Post transplant lymphoproliferative disorder (PTLD) is a heterogeneous disease that may occur in recipients of solid organ transplants (SOT) and hematopoietic stem cell transplant. The risk of lymphoma is increased 20-120% compared with the general population with risk dependent in part on level of immune suppression. In addition, recent data have emerged, including HLA and cytokine gene polymorphisms, regarding genetic susceptibility to PTLD. Based on morphologic, immunophenotypic, and molecular criteria, PLTD are classified into 4 pathologic categories: early lesions, polymorphic, monomorphic, and classical Hodgkin lymphoma. Evaluation by expert hematopathology is critical in establishing the diagnosis. The aim of therapy for most patients is cure with the concurrent goal of preservation of allograft function. Given the pathologic and clinical heterogeneity of PTLD, treatment is often individualized. A mainstay of therapy remains reduction of immune suppression (RI) with the level of reduction being dependent on several factors (e.g., history of rejection, current dosing, and type of allograft). Outside of early lesions and/or low tumor burden, however, RI alone is associated with cure in a minority of subjects. We approach most newly-diagnosed polymorphic and monomorphic PTLDs similarly using frontline single-agent rituximab (4 weeks followed by abbreviated maintenance) in conjunction with RI. Frontline combination chemotherapy may be warranted for patients with high tumor burden in need of prompt response or following failure of RI and/or rituximab. Due to chemotherapy-related complications in PTLD, especially infectious, we advocate comprehensive supportive care measures. Surgery or radiation may be considered for select patients with early-stage disease. For PTLD subjects with primary CNS lymphoma, we utilize therapeutic paradigms similar to immunocompetent CNS lymphoma using high-dose methotrexate-based therapy with concurrent rituximab therapy and sequential high-dose cytarabine. Finally, novel therapeutic strategies, especially adoptive immunotherapy, should continued to be explored.

SUMMARY Background MYC gene rearrangement (MYC-R) is present in approximately 10% of aggressive B-cell lymphomas with approximately half harboring a BCL2 gene rearrangement (BCL2-R). Multiple retrospective studies of R-CHOP show an inferior outcome in patients with MYC-R, both alone and with BCL2-R and/or BCL6-R, and suggest better outcomes with more aggressive treatment. In the current study, we aimed to determine the outcome of DA-EPOCH-R, an aggressive infusional treatment regimen, in untreated MYC-R aggressive B-cell lymphomas. Methods Final analysis of a prospective multi-center study of DA-EPOCH-R (dose-adjusted treatment: etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituxiomab) in 53 patients with untreated MYC-R aggressive B-cell lymphomas. DAEPOCH-R was scheduled to be administered with central nervous system prophylaxis for 6 cycles. Primary endpoints included event-free and overall survival. The study was registered at ClinicalTrials.gov (NCT01092182). Findings Patient characteristics included median age 61 (range 29–80) years, stage III/IV disease in 43 (81%), and high-intermediate/high international prognostic score (IPI) in 26 (49%) patients. Characteristics were similar among patients with confirmed MYC-R single-hit (n=19) versus those with a BCL2-R and/or BCL6-R, termed double-hit, (n=24) lymphomas. With a median follow up of 55.6 (Interquartile range: 50.5–61.1) months, the 48-month EFS and OS for all patients was 71% and 77%, respectively, with no differences among patients with single versus double-hit tumors or age < versus ≥ 60 years. The EFS at 48-months for low/low-intermediate (0–2) versus high-intermediate/high (3–5) IPI was 89% versus 50%, respectively, for all patients, and 92% versus 55% for double-hit patients. Toxicity included grade 4 neutropenia and thrombocytopenia on 53% and 13% of cycles, respectively, and fever with neutropenia occurred on 19% of cycles. There were 3 treatment related deaths. Interpretation In this study, DA-EPOCH-R produced durable remissions in MYC-R aggressive B-cell lymphomas and should be considered for the treatment of these diseases. Funding Cancer Trials Support Unit and Center for Cancer Research, National Cancer Institute, USA, and Genentech Inc.

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PURPOSE Burkitt lymphoma is an aggressive B-cell lymphoma curable with dose-intensive chemotherapy derived from pediatric leukemia regimens. Treatment is acutely toxic with late sequelae. We hypothesized that dose-adjusted etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and rituximab (DA-EPOCH-R) may obviate the need for highly dose-intensive chemotherapy in adults with Burkitt lymphoma. METHODS We conducted a multicenter risk-adapted study of DA-EPOCH-R in untreated adult Burkitt lymphoma. Low-risk patients received three cycles without CNS prophylaxis, and high-risk patients received six cycles with intrathecal CNS prophylaxis or extended intrathecal treatment if leptomeninges were involved. The primary endpoint was event-free survival (EFS), and secondary endpoints were toxicity and predictors of EFS and overall survival (OS). RESULTS Between 2010 and 2017, 113 patients were enrolled across 22 centers, and 98 (87%) were high risk. The median age was 49 (range, 18-86) years, and 62% were ≥ 40 years. Bone marrow and/or CSF was involved in 29 (26%) of patients, and 28 (25%) were HIV positive. At a median follow-up of 58.7 months, EFS and OS were 84.5% and 87.0%, respectively, and EFS was 100% and 82.1% in low- and high-risk patients. Therapy was equally effective across age groups, HIV status, and International Prognostic Index risk groups. Involvement of the CSF identified the group at greatest risk for early toxicity-related death or treatment failure. Five treatment-related deaths (4%) occurred during therapy. Febrile neutropenia occurred in 16% of cycles, and tumor lysis syndrome was rare. CONCLUSION Risk-adapted DA-EPOCH-R therapy is effective in adult Burkitt lymphoma regardless of age or HIV status and was well tolerated. Improved therapeutic strategies for adults with CSF involvement are needed (funded by the National Cancer Institute; ClinicalTrials.gov identifier: NCT01092182 ).

We performed a multicenter, International analysis of solid organ transplant (SOT)-related primary central nervous system (PCNS) posttransplant lymphoproli-ferative disease (PTLD). Among 84 PCNS PTLD patients, median time of SOT-to-PTLD was 54 months, 79% had kidney SOT, histology was monomorphic in 83% and tumor was EBVþ in 94%. Further, 33% had deep brain involvement, 10% had CSF involvement, while none had ocular disease. Immunosuppression was reduced in 93%; additional first-line therapy included high-dose methotrexate (48%), high-dose cytarabine (33%), brain radiation (24%) and/or ritux-imab (44%). The overall response rate was 60%, while treatment-related mortality was 13%. With 42-month median follow-up, three-year progression-free survival (PFS) and overall survival (OS) were 32% and 43%, respectively. There was a trend on univariable analysis for improved PFS for patients who received rituximab and/or high-dose cytarabine. On multivariable Cox regression, poor performance status predicted inferior PFS (HR 2.61, 95% CI 1.32-5.17, p ¼ 0.006), while increased LDH portended inferior OS (HR 4.16, 95% CI 1.29-13.46, p ¼ 0.02). Moreover, lack of response to first-line therapy was the most dominant prognostic factor on multivariable analysis (HR 8.70, 95% CI 2.56-29.57, p ¼ 0.0005). Altogether, PCNS PTLD appears to represent a distinct clinicopathologic entity within the PTLD spectrum that is associated with renal SOT, occurs late, is monomorphic and retains EBV positivity.