Targeted monitoring of patients at high risk of post‐transplant lymphoproliferative disease by quantitative Epstein–Barr virus polymerase chain reaction

The largest study on post-allogeneic hematopoietic cell transplant lymphoproliferative disorder (PTLD) epidemiology showed a cumulative incidence of 1.7% in patients receiving antithymocyte globulin (ATG). We had noted an apparently higher incidence in our transplant recipients whose conditioning included ATG. Therefore, we formally determined the incidence of PTLD through chart review. We also evaluated whether counts of EBV-specific T lymphocytes measured by cytokine flow cytometry could identify patients at risk of developing PTLD. Among 307 allogeneic transplant recipients, 25 (8.1%) developed PTLD. This was biopsy proven in 11 patients, and was fatal in seven patients. Patient age, EBV serostatus, donor type/match or GVHD did not influence PTLD risk significantly. Median onset of PTLD was 55 (range, 28-770) days post transplant. Day 28 EBV-specific T lymphocyte counts were not significantly different in 11 patients who developed PTLD and 31 non-PTLD patients matched for published risk factors for PTLD. In summary, when using conditioning with thymoglobulin 4.5 mg/kg, the incidence of PTLD is relatively high and cannot be predicted by day 28 cytokine flow cytometry-determined EBV-specific T lymphocyte counts. Thus, in this scenario PTLD prevention may be warranted, for example, using EBV DNAemia monitoring with preemptive therapy.

Section: Discussionmentioning

confidence: 99%

High incidence of post transplant lymphoproliferative disorder after antithymocyte globulin-based conditioning and ineffective prediction by day 28 EBV-specific T lymphocyte counts

Hoegh-Petersen

Goodyear

Geddes

et al. 2010

“…We were struck by the vast variation in peripheral blood EBV load at the time of PTLD presentation; ranging over a sevenfold log 10 scale. However, viral load at symptomatic presentation of SCT-PTLD was frequently below conventionally adopted thresholds; 16,[18][19][20][21]27 p40 000 copies/mL and p10 000 copies/mL in 45% and 23% of cases, respectively. It follows that reliance on a viral load threshold per se to predict SCT-PTLD jeopardises timely diagnoses.…”

Section: Survivalmentioning

confidence: 99%

“…[16][17][18] Furthermore, 'pre-emptive' treatment strategies in response to EBV DNAemia, with or without accompanying clinical evidence of EBV-associated disease, have been widely incorporated into clinical practice. 14,16,[18][19][20][21] However, this has been predominantly based on uncontrolled, single-centre studies encompassing heterogeneous methods of T-cell depletion and small numbers of PTLD events.…”

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

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.

“…The presence of rising EBV copy numbers in the peripheral blood of HCT recipients was reported to be associated with the manifestation of EBV-PTLD later on, particularly when having failed to initiate pre-emptive treatment immediately. 9,10 Whether serological determination of previous EBV encounters in donor and recipient is of predictive value for later EBV-PTLD development is not yet clear. Nevertheless, the presence of an EBV sero-mismatch between donor and recipient has been described to increase the risk of EBV-PTLD after HCT.…”

Section: Introductionmentioning

confidence: 99%

EBV-induced post transplant lymphoproliferative disorders: a persisting challenge in allogeneic hematopoetic SCT

Rasche

Kapp

Einsele

et al. 2013

118

EBV-induced post transplantation lymphoproliferative disorder (EBV-PTLD) is a life-threatening complication after allogeneic hematopoietic cell transplantation. Profound T-cell depletion of the allograft represents a major risk factor for EBV-PTLD. With regard to the increasing use of alternative stem cell sources such as cord blood or purified haploidentical stem cell grafts both associated with impaired immune reconstitution, the frequent occurrence of EBV-PTLD demands particular vigilance on laboratory changes and early symptoms. Here we have summarized today's knowledge about EBV-PTLD in a comprehensive review explaining the underlying mechanisms of EBV-based transformation, EBV-PTLD development, clinical presentation, incidence, diagnosis, screening, therapy and prognosis. In this context, we emphasize on the necessity of regularly applied screening tools and pre-emptive treatment strategies including anti-CD20 Abs particularly in high-risk patients to avoid disease progression to malignant lymphoma. Although EBV-PTLD has always been associated with a high mortality rate, novel immunotherapeutic approaches such as the transfer of EBV-specific T cells nowadays offer improved chances of disease control even at late stages.