EBV-associated post-transplant lymphoproliferative disorder following in vivo T-cell-depleted allogeneic transplantation: clinical features, viral load correlates and prognostic factors in the rituximab era

Fox, Christopher P.; Burns, David M.; Parker, Anne; Peggs, Karl S.; Harvey, Caroline; Natarajan, Shiva; Marks, David I.; Jackson, Bridget; Chakupurakal, Geothy; Dennis, Michael; Lim, ZiYi; Cook, Gordon; Carpenter, Ben; Pettitt, AR; Mathew, Susan; Connelly‐Smith, Laura; Yin, John; Viskaduraki, Maria; Chakraverty, Ronjon; Orchard, Kim; Shaw, Bronwen E.; Byrne, J L; Brookes, Cassandra; Craddock, Charles; Chaganti, Sridhar

doi:10.1038/bmt.2013.170

Cited by 82 publications

(68 citation statements)

References 31 publications

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“…2 No other classical risk factors were found such as recipient age, baseline disease or presence of acute or chronic GVHD. 20 CMV reactivation and BK poliomavirus hemorrhagic cystitis were frequently associated, likely reflecting severe immunosuppression. In contrast to a recent report, 17 we did not show differences in the risk of EBV disease between patients with and without CMV reactivation.…”

Section: Discussionmentioning

confidence: 99%

Impact of Epstein Barr virus-related complications after high-risk allo-SCT in the era of pre-emptive rituximab

García‐Cadenas

Castillo

Martino

et al. 2015

Bone Marrow Transplant

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We monitored 133 high-risk allo-SCT recipients for 6 months after transplant for EBV reactivation by quantitative real-time PCR. Rituximab was given as pre-emptive therapy for viremia 41000 copies/mL. The 1-year cumulative incidence of EBV reactivation was 29.4% (95% confidence interval (CI): 18-40) in patients monitored due to initial high-risk characteristics (n = 93) and 31.8% (95% CI: 19.7-44) in those followed because of the development of refractory GVHD (n = 40). Overall response rate to Rituximab was 83%. Nine patients (9.6%) developed post-transplant lymphoproliferative disorder (PTLD) at a median of +62 days after SCT. Eight of them showed a concomitant CMV reactivation. Second SCT was the only risk factor associated with EBV infection and PTLD in multivariate analysis (hazard ratio (HR) 2.6 (95% CI: 1.1-6.4; P = 0.04) and HR 6.4 (95%CI: 1.3-32; P = 0.02)). The development of EBV reactivation was not associated with non-relapse mortality or OS (P = 0.97 and P = 0.84, respectively).Bone Marrow Transplantation (2015) 50, 579-584; doi:10.1038/bmt.2014.298; published online 12 January 2015 INTRODUCTION Epstein-Barr virus-related post-transplant lymphoproliferative disorder (PTLD) is a serious complication after SCT with a mortality as high as 85%. 1 Major risk factors for PTLD include HLA disparity, graft T-cell depletion and administration of anti-thymocyte globulin (ATG) or other anti T-cell antibodies. 2,3 PTLD is usually preceded by a preclinical phase characterized by rising EBV copies in peripheral blood which can be quantified by polymerase-chain reaction (PCR). Recent guidelines recommend monitoring EBV viral load in high-risk allo-SCT recipients, according to the mentioned predisposing factors. 4 The real incidence and prognosis of EBV disease are difficult to evaluate due to differences in the PCR methods used to test EBV DNA, the quantitative PCR thresholds for therapeutic intervention and the diversity of criteria for defining high-risk patients. 5 Efforts to improve immune responses by reducing immunosuppressive drugs remain as one of the cornerstones of management but are not applicable to patients with active GVHD; 6,7 thus, eliminating B lymphocytes with the anti-CD20 monoclonal ab Rituximab is the most feasible treatment. 7 In the current study we compare the incidence and prognosis of EBV-related complications between patients with baseline highrisk characteristics for PTLD and patients affected by refractory GVHD, prospectively monitored for EBV DNAemia with early institution of Rituximab as pre-emptive therapy.

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Section: Discussionmentioning

confidence: 99%

Impact of Epstein Barr virus-related complications after high-risk allo-SCT in the era of pre-emptive rituximab

García‐Cadenas

Castillo

Martino

et al. 2015

Bone Marrow Transplant

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“…23 The median time to development of EBV-PTLD after HSCT is 2-4 months. 3,29 Only 4% of cases develop later than 12 months after HSCT, and cases occurring >5 years after HSCT are extremely rare. 3 PTLD after autologous-HSCT is very rare.…”

Section: Epidemiologymentioning

confidence: 99%

“…Indeed, probable/proven PTLD has been described in a significant proportion of patients with EBV DNA levels below commonly adopted intervention thresholds. 29 Threshold value. In the absence of universal standards for Nucleic Acid Test assays, ECIL cannot recommend a specific threshold value of EBV DNA-emia for giving preemptive therapy.…”

Section: Ecil Recommendations For Preemptive Therapy Against Ebv Diseasementioning

confidence: 99%

“…However, if this is impossible due to the clinical status of the patient, a non-invasive approach, encompassing quantitative EBV DNA-emia combined with PET-CT/CT imaging, can be considered. 29,46,47 The diagnostic work-up of EBV-PTLD includes: (a) physical examination, including an examination for fever, tonsillitis, adenopathy and organomegaly; (b) PET-CT/CT imaging; (c) endoscopy in case of gastro-intestinal symptoms; (d) tissue biopsy with histological examination, including EBER ISH and/or immunohistochemistry for viral antigens, and/or flow cytometry; (e) peripheral blood EBV viral load by PCR.…”

Section: Ecil Recommendations For Diagnosis Of Ebv-disease/ptldmentioning

confidence: 99%

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Management of Epstein-Barr Virus infections and post-transplant lymphoproliferative disorders in patients after allogeneic hematopoietic stem cell transplantation: Sixth European Conference on Infections in Leukemia (ECIL-6) guidelines

Styczyński¹,

Velden²,

Fox³

et al. 2016

Haematologica

281

375

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E pstein-Barr virus-related post-transplant lymphoproliferative disorders are recognized as a significant cause of morbidity and mortality in patients undergoing hematopoietic stem cell transplantation. To better define current understanding of post-transplant lymphoproliferative disorders in stem cell transplant patients, and to improve its diagnosis and management, a working group of the Sixth European Conference on Infections in Leukemia 2015 reviewed the literature, graded the available quality of evidence, and developed evidence-based recommendations for diagnosis, prevention, prophylaxis and therapy of post-transplant lymphoproliferative disorders exclusively in the stem cell transplant setting. The key elements in diagnosis include non-invasive and invasive methods. The former are based on quantitative viral load measurement and imaging with positron emission tomography; the latter with tissue biopsy for histopathology and detection of Epstein-Barr virus. The diagnosis of post-transplant lymphoproliferative disorder can be established on a proven or probable level. Therapeutic strategies include prophylaxis, preemptive therapy and targeted therapy. Rituximab, reduction of immunosuppression and Epstein-Barr virusspecific cytotoxic T-cell therapy are recommended as first-line therapy, whilst unselected donor lymphocyte infusions or chemotherapy are options as second-line therapy; other methods including antiviral drugs are discouraged. Management of Epstein-Barr Virus infections

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“…Consequently a significant proportion of allo-HSCT patients develop high levels of circulating EBV DNA, referred to as EBV reactivation or DNAemia. [5][6][7][8][9][10][11] These viral reactivations usually occur within the first few months posttransplant [11][12][13][14][15][16][17] and, if left untreated, can progress to lifethreatening posttransplant lymphoproliferative disease (PTLD). Accordingly, most transplant centers routinely monitor the levels of EBV DNA in the blood of allo-HSCT recipients for several months after transplant and preemptively administer rituximab, an anti-CD20 monoclonal antibody, to those individuals who exhibit rapidly increasing viral loads.…”

Section: Introductionmentioning

confidence: 99%

Memory B-cell reconstitution following allogeneic hematopoietic stem cell transplantation is an EBV-associated transformation event

Burns

Tierney

Shannon-Lowe

et al. 2015

Blood

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Key Points• CD191 CD27 1 memory B cells are detectable at supranormal frequencies in patients with high-level EBV DNAemia following allogeneic HSCT.• These memory B cells are frequently positive for EBV genomes and bear many of the hallmarks of lymphoblastoid transformation.Allogeneic stem cell transplantation (allo-HSCT) provides a unique opportunity to track Epstein-Barr virus (EBV) infection in the context of the reconstituting B-cell system. Although many allo-HSCT recipients maintain low or undetectable levels of EBV DNA posttransplant, a significant proportion exhibit elevated and rapidly increasing EBV loads which, if left untreated, may lead to potentially fatal EBV-associated posttransplant lymphoproliferative disease. Intriguingly, this high-level EBV reactivation typically arises in the first 3 months posttransplant, at a time when the peripheral blood contains low numbers of CD27 1 memory cells which are the site of EBV persistence in healthy immunocompetent donors. To investigate this apparent paradox, we prospectively monitored EBV levels and B-cell reconstitution in a cohort of allo-HSCT patients for up to 12 months posttransplant. In patients with low or undetectable levels of EBV, the circulating B-cell pool consisted predominantly of transitional and naive cells, with a marked deficiency of CD27 1 memory cells which lasted >12 months. However, among patients with high EBV loads, there was a significant increase in both the proportion and number of CD27 1 memory B cells. Analysis of sorted CD27 1 memory B cells from these patients revealed that this population was preferentially infected with EBV, expressed EBV latent transcripts associated with B-cell growth transformation, had a plasmablastic phenotype, and frequently expressed the proliferation marker Ki-67. These findings suggest that high-level EBV reactivation following allo-HSCT may drive the expansion of latently infected CD27 1 B lymphoblasts in the peripheral blood. (Blood. 2015;126(25):2665-2675

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EBV-associated post-transplant lymphoproliferative disorder following in vivo T-cell-depleted allogeneic transplantation: clinical features, viral load correlates and prognostic factors in the rituximab era

Cited by 82 publications

References 31 publications

Impact of Epstein Barr virus-related complications after high-risk allo-SCT in the era of pre-emptive rituximab

Impact of Epstein Barr virus-related complications after high-risk allo-SCT in the era of pre-emptive rituximab

Management of Epstein-Barr Virus infections and post-transplant lymphoproliferative disorders in patients after allogeneic hematopoietic stem cell transplantation: Sixth European Conference on Infections in Leukemia (ECIL-6) guidelines

Memory B-cell reconstitution following allogeneic hematopoietic stem cell transplantation is an EBV-associated transformation event

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