Rituximab Treatment for Epstein-Barr Virus DNAemia after Alternative-Donor Hematopoietic Stem Cell Transplantation

EBV-associated post-transplant lymphoproliferative disease (PTLD) following Alemtuzumab-based allo-SCT is a relatively uncommon and challenging clinical problem but has not received detailed study in a large cohort. Quantitative-PCR (qPCR) monitoring for EBV reactivation post allo-SCT is now commonplace but its diagnostic and predictive value remains unclear. Sixtynine patients with PTLD following Alemtuzumab-based allo-SCT were studied. Marked clinicopathological heterogeneity was evident; lymphadenopathy was frequently absent, whereas advanced extranodal disease was common. The median viral load at clinical presentation was 49 300 copies/mL (50-65 200 000 copies/mL) and, notably, 23% and 45% of cases, respectively, had p10 000 and p40 000 copies/mL. The overall response rate to rituximab as first-line therapy was 70%. For rituximab failures, chemotherapy was ineffectual but DLIs were successful. A four-parameter prognostic index predicted response to therapy (OR 0.30 (0.12-0.74); P ¼ 0.009] and PTLD mortality (hazard ratio (HR) 1.81 (1.12-2.93) P ¼ 0.02) on multivariate analysis. This is the largest detailed series of EBV-associated PTLD after allo-SCT. At clinical presentation, EBV-qPCR values are frequently below customary thresholds for pre-emptive therapy, challenging current paradigms for monitoring and intervention. A four-point score identifies a proportion of patients at risk of rituximab-refractory disease for whom alternative therapy is needed.

Section: Introductionmentioning

confidence: 99%

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

Burns

Parker

et al. 2013

“…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.…”

Section: Introductionmentioning

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

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.

“…Use of rituximab to reduce CD20 þ cells forms a second pillar and appears most effective when employed early. 9 However, combination immune-chemotherapy may be required to treat monomorphic PTLD. 10,11 Novel approaches have been designed to enhance the T-cell reactivity, and include the use of DLI and EBV-specific cytotoxic T cells.…”

Section: Introductionmentioning

confidence: 99%

“…Early detection of infection is important as it allows prompt reduction of immune-suppressive treatment and rituximab to be given pre-emptively, and this approach is increasingly being advocated in guidelines for managing high-risk SCT recipients. 9,13,14 A cut-off value for PCR of 1000 copies per mL is thought to be predictive of the development of EBV disease. 15,16 Several studies have shown that EBV monitoring and early treatment is feasible, and can prevent EBV disease.…”

Section: Introductionmentioning

confidence: 99%

Reduced PTLD-related mortality in patients experiencing EBV infection following allo-SCT after the introduction of a protocol incorporating pre-emptive rituximab

Velden

Mori

Stevens

et al. 2013

The mortality associated with post-transplant lymphoproliferative disorder (PTLD) induced by EBV infection can be reduced by monitoring EBV by polymerase-chain-reaction and rituximab given pre-emptively. We performed a retrospective analysis of the risk factors for the occurrence of EBV infection/disease and EBV-related mortality among 273 consecutive recipients of a T-cell-depleted allo-SCT during two periods: (a) before the implementation of a comprehensive protocol (2006)(2007)(2008) and (b) afterwards (2009)(2010)(2011). EBV infection was detected in 61 (22%) cases, and 28 cases were considered to have had EBV disease. Treatment with antithymocyte globulin was the most important risk factor (odds ratio (OR) 2.4; 95% confidence interval (CI) 1.3-4.2, P ¼ 0.001). After implementation of the protocol, in patients experiencing EBV infection, pre-emptive therapy was started more often and sooner (median 3 vs 6 days, P ¼ 0.002). Moreover, there were fewer cases of monomorphic PTLD (4/33 (12%) vs 11/28 (39%), P ¼ 0.01), and the EBV-related mortality was lower for patients experiencing EBV infection (2/33 (6%) vs 8/28 (29%), OR 0.2; 95% CI 0.05-0.9, P ¼ 0.03). The EBV protocol proved feasible and resulted in faster initiation of pre-emptive therapy, the diagnosis in an earlier stage of EBV disease, and decreased EBV-related mortality.