Reduction in immunosuppression is an effective initial therapy for PTLD. Clinical prognostic factors may allow clinicians to identify which patients are likely to respond to reduction in immunosuppression.

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Summary:Post-transplant lymphoproliferative disorder (PTLD) represents a spectrum of Epstein-Barr virus-related (EBV) clinical diseases, from a benign mononucleosis-like illness to a fulminant non-Hodgkin's lymphoma. In the setting of hematopoietic stem cell transplantation, PTLD is an often-fatal complication occurring relatively early after transplant. Risk factors for the development of PTLD are well established, and include HLA-mismatching, T-cell depletion, and the use of antilymphocyte antibodies as conditioning or treatment of graft-versushost disease. Early recognition of PTLD is particularly important in the SCT setting, because PTLD in these patients tends to be rapidly progressive. Familiarity with the clinical features of PTLD and a heightened level of suspicion are critical for making the diagnosis. Surveillance techniques with EBV antibody titers and/or polymerase chain raction (PCR) may have a role in some highrisk settings. Immune-based therapies such as monoclonal anti-B-cell antibodies, interferon-a, and EBV-specific donor T cells, either as treatment for PTLD or as prophylaxis in high-risk patients, represent promising new directions in the treatment of this disease.

Information regarding treatment of post-transplant lymphoproliferative disease (PTLD) beyond reduction in immunosuppression (RI) is limited. We retrospectively evaluated patients receiving rituximab and/or chemotherapy for PTLD for response, time to treatment failure (TTF) and overall survival (OS). Thirtyfive patients met inclusion criteria. Twenty-two underwent rituximab treatment, with overall response rate (ORR) 68%. Median TTF was not reached at 19 months and estimated OS was 31 months. In univariable analysis, Epstein-Barr virus (EBV) positivity predicted response and TTF. LDH elevation predicted shorter OS. No patient died of rituximab toxicity and all patients who progressed underwent further treatment with chemotherapy. Twenty-three patients received chemotherapy. ORR was 74%, median TTF was 10.5 months and estimated OS was 42 months. Prognostic factors for response included stage, LDH and allograft involvement by tumor. These factors and lack of complete response (CR) predicted poor survival. Twentysix percent of the patients receiving chemotherapy died of toxicity. Rituximab and chemotherapy are effective in patients with PTLD who fail or do not tolerate RI. While rituximab is well tolerated, toxicity of chemotherapy is marked. PTLD patients requiring therapy beyond RI should be considered for rituximab, especially with EBV-positive disease. Chemotherapy should be reserved for patients who fail rituximab, have EBV-negative tumors or need a rapid response.

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We examined the associations of Epstein-Barr virus (EBV) status with characteristics and outcomes of post-transplantation lymphoproliferative disorder (PTLD) by studying 176 adult solid organ transplant recipients diagnosed with PTLD between 1990 and 2013 [58 (33%) EBV-negative; 118 (67%) EBV-positive]. The proportion of EBV-negative cases increased over time from 10% (1990–1995) to 48% (2008–2013) (P<.001). EBV-negative PTLD had distinct characteristics (monomorphic histology, longer latency) though high-risk features (advanced stage, older age, high lactate dehydrogenase, central nervous system involvement) were not more common compared to EBV-positive PTLD. In multivariable analysis, EBV negativity was not significantly associated with worse response to initial therapy (adjusted odds ratio, 0.84; P=.75). The likelihood of achieving a complete remission (CR) was not significantly different for EBV-negative versus EBV-positive PTLD including when therapy was reduction of immunosuppression alone (35% vs 43% respectively, P= .60) or rituximab (43% vs 47%, P=1.0). EBV negativity was also not associated with worse overall survival (adjusted hazard ratio, 0.91; P=.71). Our findings indicate that EBV status is not prognostic or predictive of treatment response in adults with PTLD. The high proportion of EBV-negative disease diagnosed in recent years highlights the need for new strategies for prevention and management of EBV-negative PTLD.

While EBV PCR is used in the management of PTLD, the optimal primer set, relative importance of intracellular versus free plasma EBV, and the baseline profile in an organ transplant population remains unclear. We performed a prospective 2-arm trial utilizing an EBV PCR panel measuring LMP-1, EBER-1 and EBNA-1 in both free plasma as well as intracellular whole blood. Control Arm A consisted of 31 lung transplant patients and Arm B consisted of 35 transplant patients being evaluated for possible PTLD. In Arm A, 1/31 (3%) patients developed a transient plasma EBV load. Thirteen of 31 (42%) had detectable intracellular EBV. In Arm B, 17 (49%) patients were diagnosed with PTLD. Thirteen (76%) had EBV-positive PTLD with 12/13 (92%) having detectable EBV by PCR. The EBV PCR panel had a high sensitivity (92%), specificity (72%), positive predictive value (PPV) (71%) and negative predictive value (NPV) (93%) for diagnosing EBV-positive PTLD and followed patients' clinical course well (p < 0.001). Comparing the individual PCR assays, plasma EBNA PCR was superior with high sensitivity (77%), specificity (100%), PPV (100%) and NPV (86%). We conclude that EBV PCR is a useful test for managing PTLD patients. While plasma EBNA PCR is the best single assay for diagnos- ing and monitoring PTLD, the complete PCR panel is superior for ruling out its presence.

The U1snRNP-A (U1-A) protein was used to select specific RNA sequences from a degenerate pool of transcripts using direct RNA binding and polymerase chain reaction amplification (PCR). Sequences were randomized in loops of 10 or 13 nucleotides or as a linear stretch of 25 nucleotides. From all three structural contexts, an unpaired ten nucleotide consensus sequence was obtained. A selected stem-loop structure that resembled the natural U1-A protein binding site on loop II of U1 RNA demonstrated the highest affinity of binding in comparison with the other structural contexts. A data profile of selected sequences identified U1 RNA upon searching the GenBank database. Thus, this method was useful in determining the sequence specificity of an RNA binding protein and may complement the use of phylogenetic comparisons to predict conserved recognition elements. These findings also suggest that the evolutionary conservation of loop II of U1 RNA results from constraints imposed by protein binding.