Pre-emptive therapy with rituximab for prevention of Epstein–Barr virus-associated lymphoproliferative disease after hematopoietic stem cell transplantation

Gruhn, Bernd; Meerbach, Astrid; Häfer, Ralf; Zell, Roland; Wutzler, Peter; Zintl, F

doi:10.1038/sj.bmt.1704061

Cited by 53 publications

(38 citation statements)

References 12 publications

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“…23,26 Rituximab has also been used as therapy for EBV reactivation and posttransplantation lymphoproliferative disease. [27][28][29][30][31][32][33][34] In our study, responses were noted in patients with cutaneous and musculoskeletal disease, a finding that has previously been reported. 14,16,17 Although it is possible that other involved organs (such as the eyes and oral mucosa) did not respond because of the destruction of target tissues (such as the lacrimal and salivary glands), or because our clinical measurement tools were inadequate to detect improvement, it is notable that rituximab is now being used successfully in autoimmune conditions resembling cutaneous and musculoskeletal chronic GVHD.…”

Section: Discussionsupporting

confidence: 66%

Rituximab for steroid-refractory chronic graft-versus-host disease

Cutler

Miklos

Kim

et al. 2006

Blood

401

291

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B cells may be implicated in the pathophysiology of chronic graft-versus-host disease (GVHD), as evidenced by antibody production against sex-mismatched, Y chromosome-encoded minor HLA antigens in association with chronic GVHD. We therefore designed a phase 1/2 study of anti-B-cell therapy with rituximab in steroid-refractory chronic GVHD. Twentyone patients were treated with 38 cycles of rituximab. Rituximab was tolerated well, and toxicity was limited to infectious events. The clinical response rate was 70%, including 2 patients with complete responses. Responses were limited to patients with cutaneous and musculoskeletal manifestations of chronic GVHD and were durable through 1 year after therapy. The median dose of prednisone among treated subjects fell from 40 mg/day to 10 mg/day, 1 year after rituximab therapy (P < .001). A chronic GVHD symptom score improved in the majority of treated patients. Antibody titers against Y chromosome-encoded minor HLA antigens fell and remained low, whereas titers against infectious antigens (EBV, tetanus) remained stable or rose during the treatment period. We conclude that specific anti-B-cell therapy with rituximab may be beneficial for patients with steroidrefractory chronic GVHD. This trial was registered at www.clinicaltrials.gov as #NCT00136396. (Blood. 2006;108:756-762)

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Section: Discussionsupporting

confidence: 66%

Rituximab for steroid-refractory chronic graft-versus-host disease

Cutler

Miklos

Kim

et al. 2006

Blood

401

291

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“…The administration of rituximab induced a dramatic decrease of EBV-genome copies in peripheral blood mononuclear cells and plasma and effective depletion of B lymphocytes [Gruhn et al, 2003]. Rituximab was given to four patients of the presented study in combination with the antiviral agent cidofovir.…”

Section: Cut-offmentioning

confidence: 90%

“…Regarding the therapeutic measures for prevention of EBV lymphoproliferative di- [2002] and confirmed by Gruhn et al [2003] and Dominietto et al [2004]. The administration of rituximab induced a dramatic decrease of EBV-genome copies in peripheral blood mononuclear cells and plasma and effective depletion of B lymphocytes [Gruhn et al, 2003].…”

Section: Cut-offmentioning

confidence: 94%

Monitoring of Epstein‐Barr virus load after hematopoietic stem cell transplantation for early intervention in post‐transplant lymphoproliferative disease

Meerbach

Wutzler

Häfer

et al. 2008

Journal of Medical Virology

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Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disease is a lifethreatening complication following hematopoietic stem cell transplantation. A quantitative polymerase chain reaction to evaluate EBV-genome copy numbers based on a nested polymerase chain reaction and an end-point dilution was used. Applying this assay EBV load was prospectively screened weekly in 123 patients after transplantation. The results demonstrate that EBV reactivations with more than 1,000 EBV-genome copies measured in 10(5) peripheral blood mononuclear cells were observed in 31 patients (25.2%). Three patients developed lymphoproliferative disease with extremely high EBV-genome copies in peripheral blood mononuclear cells (>100,000 copies/10(5) cells) and plasma. After combined antiviral and immune therapy two of three patients showed a dramatic decrease of EBV load and survived, while the third patient died of lymphoma. A subclinical EBV reactivation was observed in 24 cases (19.5%) with EBV-genome copies in 10(5) peripheral blood mononuclear cells ranging between 2,500 and mostly 10,000. After reduction of immunosuppression the EBV levels normalized. In four patients, the high copy number of > or =80,000 copies/10(5) peripheral blood mononuclear cells and plasma positivity prompted us to start pre-emptive therapy with rituximab and cidofovir for prevention of lymphoproliferative disease. After drug administration the high EBV load was reduced remarkably. Ninety-two patients (74.8%) who had < or =1,000 copies/10(5) peripheral blood mononuclear cells did not develop EBV-associated lymphoproliferative disease. In conclusion, monitoring of EBV load is a sensitive and useful parameter in the surveillance of EBV reactivation for early intervention in EBV-associated lymphoproliferative disease as well as for follow-up of the efficacy of therapy. Applying this assay EBV load was prospectively screened weekly in 123 patients after transplantation. The results demonstrate that EBV reactivations with more than

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“…Four additional studies have described patients with elevated viral loads who were treated with preemptive donor leukocytes, CTLs and/or rituximab. 17,[36][37][38] The small number of patients in these studies and the absence of a randomized comparison preclude any definitive statement about the efficacy of PCR screening and preemptive rituximab. Nevertheless, preemptive rituximab is becoming a common approach at some transplant centers.…”

Section: Studies Outlining Preemptive Treatment Based On Pcr Screeningmentioning

confidence: 99%

Preemptive diagnosis and treatment of Epstein–Barr virus-associated post transplant lymphoproliferative disorder after hematopoietic stem cell transplant: an approach in development

Weinstock

Ambrossi

Brennan

et al. 2006

Bone Marrow Transplant

103

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Hematopoietic stem cell transplant (HSCT) recipients are at risk for Epstein-Barr virus (EBV)-associated, post transplant lymphoproliferative disorder (PTLD). Studies have suggested that early treatment may improve the outcome of patients with PTLD. Thus, significant attention has been focused on PCR-based approaches for preemptive (i.e., prior to clinical presentation) diagnosis. Reports from several transplant centers have demonstrated that HSCT recipients with PTLD generally have higher concentrations of EBV DNA in the peripheral blood than patients without PTLD. However, the PCR values of patients with PTLD typically span multiple orders of magnitude and overlap significantly with values from patients without PTLD. Thus, questions remain about the sensitivity and predictive value of these assays. Preemptive strategies using rituximab and/or EBVspecific cytotoxic T lymphocytes have been evaluated in patients with elevated EBV viral loads. We review the current literature, discuss our institutional experience and identify several areas of future research that could improve the diagnosis and treatment of this life-threatening disorder in HSCT recipients. Bone Marrow Transplantation ( EBV is associated with a spectrum of clinical presentations in hematopoietic stem cell transplant (HSCT) recipients, from fever to post transplant lymphoproliferative disorder (PTLD), which arise from the outgrowth of latently infected B cells in the absence of competent immune surveillance by cytotoxic T cells. PTLDs are extremely heterogeneous, ranging from polyclonal hyperplasia to aggressive, non-Hodgkin's lymphoma. 1-3 Thus, PTLD can present with a diverse spectrum of clinical symptoms and signs, most notably a sepsis-like syndrome with rapidly progressive lymphoma or a mononucleosis-like illness with fever, enlarged tonsils and/or cervical lymphadenopathy. PTLD may involve virtually any organ system, including the central nervous system, bone marrow, intestine and lungs. The overall frequency of PTLD after allogeneic HSCT is approximately 1%. The highest incidence occurs in the first 6 months after transplant, and the vast majority of cases develop during the first year. 4 Risk factors for PTLDMultiple published studies 4-10 have identified predisposing factors for PTLD, including in vivo and in vitro T-cell depletion. In a survey of 235 transplant centers, 4 the risk factors for PTLD in the first year after transplant included: (1) unrelated or HLA-mismatched donors (relative risk (RR) ¼ 4.1), (2) T-cell depletion (RR ¼ 12.7) and (3) the use of antithymocyte globulin (ATG) (RR ¼ 6.4) or anti-CD3 monoclonal antibodies (RR ¼ 43.2) for the prophylaxis or treatment of graft rejection and/or graft-versus-host disease (GVHD). PTLD occurred in 8% of HSCT recipients with two risk factors and 22% of recipients with three risk factors. For patients more than 1 year after HSCT, the only factor associated with PTLD was chronic GVHD (RR ¼ 4).Consistent with the essential role of T cells in controlling the proliferation of latent EBV-inf...

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Pre-emptive therapy with rituximab for prevention of Epstein–Barr virus-associated lymphoproliferative disease after hematopoietic stem cell transplantation

Cited by 53 publications

References 12 publications

Rituximab for steroid-refractory chronic graft-versus-host disease

Rituximab for steroid-refractory chronic graft-versus-host disease

Monitoring of Epstein‐Barr virus load after hematopoietic stem cell transplantation for early intervention in post‐transplant lymphoproliferative disease

Preemptive diagnosis and treatment of Epstein–Barr virus-associated post transplant lymphoproliferative disorder after hematopoietic stem cell transplant: an approach in development

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