First‐line use of rituximab correlates with increased overall survival in late post‐transplant lymphoproliferative disorders: retrospective,single‐centre study

This retrospective study evaluates the impact of rituximab on PTLD response and survival in a single‐centre cohort. PTLD cases between 1984 and 2009, including heart, kidney, liver and lung transplant recipients, were included. Survival was analysed taking into account the type of PTLD (monomorphic vs. polymorphic), EBV infection status, IPI score, Ann Arbor stage and use of rituximab. Among 1335 transplanted patients, 24 developed PTLD. Median age was 54 yr (range 29–69), median time to diagnosis 50 months (range 0–100). PTLD type was predominantly late/monomorphic (79% and 75%), mostly diffuse large B‐cell type. Overall response rate (ORR) was 62% (66% rituximab vs. 50% non‐rituximab; P = 0.5). R‐CHOP‐like regimens were used most frequently (72% of patients treated with rituximab). Median overall survival was 64 months (CI 95% 31–96). OS was significantly increased in patients treated with rituximab (P = 0.01; CI 95% rituximab 58–79 months; non‐rituximab 1–30 months). Post‐transplant immunosuppression regimen had no effect on survival or time to PTLD, except for cyclosporine A (CyA), which associated with increased time to PTLD (P = 0.02). Rituximab was associated with increased survival in our single‐centre series, and it should be considered as first‐line therapy for PTLD patients. The possible protective effect of CyA for development of PTLD should be prospectively evaluated.     

Management of post‐transplant lymphoproliferative disorders

The post‐transplant lymphoproliferative disorders (PTLDs) are a heterogeneous group of neoplasms that are one of the most serious complications of bone marrow and solid organ transplants. Because these disorders are rare, there are no randomized trials from which to derive optimal treatment. Management can be challenging and must balance the goal of PTLD eradication with the risks of graft rejection, graft‐versus‐host disease, further delays in immune reconstitution and life‐threatening infections, among others. This paper will provide a comprehensive review of PTLD following solid organ transplant and haematopoietic stem cell transplant with a focus on management. Included is a discussion of novel agents that are being studied in clinical trials and, when combined or sequenced with conventional therapy, have the potential to improve outcomes.     

Mutational landscape of B‐cell post‐transplant lymphoproliferative disorders

It is currently unclear whether post‐transplant diffuse large B‐cell lymphomas (PT‐DLBCL) display a similar genomic landscape as DLBCL in immunocompetent patients (IC‐DLBCL). We investigated 50 post‐transplant lymphoproliferative disorders (PTLDs) including 37 PT‐DLBCL samples for somatic mutations frequently observed in IC‐DLBCL. Targeted Next Generation Sequencing (NGS) using the Ion Torrent platform and a customized panel of 68 genes was performed on genomic DNA. Non‐tumoural tissue was sequenced to exclude germline variants in cases where available. A control cohort of 76 IC‐DLBCL was available for comparative analyses. In comparison to IC‐DLBCLs, PT‐DLBCL showed more frequent mutations of TP53 (P = 0·004), and absence of ATM and B2M mutations (P = 0·004 and P = 0·016, respectively). In comparison to IC‐DLBCLs, Epstein–Barr virus (EBV)⁺ PT‐DLBCL had fewer mutated genes (P = 0·007) and particularly fewer mutations in nuclear factor‐κB pathway‐related genes (P = 0·044). TP53 mutations were more frequent in EBV^‐ PT‐DLBCL as compared to IC‐DLBCL (P = 0·001). Germinal centre B cell (GCB) subtype of PT‐DLBCL had fewer mutations and mutated genes than GCB‐IC‐DLBCLs (P = 0·048 and 0·04 respectively). Polymorphic PTLD displayed fewer mutations as compared to PT‐DLBCL (P = 0·001). PT‐DLBCL differs from IC‐DLBCL with respect to mutations in genes related to DNA damage control and immune‐surveillance, and EBV association is likely to have a bearing on the mutational pattern.     

Nivolumab maintenance after salvage autologous stem cell transplantation results in long‐term remission in multiple relapsed primary CNS lymphoma

Recurrence of primary central nervous system lymphoma (PCNSL) after high‐dose chemotherapy with autologous stem cell transplantation (ASCT) usually has a poor overall prognosis with limited treatment options. Data on repeated ASCT are sparse. Checkpoint inhibitor maintenance therapy has also not been reported in PCNSL. Here, we report the first documented case of a successful third ASCT in second relapse of PCNSL. Whole‐exome sequencing identified a hypermutated tumor genotype. Additionally, immunohistochemistry on pretreatment tumor tissue revealed infiltrates of PD‐1⁺ cytolytic T cells. These alterations provided a rationale for subsequent nivolumab maintenance treatment. Therapy led to a long‐term, ongoing complete remission. In eligible patients with recurrent MTX‐sensitive PCNSL, multiple long‐term remissions can be induced by repetition of high‐dose MTX‐based chemotherapy followed by autologous retransplantation. Subsequent immune checkpoint inhibitor maintenance therapy might be able to prolong or maintain remission.     

Flow cytometry in the diagnosis of mature B‐cell lymphoproliferative disorders

B‐lineage lymphoproliferative disorders (LPD) are rather frequent diseases, associated with specific clinical or biological features but also sometimes of fortuitous discovery. Multiparameter flow cytometry plays a major role for a rapid diagnostic indication, on peripheral blood or bone marrow samples in most instances, guiding complementary analyses and allowing for the proper therapeutic management of patients. After describing the important pre‐analytical precautions required for an adequate assessment, the immunophenotypic features of small‐cell and large‐cell lymphomas are described in this review. The ubiquitous expression of CD19 is a first mandatory gating step. A possible clonal proliferation is then suspected by the demonstration of surface immunoglobulin light chain restriction. The aberrant presence of CD5 allows to segregate chronic lymphocytic leukemia and mantle cell lymphoma in most cases. Other LPD exhibit specific immunophenotypic features. A table of useful markers and a decision tree are provided. Of note, immunophenotypic data should as much as possible be interpreted in an integrated manner, involving the patient's clinical and other biological features, and be completed by further chromosomal and/or molecular investigations.     

Guidelines for the management of diffuse large B‐cell lymphoma

Richter syndrome (RS) is associated with chemotherapy resistance and a poor historical median overall survival (OS) of 8–10 months. We conducted a phase II trial of standard CHOP‐21 (cyclophosphamide, doxorubicin, vincristine, prednisolone every 21 d) with ofatumumab induction (Cycle 1: 300 mg day 1, 1000 mg day 8, 1000 mg day 15; Cycles 2–6: 1000 mg day 1) (CHOP‐O) followed by 12 months ofatumumab maintenance (1000 mg given 8‐weekly for up to six cycles). Forty‐three patients were recruited of whom 37 were evaluable. Seventy‐three per cent were aged >60 years. Over half of the patients received a fludarabine and cyclophosphamide‐based regimen as prior CLL treatment. The overall response rate was 46% (complete response 27%, partial response 19%) at six cycles. The median progression‐free survival was 6·2 months (95% confidence interval [CI] 4·9–14·0 months) and median OS was 11·4 months (95% CI 6·4–25·6 months). Treatment‐naïve and TP53‐intact patients had improved outcomes. Fifteen episodes of neutropenic fever and 46 non‐neutropenic infections were observed. There were no treatment‐related deaths. Seven patients received platinum‐containing salvage at progression, with only one patient obtaining an adequate response to proceed to allogeneic transplantation. CHOP‐O with ofatumumab maintenance provides minimal benefit beyond CHOP plus rutuximab. Standard immunochemotherapy for RS remains wholly inadequate for unselected RS. Multinational trials incorporating novel agents are urgently needed.     

Epstein‐Barr virus associated post‐transplant lymphoproliferative disorder mimicking acute graft versus host disease

We present a case series of 3 patients to highlight the fact that PTLD post‐transplant can mimic GVHD, and should be part of the differential diagnosis for diarrhea post allo‐HCT. Awareness of this presentation has important therapeutic implications, as increased immune suppression for the management of GVHD, can worsen clinical features of PTLD. Diagnostic imaging and tissue biopsies should be undertaken early in post‐transplant patients presenting with diarrhea or hepatic abnormalities, especially with atypical presentations like fever, and EBV PCR monitoring can expedite clinical decision‐making in such complicated scenarios while awaiting results of gut biopsies.     

Severe post‐transplant lymphoproliferative disorder after living donor liver transplantation

Post‐transplant lymphoproliferative disorder (PTLD) is a well‐known complication after transplantation. A living donor liver transplantation was performed on a 31‐year‐old man for fulminant hepatitis. He again developed liver dysfunction after 7 months. He was diagnosed as having acute cellular rejection and the steroid pulse therapy introduced resulted in little improvement. He gradually developed a high fever and right axillary lymphadenopathy appeared. Chest computed tomography (CT) was performed revealing small lung nodules and axillary lymphadenopathy. Because his serological status for Epstein–Barr virus was positive, PTLD was highly suspected and immunosuppression treatment was withdrawn with little improvement. One week later, he developed tachycardia. Chest CT was re‐performed revealing an infiltration to the left cardiac chamber. For diagnosis, axillary lymph node biopsy was performed and during the procedure, he developed ventricular tachycardia (VT). Immunohistological staining revealed PTLD of T lymphocytes, and chemotherapy was introduced on the same day he developed VT. After two cycles of tetrahydropyranyl, adriamycin, cyclophosphamide, vincristine, prednisolone and etoposide treatment, he completely recovered. This is a first case report of severe PTLD with VT, and our case implies the feasibility of chemotherapy after the appearance of dissemination symptoms.     

Low viral load post‐transplant lymphoproliferative disease localized within the tongue

Abstract: Post‐transplant lymphoproliferative disease (PTLD) can occur in different sites, such as lymph nodes, allograft, and central nervous system. We report a 6‐year‐old girl with end‐stage renal disease secondary to hypoplastic–dysplastic kidneys, who received a kidney transplant. Thirty months post transplant, she developed PTLD in the tongue, an area of muscular tissue only. At that time her peripheral blood Epstein–Barr viral (EBV) load was only 40 copies/10⁵ lymphocytes, though the tumor was EB early RNA (EBER) positive. Immunosuppression was reduced with initial improvement in her symptoms. One month later, she returned with abdominal complaints and a contained cecal abscess. The excised cecal tissue revealed CD20 and EBER‐positive lymphoid cells. At the same time, her peripheral blood EBV copy number rose to 400 copies/10⁵ lymphocytes. She was successfully treated for the progressive PTLD by complete cessation of immunosuppression and a modified reduced‐dose chemotherapy protocol plus rituximab. Partial immunosuppression was eventually re‐introduced with sirolimus and prednisone. She remains in remission 60 months post transplant, and 30 months post PTLD, with serum creatinine value maintained at 1.3 mg/dL. Unusual localization of PTLD to areas in non‐lymphoid tissue without regional lymphoid involvement may result in misleading low peripheral blood EBV viral loads.     

A retrospective analysis of post‐transplant lymphoproliferative disorder following liver transplantation

Objective

To evaluate response rates and survival in adults developing post‐transplant lymphoproliferative disorder (PTLD) following liver transplantation.

Methods

Patients were identified retrospectively and data collected through local liver and haematology electronic databases and pharmacy records.

Results

Forty‐five patients were identified. The median age at first transplant and at development of PTLD was 48 and 54 years, respectively, with the median time from transplant to PTLD diagnosis of 56 months. The majority of cases (76%) were monomorphic B‐cell lymphomas, and 36% of tumours were EBV positive. Treatment involved reduction in immune‐suppression (RIS) in 30 (67%) with RIS the only treatment in 3. Ten (22%) patients were treated with rituximab alone, 13 (29%) with chemotherapy alone and 14 (31%) patients were treated with rituximab and chemotherapy. Twenty‐six (58%) patients achieved a complete response (CR). At a median follow‐up of 27 months, the median overall survival (OS) was 50 months. Response and OS were not associated with clinical factors or the use of rituximab.

Conclusion

Outcomes reported in this study are favourable and comparable to those reported previously. The addition of rituximab did not appear to have improved outcomes in this series, although a significant proportion of patients were able to avoid chemotherapy.     

Long‐term remission in an adult heart transplant recipient with advanced Burkitt’s lymphoma post‐transplant lymphoproliferative disorder after anthracycline‐free chemotherapy: A case report and literature review

Incidence of Burkitt's lymphoma post‐transplant lymphoproliferative disorder (BL‐PTLD) in solid organ transplant (SOT) recipients in 1.4%‐1.6% with unknown cure rate. We report a case of Epstein‐Barr virus (EBV) positive, late‐onset BL‐PTLD in a 24‐year‐old EBV donor positive/recipient negative female. This is the first reported case of advanced BL‐PTLD post‐heart transplant in an adult. This is also the first reported case of treatment of advanced BL‐PTLD in a heart transplant recipient with a combined chemotherapy regimen without anthracyclines to avoid cardiotoxicity. The patient received 6 cycles of R‐COEP (rituximab with cyclophosphamide, vincristine, etoposide, prednisone) over 6 months and subsequently 3 cycles of high‐dose methotrexate (MTX) over 3 months for CNS prophylaxis. She remains without evidence of disease at 19 months post‐treatment. This case demonstrates that an anthracycline‐free regimen can be the therapy option for patients with BL‐PTLD after heart transplantation.     

Umbilical cord blood transplantation in adults with advanced hodgkin's disease: high incidence of post‐transplant lymphoproliferative disease

We report the outcome of 30 consecutive patients with Hodgkin disease (HD) who underwent single‐unit UCBT. Most (90%) patients had failed previous autologous hematopoietic stem cell transplantation. The conditioning regimens were based on combinations of thiotepa, busulfan, cyclophosphamide or fludarabine, and antithymocyte globulin. The cumulative incidence (CI) of myeloid engraftment was 90% [95% confidence interval (C.I.), 74–98%] with a median of 18 d (range, 10–48). CI of acute graft‐versus‐host disease (GvHD) grades II–IV was 30% (95% C.I., 17–44%), while the incidence of chronic GVHD was 42% (95% C.I., 23–77%). The non‐relapse mortality (NRM) at 100 d and 4 yr was 30% (95% C.I., 13–46%) and 47% (95% C.I., 29–65%), respectively. EBV‐related post‐transplant lymphoproliferative disease (EBV‐PTLD) accounted for more than one‐third of transplant‐related death, with an estimate incidence of 26% (95% C.I., 9–44). The incidence of relapse at 4 yr was 25% (95% C.I., 9–42%). Four‐year event‐free survival (EFS) and overall survival (OS) were 28% and 30%, respectively. Despite a high NRM and an unexpected high incidence of EBV‐PTLD, UCBT in heavily pretreated HD patients is an option for patients lacking a suitable adult donor, provided the disease is not in refractory relapse.     

Recursive partitioning analysis of prognostic factors in post‐transplant lymphoproliferative disorders (PTLD): a 120 case single institution series

The post‐transplant lymphoproliferative disorders (PTLD) comprise a heterogeneous group of lymphocytic and plasma cell proliferations occurring in recipients of tissue allografts in the setting of immunosuppression. We describe our experience of 120 patients with PTLD seen between 1990 and 2009, one of the largest series reported by a single institution. Post‐transplant lymphoproliferative disorders characteristics were analysed with regard to paediatric and adult patients, and with regard to the decade of diagnosis, 1990–1999 (pre‐rituximab era) versus 2000–2009 (the rituximab era). We present a new prognostic score using the recursive partitioning model, consisting of the Eastern Cooperative Oncology Group (ECOG) score (0–1 vs. 2–4), age [paediatrics (<16 years old), adults (16–60 years old) and elderly (>60 years old)] and CD20 status (positive vs negative); separating patients into 4 risk categories based on overall survival. Low‐risk included paediatric patients with ECOG score of 0–1; intermediate‐low‐risk included adults aged 16–60 years with an ECOG score of 0–1; intermediate‐high‐risk included elderly patients with an ECOG score 0–1 or paediatric patients and adults aged 16–60 years with an ECOG score of 2–4 and CD20 positive; high‐risk group included patients of any age with an ECOG score of 2–4 and CD20 negative, and elderly patients with an ECOG score of 2–4 with CD20‐positive PTLD.     

Management of post‐transplant lymphoproliferative disorder in adult solid organ transplant recipients – BCSH and BTS Guidelines

A joint working group established by the Haemato‐oncology subgroup of the British Committee for Standards in Haematology (BCSH) and the British Transplantation Society (BTS) has reviewed the available literature and made recommendations for the diagnosis and management of post‐transplant lymphoproliferative disorder in adult recipients of solid organ transplants. This review details the therapeutic options recommended including reduction in immunosuppression (RIS), transplant organ resection, radiotherapy and chemotherapy. Effective therapy should be instituted before progressive disease results in declining performance status and multi‐organ dysfunction. The goal of treatment should be a durable complete remission with retention of transplanted organ function with minimal toxicity.     

Diagnosis of post‐transplant lymphoproliferative disorder in solid organ transplant recipients – BCSH and BTS Guidelines

A joint working group established by the Haemato‐oncology subgroup of the British Committee for Standards in Haematology (BCSH) and the British Transplantation Society (BTS) has reviewed the available literature and made recommendations for the diagnosis and management of post‐transplant lymphoproliferative disorder (PTLD) in adult recipients of solid organ transplants. This review details the risk factors predisposing to development, initial features and diagnosis. It is important that the risk of developing PTLD is considered when using post transplant immunosuppression and that the appropriate investigations are carried out when there are suspicions of the diagnosis. These must include tissue for histology and computed tomography scan to assess the extent of disease. These recommendations have been made primarily for adult patients, there have been some comments made with regard to paediatric practice.