Treatment Of Post-transplant Lymphoproliferative Disorder Research Articles

EBV Reactivation and Disease in Allogeneic Hematopoietic Stem Cell Transplant (HSCT) Recipients and Its Impact on HSCT Outcomes.

The acquisition or reactivation of Epstein-Barr virus (EBV) after allogeneic Hematopoietic Stem Cell Transplant (HSCT) can be associated with complications including the development of post-transplant lymphoproliferative disorder (PTLD), which is associated with significant morbidity and mortality. A number of risk factors for PTLD have been defined, including T-cell depletion, and approaches to monitoring EBV, especially in high-risk patients, with the use of preemptive therapy upon viral activation have been described. Newer therapies for the preemption or treatment of PTLD, such as EBV-specific cytotoxic T-cells, hold promise. Further studies to help define risks, diagnosis, and treatment of EBV-related complications are needed in this at-risk population.

The IPTA Nashville consensus conference on post-transplant lymphoproliferative disorders after solid organ transplantation in children: IV-consensus guidelines for the management of post-transplant lymphoproliferative disorders in children and adolescents.

The International Pediatric Transplant Association convened an expert consensus conference to assess current evidence and develop recommendations for various aspects of care relating to post-transplant lymphoproliferative disorders (PTLD) after pediatric solid organ transplantation. This report addresses the outcomes of deliberations by the PTLD Management Working Group. A strong recommendation was made for reduction in immunosuppression as the first step in management. Similarly, strong recommendations were made for the use of the anti-CD20 monoclonal antibody (rituximab) as was the case for chemotherapy in selected scenarios. In some scenarios, there is uncoupling of the strength of the recommendations from the available evidence in situations where such evidence is lacking but collective clinical experiences drive decision-making. Of note, there are no large, randomized phase III trials of any treatment for PTLD in the pediatric age group. Current gaps and future research priorities are highlighted.

#99 Clinical characteristics and outcomes of PTLD after kidney transplant: a single center experience

Abstract Background and Aims Post-Transplant Lymphoproliferative Disorder (PTLD) is a serious and potentially fatal complication of immunosuppression in kidney transplantation. Given the rarity of this entity, a high index of suspicion is necessary. We aimed to review the incidence, clinical presentation, histological subtypes, treatment, patient and graft survival of PTLD in kidney transplant patients in our unit. Methods Observational retrospective study, including adults diagnosed with PTLD between 1998 and 2023 in a Kidney Transplantation Center. Results Of 1390 kidney transplant recipients, 4 (0.3%) developed PTLD with a mean age of 52 ± 12.5 years. All cases were late-onset, occurring one year after transplantation with a median time from transplantation to diagnosis of 16.7 ± 7.3 years (range: 5-22 years). Of these, none had EBV donor/recipient mismatch. Two patients had prior rejection episodes (one patient, acute T cell-mediated rejection and the other patient, acute T cell-mediated rejection and active antibody mediated rejection). Clinical presentation was variable. Non-specific constitutional symptoms such as fever, fatigue and night sweats were present in all patients. Organ-specific symptoms were also present: lumbar pain in one patient with bone involvement, and delirium and lethargy in two patients with central nervous system involvement. Laboratory analyses revealed an increase in serum LDH in all patients. The primary sites of involvement were central nervous system (50%), lymph nodes (25%) and bone (25%). At PTLD diagnosis, immunosuppression included: tacrolimus (100%), mycophenolate mofetil (75%), low-dose of steroids (50%) and everolimus (25%). Regarding histologic classification, 75% were monomorphic and 25% polymorphic. In the monomorphic group, all patients had Diffuse Large B Cell Lymphoma (CD20 positive). In the polymorphic group, the patient had a Mixed Cellularity Classic Hodgkin Lymphoma (CD20 negative). Immunosuppression therapy was reduced in all patients with discontinuation of mycophenolate mofetil and tacrolimus. In the patient who was taking everolimus, the dose was increased due to the potential clinical antitumor effects of mTOR inhibition. Additional therapies included, rituximab in monotherapy or in combination with chemotherapy (R-CHOP) in the monomorphic group. Palliative measures were selected for one patient of this group due to advanced disease. The patient with Mixed Cellularity Classic Hodgkin Lymphoma (CD20 negative) did chemotherapy with ABVD. None of the patients underwent surgery or radiation therapy. Two patients needed dialysis. Three patients died in the first four weeks after PTLD diagnosis, all due to infectious complications. Patient survival was 25% one year after diagnosis. Conclusions Although the incidence of PTLD was low following kidney transplantation, its impact was significant in kidney graft and overall patient survival. Given the poor prognosis, new therapies combining high efficacy and low toxicity are an urgent unmet medical need in this field.

Ibrutinib as part of risk-stratified treatment for posttransplant lymphoproliferative disorder: the phase 2 TIDaL trial

AbstractPosttransplant lymphoproliferative disorder (PTLD) is a rare complication of solid organ transplantation, and cytotoxic chemotherapy is associated with treatment-related morbidity and mortality. Current treatment takes a sequential, risk-stratified approach, and patients with low-risk disease after initial immunotherapy can avoid escalation to immunochemotherapy. TIDaL is a prospective, single-arm phase 2 trial investigating the activity and tolerability of ibrutinib combined with risk-stratified therapy for first-line treatment of PTLD. Eligible patients were adults with newly diagnosed CD20+ B-cell PTLD after solid organ transplant and performance status 0 to 2. Initial treatment comprised 49 days of ibrutinib 560 mg once daily, with 4 doses of weekly rituximab. Treatment response on interim scan and baseline International Prognostic Index were used to allocate patients to either a low-risk arm (who continued ibrutinib, alongside 4 further doses of 3-weekly rituximab) or high-risk (escalation to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP] immunochemotherapy, with ibrutinib continuing in patients aged <65 years). The primary outcome was complete response on interim scan, achieved by 11 of 38 patients (29%; 95% confidence interval [CI], 15-46). This did not reach the prespecified threshold for clinically significant activity. Secondary outcomes included allocation to the low-risk arm (41% of patients), 2-year progression-free survival (58%; 95% CI, 44-76), and 2-year overall survival (76%; 95% CI, 63-91). Adverse events were mostly hematological, gastrointestinal, and infective. Although TIDaL does not support adding ibrutinib into first-line treatment of PTLD, increasing the proportion of patients who can be treated without cytotoxic chemotherapy remains an important aim of future research. This trial was registered at www.clinicaltrials.gov as #ISRCTN32667607.

Post-transplant Lymphoproliferative Disorder (PTLD) in the US Population: Demographics, Treatment Characteristics, and Survival Analysis.

Post-transplant lymphoproliferative disorder (PTLD) is a lymphoplasmacytic proliferative disorder in the setting of hematopoietic stem cells and solid organ transplants. PTLD is divided into nondestructive, polymorphic, monomorphic, and classical Hodgkin lymphoma subtypes. Most cases of PTLDs are Epstein-Barr virus (EBV) related (two third of the cases), and most are of B cell (80-85%) origin. The polymorphic PTLD subtype can be locally destructive and show malignant features. Treatment for PTLD includes a reduction in immunosuppression, surgery, cytotoxic chemotherapy and/or immunotherapy, anti-viral agents, and/or radiation. The aim of this study was to examine the demographic factors and treatment modalities that influence survival in patients with polymorphic PTLD. About 332 cases of polymorphic PTLD were identified from 2000 to 2018 using the Surveillance, Epidemiology, and End Results (SEER) database. The median age of the patients was found to be 44 years. The most common age groups were between the ages of 1-19 years (n=100. 30.1%) and 60-69 years (n=70. 21.1%). The majority of cases in this cohort underwent systemic (cytotoxic chemo and/or immuno) therapy only (n=137, 41.3%), while 129 (38.9%) cases did not undergo any treatment. The overall five-year observed survival was 54.6% (95% confidence interval (CI), 51.1 - 58.1). One-year and five-year survival with systemic therapywas 63.8% (95% CI, 59.6 - 68.0) and 52.5% (95% CI, 47.7 - 57.3), respectively. The one-year and five-year survival with surgerywas 87.3% (95% CI, 81.2-93.4) and 60.8% (95% CI., 42.2 - 79.4), respectively. The one-year and five-year without therapy were 67.6% (95% CI, 63.2-72.0) and 49.6% (95% CI, 43.5-55.7), respectively. Univariate analysis revealed thatsurgery alone (hazard ratio (HR) 0.386 (0.170-0.879), p = 0.023) was a positive predictor of survival. Race and sex were not predictors of survival, although age >55 years was a negative predictor for survival (HR 1.128 (1.139-1.346), p <0.001). Polymorphic PTLD is a destructive complication of organ transplantation that is usually associated with EBV positivity. We found that it most often presents in the pediatric age group, and its occurrence in those older than 55 years was associated with a worse prognosis. Treatment with surgery alone is associated with improved outcomes and should be considered in addition to a reduction in immunosuppression in cases of polymorphic PTLD.

(1125) Use of Donor-Derived Cell Free DNA for Rejection Surveillance in Pediatric Heart Transplant Patients Undergoing Treatment for Post-Transplant Lymphoproliferative Disorder: A Pilot Study

(1125) Use of Donor-Derived Cell Free DNA for Rejection Surveillance in Pediatric Heart Transplant Patients Undergoing Treatment for Post-Transplant Lymphoproliferative Disorder: A Pilot Study

Post‐transplant lymphoproliferative disorder: Update on treatment and novel therapies

Post-transplant lymphoproliferative disorder (PTLD) is rare and heterogeneous lymphoid proliferations that occur as a result of immunosuppression following solid organ transplant (SOT) and haematopoietic stem cell transplant (HSCT) with the majority being driven by EBV. Although some histologies are similar to lymphoid neoplasms seen in immunocompetent patients, treatment of PTLD may be different due to difference in pathobiology and higher risk of treatment complications. The most common treatment approach in SOT PTLD after failing immunosuppression reduction (RIS) takes into consideration a risk-stratified sequential algorithm with rituximab +/- chemotherapy based on phase 2 studies. In HSCT PTLD, RIS alone and chemotherapy are usually ineffective making rituximab +/- RIS as the gold standard of frontline treatment. In this review, we give an update on the treatment of PTLD beyond RIS. We highlight the most recent studies that attempted to incorporate more aggressive chemotherapy regimens and novel treatments into the traditional risk-stratified sequential approach. We also discuss the role of EBV-cytotoxic T lymphocytes in treatment of EBV-driven PTLD. Other novel agents with potential role in PTLD will be discussed in addition to the challenges that could arise with chimeric antigen receptor T-cell therapy and immune checkpoint inhibitors in this population.

Rituximab, Cyclophosphamide, Etoposide and Prednisone for the Treatment of Post-Transplantation Lymphoproliferative Disorder

Introduction: Post-transplantation lymphoproliferative disorder (PTLD) is a rare disorder with few established therapies. Solid organ transplant (SOT) patients who develop PTLD are often frail. While some patients respond to reduction of immunosuppression (RI) or rituximab monotherapy, aggressive or relapsed disease frequently requires chemoimmunotherapy. Rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) is a standard of care first-line chemoimmunotherapy for large B-cell lymphomas, but this regimen is often poorly tolerated by frail SOT patients with significant mortality, early discontinuation of therapy, neuropathy and cardiac toxicity. We report our institutional experience with rituximab, cyclophosphamide, etoposide, prednisone (R-CEP), as an alternative, anthracycline-sparing regimen for patients with PTLD. Methods: We retrospectively reviewed records within the Lymphoma Program of the University of Pennsylvania to identify patients who received R-CEP for PTLD. R-CEP was administered on day 1 of each cycle, every 3 weeks for six total cycles in outpatient clinic: rituximab 375 mg/m2 IV, cyclophosphamide 750 mg/m2 IV, and etoposide 100 mg/m2 IV. Three patients received alternative etoposide dosing administered as 50mg/m2 IV on days 1-3. Prednisone was optional and administered at physician discretion; doses ranged from continuous SOT immunosuppression dose to 100 mg daily on days 1 to 5 of each cycle. Overall response rates (ORR), progression free survival (PFS), response duration (RD), and overall survival (OS) were assessed. Adverse effects were described by CTCAE v5. Results: Thirty-four patients were identified (see Table 1 for Patient Characteristics). Eleven patients (32%) initially were managed with RI alone; 2 of 11 (18%) responded for ≥ 6 months before progressive disease (PD). Twenty-four patients (71%) received rituximab monotherapy (either initially or for PD after RI) with 14 of 24 (58%) responding for ≥ 6 months before PD. All who received RI and/or rituximab monotherapy had PD before starting R-CEP. Seven patients (21%) were first treated with R-CEP due to aggressive initial presentation of PTLD. ORR at six months after completion of R-CEP was 47% with 15 complete responses (CR) and 1 partial response (PR). Median follow-up was 9.8 years (range 0.25-12 years). 46% and 41% of patients remained progression-free at 24 and 60 months, respectively (Figure 1). Median response duration (RD) was 47 months (95%CI: 5-NE). Of those who achieved CR at 6 months, median RD was not reached; 93% and 83% of patients in CR maintained responses at 24 and 60 months, respectively. Median OS was 45 months (95%CI: 13-NE), with 58% and 47% of patients alive at 24 and 60 months, respectively. Of the 21 patients who died, 12 (57%) died from PD, 2 (9%) from infections after receiving further salvage therapy, and the remainder from causes unrelated to PTLD. Fifty percent of patients received their first cycle while hospitalized. Seventy-four percent of patients had neutropenia (41% grade 3-4 neutropenia) and 23% had febrile neutropenia. Eight patients had grade 3-4 anemia and 6 developed grade 3-4 thrombocytopenia. Ten patients (29%) required hospitalization during treatment, most commonly for febrile neutropenia, anemia, or dehydration. There were no instances of neuropathy, cardiac toxicity, or treatment-related mortality. Of the 18 patients who did not complete all 6 cycles of chemoimmunotherapy, 11 (61%) stopped due to PD, 4 (22%) due to toxicity (most commonly cytopenias), 2 (11%) elected early stop after achievement of CR, and 1 (6%) due to a need for treatment of a secondary primary malignancy. Patients with PD commonly received R-CHOP for systemic progression (including heart transplant recipients) or radiation therapy for localized disease. Conclusions: R-CEP is a promising alternative to R-CHOP for frail PTLD patients based on our observed efficacy and toxicity and warrants further investigation. Cytopenias were less common than historically reported for PTLD patients treated with R-CHOP (Trappe et al 2012). There was no treatment-related mortality, whereas reported treatment-related mortality with R-CHOP for PTLD is 11% (Trappe et al 2012). Study limitations include its retrospective nature, small sample size, and heterogeneous PTLD population with respect to SOT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

End of Treatment Positron Emission Tomography Response and Outcomes in Post-Transplant Lymphoproliferative Disorder

Introduction: Although end of treatment (EOT) response assessment using Fluorine-18-fluorodeoxyglucose positron emission tomography (PET) has proven highly predictive of disease remission in Hodgkin lymphoma (HL) and aggressive non-Hodgkin lymphoma, there is little data on the prognostic significance of PET response in patients with post-transplant lymphoproliferative disorder (PTLD). Optimal treatment of patients with PTLD is complex and better understanding of the significance of EOT imaging could help guide subsequent therapeutic decisions. Methods: As part of a multi-institutional study of viral genomes in PTLD, we collected clinical data (demographics, transplant and PTLD characteristics, treatment, imaging, and patient survival) from three large organ transplant centers in the United States from 1991 onwards. Patients who were PET negative at EOT considered to have a complete remission (CR), patients with decrease in FDG avidity who were still PET positive considered to have a partial remission (PR), and patients with stable or increasing FDG avidity considered to have no remission or progressive disease (NR/PD). Time-to-event outcomes (time to death and time to death or relapse) were analyzed using the Kaplan Meier method. Results: Among 147 pediatric and adult patients with PTLD, imaging at diagnosis and EOT included PET n=94 (64%), computed tomography (CT) n=77 (53%), and/or magnetic resonance imaging (MRI) n=14 (10%). Median recipient age at first transplant was 29.6 years (IQR 14.8 to 25.9), and 57.5% were male. Transplants included kidney (29%), heart (27%), liver (18%), lung (18%), hematopoietic (7%), intestine (6%), or pancreas (3%). Sites of PTLD were lymph node (57%), gastrointestinal tract (34%), lung (19%), disseminated (10%), liver (8%), central nervous system (4%), kidney (3%), bone marrow (3%), or other (41%). PTLD subtypes included monomorphic diffuse large B-cell lymphoma (DLBCL) (69%), polymorphic (17%), classical HL (8%), or non-destructive (5%). All non-destructive and polymorphic PLTD was Epstein-Barr virus (EBV) positive while 60.6% of DLBCL and 75% of classical HL were EBV positive. Treatments varied but included reduction of immunosuppression in 65.6% and rituximab or chemotherapy in 62.4% of patients. For 84 patients with PET scans and outcome data, patients who achieved CR (59/84; 70.2%) experienced a subsequent progression-free median survival of 13.5 years compared with 8.8 years for patients with PR (11/84; 13.1%) and 1.4 years for patients with NR/PD (14/84; 16.7%) (p<0.0001, Figure A). Median overall survival was 14.7 years for patients with CR (60/85; 70.6%), not reached for patients with PR (11/85; 12.9%), and 1.4 years for patients with NR/PD (14/85; 16.5%) (p=0.0026, Figure B). 20.8% of patients who achieved CR subsequently relapsed compared to 42.9% of patients with PR. 81.8% of patients with NR/PD experienced relapse or death. Conclusion: End of therapy PET identifies a subgroup of patients with CR who are at low risk for relapse. While patients with NR/PD had poor prognosis, patients with PR represent an intermediate group who are PET positive at the EOT but can achieve long-term remission without additional therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Posttransplant Lymphoproliferative Disorder (PTLD) Following Transplantation at Northwestern University: Choice of Immunosuppressive Agents Does Not Impact Outcomes in PTLD

Background: Posttransplant lymphoproliferative disorder (PTLD) is a spectrum of lymphoid diseases associated with the use of potent immunosuppressive drugs following solid organ or hematopoietic stem cell transplantation. The most widely accepted mechanism of PTLD pathogenesis is diminished cytotoxic T-lymphocyte and natural killer cell function, resulting from post-transplant immunosuppressive therapy, allowing for unregulated proliferation of lymphocytes infected with Epstein-Barr virus (EBV). However, approximately 1/3 of the cases of PTLD occur in EBV-negative individuals, suggesting additional immunopathologic mechanisms of disease pathogenesis. Immunosuppressive therapy with the calcineurin inhibitor tacrolimus and antimetabolite azathioprine have both demonstrated higher risk for developing PTLD than other immunosuppressive regimens. However, limited information exists regarding the relationship between immunosuppressive agents and outcomes in PTLD. Here we report the results of a single-center, retrospective analysis with the primary objective to examine whether post-transplant immunosuppressive agents impact outcomes in PTLD. Methods: Patients (pts) with a diagnosis of PTLD were identified by Electronic Medical Records database query. Inclusion criteria were age ≥ 18 years at the time of diagnosis, confirmation of PTLD by internal pathology review, primary diagnosis from 2008-2018, and receipt of therapy and surveillance care at Northwestern University in Chicago, Illinois, USA. Exploratory univariate analyses were performed using Kaplan-Meier estimates with 95% confidence intervals and log-rank p-values for time-to-event outcomes; significance was set at p < 0.05. Response to treatment and disease progression were classified per provider-specific interpretations of clinical data as assessed by patient chart review. Results: A total of 182 pts with a diagnosis of PTLD were identified by database query and 111 pts met inclusion criteria. Of the 111 pts included in this analysis; 82 pts (73.9%) were male with a median age at diagnosis of 56yrs (range 19-85) [Table 1]. The median time from transplant to diagnosis of PTLD was 78.9 months (range 2-324). Eighty-four pts (75.7%) received immunosuppression with a multi-drug regimen, with the most common combination of medications being mycophenolate mofetil and tacrolimus (n=54, 48.6%). Overall, 85 pts (76.6%) were treated with a tacrolimus containing regimen, 68 pts with mycophenolate, 26 pts with prednisone, 11 pts with azathioprine, 8 pts with cyclosporine, 5 pts with sirolimus, and 3 pts with a disease-modifying antirheumatic drug (DMARD) [Table 2]. Immunosuppression was decreased in 100 out of the 111 pts prior to starting treatment for PTLD and 11 pts were treated with immunosuppression reduction alone [Table 1]. Eighteen pts (16.2%) experienced graft rejection, of which 27.8% required re-transplantation. For all pts, the five-year OS and PFS were 70.7% and 49.7%, respectively. When stratified by exposure to different immunosuppressive agents, there was no difference in outcomes across all groups [Table 2]. Conclusions: Here we report one of the largest retrospective cohorts of pts with PTLD reported in the literature. Our analysis suggests that choice of immunosuppressive agent in the post-transplant setting does not impact outcomes in PTLD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Management of Resistant Post-transplant Lymphoproliferative Disorder: CAR-T Is a New Option.

This is a review of the therapeutic options for resistant/refractory post-transplant lymphoproliferative disorder (PTLD) in relation to Chimeric antigen receptor-T cell (CAR-T) therapy. Out of a number of possible future strategies for the treatment of PTLD, the following methods were implemented in real-world practice: anti-PD1 therapy with checkpoint inhibitor nivolumab, new anti-CD20 ofatumumab, brentuximab vedotin, and zanubrutinib. However, for all these innovative methods, only individual cases of successful treatment of rituximab-resistant Epstein-Barr Virus (EBV)-PTLD patients have been reported so far. CAR-T is an innovative method of treatment, based on genetic modification of receptors of T autologous lymphocytes, creating the "living drug". This therapy can be potent against resistant PTLD, which is a lymphoproliferation of B-lymphocytes. The published real-world data of 17 patients treated with CAR-T for PTLD indicate a success rate of 76.5%. There is development of innovative methods of treatment of resistant/refractory PTLD, with high rate of resolution after CAR-T therapy.

424.13: The Diagnosis and Treatment of Posttransplant Lymphoproliferative Disorder in Pediatric Liver Transplant Recipients

424.13: The Diagnosis and Treatment of Posttransplant Lymphoproliferative Disorder in Pediatric Liver Transplant Recipients

Reduction of Immunosuppression Based on Whole Blood EBV-Viral Loads in Lung Transplant Recipients

<h3>Purpose</h3> Post-transplant lymphoproliferative disorder (PTLD) is a rare but serious complication of transplantation affecting 10% of lung transplant recipients with an overall survival of 39%. Reduction of immunosuppression (RIS) for clinically suspected PTLD is included in guidelines for the treatment of PTLD. Pre-emptive RIS based on EBV DNA load is controversial with small scale studies with anecdotal evidence guiding clinical practice. We evaluated our policy of pre-emptive RIS for PTLD incidence, acute rejection, survival and CLAD in a patient control study. <h3>Methods</h3> 26 patients underwent RIS, eight of these patients received prophylactic rituximab. 52 patients were matched for age, date of transplantation, gender, and cystic fibrosis. 26 of these patients were additionally chosen for high EBV-DNA load. Risk of PTLD, acute rejection, overall survival and CLAD was analysed using Kaplan-Meier survival analysis. <h3>Results</h3> EBV DNA loads were different between the groups (p<0.001) with the RIS group having the highest level and more primary EBV infections (table 1). Acute rejection was seen 7.3 years after RIS and 11.7 and 12.3 in the matched groups (p=0,1). Overall CLAD developed earlier in the RIS group but only years after RIS (table 1). Survival and development of PTLD were not different between the groups. Time to PTLD from RIS was also not different (p=0.5, log-rank test). <h3>Conclusion</h3> Pre-emptive RIS based on EBV DNA load did not lead to a concomitant increase in acute rejection episodes, a change in overall survival or a short term increase in chronic lung allograft rejection (CLAD) diagnosis. We conclude that RIS was safe although this analysis cannot prove a reduction in the incidence of PTLD in this high risk PTLD group. A prospective randomized study for EBV DNA guided RIS possibly with pre-emptive rituximab is needed.

Epstein-Barr virus-associated lymphoproliferative disorder of donor origin after heart transplantation

Post-Transplant Lymphoproliferative Disorder (PTLD) represents a group of lymphomas, which may develop after solid organ transplantation and decrease the survival of transplant recipients. The main challenge of treatment is to achieve disease remission by avoiding the risk of allograft rejection. This report describes a successful treatment of PTLD in an adult patient who underwent allogeneic stem cell transplantation as a child and cardiac transplantation as a young adult. We present the case of a 33-year-old female, who was diagnosed with a Diffuse Large B-Cell Lymphoma (DLBCL) triggered by Epstein - Barr virus (EBV) 8 months after receiving orthotopic heart transplantation from an EBV-positive donor. The patient was treated with R-CHOP chemotherapy followed by maintenance therapy with rituximab, resulting in complete morphologic and metabolic remission of the lymphoma. The echocardiographic examinations and routine endomyocardial biopsies performed during and after chemotherapy did not reveal any signs of cardiac allograft rejection. The patient was asymptomatic on Heart Failure (HF) therapy and continued to remain in complete remission after the cancer treatment. This case underlines the importance of timely surveillance and treatment of seronegative patients after receiving EBV-positive donor organs. Keywords: post-transplant lymphoproliferative disorder; EpsteinBarr virus; immunosuppression; cardiac transplantation; chemotherapy

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

Clinical Outcomes of Solid Organ Transplant Patients with Epstein-Barr Virus-Driven (EBV +) Post-Transplant Lymphoproliferative Disorder (PTLD) Who Fail Rituximab Plus Chemotherapy: A Multinational, Retrospective Chart Review Study

Introduction: Post-transplant lymphoproliferative disorder (PTLD) is a rare and often aggressive disease in the setting of immunosuppression following solid organ transplant (SOT). Epstein-Barr virus (EBV) infection of B cells is responsible for about 50% of cases, either due to reactivation of the virus after transplantation or primary EBV infection. Although there is no approved therapy for patients (pts) with PTLD, guidelines include reduction of immunosuppression (RIS) as a part of initial treatment and may be sufficient for pts with early lesions. Rituximab, either as monotherapy or in combination with chemotherapy (CT), is used in addition to RIS as initial treatment. Pts with EBV + PTLD following SOT who fail rituximab plus CT have poor outcomes with limited treatment options. There are ongoing clinical studies investigating innovative therapies to address unmet needs in these pts. Published data on clinical outcomes of these pts remain limited and not well documented. We aimed to characterize the outcomes for pts diagnosed with EBV + PTLD following SOT who fail initial rituximab plus CT in a multi-national real-world setting.Methods: We conducted a large multinational, multicenter, retrospective chart review study of pts with EBV + PTLD following allogeneic hematopoietic cell transplantation (HCT) or SOT who received rituximab or rituximab plus CT between January 2000‒December 2018 and were refractory (failed to achieve complete response [CR] or partial response [PR]) or relapsed at any point after such therapy. Treatment response was assessed either by clinical diagnosis, radiographic/imaging, biopsy/cytology, or a combination of such assessments. Data were collected from 29 centers across North America (United States and Canada) and the European Union. Study population was aligned to the ongoing investigational trial (Clinicaltrials.gov Identifier: NCT03394365). This analysis includes pts with EBV + PTLD following SOT who were refractory/relapsed to rituximab plus CT. The Kaplan-Meier method was utilized to estimate the overall survival (OS).Results: A total of 86 pts with EBV + PTLD following SOT who failed rituximab plus CT were included in the analysis; 65 (75.6%) pts were refractory while 21 (24.4%) relapsed after initial response of CR or PR. Median age at PTLD diagnosis was 43 years (range 1‒78) and median time to PTLD onset from transplant was 1.7 years (range 0.1‒27.9). Median follow up time was 12.9 months from the date of PTLD diagnosis. PTLD histological subtypes were 66 (76.7%) monomorphic, 18 (20.9%) polymorphic, and 2 (2.3%) early lesions. The most common PTLD subtype was diffuse large B-cell lymphoma (DLBCL) (58, 67.4%).Of the 86 pts, 49 (57%) received CT following rituximab monotherapy while 37 (43%) pts received CT concurrently with rituximab. Overall, 63 (73.3%) pts died. PTLD-specific mortality was observed in 41 (65.1%) pts, treatment-related mortality in 10 (15.9%) pts, mortality due to organ rejection/failure in 2 (3.2%) pts, mortality due to other causes in 7 (11.1%) pts, and mortality due to unknown causes in 3 (4.8%) pts. Median OS was 15.5 months (95% confidence interval [CI]: 8.3‒22.9) from PTLD diagnosis, and was 4.1 months (95%CI: 1.9‒8.5) from the earliest date when pts became refractory or relapsed following rituximab plus CT.Conclusions: The prognosis for pts with EBV + PTLD following SOT who fail rituximab plus CT remains poor, with an estimated median OS of about 4 months and a majority of pts dying from PTLD and related treatment. In this specific population, there remains a significant unmet medical need for effective and well-tolerated therapies. [Display omitted] DisclosuresDharnidharka: Merck, Pfizer, Medronic, Cardinal Health: Current holder of stock options in a privately-held company; CareDx: Honoraria, Research Funding; Atara Bio, MedinCell: Consultancy. Thirumalai: Atara Biotherapeutics: Current Employment. Jaeger: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Norvartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zhao: Atara Biotherapeutics: Current Employment. Dierickx: Roche: Consultancy, Research Funding; Novartis: Consultancy; Sanofi: Consultancy; Sandoz: Consultancy; Takeda, Incyte, Atara: Consultancy. Xun: Atara Biotherapeutics: Current Employment. Sawas: Flat Iron Health: Current Employment; Roche: Current holder of stock options in a privately-held company; Seattle Genetics, Acrotech: Consultancy; Daiichi-Sankyo, Seattle Genetics, Gilead: Other: Travel, accommodation, expenses, Speakers Bureau; Affimed, Trillium: Research Funding. Sadetsky: Atara Biotherapeutics: Current Employment. Barlev: Atara Biotherapeutics: Current Employment. Zimmermann: Roche, Atara: Research Funding; Celgene, Roche, Atara, Jansen: Other: Travel accomodations. Trappe: Celgene: Other: Travel support; Roche: Other: Travel support; Atara Biotherapeutics: Consultancy, Other: Travel support, Research Funding; Jansen: Other: Travel support; GSK: Other: Travel support; AbbVie: Other: Travel support.

EBV‐specific cytotoxic T lymphocytes for refractory EBV‐associated post‐transplant lymphoproliferative disorder in solid organ transplant recipients: a systematic review

The use of Epstein-Barr virus-specific cytotoxic T lymphocytes (EBV-CTLs) in adoptive immunotherapy in hematopoietic stem cell transplantation (HSCT) patients with post-transplantation lymphoproliferative disorder (PTLD) has demonstrated safety and effectiveness. EBV-CTLs might also be the effective treatment of refractory PTLD of solid organ transplantation (SOT) recipients. Two independent assessors searched Pubmed, Embase, Cochrane Library, and Web of Science from their inception to November 2020. Eleven studies with 76 patients (42, 55% male) were included. We extracted the data and completed the quality assessments. Most of the studies were from Europe and the USA. Liver and kidney transplantation accounted for most of the transplant types. Thirty-five (46.1%) patients were diagnosed with monomorphic PTLD, and B lymphocyte type was the most common. All the patients received primary treatment for PTLD while it was ineffective. CTLs included autologous EBV-CTLs (15/76, 22%) and HLA-matched third-party EBV-CTLs (61/76, 78%). The response rate for EBV-CTL treatment of refractory PTLD was 66%. Of 50 patients, 36 achieved complete remission and 14 achieved partial remission. EBV-DNA level decreased in 39 patients. Adverse reactions were rare and mild. We conclude that adoptive therapy with EBV-specific CTLs is safe, well-tolerated, and effective in PTLD.

Effect of preoperative long-term use of corticosteroids on the development of post-transplant lymphoproliferative disorders after lung transplantation: a single-center experience in Japan.

Post-transplant lymphoproliferative disorder (PTLD) is a major complication of lung transplantation (LTx). However, few studies on PTLD in Asian populations have been reported. We explored the characteristics of Japanese PTLD cases after LTx. We retrospectively reviewed 195 cases of LTx at our institute. We summarized the clinical experiences of 7 PTLD cases and analyzed the patient characteristics and survival outcomes of patients with (n = 7) and without (n = 188) PTLD. All PTLD patients were taking corticosteroids preoperatively (p = 0.0030), and the duration of preoperative corticosteroid therapy was significantly longer in the PTLD group (p = 0.0064) than in the non-PTLD group. The overall survival after LTx was significantly worse in the PTLD group (p = 0.027) than in the non-PLTD group. Among the three patients who died within 1year after the PTLD onset, two died of opportunistic infections without residual PTLD lesions. Chronic lung allograft dysfunction (CLAD) or bronchiolitis obliterans at an autopsy were diagnosed after PTLD treatment in four cases. Long-term preoperative corticosteroid therapy may be a risk factor for PTLD after LTx. Opportunistic infections are lethal complications of PTLD, regardless of the effectiveness of PTLD treatment. CLAD occurs at a high rate after PTLD treatment, and close monitoring is required.

Epstein Barr Virus: Development of Vaccines and Immune Cell Therapy for EBV-Associated Diseases.

Epstein-Barr virus (EBV) is the first human tumor virus discovered and is strongly implicated in the etiology of multiple lymphoid and epithelial cancers. Each year EBV associated cancers account for over 200,000 new cases of cancer and cause 150,000 deaths world-wide. EBV is also the primary cause of infectious mononucleosis, and up to 70% of adolescents and young adults in developed countries suffer from infectious mononucleosis. In addition, EBV has been shown to play a critical role in the pathogenesis of multiple sclerosis. An EBV prophylactic vaccine that induces neutralizing antibodies holds great promise for prevention of EBV associated diseases. EBV envelope proteins including gH/gL, gB and gp350 play key roles in EBV entry and infection of target cells, and neutralizing antibodies elicited by each of these proteins have shown to prevent EBV infection of target cells and markedly decrease EBV titers in the peripheral blood of humanized mice challenged with lethal dose EBV. Recent studies demonstrated that immunization with the combination of gH/gL, gB and/or gp350 induced markedly increased synergistic EBV neutralizing activity compared to immunization with individual proteins. As previous clinical trials focused on gp350 alone were partially successful, the inclusion of gH/gL and gB in a vaccine formulation with gp350 represents a promising approach of EBV prophylactic vaccine development. Therapeutic EBV vaccines have also been tested clinically with encouraging results. Immunization with various vaccine platforms expressing the EBV latent proteins EBNA1, LMP1, and/or LMP2 promoted specific CD4+ and CD8+ cytotoxic responses with anti-tumor activity. The addition of EBV envelope proteins gH/gL, gB and gp350 has the potential to increase the efficacy of a therapeutic EBV vaccine. The immune system plays a critical role in the control of tumors, and immune cell therapy has emerged as a promising treatment of cancers. Adoptive T-cell therapy has been successfully used in the prevention and treatment of post-transplant lymphoproliferative disorder. Chimeric antigen receptor T cell therapy and T cell receptor engineered T cell therapy targeting EBV latent proteins LMP1, LMP2 and/or EBNA1 have been in development, with the goal to increase the specificity and efficacy of treatment of EBV associated cancers.

Validation of a Post-Transplant Lymphoproliferative Disorder Risk Prediction Score and Derivation of a New Prediction Score Using a National Bone Marrow Transplant Registry Database.

We externally validated Fujimoto's post-transplant lymphoproliferative disorder (PTLD) scoring system for risk prediction by using the Taiwan Blood and Marrow Transplant Registry Database (TBMTRD) and aimed to create a superior scoring system using machine learning methods. Consecutive allogeneic hematopoietic cell transplant (HCT) recipients registered in the TBMTRD from 2009 to 2018 were included in this study. The Fujimoto PTLD score was calculated for each patient. The machine learning algorithm, least absolute shrinkage and selection operator (LASSO), was used to construct a new score system, which was validated using the fivefold cross-validation method. We identified 2,148 allogeneic HCT recipients, of which 57 (2.65%) developed PTLD in the TBMTRD. In this population, the probabilities for PTLD development by Fujimoto score at 5 years for patients in the low-, intermediate-, high-, and very-high-risk groups were 1.15%, 3.06%, 4.09%, and 8.97%, respectively. The score model had acceptable discrimination with a C-statistic of 0.65 and a near-perfect moderate calibration curve (HL test p = .81). Using LASSO regression analysis, a four-risk group model was constructed, and the new model showed better discrimination in the validation cohort when compared with The Fujimoto PTLD score (C-statistic: 0.75 vs. 0.65). Our study demonstrated a more comprehensive model when compared with Fujimoto's PTLD scoring system, which included additional predictors identified through machine learning that may have enhanced discrimination. The widespread use of this promising tool for risk stratification of patients receiving HCT allows identification of high-risk patients that may benefit from preemptive treatment for PTLD. This study validated the Fujimoto score for the prediction of post-transplant lymphoproliferative disorder (PTLD) development following hematopoietic cell transplant (HCT) in an external, independent, and nationally representative population. This study also developed a more comprehensive model with enhanced discrimination for better risk stratification of patients receiving HCT, potentially changing clinical managements in certain risk groups. Previously unreported risk factors associated with the development of PTLD after HCT were identified using the machine learning algorithm, least absolute shrinkage and selection operator, including pre-HCT medical history of mechanical ventilation and the chemotherapy agents used in conditioning regimen.