B-cell Post-transplant Lymphoproliferative Disorder Research Articles

Infectious Complications and Mortality in Post-Transplant Lymphoproliferative Disorder Following Solid Organ Transplantation: Experiences of 10 Years in a Single Center

Introduction: An estimated 2 to 20% of patients with solid organ transplants (SOT) are later diagnosed with post-transplant lymphoproliferative disorder (PTLD). These patients receive immunosuppression therapy for SOT, however, there is a paucity of research examining the infection complications and morbidity in those diagnosed with PTLD. Our single center study examined infections following a PTLD diagnosis and the potential risk of morbidity. Methods: We reviewed the Cleveland Clinic electronic medical record (EMR) of SOT patients who were diagnosed with PTLD between 2010 and 2020. 98 patients met the inclusion criteria. These were further stratified by transplant type: 26 liver, 24 renal, 22 lung, 19 heart, and 2 combined heart and lung transplant patients. All data were analyzed using R software. Results: The mean onset of biopsy confirmed PTLD following transplant was 7.13 ± 7.28 years,. Abdominal pain was the most common presenting symptom prompting further work up, seen in 29% of patients. Patients were also diagnosed based on other chief complaints, including fatigue (n = 20), weight loss (n = 16), and fever (n = 14). Additionally, a smaller subset of patients were diagnosed incidentally on imaging. The most frequent primary site of PTLD was the lymphoid tissue / enlarged lymph nodes (34% of patients) and followed by gastrointestinal tract (29%). Elevated lactate dehydrogenase was present in 42% of patients, diagnostic criteria for acute kidney injury in 23%, and hyperuricemia was noted in 16%. Diffuse large B-lymphoma was the most common subtype diagnosed in 72 of 98 patients followed by EBV related. After diagnosis, 60% of PTLD patients presented to the hospital due to infections, with a mean of 49.9 ± 55.3 days following PTLD diagnosis. Of those patients, bacterial infections were the most common (49.3%), followed by viral infections (34.5%), fungal infections (14.9%), and parasitic infections (1.15%). The bacterial infections were predominantly encapsulated organisms including Pseudomonas aeruginosa (33%), Escherichia coli (19%), and Streptococcus pneumoniae (14%). Rituximab was used in 40% of patients following diagnosis while rituximab, cyclophosphamide, doxorubicin, and vincristine (R-CHOP) was used in 41% of patients. There was no significant difference in infection risk in the first 100-days, following initiation of rituximab infections were seen in 33%, while the infection risk with R-CHOP was 35% (p = 0.31). Moreover, the most common cause of death was infection seen in 39% of patients, while PTLD itself with progressive disease was the second most common cause of death in 27%. The 6-month mortality following PTLD was 16% with 56% of those deaths being attributed to infection. The one-year mortality rate following PTLD was 25% with 48% of those being attributed to infection. Conclusions: In patients with PTLD diagnosis, the most common cause of death was infection (39%), followed by complications related to PTLD such as progressive disease with multi-organ failure. High serious infection risk may be due to aberrant monoclonal B-cell proliferation which paradoxically leads to decreased cellular immunity. The increased risk of B-cell PTLD in patients with SOT is likely due to the chronic immunosuppression, where patients gain acquired somatic driver mutations leading to a malignant state yet with an increased infection risk. Additionally, there was no difference in infection at 100 days between rituximab chemotherapy compared to R-CHOP. This necessitates the question of initiating viral, bacterial and fungal infection prophylaxis, similar to that following splenectomy or post BMT, should be implemented in patients diagnosed with PTLD. Further larger prospective studies are needed to further analyze the potential need and benefit of prophylactic vaccinations at the time of diagnosis in the PTLD patient population.

Primary Cutaneous Marginal Zone Lymphoproliferative Disorder of Donor Origin after Allogeneic Hematopoietic Stem Cell Transplantation.

Primary cutaneous posttransplant lymphoproliferative disorders (PTLDs) after allogeneic hematopoietic stem cell transplant (allo-HSCT) are exceedingly rare, with only 6 published cases, all of them consisting in T-cell neoplasms. In this report, we present for the first time a donor-derived B-cell PTLD consisting in a primary, cutaneous, B-cell, marginal zone, lymphoproliferative disorder (PCMZLPD). The patient, a 37-year-old woman with a history of Hodgkin lymphoma received an allo-HSCT from her healthy, matched, related father, achieving complete host chimerism in the bone marrow and peripheral blood. However, 8 years after the allo-HSCT, she presented asymptomatic skin lesions consisting in oval, well-defined, slightly raised erythematous plaques, located on the arms, trunk, and legs. Skin biopsies of 2 lesions demonstrated a class-switched IgG+, EBV-, PCMZLPD, showing kappa light chain restriction and monoclonal rearrangement of the IgH gene. Microsatellite genotyping and 2-color fluorescence in situ hybridization (X and Y chromosomes) confirmed that the origin of the neoplastic cells was the donor graft. The lesions showed an indolent behavior, good response to topical corticosteroids, and no need for systemic treatment. Our case broadens the spectrum of PTLD, a diverse group of lymphoid and/or plasmacytic proliferations with variable clinical presentations and histopathological features.

Tumor Infiltrating Lymphocytes Predict Survival in Solid Organ Transplant Recipients With Monomorphic Post-transplant Lymphoproliferative Disorders.

The tumor microenvironment (TME) in post-transplant lymphoproliferative disorders (PTLDs) remains unexplored. Tumor infiltrating lymphocytes (TILs) are prognostic in other lymphomas. We assessed the prognostic impact of TILs in monomorphic B-cell PTLD. TIL density (CD3+ cells/mm2) was determined by CD3 immunohistochemistry in archived diagnostic biopsies from patients diagnosed with monomorphic B-cell PTLD. Amongst monomorphic PTLDs (N=107), low TIL-count was associated with inferior 2-year progression-free survival (PFS) (41% versus 86%, P=.003) and 2-year overall survival (OS) (52% versus 93%, P=.003) by Kaplan-Meier analysis. Low TIL-count was significant on Cox univariate regression for inferior PFS (HR 4.5, 95% CI 2.0-9.9, P < .001) and OS (HR 4.6, 95% CI 1.8-11.8, P < .001). Multivariate analysis with clinical variables (age ≥60 years, high LDH, stage III/IV, CNS involvement) and TIL-count showed significance for PFS (HR 3.3, 95% CI 1.3-8.3, P=.010) and a non-significant trend for OS (HR 2.6, 95% CI 0.9-7.3, P=.064). A composite score including TILs and clinical variables (age ≥60 years, high LDH, stage III/IV, CNS involvement) effectively stratified monomorphic PTLD patients by PFS and OS (2-year OS: low-risk 93%, intermediate-risk 61%, high-risk 23%, P < .001). The TME and TILs are prognostically relevant in monomorphic PTLD. Prognostic models including measures of the TME may improve risk stratification for patients with monomorphic PTLDs.

Modified risk-stratified sequential treatment (subcutaneous rituximab with or without chemotherapy) in B-cell Post-transplant lymphoproliferative disorder (PTLD) after Solid organ transplantation (SOT): the prospective multicentre phase II PTLD-2 trial

The prospective multicentre Phase II PTLD-2 trial (NCT02042391) tested modified risk-stratification in adult SOT recipients with CD20-positive PTLD based on principles established in the PTLD-1 trials: sequential treatment and risk-stratification. After rituximab monotherapy induction, patients in complete remission as well as those in partial remission with IPI < 3 at diagnosis (low-risk) continued with rituximab monotherapy and thus chemotherapy free. Most others (high-risk) received R-CHOP-21. Thoracic SOT recipients who progressed (very-high-risk) received alternating R-CHOP-21 and modified R-DHAOx. The primary endpoint was event-free survival (EFS) in the low-risk group. The PTLD-1 trials provided historical controls. Rituximab was applied subcutaneously. Of 60 patients enrolled, 21 were low-risk, 28 high-risk and 9 very-high-risk. Overall response was 45/48 (94%, 95% CI 83–98). 2-year Kaplan–Meier estimates of time to progression and overall survival were 78% (95% CI 65–90) and 68% (95% CI 55–80) – similar to the PTLD-1 trials. Treatment-related mortality was 4/59 (7%, 95% CI 2–17). In the low-risk group, 2-year EFS was 66% (95% CI 45–86) versus 52% in the historical comparator that received CHOP (p = 0.432). 2-year OS in the low-risk group was 100%. Results with R-CHOP-21 in high-risk patients confirmed previous results. Immunochemotherapy intensification in very-high-risk patients was disappointing.

Modified Risk-Stratified Sequential Treatment in B-Cell Post-Transplant Lymphoproliferative Disorder (PTLD) after Solid Organ Transplantation (SOT): The Prospective Multicenter Phase II PTLD-2 Trial

Modified Risk-Stratified Sequential Treatment in B-Cell Post-Transplant Lymphoproliferative Disorder (PTLD) after Solid Organ Transplantation (SOT): The Prospective Multicenter Phase II PTLD-2 Trial

Real World Evidence (RWE) of Safety, Efficacy, and Outcomes of CD19 CAR-T Therapy in 20 Patients with Solid Organ Transplant (SOT)-Related Post-Transplant Lymphoproliferative Disorder (PTLD)

Real World Evidence (RWE) of Safety, Efficacy, and Outcomes of CD19 CAR-T Therapy in 20 Patients with Solid Organ Transplant (SOT)-Related Post-Transplant Lymphoproliferative Disorder (PTLD)

O01 Post-transplant lymphoproliferative disorder (PTLD) in a patient with rheumatoid arthritis

O01 Post-transplant lymphoproliferative disorder (PTLD) in a patient with rheumatoid arthritis

Characteristics of T- and NK-cell Lymphomas After Renal Transplantation: A French National Multicentric Cohort Study.

Posttransplant lymphoproliferative disorders (PTLDs) encompass a spectrum of heterogeneous entities. Because the vast majority of cases PTLD arise from B cells, available data on PTLD of T or NK phenotype (T/NK-cell PTLD) are scarce, which limits the quality of the management of these patients. All adult cases of PTLD diagnosed in France were prospectively recorded in the national registry between 1998 and 2007. Crosschecking the registry data with 2 other independent national databases identified 58 cases of T/NK-cell PTLD. This cohort was then compared with (i) the 395 cases of B-cell PTLD from the registry, and of (ii) a cohort of 148 T/NK-cell lymphomas diagnosed in nontransplanted patients. T/NK-cell PTLD occurred significantly later after transplantation and had a worse overall survival than B-cell PTLD. Two subtypes of T/NK-cell PTLD were distinguished: (i) cutaneous (28%) and (ii) systemic (72%), the latter being associated with a worse prognosis. Compared with T/NK-cell lymphomas of nontransplanted patients, overall survival of systemic T/NK-cell PTLD was worse (hazard ratio: 2.64 [1.76-3.94]; P < 0.00001). This difference, which persisted after adjustment on tumoral mass, histological subtype, and extension of the disease at diagnosis could be explained by the fact that transplanted patients were less intensively treated and responded less to chemotherapy.

Long-Term Follow-up of a Prospective Phase II Trial of Extended Treatment with Rituximab in Patients with B-Cell Post-Transplant Lymphoproliferative Disease and Comparison with a Cohort of Patients Treated in Real Life. Analysis on Behalf of the Spanish Lymphoma Group (GELTAMO)

Background and Objectives: The outcome of patients with B-cell post-transplant lymphoproliferative disorders (PTLD) has improved with the introduction of rituximab as first line therapy. The purpose of this report is to provide longer follow-up of the phase II trial (González-Barca et al, Hematologica 2008;92:1489) with extended doses of rituximab in patients with PTLD after solid organ transplantation, and to compare these results with a cohort of patients diagnosed of PTLD after the trial was closed, and treated in real life with the same therapeutic regimen.Patients and Methods: The phase II trial included 38 patients that were treated with reduction of immunosuppression and four to eight weekly infusions of rituximab. Patients without complete response (CR) or progression were allowed to receive a short course of 3-4 cycles of R-CHOP /R-CHOP-like chemotherapy. A cohort of 21 pts treated with the same regimen in real life was used for comparative purposes. The real life patients were significantly older (median age 63.0 vs 55.4 yrs, p=0.013), but all the other characteristics at diagnosis were comparable. Response was evaluated with CT scans in patients included in the clinical trial and with PET/CT in 86% of real life patients. Progression free survival (PFS) was calculated from the time of diagnosis to the time of progression / relapse or death due to lymphoma; deaths from other causes were censored. Predictive factors for CR to rituximab were analyzed with a binary logistic regression model. Univariate analysis for survival was performed with Kaplan-Meier estimation and Log-rank test, and multivariate analysis with a Cox regression model. Factors included in the different analyses were: age, gender, Ann Harbor stage, graft involvement, bulky disease, extranodal involvement, B symptoms, ECOG, LDH, and time from transplant to PTLD.Results: Twenty-three (60.5%) out of 38 patients treated within the clinical trial achieved a CR/CRu after rituximab treatment. With a median follow-up for the alive patients of 13.0 yrs, 21 (55.3%) died; 13 (34%) due to progression, 3 due to infections (pneumonia, hepatic abscesses, septic shock), 1 of a secondary malignancy, a Hodgkin Lymphoma. PFS at 5 and 10 yrs was 68.6% (95%CI: 52.9% - 84.3%) and 64.7% (95%CI: 48.2% - 81.2%), respectively. Overall survival (OS) at 10 yrs was 49.5% (95%CI: 32.8% - 66.2%). For those patients that achieved a CR with rituximab, PFS at 5 and 10 yrs was 94.4% (95%CI: 83.8% - 100%) and 88.1% (95%CI: 72.6% - 100 %), respectively. Among the 21 real life patients, 8 (38.1%) achieved CR with rituximab. With a median follow-up for the alive patients of 6.5 yrs, 7 (33%) patients died; 4 (19%) due to progression. PFS and OS at 5 yrs was 75.2% (95%CI: 56.4% - 94.0%) and 62.7% (95%CI: 40.4% - 85.0%), respectively. PFS at 5 yrs was 87.5% (95%CI 64.6% - 100%) in those patients that achieved CR with rituximab. Factors that could predict a CR to rituximab therapy were not found. ECOG 2-4 was the only significant independent prognostic factor for DFS [HR 3.2 (95%CI 1.05-9.3)]Conclusions: Patients with PTLD who achieve CR with rituximab monotherapy have an excellent long term outcome in both clinical trial and real life; unfortunately, factors at diagnosis that could predict response to rituximab were not found. Patients with prolonged CR have a very low risk of progression after 5 years. However, around one third of PTLD patients still die due to progressive disease. Patients that do not achieve a CR with rituximab should be included in prospective clinical trials. DisclosuresGonzalez-Barca:Gilead: Consultancy; Sandoz: Consultancy; Janssen: Speakers Bureau; Roche: Speakers Bureau. Capote Huelva:Roche: Speakers Bureau; Janssen: Speakers Bureau; Celgene: Speakers Bureau; Takeda: Speakers Bureau. Gomez Codina:Roche: Consultancy. Salar:Roche: Speakers Bureau; Janssen: Speakers Bureau; Servier: Speakers Bureau. Ribera:Janssen: Honoraria; Gilead: Honoraria; Celgene: Honoraria; Amgen Inc.: Research Funding, Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Roche: Honoraria; ARIAD: Research Funding, Speakers Bureau; Incyte: Research Funding, Speakers Bureau.

Epstein-Barr virus infection-related post-transplant lymphoproliferative disorders in transplanted lung: a clinicopathological analysis

Objective: To investigate the clinicpathological characteristics of post-transplant lymphoproliferative disorders (PTLD) in transplanted lung, and to improve its diagnosis and treatment. Methods: The clinicopathological characteristics of PTLD in three transplanted lungs were evaluated at Wuxi People's Hospital Affiliated to Nanjing Medical University from 2014 to 2019. HE, immunohistochemical staining and in situ hybridization were performed. The relevant literature of PTLD was reviewed. Results: All three patients had chronic obstructive pulmonary disease (COPD) before lung transplantation. After receiving both lung transplants, they were all treated with anti-rejection drugs tacrolimus or mycophenolate mofetil, and combined with antiviral and/or rituximab. The time from transplantation to diagnosis of PTLD was four years, seven months, and five months, respectively. Two patients died one month and five months after initial diagnosis, and one patient was alive with no disease after one year. Histologically, all cases were monomorphic B-cell PTLD (diffuse large B-cell lymphoma, unspecified), and the tumor cells were positive for Epstein-Barr virus by in situ hybridization; one of the late-onset patients had herpes simplex virus infection. Conclusions: PTLD in the post-transplant lung tissue shows unique morphology and clinical characteristics, and is closely related to Epstein-Barr virus infection. Patients who receive lung transplantation due to COPD are more susceptible to develop PTLD, while late-onset ones occur more commonly in the hilum of lungs, and the prognosis is relatively poor.

Distinctive Clinicopathologic Features of Monomorphic B-cell Post-transplant Lymphoproliferative Disorders in Children.

Post-transplant lymphoproliferative disorders (PTLDs) comprise a heterogeneous group of Epstein-Barr virus (EBV)-positive or negative lymphoid or plasmacytic lesions in solid organ or hematopoietic stem cell (HSC) transplant recipients. Although PTLDs in adults have been extensively studied, the clinicopathologic features of monomorphic B-cell PTLD in children, particularly EBV-negative forms, are still poorly understood. We retrospectively reviewed all our pediatric cases of monomorphic B-cell PTLDs diagnosed in the past 10 years. Clinical data were reviewed. Pathologic data including histologic types and EBV status were analyzed. Additional immunohistochemical stains, FISH studies, and TP53 gene mutational status were performed. 4 of 18 cases were EBV-negative. All 4 EBV-negative cases were strikingly confined to the gastrointestinal (GI) tract or abdominal lymph nodes, while tumors in EBV-positive cases were found at various anatomic sites; 2 of 4 EBV-negative cases carried mutations in TP53 gene. Our cohort also included 2 rare types of PTLD, one plasmablastic lymphoma and one high-grade B-cell lymphoma, not otherwise specified (HGBL, NOS). We report that monomorphic B-cell PTLDs in children have distinctive clinical and pathological features. More studies are needed to clarify whether and how much these pediatric PTLDs differ from their adult counterparts.

Successful Treatment of Pediatric Refractory Burkitt Lymphoma PTLD after Liver Transplantation using Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy

In the immunocompromised setting, recipients of solid-organ or hematopoietic stem-cell transplants carry an increased risk of post-transplant lymphoproliferative disorder (PTLD). Burkitt lymphoma (BL) PTLD is a rare form of monomorphic B-cell PTLD, which lacks a standard best treatment. Here, we report the successful treatment of refractory BL-PTLD with autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy. A male patient was diagnosed with BL-PTLD, with an increasing Epstein-Barr virus (EBV) viral load, at 21 months after undergoing living liver transplantation from his mother due to neonatal biliary atresia. After 10 cycles rituximab +/− intensive chemotherapy and surgical tumor resection, the tumors significantly advanced. Next-generation sequencing (NGS) was performed on formalin-fixed paraffin-embedded tumor tissue, revealing one mutation in exon 5, TP53: p.A159 V, which may be associated with chemo-resistance. Thus, treatment was started with autologous anti-CD19 CAR T-cell therapy. We administered 9.0 × 106/kg autologous anti-CD19 CAR T-cells, after conditioning with cyclophosphamide and fludarabine. Unexpectedly, the patient experienced only mild (Grade II) cytokine release syndrome (CRS) without neurotoxicity. Finally, he went into complete remission (CR), and has achieved 16-month event-free survival to date. In addition, liver function has remained stably within the normal range without any immunosuppressive therapy. The literature includes only five previously reported BL cases treated with CAR T-cell therapy. In conclusion, the present case suggests that autologous anti-CD19 CAR T-cell therapy may represent a new therapeutic option for some cases of refractory BL-PTLD. Clinical trial number: ChiCTR2000032211.

S3511 Management of Complications After Liver Transplantation for Hepatitis C Negative Patients Receiving Hepatitis C Positive Organs

INTRODUCTION: More than 16,000 patients are awaiting a liver transplant with less than 6,700 successful liver transplants in the U.S. that occur each year. Using a hepatitis C virus (HCV) positive donor liver for transplantation increases the donor pool. When HCV negative patients receive an HCV positive liver, they are at risk of acquiring HCV infection. We report two cases of patients who were HCV negative and received HCV positive donor liver subsequently acquiring HCV infection and developing associated complications. CASE DESCRIPTION/METHODS: The first patient is a 71 year old male with a history of non-alcoholic steatohepatitis (NASH) cirrhosis, hepatocellular carcinoma, and hepatic encephalopathy. He developed HCV infection status-post orthotopic liver transplantation from HCV donor. Imaging before transplant and explant pathology showed hepatocellular carcinoma. He was found to have HCV genotype 2B infection 2 weeks post-transplant as part of protocol testing. He was treated with sofosbuvir/velpatasvir for 12 weeks and achieved sustained viral response (SVR). Imaging at 5 months post-op revealed 2 hypovascular masses diagnosed as epstein barr virus associated B-cell post-transplant lymphoproliferative disorder (PTLD). Treatment was initiated with rituximab and his hospital course was complicated by bacteremia and atrial fibrillation. The second patient is a 52 year old male with NASH cirrhosis status-post orthotopic HCV positive liver transplant. His post-transplant course was complicated by elevated liver enzymes and renal insufficiency. He was found to have HCV genotype 1a, 3 months after transplant, and was treated with sofosbuvir/velpatasvir for 12 weeks with achieving SVR. Liver tests subsequently returned to normal with treatment. DISCUSSION: Although using HCV positive donor liver increases the donor pool it is associated with increased risk of HCV transmission to the recipient. These recipients need to be closely monitored so they could be treated in a timely manner to prevent any associated complications.Figure 1.: CT scan showing two hypovascular hepatic masses in the right and left lobes, measuring up to 3 cm.

T-cell posttransplant lymphoproliferative disorders after allogeneic hematopoietic cell transplantation.

Posttransplant lymphoproliferative disorder (PTLD) after allogeneic hematopoietic cell transplantation (HCT) is usually donor derived, associated with Epstein-Barr virus (EBV), and of B-cell origin. T-cell PTLD (T-PTLD) after allogeneic HCT is extremely rare. Four of 1015 (0.39%) allogeneic HCT patients were diagnosed with T-PTLD; peripheral T-cell lymphoma-not otherwise specified, anaplastic large cell lymphoma, monomorphic T-cell PTLD and polymorphic PTLD with chronic active EBV infection-like symptoms. Three of the four patients developed T-PTLD within 6months after HCT from HLA-mismatched unrelated donor. Three (75%) and 4 (100%) cases were positive for EBV-encoded small RNA in situ hybridization and EBV-DNA load in peripheral blood, respectively. Chimerism analysis showed that 75% of T-PTLD tissues (3/4) were recipient derived. T-PTLD was refractory to salvage chemotherapy and fatal in all four patients. Including the 10 patients in the literature, the median interval from HCT to diagnosis of T-PTLD was 5months (range 1-72months), 55% were negative for EBV, and 56% were recipient-derived. T-PTLD, which often occurred early after allogeneic HCT, was more likely to be EBV negative and recipient derived than B-cell PTLD after allogeneic HCT. Like T-PTLD after solid organ transplant, T-PTLD after allogeneic HCT demonstrated morphological heterogeneity and poor prognosis.

Post-transplant Lymphoproliferative Disorder of Appendix Mimicking Acute Appendicitis: A Case Report

Post-transplant lymphoproliferative disorder (PTLD) can be Epstein-Barr virus (EBV)-positive lymphoproliferations occurring in the first year after transplantation or EBV-negative lymphoma occurring many years after transplantation. Both B-cell and T-cell type of PTLD are described in the literature. In the gastrointestinal tract, the small and large intestine are the common sites of involvement. PTLD of the appendix is a lesser-known entity and cases described previously presented clinically as acute appendicitis. We report a case of EBV-negative B-cell PTLD of the appendix mimicking acute appendicitis in a live young renal allograft recipient 7 years after transplantation.

End-of-Treatment Positron Emission Tomography After Uniform First-Line Therapy of B-Cell Posttransplant Lymphoproliferative Disorder Identifies Patients at Low Risk of Relapse in the Prospective German PTLD Registry.

Fluorine-18 fluorodeoxyglucose (18F-FDG)-positron emission tomography (PET) is a recommended standard in the staging and response assessment of 18F-FDG-avid lymphoma. Posttransplant lymphoproliferative disorder (PTLD) can be detected by 18F-FDG-PET at diagnosis with high sensitivity and specificity. However, the role of response assessment by end-of-treatment (EOT) PET has only been addressed in small case series. We performed a retrospective, multicenter study of 37 patients with CD20-positive PTLD after solid organ transplantation treated with uniform, up-to-date, first-line protocols in the prospective German PTLD registry who had received EOT 18F-FDG-PET between 2006 and 2014. Median follow-up was 5.0 years. Any nonphysiological 18F-FDG uptake (Deauville score greater 2) was interpreted as PET-positive. By computed tomography (CT) final staging, 18 of 37 patients had a complete response, 18 had a partial response and 1 patient had stable disease. EOT PET was negative in 24 of 37 patients and positive in 13 of 37 patients. The positive predictive value of EOT PET for PTLD relapse was 38%, and the negative predictive value was 92%. Time to progression (TTP) and progression-free-survival were significantly longer in the PET negative group (P = 0.019 and P = 0.013). In the 18 patients in a partial response by CT staging, we noted highly significant differences in overall survival (P = 0.001), time to progression (P = 0.007), and progression-free survival (P < 0.001) by EOT PET. Even without baseline imaging, EOT PET in PTLD identifies patients at low risk of relapse and offers clinically relevant information, particularly in patients in a partial remission by CT staging.

Impact of the posttransplant lymphoproliferative disorder subtype on survival.

Posttransplant lymphoproliferative disorder (PTLD) is a life-threatening complication of solid organ transplantation. Histologic heterogeneity and a lack of treatment standards have made evaluating clinical outcomes in specific patient populations difficult. This systematic literature review investigated the impact of the PTLD histologic subtype on survival in a large data set. Case series were identified on PubMed with the search terms post-transplant lymphoproliferative disorder/disease, PTLD, and solid organ transplantation, with additional publications identified through reference lists. The patient characteristics, immunosuppressive regimen, treatment, survival, and follow-up time for 306 cases were extracted from 94 articles, and these cases were combined with 11 cases from Emory University Hospital. Patients with a recorded subtype were included in a Kaplan-Meier survival analysis (n = 234). Cox proportional hazards regression analyses identified predictors of overall survival (OS) for each subtype and B-cell subgroup. OS differed significantly between monomorphic T-cell neoplasms (median, 9 months) and polymorphic, monomorphic B-cell, and Hodgkin-type neoplasms, for which the median OS was not reached (P = .0001). Significant differences in OS among B subgroups were not detected, but there was a trend toward decreased survival for patients with Burkitt-type PTLD. Kidney transplantation and a reduction of immunosuppression were associated with increased OS for patients with B-cell neoplasms in a multivariate analysis. Immunosuppression with azathioprine was associated with decreased OS for patients with T-cell neoplasms, whereas radiotherapy was associated with improved OS for patients with that subtype. The histologic subtype represents an important prognostic factor in PTLD, with patients with T-cell neoplasms exhibiting very poor OS. Possibly lower survival for certain subsets of patients with B-cell PTLD should be explored further and suggests the need for subtype-specific therapies to improve outcomes. Cancer 2018;124:2327-36. © 2018 American Cancer Society.

B-cell posttransplant lymphoproliferative disorder isolated to the central nervous system is Epstein-Barr virus positive and lacks p53 and Myc expression by immunohistochemistry

In this retrospective study from one institution, we performed a clinicopathological study of a cohort of patients with posttransplant lymphoproliferative disorder (PTLD) confined to the central nervous system. We also identified a comparison cohort of patients with de novo primary diffuse large B-cell lymphoma of the central nervous system. We performed a detailed morphologic review, evaluated Epstein-Barr virus (EBV) by in situ hybridization, and interpreted a panel of immunohistochemical stains in a subset of cases including Hans classification markers (CD10, BCL6, MUM1), p53, CD30, Myc, and BCL2. All 17 of the posttransplant and none of 11 de novo cases were EBV positive (P < .005). Morphologic patterns identified in the PTLD cases were monomorphic diffuse large B-cell lymphoma pattern (10 patients) and "T-cell-rich" pattern (7 patients). The monomorphic posttransplant cases were more likely to be Myc negative (P = .015) and CD30 positive (P < .005) than the de novo cases, and showed a similarly low rate of p53 positivity by immunohistochemistry. No prognostic factors for overall survival were identified. Central nervous system PTLD is EBV positive, typically lacks p53 and Myc expression by immunohistochemistry, and can present with numerous background T lymphocytes.

DA-R-EPOCH in Post Transplant Lymphoproliferative Disorders (PTLD) and EBV-Positive High Grade B-Cell Lymphomas with Rearrangements of MYC and BCL2 (HGBL)

Introduction: Immunotherapy with rituximab alone or in combination with sequential chemotherapy such as CHOP, in addition to a reduction in immunosuppression (IST), has been shown to be effective in achieving long-term, disease-free survival in patients with B-cell PTLD. We have recently observed an increased incidence of HGBL in patients receiving IST following solid-organ transplant. Intensive induction regimens (ex: DA-R-EPOCH) in non-transplant HGBL has been associated with improved complete responses. Intensive regimens have not been previously evaluated in patients with PTLD. The aim of this study is to compare the tolerability of DA-R-EPOCH to R-CHOP in post-transplant patients with HGBL.Methods: Patients treated with either DA-R-EPOCH or R-CHOP were included in this study following IRB approval. Eligible patients were ≥18 years, had biopsy-confirmed B-cell PTLD, and were treated with at least one cycle of DA-R-EPOCH or R-CHOP. The primary outcome was progression-free survival (PFS); secondary outcomes were overall survival (OS), toxicities, and hospitalizations due to treatment-related toxicities. Statistical analysis was performed using SPSS.22 softwareResults: Sixty-three patients had biopsy-confirmed PTLD. Of these, 26 met inclusion criteria. Among these 26 patients, 19 (73.1%) were men; median age was 57 years (18-75 years); and transplants included 3 (11.5%) lung, 4 (15.4%) heart, 9 (34.6%) kidney, 8 (30.8%) liver, 2 (7.7%) pancreas, and 1 (3.8%) stem cell. All patients were receiving IST at the time of diagnosis of PTLD. Pathology reports found that 24 (92.3%) had diffuse large B-cell lymphoma (DLBCL)-like PTLD, and 11 (57.9%) had EBV-positive disease. HGBL was observed in 10 (38.5%) patients. Seven patients received DA-R-EPOCH, and 19 received R-CHOP. Baseline characteristics were similar between treatment groups. There was a significantly higher number of patients with HGBL in the DA-R-EPOCH arm compared with the R-CHOP arm (100% [7/7] vs. 15.8% [3/19]; 95% CI, -0.01-1.00; p=0.001). The median number of cycles administered was not significantly different between the groups (4.6 cycles vs. 5 cycles; 95% CI, 4.33-6.07; p=0.645). Dose intensification occurred in 8 of 32 cycles for patients who received DA-R-EPOCH. The median follow-up time for patients treated with DA-R-EPOCH was shorter (10 months) than for patients treated with R-CHOP (29 months). PFS was not found to be significantly different between the DA-R-EPOCH and R-CHOP arms (10.4 months vs. 61.4 months; 95% CI, 1.80-18.99; p=0.31). Patients with EBV-positive disease had inferior PFS compared with EBV-negative disease (7.37 months vs. NR; 95% CI, 1.02-10.2; p=0.046). In addition, OS, neutropenia, thrombocytopenia, hospitalizations, and hospitalizations due to febrile neutropenia were not significantly different between groups, though trends toward higher rates of grade 3 or 4 neutropenia, thrombocytopenia, and hospitalizations was observed in the DA-R-EPOCH group.Conclusion: To our knowledge, this is the first study evaluating the role of intensive induction therapy in patients with HGBL with MYC and BCL2 rearrangements observed in solid organ transplant recipients. In patients with PTLD, DA-R-EPOCH is a well-tolerated regimen with concurrent taper in IST. However, this strategy may not overcome the poor prognosis of HGBL. Dose adjustments beyond level 2 were limited by cytopenias. [Display omitted] DisclosuresReddy:KITE: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees; GILEAD: Membership on an entity's Board of Directors or advisory committees; INFINITY: Membership on an entity's Board of Directors or advisory committees.

EBV-negative monomorphic B-cell post-transplant lymphoproliferative disorders are pathologically distinct from EBV-positive cases and frequently contain TP53 mutations

AbstractMonomorphic post-transplant lymphoproliferative disorder commonly resembles diffuse large B-cell lymphoma or Burkitt lymphoma, and most are Epstein–Barr virus (EBV) positive. We retrospectively identified 32 cases of monomorphic post-transplant lymphoproliferative disorder from two institutions and evaluated EBV in situ hybridization; TP53 mutation status; p53, CD30, myc, and BCL2 expression by immunohistochemistry; proliferation index by Ki67; and germinal center vs non-germinal center immunophenotype by Hans criteria. Post-transplant lymphoproliferative disorder arose after hematopoietic stem cell transplant in five and solid organ transplant in 27 patients, a median of 4 and 96 months after transplant, respectively (overall median latency 71 months, range 2–295). The most common morphology was diffuse large B-cell lymphoma (28 cases), with three cases of Burkitt lymphoma, and one case of plasmablastic lymphoma. Ten cases (31%) were EBV negative. Of those with the morphology of diffuse large B-cell lymphoma, the EBV-negative cases were more frequently TP53-mutated (P<0.001), p53 positive by immunohistochemistry (P<0.001), CD30 negative (P<0.01), and of germinal center immunophenotype (P=0.01) compared with EBV-positive cases. No statistically significant difference in overall survival was identified based on EBV, TP53 mutation status, germinal center vs non-germinal center immunophenotype, or other immunohistochemical parameters evaluated. Patients who died of post-transplant lymphoproliferative disorder were older with a longer latency from time of transplant to diagnosis (P<0.05). Our study demonstrates that diffuse large B-cell lymphoma-related immunohistochemical prognostic markers have limited relevance in the post-transplant setting and underscores differences between EBV-positive and EBV-negative post-transplant lymphoproliferative disorder in terms of immunophenotype and TP53 mutation frequency, supporting an alternative pathogenesis for EBV-negative post-transplant lymphoproliferative disorder.