© Borgis - Postępy Nauk Medycznych 4/2014, s. 261-265
*Jan Styczyński1, Krzysztof Kałwak2, Krzysztof Czyżewski1, Joanna Owoc-Lempach2, Anna Krenska1, Robert Dębski1, Ewa Gorczyńska2, Alicja Chybicka2, Mariusz Wysocki1
Wyniki terapii przeciwciałami anty-CD20 u dzieci z EBV-zależnym poprzeszczepowym zespołem limfoproliferacyjnym
Results of therapy with anti-CD20 antibodies in EBV-related post-transplant lymphoproliferative disorder
1Department of Pediatric Hematology and Oncology, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz
Head of Department: prof. Mariusz Wysocki, MD, PhD
2Department of Pediatric Transplantology, Hematology and Oncology Medical University, Wrocław
Head of Department: prof. Alicja Chybicka, MD, PhD
Streszczenie
Wstęp. Poprzeszczepowy zespół limfoproliferacyjny (PTLD) jest zagrażającym życiu powikłaniem po przeszczepieniu komórek krwiotwórczych (HSCT).
Cel pracy. Celem tej pracy jest analiza wyników terapii EBV-PTLD, opartej na zastosowaniu rituximabu u dzieci po allo-HSCT.
Materiał i metody. Retrospektywnej analizie poddano 369 pacjentów w wieku < 20 lat po allo-HSCT wykonanym w latach 2005-2011 w dwóch ośrodkach pediatrycznych w kierunku PTLD pewnej lub prawdopodobnej.
Wyniki. U 20 pacjentów rozpoznano EBV-PTLD. Częstość EBV-PTLD wyniosła 5,4%, w tym 2,3% dla HSCT od zgodnych dawców rodzinnych, 5,6% dla HSCT od zgodnych dawców niespokrewnionych oraz 16,2% dla HSCT od częściowo zgodnych dawców niespokrewnionych. Rozwój EBV-PTLD nastąpił w czasie 0,7-8 miesięcy (mediana 1,6) po allo-HSCT. Przeżycie 120-dniowe po rozpoznaniu PTLD wyznaczone metodą Kaplana-Meiera wyniosło 75%. W analizie jednowariantowej czynnikami wpływającymi na niepowodzenie terapii były: choroba wielosystemowa, ostra lub przewlekła GVHD oraz wzrost EBV-DNA-emii po pierwszym tygodniu terapii rituximabem. W analizie wielowariantowej jedynym czynnikiem wpływającym na niepowodzenie terapii była obecność ostrej lub przewlekłej choroby GVHD. Redukcja immunosupresji o co najmniej 20% dawki sprzyjała niższej śmiertelności z powodu PTLD (8 vs 50%).
Wnioski. Trzy czwarte pacjentów z EBV-PTLD uzyskało remisję PTLD po zastosowaniu terapii opartej na rituximabie. Redukcja immunosupresji w momencie rozpoznania PTLD była związana z lepszymi wynikami terapii, podczas gdy choroba wielosystemowa, ostra lub przewlekła GVHD oraz wzrost EBV-DNA-emii po pierwszym tygodniu terapii były niekorzystnymi czynnikami prognostycznymi.
Summary
Introduction. Post-transplant lymphoproliferative disorder (PTLD) is a life-threatening malignant disease developing after hematopoietic stem cell transplantation (HSCT).
Aim. The objective of this study is the analysis of the outcome of EBV-related PTLD after a rituximab-based treatment in children after allo-HSCT.
Material and methods. 369 patients aged < 20 years after allo-HSCTs performed between 2005-2011 in 2 pediatric centres have been retrospectively analysed for PTLD, either biopsy-proven or probable disease.
Results. 20 PTLD cases were identified, indicating an overall EBV-PTLD frequency of 5.4%, ranging from 2.3% for matched-family donor, 5.6% in matched unrelated donor, to 16.2% in mismatched unrelated donor recipients. EBV-PTLD occurred at a median of 1.6 months (range, 0.7-8) after HSCT. 120-days survival from PTLD determined by Kaplan-Meier method was 75%. Univariate analysis showed that a poor response of PTLD to rituximab was associated with initial multiorgan involvement, acute/chronic GVHD, and increase of EBV-DNA-emia after one week therapy with rituximab. In multivariate analysis, poor response of PTLD to rituximab was associated with acute/chronic GVHD upon PTLD diagnosis. Immunosuppression tapering by at least 20% of dose was associated with a lower PTLD mortality (8 vs 50%).
Conclusions. Three-fourths of patients with EBV-PTLD survived after rituximab-based treatment. Reduction of immunosuppression was associated with improved outcome while multiorgan disease, acute/chronic GVHD, and increase of EBV-DNA-emia after one week therapy predicted poor outcome.
Introduction
Post-transplant lymphoproliferative disorders (PTLD) is a life-threatening malignant disease developing after transplantation, caused by iatrogenic suppression of T-cell function. The most common form of PTLD after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is related to Epstein-Barr virus disease (EBV-PTLD). Fifteen years ago, EBV-PTLD was reported to have an attributable mortality of 84.6% (1). Since then, therapeutic approaches have been advanced for the prevention and treatment of EBV-PTLD, summarised in the ECIL recommendations (2, 3). These include the administration of rituximab, reduction of immunosuppression (RI) and cellular therapy, such as the use of EBV-specific cytotoxic T-lymphocytes (EBV-CTL). However, CTLs are not available to most transplant centers, and tapering of immunosuppression has limited efficacy and is not always feasible in the presence of graft-versus-host disease (GVHD). Consequently treatment with rituximab seems to be the most promising method of prevention and therapy of PTLD after HSCT (4-6).
Within Infectious Diseases Working Group (IDWP) of European Group for Blood and Marrow Transplantation (EBMT) a multicenter, retrospective analysis of 4466 allogeneic HSCTs performed in 19 pediatric and adult EBMT transplant centers in Europe was conducted (7). Finally 144 pediatric and adult patients who had been treated with rituximab for PTLD after allo-HSCT were analyzed, and the factors that might be associated with survival were taken into account. In final report, children and adults were pooled together as one group (7). However, it has been suggested that these two age populations were different in outcome. To address this, a retrospective analysis was undertaken to find out specific aspects of results of therapy in children.
Aim
Thus, the objective of this study was the analysis of the outcome of EBV-related PTLD after a rituximab-based treatment in children after allo-HSCT performed in two Polish pediatric transplant centrs.
Material and methods
We retrospectively analyzed 369 allogeneic HSCTs performed in 2 pediatric transplant centers between 2005 and 2011 for PTLD. The following inclusion criteria were used for the study: proven or probable PTLD diagnosis and rituximab treatment administered either alone or combined with other therapeutic approaches. The study was approved by the Institutional Review Board of the Medical College, Nicolaus Copernicus University, Bydgoszcz.
The diagnosis of EBV-related PTLD was defined as proven or probable according to published definition (2). Proven PTLD was diagnosed when EBV was detected in a specimen obtained from an organ by biopsy or other invasive procedure, with a test with appropriate sensitivity and specificity together with symptoms and signs from the affected organ. Probable PTLD was defined as significant lymphoadenopathy or other endorgan disease accompanied by a high EBV-DNA blood load, in the absence of other etiologic factors or established diseases (2, 4). EBV-DNA-emia was measured by quantitative or qualitative PCR in peripheral blood. Repeated PCR testing was done at local sites using the same methodology throughout the study period. EBV-DNA levels were determined before the beginning of therapy and one week after each dose of rituximab. PTLD occurring within the first 100 days after transplantation was defined as early onset disease.
Reduction of immunosuppression (RI) was defined as a sustained decrease of at least 20% of the daily dose of immunosuppressive drugs with the exception of low-dose corticosteroid therapy, i.e. ≤ 0.2 mg/kg in patients < 40 kg of body weight or ≤ 10 mg/day in patients with > 40 kg of body weight (8). Response to given treatment was assesed on clinical level as complete remission, partial response, stable or progressive disease, according to standard definition (9). The virologic response was also assessed based on EBV-DNA-emia reduction. Failure of PTLD treatment was defined by death due to PTLD. The cause of death was reported as being related to PTLD or due to other causes.
Statistical analysis
The probability of survival from PTLD (PS) were estimated by the Kaplan-Meier method and univariate comparisons were performed using the log-rank test (10, 11). The time from the date of PTLD diagnosis to the date of death due to PTLD, death due to other causes or to the date of the latest follow-up was considered. Uni- and multivariate analysis for survival from PTLD was performed by using the Cox regression (12). In order to analyse the influence of the viral load after 1 and 2 weeks on survival from PTLD, a landmark analysis was performed using data on only those patients who survived up to 1 and 2 weeks after PTLD diagnosis. A P-value below 0.05 was regarded as statistically significant.
Results
Baseline characteristics
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Piśmiennictwo
1. Curtis RE, Travis LB, Rowlings PA et al.: Risk of lymphoproliferative disorders after bone marrow transplantation: a multi-institutional study. Blood 1999; 94: 2208-2216.
2. Styczynski J, Reusser P, Einsele H et al.: Management of HSV, VZV and EBV infections in patients with hematological malignancies and after SCT: guidelines from the Second European Conference on Infections in Leukemia. Bone Marrow Transplant 2009; 43: 757-770.
3. Gil L, Styczynski J, Komarnicki M: Strategy of pre-emptive management of Epstein-Barr virus post-transplant lymphoproliferative disorder after stem cell transplantation: results of European transplant centers survey. Contemp Oncol 2012; 16: 338-340.
4. Styczynski J, Einsele H, Gil L, Ljungman P: Outcome of treatment of Epstein-Barr virus-related post-transplant lymphoproliferative disorder in hematopoietic stem cell recipients: a comprehensive review of reported cases. Transpl Infect Dis 2009; 11: 383-392.
5. Czyzewski K, Styczynski J, Krenska A et al.: Intrathecal therapy with rituximab in central nervous system involvement of post-transplant lymphoproliferative disorder. Leuk Lymphoma 2013; 54: 503-506.
6. Styczynski J, Gil L: Prevention of infectious complications in pediatric HSCT. Bone Marrow Transplant 2008; 42 (suppl. 2): S77-81.
7. Styczynski J, Gil L, Tridello G et al.: Response to rituximab-based therapy and risk factor analysis in epstein barr virus-related lymphoproliferative disorder after hematopoietic stem cell transplant in children and adults: a study from the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation. Clin Infect Dis 2013; 57: 794-802.
8. Cesaro S, Pegoraro A, Tridello G et al.: A prospective study on modulation of immunosuppression for Epstein-Barr virus reactivation in pediatric patients who underwent unrelated hematopoietic stem-cell transplantation. Transplantation 2010; 89: 1533-1540.
9. Cheson BD, Pfistner B, Juweid ME et al.: Revised response criteria for malignant lymphoma. J Clin Oncol 2007; 25: 579-586.
10. Kaplan EL, Meier P: Non parametric estimation for incomplete observations. J Am Stat Assoc 1958; 53: 457-481.
11. Peto R, Peto J: Asymptotically efficient rank invariant test procedures. J R Stat Assoc 1972; 135: 185-198.
12. Cox DR: Regression model and life tables. J R Stat Soc Ser B 1972; 34: 187-220.
13. Stevens SJ, Verschuuren EA, Pronk I et al.: Frequent monitoring of Epstein-Barr virus DNA load in unfractionated whole blood is essential for early detection of posttransplant lymphoproliferative disease in high-risk patients. Blood 2001; 97: 1165-1171.
14. Sundin M, Le Blanc K, Ringden O et al.: The role of HLA mismatch, splenectomy and recipient Epstein-Barr virus seronegativity as risk factors in post-transplant lymphoproliferative disorder following allogeneic hematopoietic stem cell transplantation. Haematologica 2006; 91: 1059-1067.
15. Landgren O, Gilbert ES, Rizzo JD et al.: Risk factors for lymphoproliferative disorders after allogeneic hematopoietic cell transplantation. Blood 2009; 113: 4992-5001.
16. Larouche JF, Berger F, Chassagne-Clement C et al.: Lymphoma recurrence 5 years or later following diffuse large B-cell lymphoma: clinical characteristics and outcome. J Clin Oncol 2010; 28: 2094-2100.
17. Diepstra A, van Imhoff GW, Schaapveld M et al.: Latent Epstein-Barr virus infection of tumor cells in classical Hodgkin’s lymphoma predicts adverse outcome in older adult patients. J Clin Oncol 2009; 27: 3815-3821.
18. Cesaro S, Murrone A, Mengoli C et al.: The real-time polymerase chain reaction-guided modulation of immunosuppression enables the pre-emptive management of Epstein-Barr virus reactivation after allogeneic haematopoietic stem cell transplantation. Br J Haematol 2005; 128: 224-233.
19. Christopeit M, Schutte V, Theurich S et al.: Rituximab reduces the incidence of acute graft-versus-host disease. Blood 2009; 113: 3130-3131.
20. Cutler C, Miklos D, Kim HT et al.: Rituximab for steroid-refractory chronic graft-versus-host disease. Blood 2006; 108: 756-762.
