains a major cause of morbidity and mortality in HSCT, occurring in 30–60% of recipients of human leukocyte antigen (HLA) – identical sibling donor transplants despite adequate post-transplant immunosuppressive therapy.23 Ferrara et al. described a three-step model of acute GvHD pathophysiology, in which damage of the host tissues during the conditioning regimen resulted in donor T-cell activation and subsequent recruitment of effector cells. The activated donor T-cells, effector cells and cytokine dysregulation all contribute to tissue damage in the recipient.1 This session reviewed the role of T-cell subsets in the pathophysiology of acute GvHD and assessed the current state of knowledge regarding prophylactic and treatment options for acute GvHD.
Matthias G Edinger (Department of Hematology/Oncology at the University Hospital Regensburg, Germany) initiated the session by reviewing the role of Tregs in HSCT and in the pathophysiology of acute GvHD. CD4+CD25+ Tregs are thymus-derived; polyclonal; constitutively express CTLA-4, GITR and FOXP3; and represent approximately 5–10% of peripheral CD4+ T cells.24 These cells maintain self-tolerance and provide protection from autoimmune diseases; may control T-cell homeostasis in vivo; and modulate immune responses to infection, tumors and allogeneic organ grafts. Studies in murine models have demonstrated that the infusion of donor grafts enriched in CD4+CD25+ T cells may suppress the incidence of lethal GvHD and may even facilitate allogeneic transplantation across HLA barriers.24, 25, 26 This protective effect is mediated by donor-type Tregs and requires IL-10 production.25 In addition, it has been demonstrated that CD62L is an important determinant of T-cell entry into lymph nodes and that only the subset of Tregs expressing CD62L can protect from lethal GvHD.26 Of note, Tregs have the ability to suppress GvHD without loss of graft-versus-leukemia (GvL) activity.24 These experiments suggest that CD4+CD25+ Tregs are a good candidate for an immunoregulatory population that may be exploited therapeutically to decrease the incidence or severity of GvHD in humans.
Ernst Holler (Department of Hematology/Oncology at the University Hospital Regensburg, Germany) reviewed current standard prophylaxis and therapy for acute GvHD. There are several ways to prevent GvHD: depletion of donor T cells from the stem cell graft (ex vivo T-cell depletion); administration of T-cell antibodies to the patient (in vivo T-cell depletion); and use of immunosuppressive drugs, such as cyclosporine A (CsA), methotrexate (MTX), tacrolimus and mycophenolate mofetil (post-transplant immunosuppression).23
New strategies of GvHD prophylaxis include the infusion of expanded mesenchymal stem cells and modulation of the APC/donor T-cell interaction using hydroxychloroquine,27 anti-CD52 monoclonal antibodies, UVB prophylaxis and depletion of APCs by alloreactive donor natural killer (NK) cells in haploidentical HSCT. Other options are a modulation of epithelial damage and inflammation during pretransplantation conditioning by reducing the intensity of the conditioning regimens28 and modulation of endotoxin and intestinal floral translocation.29
Efficient prevention and treatment of GvHD has to be balanced with maintaining GvL effects and anti-infectious immunity. A better definition of the function of different T-cell populations and the role of effector molecules such as TNFα in GvHD, the role of endothelial cells, and the chemokine repertoire in different manifestations of GvHD are prerequisites for a future organ-specific therapy. Developing risk-adapted strategies, such as early intensification of GvHD therapy in high-risk patients, may also improve clinical care and long-term outcomes.
Holler also noted that the ECP-related challenges for the treatment of acute GvHD mirror the challenges faced in the treatment of acute GvHD. A balance of ECP-related T-cell effects must be achieved, and the organ-specific effects of ECP must be determined, including effects in the intestine, liver, and skin as well as the protective effects in lung and endothelial tissues. Potential roles of ECP in the treatment of acute GvHD include early intensification in high-risk patients, primary treatment, and prophylaxis. Ultimately, synergistic immunosuppressive effects might be achieved in combination with anti-inflammatory medications.
Andrea Bacigalupo (Department of Hematology at the Hospital San Martino, Genova, Italy) discussed the perspective that first-line therapy of acute GvHD with corticosteroids remains unsatisfactory. Durable complete responses (CR) have been reported in 35% of patients, resulting in 1-year survival rates of 53%.30 Bacigalupo then presented the results of a study using prednisone 2 mg/kg/day for 5 days as first-line treatment for 211 patients with acute GvHD at his institution.31, 32 GvHD in 71% of patients (n=150) responded as indicated by compliance with reduction schedule of steroid dose. Probability of transplant-related mortality (TRM) was 27% in steroid responders compared with 49% in steroid nonresponders. Nonresponders (n=61) were randomized to receive either 5 mg/kg/day prednisone (n=34) or 5 mg/kg/day prednisone plus low-dose antithymocyte globulin (ATG) (n=27) as second-line treatment of acute GvHD. Inclusion of ATG had no significant influence on 3-year survival (33 vs 38%), relapse-related death (7 vs 18%), and TRM (51 vs 44%) compared to patients given prednisone alone.
Bacigalupo and co-workers subsequently designed a study of preemptive ATG treatment in patients at high risk of developing acute GvHD in the setting of unrelated donor transplants. The risk of GvHD was based on a validated scoring system.32 TRM predicted in this model was 69% for high-risk patients, 40% for intermediate-risk patients and 15% for low-risk patients.32 In a pilot study, the administration of ATG on day +7 reduced TRM in high-risk patients.33 A prospective randomized study comparing the addition of low-dose ATG on day +7 is now ongoing.
Bacigalupo concluded that both first- and second-line treatment of acute GvHD are unsatisfactory and that incorporation of ECP into conditioning before or early after transplantation should be studied to determine whether preemptive ECP is able to change the course of acute GvHD.
Hildegard T Greinix (Department of Internal Medicine I/BMT, Medical University of Vienna, Austria) discussed the use of ECP for the treatment of steroid-refractory and steroid-dependent acute GvHD because current therapeutic options for these patients are limited. A pilot study of ECP as second-line treatment (in addition to steroids at 2 mg/kg/day and CsA) in 21 patients with steroid-refractory acute GvHD demonstrated statistically significantly (P<0.0001) better survival rates in patients who had a complete response (CR) to ECP.34 In a phase II study (n=38) with steroid-refractory and steroid-dependent acute GvHD patients, ECP was intensified and given on 2 consecutive days at weekly intervals and ECP was stopped immediately after achieving maximal response. As ECP was initiated earlier in the course of treatment compared with the pilot study, patients in the phase II study had significantly shorter steroid pretreatment times (median of 15 vs 21 days). Maximal response to ECP was observed after a median of 4 (range, 1–13) cycles, equaling a median of 1.3 months of therapy. In responders, steroids could be discontinued after a median of 55 (range, 17–284) days and no flares of acute GvHD were observed. In the cumulative analysis of data from both studies, CR of acute GvHD, as previously defined,35 was achieved in 86% of patients with grade II, 55% of patients with grade III and 30% of patients with grade IV acute GvHD.36 Complete resolution of GvHD occurred in 82% of patients with skin, 61% with liver, and 61% with gut involvement. Whereas 87 and 62% of patients with exclusive involvement of skin, or skin and liver, respectively achieved CR, only 25% of patients with skin, liver, and gut and 40% of patients with skin and gut involvement obtained CRs to ECP. Compared with the pilot study, substantially higher CR rates were obtained in the phase II study patients with gut involvement (25 vs 73%) and grade IV acute GvHD (12 vs 60%). The cumulative incidence of TRM at 4 years was 14% (95% CI, 10–31%) in patients receiving a CR and 73% (95% CI, 56–94%) in patients who did not achieve a CR (P<0.0001). At a median of 46 (range, 9–95) months after discontinuation of ECP, 22 of 28 surviving patients (79%) have no signs of chronic GvHD, whereas three suffer from chronic limited GvHD and an additional three from chronic extensive GvHD. The Kaplan–Meier estimates for overall survival at 4 years were 59% for patients achieving a CR to ECP compared with 11% without CR and, thus, significantly different (P<0.0001).
Based on the results of these studies, ECP appears to be an effective adjunctive therapy for acute steroid-refractory and steroid-dependent GvHD. Early initiation of ECP can improve response rates in patients with severe GvHD, including those with grade IV disease and intestinal or liver involvement. Adjunctive ECP was associated with rapid tapering of the steroid dose, significantly reducing TRM and improving overall survival, indicating a durable response with few adverse effects. Currently, at the Medical University of Vienna, Austria, patients with acute GvHD who do not respond to 7 days of steroids at 2 mg/kg/day are assigned to ECP treatment.
To date, few studies of patients with acute GvHD treated with ECP have been reported.34, 37, 38, 39 Messina et al.38 treated 33 children with ECP as adjunct second-line therapy, achieving a response rate of 82% in skin, 60% in liver and 75% in gut involvement of GvHD with an overall survival rate of 58%. Messina updated her results, reporting that 83 children with steroid-refractory acute GvHD had been given ECP after a median of 14 days of steroids on 2 consecutive days per week for 4 weeks, and every other week thereafter. CRs were observed in 75% of patients. A randomized, prospective study is ongoing in Italy for the treatment of acute GvHD unresponsive or progressive after 7 days of prednisone at 2 mg/kg/day. In this trial, patients are randomized to receive 5 mg/kg/day prednisone, with or without ECP.
Greinix emphasized the need for more studies of ECP as first- or second-line treatment as a means to reduce the duration and dose of steroids in patients who are at high risk for opportunistic infections and subsequent mortality. Introducing of any therapy late in the course of GvHD has less benefit. Her data, together with the minimal toxicity of ECP, suggest that earlier administration is highly desirable.
All participants further emphasized the importance of early intervention in acute GvHD, and they discussed differences in ECP use at various transplant centers with regard to patient selection, duration of GvHD, pretreatment, ECP schedule, and concomitant immunosuppressive medication complicating comparability of ECP results. The effect of ECP in patients with newly diagnosed acute GvHD grades II to III will be investigated in a randomized controlled comparison of ECP in addition to steroids and CsA vs steroids and CsA alone (protocol approved by the US FDA in August 2005). Efficacy and safety end points were discussed, including rates of bacterial, viral, and fungal infections, and relapse of hematological disease, which will be secondary end points. Currently, there are no concerns about an increase of infections or relapse rates associated with ECP treatment of acute GvHD, but longer-term outcome data are necessary to compare ECP-associated relapse rates to other adjunctive interventions for acute GvHD. Prospective multicenter trials are needed to answer these questions.
Chronic GvHD is a major late complication after allogeneic HSCT and occurs in approximately 50% of patients from 3 to 24 months after transplant. The number of chronic GvHD cases is on the rise as a result of increasing numbers of older transplant recipients, peripheral blood stem cells as the source of HSCT, use of mismatched and unrelated donors, and treatment with donor lymphocyte infusion for recurrent malignancy after HSCT. Chronic GvHD resembles several collagen vascular diseases, usually of the skin, mouth, eyes, liver, GI tract, fascia and immune system. Chronic GvHD is a significant barrier to successful transplantation, resulting in markedly reduced quality of life in affected patients.40 Chronic GvHD is the cause of death in 25% of patients receiving a transplant for leukemia and 66% of patients receiving a transplant for severe aplastic anemia.41, 42
The presentations within this session reviewed the pathophysiology of chronic GvHD, the rationale for current standard first- and second-line treatment regimens, and the definition of successful treatment of chronic GvHD, including the importance of assessing response by organ.
Ferrara initiated the session by discussing new insights into the pathophysiology of chronic GvHD, which in general, is poorly understood. The importance of autoreactivity is suggested by clinical manifestations of chronic GvHD that frequently mimic those of autoimmune diseases, and the finding of auto-antibodies derived from B cells after TH2-mediated stimulation and cytokine release.43 Pathophysiologically, B cells may be an effector cell type that contributes to damage through antigen production and may have a role in maintaining, but not initiating, GvHD.
A second probable mechanism for chronic GvHD is dysfunctional T-cell selection in the thymus leading to a population of TH2 self (host)-reactive T-cells that travel to the spleen and intestine. A third mechanism may be a difference in TH1 and TH2 responses by donor cells to host antigens. He emphasized that the primary target organ of acute and chronic GvHD is the lympho-hematopoietic system, and chronic GvHD is ultimately a disorder of immune dysregulation, not merely immunodeficiency.
Mouse models of chronic GvHD fit into two categories, the haploidentical parent model and the unrelated major histocompatibility complex (MHC) identical donor model. Manipulation of either system highlights the high degree of overlap between acute and chronic GvHD.43 In the haploidentical model, there are differences in MHC class I and class II and minor H antigens. Transplantation from one parent vs the other can lead to differing responses in the same recipient: the B6 to B6D2F1 model results in acute GvHD, whereas the D2 to B6D2F1 model results in chronic GvHD. However, if the cell population in the chronic GvHD model is manipulated (e.g., by increasing the proportion of CD8+ cells) then chronic GvHD can be converted to acute GvHD. An unrelated MHC identical donor/recipient combination (B10.D2 to Balb/c) and multiple minor histocompatibility antigens stimulate a chronic GvHD-type response, with skin involvement and immunodeficiency. Lethal radiation converts this chronic GvHD model into an acute GvHD model. This result suggests that mixed chimerism and donor APCs might contribute to chronic GvHD. Ferrara emphasized that although there is a clear utility for continued use of animal models to further investigate the pathophysiology of chronic GvHD and possible treatment strategies, the data derived from these models must be interpreted cautiously in light of differences in some clinical end points, particularly renal disease.
Jane F Apperley (Department of Hematology, Hammersmith Hospital, London, UK) provided an overview of current standards of clinical care for chronic extensive GvHD. Despite improvement in other areas of supportive care, little significant progress has been made in the treatment of chronic GvHD, where the regimen of prednisone and CsA has become the standard primary treatment.44 Long-term follow-up in a large randomized study comparing the combination of prednisone and CsA to prednisone alone, however, has shown no additional survival benefit to the use of CsA.45 Importantly, in higher-risk patients with progressive onset chronic GvHD, the addition of CsA did not improve survival and, overall, may have worsened it due to increased TRM or relapse.45
Patients who fail to respond to initial corticosteroid-based therapy have a poor outcome, with no standard approach uniformly accepted. Therefore, a large number of agents have been investigated, reflecting the lack of consistently effective treatment in this setting and underscoring the need for properly conducted clinical trials. Mycophenolate mofetil has been widely used as a salvage treatment option for chronic GvHD, achieving responses in 46–75% of patients in combination with calcineurin inhibitors.46, 47 Some second-line agents for the treatment of chronic GvHD have been associated with excessive toxicity, including thalidomide, which was discontinued in most controlled trials, and azathioprine, which may contribute to secondary malignancy. Other possible salvage treatments for chronic GvHD include rapamycin, hydroxychloroquine, clofazimine, daclizumab, infliximab, rituximab, ATG and cladribine (2-CdA),47, 48 all of which require well-controlled studies to fully evaluate safety and efficacy. However, in both clinical practice and clinical trials, criteria for definition and evaluation of response by organ should be consistent across studies so that the efficacy of treatment options for chronic GvHD can be compared.
Robert M Knobler (Department of Dermatology, Medical University of Vienna, Austria) discussed the current use of skin assessment scores in patients with chronic GvHD. Extensive skin involvement (>50% of body surface area) is a highly significant determinant of poor prognosis and is directly correlated with nonrelapse mortality in patients with chronic GvHD.49 Given the increasing incidence and severity of chronic GvHD in recent years and the prognostic value of this indicator, accurate and consistent assessment of skin involvement – both in clinical practice and in clinical trials – is increasingly pertinent to the provision of optimal patient care. Owing to the heterogeneity of both patients and disease presentation, and a lack of consensus for an optimal skin grading system for chronic GvHD, no validated tool to quantify and document skin manifestations of chronic GvHD is currently available. A skin scoring system for chronic GvHD must be feasible, accessible, noninvasive, inexpensive, relevant, reproducible and validated.
Frequently, the modified Rodnan skin score developed in the late 1960s for patients with systemic sclerosis50 is used in chronic GvHD, which considers only skin thickening and, therefore, is not always entirely suitable for the heterogeneous skin manifestations of chronic GvHD. A modified scleroderma skin scoring method developed by Kahaleh et al.51 and validated for use in scleroderma is the basis for the evaluation of skin involvement in patients with chronic GvHD at the Medical University of Vienna. This method quantifies the degree of skin involvement by numerical units of 0–4 in 10 different body areas. Currently, the National Institutes of Health (NIH) Consensus Group on Chronic GvHD is developing a skin atlas that may help clinicians to assess skin chronic GvHD.
Greinix reviewed the clinical results on ECP for the treatment of chronic GvHD. A pilot study of 15 patients with chronic extensive GvHD used ECP every 2–4 weeks until maximal response. Twelve of 15 patients with skin involvement, seven of 10 with liver and 11 of 11 with oral mucosa achieved a CR.35 Fourteen of 15 patients survived with >90% Karnofsky scores. In addition, a steroid-sparing effect was observed in responding patients with no increase in infectious complications. A larger study of ECP treatment for chronic GvHD in Vienna enrolled 47 patients, 29 had quiescent onset, 14 progressive and four de novo chronic GvHD with a median time of diagnosis at 8 months after HSCT. CR rates, as previously defined,35 were 68% for skin, 81% for mouth, 68% for liver, 28% for ocular, and 11% for joint manifestations. Of the 47 patients, 42 (89%) are currently alive, including 22 patients without GvHD and 18 without immunosuppression.
In the literature, ECP given in retrospective studies to heterogeneous patient populations is associated with high response rates in chronic extensive GvHD with skin, liver and oral involvement.35, 37, 38, 39, 52, 53 Based on these results, ECP has become standard therapy at the Medical University of Vienna for patients with chronic extensive GvHD who are steroid-refractory or steroid-intolerant. The standard treatment regimen includes CsA or tacrolimus plus steroids (1 mg/kg) plus ECP on 2 consecutive days every 2 weeks. As soon as GvHD responds, the interval between ECP cycles is increased from 4 to 6 weeks. ECP does not induce general immunosuppression, and the safety profile is excellent based on available data.
Johanna Ullman (Klinikum Grosshadern, Munich, Germany) reported on the use of ECP in 25 patients with steroid-refractory chronic extensive GvHD with predominantly sclerodermic and liver manifestations. Patients (80%) responded, including 50% CR rate. Of five patients with severe liver dysfunction (γGT ⩾3000 U), three had a CR to ECP.
A recent multicenter, prospective, randomized, phase II study of ECP in steroid-intolerant, steroid-dependent or steroid-refractory chronic GvHD, patients were randomized to either standard treatment (prednisone plus CsA (or tacrolimus) or standard treatment plus ECP for 24 weeks. The primary objective was to assess improvement in skin GvHD. Secondary objectives were the assessment of total steroid use, changes in quality of life, the effect of treatment on other organ manifestations of GvHD, and the safety of ECP. Patient accrual was rapid, underscoring the feasibility of these trials, and data analysis is ongoing.
In view of the poor prognosis of patients with chronic extensive GvHD and the promising results of ECP with few side effects reported in small retrospective clinical studies, future trials should define the optimal role of ECP in these patients. Prospective well-controlled studies in homogenous patient groups are necessary to determine the safety and efficacy of ECP in patients with high- or low-risk GvHD; defined organ involvements; and preemptive, upfront or salvage treatment. In addition, these studies should assess whether ECP can reduce the total amount of immunosuppressive medication used.
Gérard Socié (Hospital Saint Louis, Paris, France) reviewed the criteria used for successful treatment of chronic GvHD in clinical studies. The definition of chronic GvHD as GvHD that occurs 100 or more days after HSCT has become increasingly dysfunctional. New categories, based on clinical manifestations rather than time of onset, are needed and are currently being considered by the NIH consensus conference on chronic GvHD.54 A crisp definition of chronic GvHD is particularly important for clinical trials in order to allow comparisons of outcomes following various treatments.
Discontinuation of immunosuppressive therapy may be a surrogate end point for the resolution of chronic GvHD.45, 55 Stewart and co-workers analyzed 751 patients with chronic GvHD and identified six factors that significantly increased the duration of immunosuppressive treatment: (1) use of granulocyte colony-stimulating factor-mobilized blood cells vs marrow; (2) female donor for male recipient; (3) number of organs involved; (4) serum bilirubin >2 mg/dl at diagnosis; (5) number of mismatched HLA loci; and (6) year of transplantation. The NIH consensus conference considered the following endpoints as useful in defining successful treatment: GvHD response, time to GvHD progression, GvHD-specific mortality, overall survival, survival to resolution of chronic GvHD and survival to permanent discontinuation of immunosuppression. Currently, there are no validated biomarkers for the diagnosis of chronic GvHD or its response to therapy.
Socié emphasized the importance of additional criteria that would foster more rapid clinical trials in chronic GvHD. Patient characteristics should be carefully defined by the inclusion and exclusion criteria. Immunosuppressive regimens, including dose adjustments and tapering schedules, must be carefully defined so that all investigators are following the same treatment strategy. Primary and secondary end points must be clearly defined and strictly adhered to, with calendar-driven and standardized measures of response, such as those suggested by the NIH consensus conference. Clinical trials that use homogeneous patient groups and consistent definitions of response will facilitate the interpretation and comparison of treatment options. Prospectively collected data on organ-specific treatment responses of chronic GvHD are not currently available, negating the ability to select immunosuppressive treatment according to organ manifestations.
GvHD remains a source of significant morbidity and mortality in the setting of allogeneic HSCT. Improving outcomes for HSCT recipients requires additional therapeutic modalities for GvHD, especially for those patients who fail to respond to initial therapy with steroids. ECP has objective activity in the treatment of acute and chronic GvHD and is well-tolerated. Further evaluation of the efficacy of ECP in well-designed, prospective, controlled studies is warranted. A better understanding of the relative contributions of transplant conditioning, effector and Tregs, and inflammatory cytokines in the initiation and maintenance phases of GvHD is essential for development of innovative treatment strategies, including a more sophisticated use of ECP. Investigation of apoptotic cell engagement during and after ECP and its influence on APCs will be of vital interest for exploration of these mechanisms. Several studies in well-designed animal models and in vitro are currently underway to address these issues.
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Greinix, H., Socié, G., Bacigalupo, A. et al. Assessing the potential role of photopheresis in hematopoietic stem cell transplant. Bone Marrow Transplant 38, 265–273 (2006). https://doi.org/10.1038/sj.bmt.1705440
- allogeneic stem cell transplantation
- graft-versus-host disease
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