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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Department of Medicine I, Bone Marrow
Transplantation Unit, University of Vienna, Vienna, Austria; Department
of Dermatology, Division of Immunology, Allergy and Infectious
Diseases, University of Vienna, Vienna, Austria; Department of Blood
Group Serology, University of Vienna, Vienna, Austria; Department of
Dermatology, Division of Special and Environmental Dermatology,
University of Vienna, Vienna, Austria.
Extracorporeal exposure of peripheral blood mononuclear cells to
the photosensitizing agent 8-methoxypsoralen and UV-A radiation has
been shown to be effective in the treatment of selected diseases mediated by T cells, rejection after solid organ transplantation, and
chronic graft-versus-host disease (GVHD). We present 21 patients with a
median age of 38 years who developed steroid-refractory acute GVHD
grades II to IV after stem cell grafting from sibling or unrelated
donors and were referred to extracorporeal photochemotherapy (ECP).
Three months after initiation of ECP 60% of patients achieved a
complete resolution of GVHD manifestations. Complete responses were
obtained in 100% of patients with grade II, 67% of patients with
grade III, and 12% of patients with grade IV acute GVHD. Three
months after start of ECP complete responses were achieved in 60% of
patients with cutaneous, 67% with liver, and none with gut
involvement. Adverse events observed during ECP included a decrease in
peripheral blood cell counts in the early phase after stem cell
transplantation (SCT). Currently, 57% of patients are alive at a
median observation time of 25 months after SCT. Probability of survival
at 4 years after SCT is 91% in patients with complete response to ECP
compared to 11% in patients not responding completely. Our findings
suggest that ECP is an effective adjunct therapy for acute
steroid-refractory GVHD with cutaneous and liver involvement. However,
in patients with acute GVHD grade IV or gut involvement other
therapeutic options are warranted.
(Blood. 2000;96:2426-2431) Acute graft-versus-host disease (GVHD) is a major
complication of allogeneic stem cell transplantation (SCT) that results in significant morbidity and mortality. Despite prophylaxis with cyclosporine (CSA) or methotrexate (MTX) or both, acute GVHD occurs in
30% to 50% of patients receiving transplants from HLA-identical sibling donors and in 50% to 80% of patients receiving transplants from HLA-matched unrelated donors.1-3 Acute GVHD is
classified into 4 grades according to published criteria.4
Long-term survival in patients developing severe acute GVHD has
generally been less than 30%.5,6 Despite advances in the
understanding of acute GVHD and its prophylaxis, little progress has
been made in the primary treatment of established
disease.7-9 Steroids constitute the main therapy, alone or
in association with antithymocyte globulin (ATG), CSA, or monoclonal
antibodies (mAb).8-10 Response and survival after acute
GVHD depend on a number of variables, including patient clinical
performance, infections, gastrointestinal bleeding, and pneumonitis,
which often are associated with acute GVHD.8,9 Patients
unresponsive to corticosteroids are at high risk of death due
to infections.
Extracorporeal photochemotherapy (ECP) is currently being used for the
treatment of cutaneous T-cell lymphoma, selected autoimmune diseases,
and rejection after solid organ transplantation.11,12 ECP
is based on the infusion of autologous peripheral blood mononuclear cells collected by apheresis, incubated with the photoactivable drug
8-methoxypsoralen (8-MOP) and UV-A irradiation. Recently, ECP has shown
considerable efficacy in treatment of steroid-refractory chronic
GVHD.13,14
So far, results of ECP treatment have been reported in only a small
number of patients with steroid-refractory acute GVHD including 6 previously treated patients at our institution.13-18 Here,
we present results of a prospective pilot study with a larger number of
patients with steroid-refractory acute GVHD grades II to IV treated
with ECP.
Patients
Evaluation criteria
The clinical diagnosis of GVHD was confirmed by histopathology of the skin in all patients and, if indicated, liver or mucous membrane biopsies were clinically graded as 0 through IV for acute GVHD by the criteria reported4 and as none, limited, or extensive for chronic GVHD.19 Complete organ responses of acute GVHD were defined as resolution of skin, liver, or gut manifestations. Partial responses were defined as a more than 50% response in organ involvement, but less than a complete response. No change was defined as stable organ involvement, despite the tapering of other immunosuppressive agents by at least 50% of the dosage. No response referred to progressive worsening of acute GVHD and the inability to taper other medications. Steroid-refractory acute GVHD was defined as either no response of organ manifestations or inability to taper steroids without increased GVHD activity when steroids were given at a dose of at least 2 mg/kg body weight for at least 7 days. ECP and treatment protocol The ECP procedure was performed using the UVAR photopheresis system (Therakos, West Chester, PA), as described.13 The mean treatment time for the photopheresis procedure was 3.5 hours. Preferentially, peripheral vein catheters were used. ECP was initiated in patients with steroid-refractory acute GVHD when the white blood cell count was more than 1 × 109/L and no acute infections were observed. Patients were treated on 2 consecutive days (one cycle) at 1- to 2-week intervals until improvement and thereafter every 2 to 4 weeks until maximal response. Then, ECP was tapered on an individual basis. All adverse effects obtained during the treatments were recorded. Informed consent was obtained from the patients, and the use of ECP was approved by the medical ethics committee of the University of Vienna.Skin biopsy Punch biopsies (4 mm) were performed in all patients at onset of cutaneous GVHD, before ECP, and after improvement or resolution of GVHD on ECP. Skin biopsies were fixed in formalin, embedded in paraffin, and stained with hematoxylin-eosin. Sections were evaluated by light microscopy. The histopathologic diagnosis of acute cutaneous GVHD grades I to IV was based on the criteria and grading as suggested by Lerner and colleagues.20Statistical methods Survival, incidence of transplant-related mortality, and relapse rates were estimated using the method of Kaplan and Meier. Comparisons were based on the generalized Wilcoxon test and the log-rank test.
All patients had restoration of normal hematopoiesis as indicated by rising blood cell counts and return of marrow cellularity within 4 weeks of stem cell grafting. Acute GVHD and response to ECP All patients experienced acute GVHD grades II to IV at a median of 19 days after SCT and did not respond to CSA and corticosteroids administered for a median of 21 days as shown in Table 2. All patients had histologically proven cutaneous GVHD grades III to IV, 12 patients had liver involvement (including 2 patients with histologic confirmation) grades I to IV, and 4 patients had gut manifestations (including 3 patients with histologic confirmation) of GVHD grades II or III. One and 3 months after initiation of ECP 33% and 60% of patients, respectively, achieved a complete resolution of GVHD manifestations as shown in Figure 1. The maximal response to ECP was achieved after a median of 4 cycles (range, 1-13 cycles) or 2 months (range, 0.5-6 months) of therapy.
Response rates of different grades of acute GVHD are shown in Figure 1. Complete responses were achieved in 9 of 9 patients (100%) with grade II acute GVHD 3 months after start of ECP. Two of 3 patients (67%) with grade III and 1 of 8 patients (12%) with grade IV acute GVHD had a complete response. In the latter group 5 of 8 patients (64%) died within 3 months after initiation of ECP. Response rates of patients with cutaneous manifestations of acute
GVHD are shown in Figure 2. Three months
after initiation of ECP complete responses were observed in 12 of 20 evaluable patients (60%) with cutaneous involvement including 11 of 13 patients (84%) with grade III and 1 of 7 patients (14%) with
grade IV GVHD. In one patient the follow-up is currently less than 3 months. Another patient with cutaneous GVHD achieved a complete
response 6 months after start of ECP. Five of 20 patients (25%)
including 1 of 13 patients (8%) with grade III and 4 of 7 patients (58%) with grade IV GVHD died within 3 months of start of
ECP.
Patients with liver involvement due to acute GVHD and responding to ECP
had a rapid normalization after a median of 3 weeks of therapy as shown
in Figure 3. Eight of 12 patients (67%)
with liver involvement experienced a complete resolution, documented in
normalization of serum bilirubin and alkaline phosphatase levels after
3 months.
Six of 9 patients (67%) with both skin and liver involvement achieved a complete response with ECP. No responses to ECP were observed in patients with combined skin, liver, and gut involvement as shown in Table 2. During ECP, steroid therapy could be discontinued in responding patients after a median of 53 days (range, 18-122 days). After termination of ECP, patients remained on CSA for 2 months, but the dosage was subsequently reduced and finally treatment was terminated. Infections and adverse events Six patients died during the study period, 5 from infections related to deteriorating GVHD (patient nos. 3, 5, 6, 16, and 19) and 1 from multiorgan failure and severe gastrointestinal bleeding (patient no. 20) related to gut GVHD. Probability of transplant-related mortality (TRM) projected at 4 years after SCT was 32% for the entire group. In patients achieving a complete response of acute steroid-refractory GVHD, the TRM was 0% compared to 75% in patients without complete response 3 months after ECP, respectively. These differences are highly significant (P = .001).Adverse events observed during a total of 230 cycles (460 procedures)
of ECP are shown in Table 3.
Survival and long-term outcome Three patients (no. 2, 8, and 11) developed chronic GVHD 5 to 28 months after SCT and 1.5 to 17 months after discontinuation of ECP. Another patient (no. 14) progressed into chronic extensive GVHD and requires combined immunosuppressive therapy.As of January 31, 2000, 12 of 21 patients (57%) are alive a median of 25 months (range, 2-53 months) after SCT. Five patients are off immunosuppression and 3 during CSA taper with a Karnofsky performance score above 90%. Probability of survival at 4 years after SCT is 53% for the entire
group as shown in Figure 5. In patients
achieving a complete response of acute steroid-refractory GVHD 6 months
after initiation of ECP, probability of survival was 91% compared to
11% in patients without complete response of GVHD to ECP. These
differences are statistically significant (P = .0001).
At present, corticosteroids are the first-line therapy for severe
acute GVHD, achieving response rates of 24% to
70%.5,8-10 In a recent study the increase of steroid dose
to 10 to 20 mg/kg body weight did not improve overall response and
survival of GVHD patients.21 Various second-line
immunosuppressive options for these patients have been
investigated.10,22-27 Using ATG in steroid-refractory acute GVHD, overall response rates of 30% to 40% have been
observed.10,22,27 Recently, Przepiorka and
coworkers28 observed complete response rates of 29% to
47% using daclizumab, a humanized anti-interleukin-2 receptor (IL-2R)
In search of further therapeutic options for patients with steroid-refractory acute GVHD and based on our results achieved with ECP in selected patients with severe resistant chronic GVHD,13 ECP was investigated as a second-line treatment in 21 patients with acute GVHD not responding to steroids at a dose of at least 2 mg/kg body weight. Three months after initiation of ECP 60% of patients achieved a complete resolution of GVHD manifestations. The maximal response to ECP was achieved after a median of 2 months. High complete response rates were achieved in patients with cutaneous (65%) and liver (67%) involvement and grades II (100%) to III (67%) of acute steroid-refractory GVHD. These results compare favorably with the ones achieved with mAbs against IL-2R or CD2.28,29 So far, only a few patients with acute GVHD treated with ECP have been reported.13-18 Whereas Sniecinski and colleagues15 and Besnier and coworkers16 observed no response in a total of 7 patients, a complete resolution of grade III GVHD was achieved by Richter and associates17 in 1 patient. Dall'Amico and Zacchello18 documented improvements of acute GVHD in 3 of 4 pediatric patients during ECP. Due to the rapid response to ECP, the dose of steroids could be reduced and discontinued after a median of 53 days in our responding patients. In view of the severe side effects of prolonged high-dose corticosteroid therapy the timely discontinuation of steroids is a major advantage for these patients. The overall survival rate of 57% after a median observation time of 25 months after SCT in our study compares favorably with published results on second-line therapy of patients with acute steroid-refractory GVHD.25-29 A significantly higher probability of survival (91%) was seen in patients achieving a complete response 6 months after initiation of ECP compared to patients not responding (11%). Recently, failure of first-line therapy of acute GVHD has been reported as a significant factor in a multivariate analysis for poor 2-year survival with 10% survival rate in nonresponders and 54% in responders.30 The deaths observed in our study consisted of GVHD-associated infections and multiorgan failure and are similar to the ones reported in patients not responding to alternative GVHD therapies. Extracorporeal photochemotherapy usually is tolerated excellently with very few side effects.14 In contrast to patients treated with ECP at our institution for chronic extensive GVHD, patients in the early phase after SCT had a marked decrease in hemoglobin levels, absolute neutrophil counts, and platelet counts after the first cycles of ECP. No increase in rate of infections during and after ECP compared with previously published results in these patients was seen in our study.5,8,9,21 The optimal duration and schedule of ECP treatment are still unclear. Our treatment schedule is based on clinical experience gained in patients with selected autoimmune diseases and chronic GVHD.11-13 Due to concerns about reactivation of GVHD activity after initial response, no abrupt discontinuation of ECP was performed and individual tapering of therapy occurred in our study. The results obtained support the use of ECP over a short treatment time because patients responding did so almost exclusively in the first 3 months, whereas little additional benefit could be obtained by continuation of ECP for a longer time. Whereas patients treated with mAbs had a hyporesponsive state of limited duration with high recurrence rates of GVHD after completion of therapy,23,29 the majority of our patients had sustained resolution of GVHD activity. The exact mechanisms by which ECP leads to the described responses in GVHD as well as other T-cell-mediated diseases have not been elucidated. ECP may be involved in augmenting the apoptotic process,31,32 which may lead to deletion of graft-reactive T cells. Another possibility is that the photoactivated 8-MOP may alter the idiotypes expressed by clones of autoreactive T cells of known or unknown specificity by up-regulation of class I expression.33 This might trigger the induction of specific autoregulatory T cells, most likely CD8+ T lymphocytes with suppressive or cytotoxic capabilities.34 Findings in the animal model support this concept.35,36 These hypotheses, however, warrant further investigation because most of the in vitro studies involving ECP, so far, have been performed in patients with neoplastic or autoimmune diseases. In summary, our results demonstrate that ECP is an efficacious and well tolerated therapy for patients with acute steroid-refractory GVHD. Timely identification of nonresponding or incomplete responding patients allows early assignment to alternate immunosuppressive treatment. The early combination of ECP with other treatment strategies including mAbs could further improve survival of patients with gastrointestinal involvement or grade IV acute GVHD. However, randomized studies are mandatory to evaluate the impact of ECP on outcome of patients with GVHD.
We thank the dedicated nurses of our stem cell transplant program and the ECP unit, our fellows and house staff, the medical technicians, and the physicians who referred patients to our unit. We are indebted to the members of Geben fuer Leben-Knochenmarkspende Oesterreich for finding suitable unrelated donors for our patients.
Submitted April 4, 2000; accepted June 8, 2000.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Hildegard T. Greinix, AKH Wien, Klinik fuer Innere I, Knochenmarktransplantation, Waehringer Guertel 18-20, A-1090, Vienna, Austria; e-mail: hildegard.greinix{at}akh-wien.ac.at.
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© 2000 by The American Society of Hematology.
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  A. Maeda, A. Schwarz, A. Bullinger, A. Morita, D. Peritt, and T. Schwarz Experimental Extracorporeal Photopheresis Inhibits the Sensitization and Effector Phases of Contact Hypersensitivity via Two Mechanisms: Generation of IL-10 and Induction of Regulatory T Cells J. Immunol., November 1, 2008; 181(9): 5956 - 5962. [Abstract] [Full Text] [PDF]
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 H. J. Deeg How I treat refractory acute GVHD Blood, May 15, 2007; 109(10): 4119 - 4126. [Abstract] [Full Text] [PDF]
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 D. Weisdorf GVHD The Nuts and Bolts Hematology, January 1, 2007; 2007(1): 62 - 67. [Abstract] [Full Text] [PDF]
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G. Gorgun, K. B. Miller, and F. M. Foss Immunologic mechanisms of extracorporeal photochemotherapy in chronic graft-versus-host disease Blood, July 18, 2002; 100(3): 941 - 947. [Abstract] [Full Text] [PDF]
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M. Guimond, A. Balassy, M. Barrette, S. Brochu, C. Perreault, and D. C. Roy P-glycoprotein targeting: a unique strategy to selectively eliminate immunoreactive T cells Blood, June 28, 2002; 100(2): 375 - 382. [Abstract] [Full Text] [PDF]
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D. G. Maloney, B. M. Sandmaier, S. Mackinnon, and J. A. Shizuru Non-Myeloablative Transplantation Hematology, January 1, 2002; 2002(1): 392 - 421. [Abstract] [Full Text]
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T. Alcindor, G. Gorgun, K. B. Miller, T. F. Roberts, K. Sprague, D. P. Schenkein, and F. M. Foss Immunomodulatory effects of extracorporeal photochemotherapy in patients with extensive chronic graft-versus-host disease Blood, September 1, 2001; 98(5): 1622 - 1625. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
-chain antibody. With anti-CD2 mAbs complete response rates of 30%
have been achieved in patients with steroid-refractory acute
GVHD.