Incidence Of Post-transplant Lymphoproliferative Disorder Research Articles

#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.

Long-term Safety in Epstein-Barr Virus-Seropositive Kidney-only Transplant Recipients Treated With Belatacept in Clinical Practice: Final Study Results From the ENLiST Registry.

Belatacept, a selective T-cell costimulation blocker, was associated with improved survival and renal function but also with a risk of posttransplant lymphoproliferative disorder (PTLD) in adult kidney transplant recipients in phase 3 trials. This registry examined long-term safety in Epstein-Barr virus (EBV)-seropositive kidney transplant recipients treated with belatacept. This US-based, prospective, voluntary, multicenter registry (Evaluating Nulojix Long-Term Safety in Transplant [ENLiST]) included adult EBV-seropositive kidney-only transplant recipients treated de novo (within 14 d of transplantation) with belatacept. Primary objectives were to estimate incidence rates of confirmed PTLD, central nervous system (CNS) PTLD, and progressive multifocal encephalopathy (PML). The minimum follow-up was 2 y. Of 985 enrolled transplant recipients, 933 EBV-seropositive patients received belatacept, with 523 (56.1%) receiving concomitant tacrolimus at transplant (for up to 12 mo). By study end, 3 cases of non-CNS PTLD (incidence rate, 0.08/100 person-years), 1 case of CNS PTLD (0.03/100 person-years), and no cases of PML had been reported. Two patients with non-CNS PTLD received concomitant belatacept and tacrolimus and 1 received belatacept and lymphocyte-depleting therapy. Incidence rates were comparable between patients who received concomitant belatacept and tacrolimus and those who did not receive tacrolimus (0.09/100 person-years and 0.07/100 person-years, respectively; P = 0.96). Two of 4 patients with PTLD died, and 2 were alive at the end of the study. Cumulatively, 131 graft losses or deaths were reported by study end. Our results from the ENLiST registry, a large, prospective real-world study, showed that the incidence rates of PTLD and CNS PTLD in belatacept-treated EBV-seropositive transplant recipients were consistent with findings from previous phase 3 trials.

The impact of induction therapy on the risk of posttransplant lymphoproliferative disorder in adult kidney transplant recipients with donor-recipient serological Epstein-Barr virus mismatch

Posttransplant lymphoproliferative disorder (PTLD) poses a significant concern in Epstein-Barr virus (EBV)–negative patients transplanted from EBV-positive donors (EBV R-/D+). Previous studies investigating the association between different induction agents and PTLD in these patients have yielded conflicting results. Using the Organ Procurement and Transplant Network database, we identified EBV R-/D+ patients >18 years of age who underwent kidney-alone transplants between 2016 and 2022 and compared the risk of PTLD with rabbit antithymocyte globulin (ATG), basiliximab, and alemtuzumab inductions. Among the 6620 patients included, 64.0% received ATG, 23.4% received basiliximab, and 12.6% received alemtuzumab. The overall incidence of PTLD was 2.5% over a median follow-up period of 2.9 years. Multivariable analysis demonstrated that the risk of PTLD was significantly higher with ATG and alemtuzumab compared with basiliximab (adjusted subdistribution hazard ratio [aSHR] = 1.98, 95% confidence interval [CI] 1.29-3.04, P = .002 for ATG and aSHR = 1.80, 95% CI 1.04-3.11, P = .04 for alemtuzumab). However, PTLD risk was comparable between ATG and alemtuzumab inductions (aSHR = 1.13, 95% CI 0.72-1.77, P = .61). Therefore, the risk of PTLD must be taken into consideration when selecting the most appropriate induction therapy for this patient population.

Incidence, Management and Outcome of Post-Transplant Lymphoproliferative Disease after 5797 Solid-Organ Transplants over a 30-Year Period in a Single Hospital

Introduction: Post-transplant lymphoproliferative disorders (PTLD) are heterogenous lymphoproliferative disorders that develop because of immunosuppression in transplant recipients. Epstein-Barr Virus (EBV) infection is a major risk factor for the development of PTLD. Its management generally involves a reduction in immunosuppression and initial treatment with rituximab monotherapy (RM). Aim: To present the epidemiology, management, and outcomes of PTLD in a large unicentric Spanish cohort of solid organ transplant (SOT) recipient who were transplanted over a 30-year period. Methods: This is a retrospective study of 5797 SOT recipients who had their first transplant between 1992 and 2021 at Hospital Universitario 12 de Octubre. For each type of transplant, we calculated the incidence rate of PTLD. OS (Overall survival) was analyzed using the Kaplan-Meier model and the log-rank test Prognostic impact of the main clinical, analytical variables and prognostic indexes were analyzed. Results: With a median follow-up of 16.4 years, 105 of 5797 SOT developed a monomorphic or Hodking-like PTLD (1.8%). The incidence was: 10% multivisceral transplantation (MVT), 2.8% heart, 2.3% liver, 2.2% lung, 1.4% kidney and 1.3% simultaneous kidney-pancreas (SPK). Median age at transplant was 48.3 (1-89) years. 12 were pediatric recipients' (1 lung, 1 kidney, 10 liver). 72% were men. Histochemical stains for Epstein-Barr virus (EBV) were performed in 75 of 105 diagnoses. EBER-positive histology was observed in the majority of patients (n = 44/77, 57%). Median time from transplantation to PTLD was 6.7 (0-16.4) years (21% in the 1st year post-transplant). In EBER-positive the onset was earlier (3.2 vs 9.2 years; p: .004) with 36% arising the 1st year post-transplant. 5-years cumulative incidence was 10% in MTV compared to 0.18%-1.6% in the rest. With a median follow-up of 6.9 years; median OS was 79.5 months, with no difference between type of organ transplanted, era of transplant, EBER histology or time from transplant to PTLD. Using logistic regression, age, beta-2-microglobulin (B2M), as well as the IPI, modified R-IPI, NCCN-IPI and GELTAMO-IPI prognostic indices were found to be significant prognostic factors for OS ( Table 1). Interestingly, the highest OS stratification was observed with the modified R-IPI, showing a median OS not reached in the low-risk group, versus 38 months at high risk and 3.2 months at very high risk (p<0.001). Immunosuppression (IS) was switched as the 1st therapeutic aptitude in 57% of the patients. Median OS was not reached in patients with IS switch (n=41) (plateau at 10 years; estimated OS 56%) vs. 15.3m for patients without IS switch (n=39) (P: .004) ( Figure 1). IS was reduced in 80%. It also reached OS impact (P: .05). There were 89 monomorphic patients who were treated as follows: RM (n=22), R-Chemotherapy (n=37), chemotherapy (n=6), no treatment (n=7), unknown (n=16). Of the 22 RM patients, 9 (41%) achieved complete remission (CR) with RM and required no further treatment. In the R-Chemotherapy (n=37) group (70% R-CHOP), 26 (70%) reached CR. There was no significant difference in OS between the two groups. 8/22 (36%) died in the RM group (2/22 (9%) due progressive disease (PD), 2/22 (9%) died pre-remission of non-PTLD causes and 4/37 (18%) died in remission of unrelated causes). In the R-Chemo group 8/37 (48%) patients dead (4/37 (10%) patients died of PD, 6/37 (16%) died pre-remission of non-PTLD causes and 8/37 (22%) died in remission of unrelated causes). Conclusion: With this SOT cohort from a center with long experience we demonstrated an incidence of PTLD of 1.8%. EBV positive PTLD emerged sooner but OS was similar to those EBV negative. Stablished prognostic indices in DLBCL such as IPI, NCCN-IPI, and modified R-IPI were also applicable in PTLD. The modified R-IPI showed the best separation between the groups. Switch or reduction of the IS is an essential point to improve its prognosis. Our data suggest that first-line RM is an interesting option to consider. Strategies to tailor treatment with the least possible toxicity are necessary in these vulnerable patients. Additionally, our results suggest the utility of modified R-IPI in the clinical practice of PTLD and may serve as a basis for the development of specific prognostic models for this entity.

Incidence and Features of Lymphoid Proliferation and Lymphomas after Solid Organ or Hematopoietic Stem Cell Transplantation in a National Database Cohort.

Post-transplantation lymphoproliferative disorders (PTLDs) after hematopoietic stem transplantation (HCT) or solid organ transplantation (SOT) result in poorer outcomes, including death. There are limited large cohort data on the incidence and natural course of PTLD in Asians. We investigated PTLD using Korean national health insurance claims data of 47,518 patients who underwent HCT or SOT in 2008-2020. Patient demographics, time and type of PTLD diagnosis, type of PTLD treatment, and death data were collected. We used Fine and Gray subdistribution hazard models to calculate the cumulative incidence and risk factors for PTLD. During median follow-up of 5.32 years, PTLD occurred in 294 of 36,945 SOT patients (0.79%) and 235 of 10,573 HCT patients (2.22%). Cumulative incidence of PTLD were 0.49% at 1 year, 1.02% at 5 years, and 1.50% at 10 years post-transplantation. Age < 20 years (subdistribution hazard ratio [SHR] of 1.67 in age 10-19, SHR 1.51 in age 0-9), HCT (SHR 3.02), heart transplantation (SHR 2.27), and liver transplantation (SHR 1.47) were significant risk factors for PTLD. The presence of PTLD was associated with an increased risk of death (hazard ratio of 2.84). Overall, 5-year survival of PTLD patients was 68.9% (95% confidence interval, 64.9 to 73.2). We observed a steady increase in PTLD over 10 years after HCT or SOT in this large cohort study. Pediatric age group, HCT, liver transplantation, and heart transplantation were suggested to be risk factors for PTLD, and PTLD was associated with a higher risk of death.

Outcome of Brain Lymphoma in a High Epstein-Barr Virus–Prevalence Country After Kidney Transplantation

The incidence of post-transplant lymphoproliferative disorder (PTLD) in adult kidney transplant (KTx) recipients is less common in Taiwan. In our institute, we observed that brain lymphoma was the most notorious type. The study describes the clinical, histologic, and radiological features of primary central nervous lymphoma (PCNSL) and the outcomes and associations with Epstein-Barr virus (EBV) infection in our center. Among 1470 KTx recipients, 5 patients had tissue-proven brain lymphoma (0.34%). The brain pathology disclosed diffuse large B-cell lymphoma in all patients. EBV was detected through in situ hybridization for Epstein-Barr encoding region (EBER) to disclose the EBV inclusion in the nuclei of lymphoma cells. The first treatment step was the reduction of immunosuppressants; 4 patients received whole-brain radiotherapy after complete resection of PCNSL, and 1 received concurrent chemoradiotherapy. Only one patient had poor performance status at the time of diagnosis and had a poor response to treatment with steroids. Four patients survived (mean 36.5 months, range 8.6 to 57.6 months), but one died after rapid neurologic deterioration. Epstein-Barr virus inclusion was found in PCNSL in our patients; however, the role of EBV in PCNSL remains to be clarified. Post-transplant lymphoproliferative disorder is a rare malignancy after KTx with a predilection of brain involvement in Taiwan. We report a successful care experience in a patient with primary CNS lymphoma with better survival.

Tonsillectomy Outcomes in Children After Solid-Organ Transplantation: A 15-Year Single-Center Experience.

Solid-organ transplantation (SOT) has become the standard of care for children with terminal organ failure. Long-term immunosuppression has improved survival substantially but is associated with secondary malignancies and impaired wound healing. Our goal was to review the incidence, outcomes, complications, and rate of posttransplant lymphoproliferative disorder on pathologic examination following tonsillectomy/adenotonsillectomy (T/AT) in children after SOT. A retrospective cohort study. Tertiary care children's hospital. Data were extracted from charts of children with a history of kidney, heart, or liver transplantation, who underwent T/AT between 2006 and 2021. A total of 110 patients met the inclusion criteria, including 46 hearts, 41 kidneys, 19 livers, and 4 liver-and-kidney transplants. The mean age at transplantation was 4.2 years, and the mean transplantation-to-T/AT time interval was 28.8 months. The posttransplantlymphoproliferative disorder was diagnosed in 52 (47.3%) patients, and 25% of these had no tonsillar hypertrophy. There was no difference in age at transplantation, organ received, transplantation-to-T/AT time interval, immunosuppressive medications, tonsil size, or tonsillar asymmetry between patients diagnosed with the posttransplant lymphoproliferative disorder and patients with benign tonsillar/adenotonsillar hypertrophy. Posttonsillectomy complications were similar between the groups. The incidence of posttransplant lymphoproliferative disorder undergoing tonsillectomy for any indication was 47.3%. There was no association between preoperative signs and symptoms and the histopathological diagnosis of posttransplant lymphoproliferative disorder. Stratification by organ received and immunosuppressive medications did not identify differences among the groups relative to the incidence of posttransplant lymphoproliferative disorder and other postoperative complications.

Induction Versus Maintenance Immunosuppression After Intestinal Transplant: Determining Which Treatment Most Impacts Long-Term Patient And Graft Survival.

Immunosuppressive strategies for intestinal transplant have changed over time. However, specific intestinal transplant-oriented protocols and reports on long-term maintenance regimens are scarce. Our objective was to evaluate the impact of 2 different initial immunosuppressive protocols based on thymoglobulin (group A) and basiliximab (anti-interleukin 2 antibody) (group B) and of changes to maintenance immunosuppression over long-term follow-up in intestinal transplant recipients. We performed a retrospective analysis of a prospectively established protocol for intestinal transplant immunosuppression, conducted between May 2006 and December 2020. We analyzed 51 intestinal transplant recipients, with 6 patients excluded because of early death or graft loss. Acute cellular rejection frequency and grade, number of acute cellular rejection episodes, time to the first acute cellular rejection episode, response to treatment, number of patients who progressed to chronic allograft rejection, kidney function, infections, incidence of posttransplant lymphoproliferative disorder and graft-versus-host disease, and patient and graft survival were analyzed. In the study groups, there were 87 acute cellular rejection episodes in 45 patients (33 in group A and 54 in group B). We found degree of acute cellular rejection to be mild in 45 patients, moderate in 18, and severe in 24 (not significant between groups). Our comparison of induction therapy (thymoglobulin [group A] vs interleukin 2 antibody [group B]) did not show any statistical difference during clinical followup. Long-term review showed that all patients were on tacrolimus. Five-year patient and graft survival rates were 62% and 45% for group A and 54% and 46% for group B, respectively (not significant). Long-term patient and graft outcomes reflected the use of an individualized follow-up with adjustments and changes in immunosuppressive medications according to the patient's clinical course and complications rather than based on the induction immunosuppressive protocol used.

Abstract 12595: De Novo Lymphoproliferative Disorders in Heart Transplant Recipients: Predictors and Clinical Outcomes

Introduction: Post-transplant lymphoproliferative disorder (PTLD) is an important cause of morbidity and mortality in heart transplant (HTx) recipients. However, clinical characteristics and predictors of PTLD in the real world have not been well studied. Methods We retrospectively analyzed clinical characteristics, predictors, and outcomes of PTLD, in 28,136 recipients of heart alone transplants between January 2000 and June 2015 from the International Society for Heart and Lung Transplantation Thoracic Organ Transplant Registry. Results Ten-year incidence of PTLD after successful discharge from HTx during 2000-2007 was 3.8%. The adjusted overall risk of mortality was significantly higher in patients diagnosed with PTLD within 3 years after HTx compared to those without PTLD (HR 2.22, 95% CI 1.86-2.65, p&lt;0.001). Bimodal age peak of the PTLD incidence within the 3 years of HTx and mortality after the diagnosis of PTLD was noted. Both adjusted risk of PTLD incidence and mortality were lower in recent HTx; lower incidence and mortality in era of 2008-2015, compared to 2000-2007 (Incidence: HR 0.75, 95% CI 0.57-0.98, p=0.038) (Mortality: HR 0.86, 95% CI 0.81-0.91, p&lt;0.001). Age at transplant, male recipient, high risk Epstein-Barr virus (EBV) mismatch (donor positive and recipient negative for EBV) were independent risk factors, while primary maintenance therapy with cyclosporine (vs. tacrolimus) at initial discharge was a protective factor for PTLD within 3 years. Conclusions The incidence as well as mortality of PTLD has decreased in recent years of HTx, possibly with advances in changed pattern of immunosuppression according to patient profile. Clinical characteristics such as age, male gender, EBV status and rejection history are key factors for assessing the risk of PTLD, which can be detrimental in the course of post HTx care.

Effects of tacrolimus intrapatient variability and CYP3A5 polymorphism on the outcomes of pediatric kidney transplantation.

The intrapatient variability (IPV) of tacrolimus (Tac) is associated with the long-term outcome of kidney transplantation. The CYP3A single-nucleotide polymorphism (SNP) may affect the IPV of Tac. We investigated the impact of IPV and genetic polymorphism in pediatric patients who received kidney transplantation. A total of 202 pediatric renal transplant recipients from 2000 to 2016 were analyzed retrospectively. The IPV was calculated between 6 and 12months after surgery. Among these patients, CYP3A5 polymorphism was analyzed in 67 patients. The group with high IPV had a significantly higher rate of de novo donor-specific human leukocyte antigen antibodies (dnDSA) development (35.7% vs. 16.7%, p=.003). The high IPV group also had a higher incidence of T-cell-mediated rejection (TCMR; p<.001). The high IPV had no significant influence on Epstein-Barr virus, cytomegalovirus, and BK virus viremia but was associated with the incidence of posttransplant lymphoproliferative disorders (p=.003). Overall, the graft survival rate was inferior in the high IPV group (p<.001). The CYP3A5 SNPs did not significantly affect the IPV of Tac. In the CYP3A5 expressor group, however, the IPV was significantly associated with the TCMR-free survival rate (p<.001). The IPV of Tac had a significant impact on dnDSA development, occurrence of acute TCMR, and graft failure in pediatric patients who received renal transplantation. CYP3A5 expressors with high IPV of Tac showed worse outcomes, while the CYP3A5 polymorphism had no impact on IPV of Tac.

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.

IJU this Issue

This issue of International Journal of Urology contains one Review Article, 10 Original Articles, and eight editorial comments. Yuan et al. (Jiangsu, China) updated a meta-analysis for the diagnostic performance of the Vesical Imaging–Reporting And Data System (VI-RADS) for predicting muscle-invasive bladder cancer (MIBC) with 20 studies published between September 2018 and July 2021. VI-RADS was introduced in 2018 to define a standardized approach to imaging and reporting multiparametric magnetic resonance imaging for patients with bladder cancer. The diagnostic performance of the VI-RADS for predicting MIBC was excellent in both cutoff points of the VI-RADS 3 and 4. Multiple image acquisition planes of diffusion-weighted imaging should be given more attention in the VI-RADS. We hope that VI-RADS will become more mature and prevalent, which should lead to better management of bladder cancer via further studies. In the original articles, Nishimura et al. (Nara, Japan) evaluated the clinical outcomes and prognostic factors in Japanese patients with bacillus Calmette-Guerin (BCG)-unresponsive nonmuscle-invasive bladder cancer (NMIBC) who underwent early radical cystectomy (RC) using a large-scale multicenter retrospective study and concluded the highest-risk status among the pre-BCG factors was associated with upstaging to extravesical tumors and poor prognosis, despite early RC procedures. The Japanese Urological Association Clinical Practice Guidelines for Bladder Cancer 2019 recommended that patients with BCG-unresponsive disease are considered unlikely to benefit from further BCG therapy and early RC. This study seems to be one of those with the evidence based on a pathological evaluation. Although some new strategies such as intravesical nadofargene firadenovec gene therapy (Lancet Oncol. 2021; 22: 107–17), pembrolizumab monotherapy (Lancet Oncol. 2021; 22: 919–30) have been reported, there is no doubt that BCG-unresponsive disease is a risk factor and RC will continue to be required in a certain proportion of patients with BCG-unresponsive NMIBC. Kato et al. (Osaka, Japan) evaluated the long-term incidence and clinical features of post-transplant lymphoproliferative disorders (PTLD) in kidney transplant recipients from two major transplantation centers in Japan. Graft survival has improved due to a reduction in the acute rejection rate by advances in immunosuppressive agents; however long-term survival after kidney transplantation remains unchanged. Therefore, it is extremely important to focus on malignancy, especially PTLD after kidney transplantation. They emphasized the strategies to identify PTLD and suggested the benefits of positron emission tomography-computed tomography for ascertaining PTLD. They also revealed that mycophenolate mofetil contributed the onset of PTLD, and rituximab was not significantly associated with the incidence of PTLD. We have to be careful for each immunosuppressive agent. Yamashita et al. (Shizuoka, Japan) examined the incidence and location of lower extremity deep vein thrombosis (DVT) in patients undergoing RC. Venous thromboembolism (VTE) including DVT and pulmonary embolism is a serious perioperative complication in urological surgery. RC, whether open or robot-assisted surgery, is the procedure with the highest risk of perioperative VTE in urological surgery according to the European Association of Urology (EAU) guidelines on thromboprophylaxis in urological surgery. They also identified that preoperative D-dimer level was a significant risk factor for preoperative DVT, and preoperative D-dimer level, type of urinary diversion (ileal neobladder), and preoperative DVT were significant risk factors for postoperative DVT. EAU guidelines strongly recommended the use of pharmacological prophylaxis in all patients undergoing open and robot-assisted RC. These results might suggest appropriate patients for pharmacological prophylaxis in RC. Unfortunately, the limited space does not allow me to introduce all the articles. However, all the papers are very interesting and informative. Please enjoy this issue of the International Journal of Urology. None declared.

Role of Cytomegalovirus in the Development of Posttransplant Lymphoproliferative Disorders With or Without Epstein-Barr Virus Infection.

Many studies have revealed the role of Epstein-Barr virus infection, in combination with chronic immunosuppression, as the main factor in the development of posttransplant lymphoproliferative disorder malignancy. Although many studies have been published on other confounding factors involved in posttransplant lymphoproliferative disorders, the role of coinfection with both cytomegalovirus and Epstein-Barr virus has not been investigated. We evaluated the role of cytomegalovirus infection as a risk factor in transplant recipients who were simultaneously infected with Epstein-Barr virus. In the current retrospective study, 143 recipients of various solid-organ transplants at Namazi Hospital from April 2018 to March 2019 were assessed for coinfection with cytomegalovirus and Epstein-Barr virus with the TaqMan real-time polymerase chain reaction assay. We collected clinical and pathology details from their medical records. Of the 143 patients, 81 (57%) were male. Children under 5 years old were the largest group with 32% prevalence, and the most common organ transplant in this study was liver transplant. The prevalence of cytomegalovirus and Epstein-Barr virus coinfection was 12.6% (18/143 patients), of whom 50% experienced posttransplant lymphoproliferative disorder (9/18 patients) during 18 months after transplant. The incidence of posttransplant lymphoproliferative disorder was significantly higher among patients coinfected with cytomegalovirus and Epstein-Barr virus than among patients without coinfection. We observed a significant correlation between cytomegalovirus viral loads, as well as Epstein-Barr virus genome load, in posttransplant lymphoproliferative disorder development. Coinfection with cytomegalovirus and Epstein-Barr virus, as well as the genome load of each virus, can serve as a strong predictive factor of posttransplant lymphoproliferative disorder in solidorgan transplant recipients.

Sirolimus-Based Immunosuppression Is Associated with Decreased Incidence of Post-Transplant Lymphoproliferative Disorder after Heart Transplantation: A Double-Center Study.

Mammalian target of rapamycin (mTOR) inhibitors have been shown to reduce proliferation of lymphoid cells; thus, their use for immunosuppression after heart transplantation (HT) may reduce post-transplant lymphoproliferative disorder (PTLD) risk. This study sought to investigate whether the sirolimus (SRL)-based immunosuppression regimen is associated with a decreased risk of PTLD compared with the calcineurin inhibitor (CNI)-based regimen in HT recipients. We retrospectively analyzed 590 patients who received HTs at two large institutions between 1 June 1988 and 31 December 2014. Cox proportional-hazard modeling was used to examine the association between type of primary immunosuppression and PTLD after adjustment for potential confounders, including Epstein–Barr virus (EBV) status, type of induction therapy, and rejection. Conversion from CNI to SRL as primary immunosuppression occurred in 249 patients (42.2%). During a median follow-up of 6.3 years, 30 patients developed PTLD (5.1%). In a univariate analysis, EBV mismatch was strongly associated with increased risk of PTLD (HR 10.0, 95% CI: 3.8–26.6; p < 0.001), and conversion to SRL was found to be protective against development of PTLD (HR 0.19, 95% CI: 0.04–0.80; p = 0.02). In a multivariable model and after adjusting for EBV mismatch, conversion to SRL remained protective against risk of PTLD compared with continued CNI use (HR 0.12, 95% CI: 0.03–0.55; p = 0.006). In conclusion, SRL-based immunosuppression is associated with lower incidence of PTLD after HT. These findings provide evidence of a benefit from conversion to SRL as maintenance therapy for mitigating the risk of PTLD, particularly among patients at high PTLD risk.

Post-transplant Lymphoproliferative Disorder in Pediatric Liver Transplantation: A Population-based Study from Shiraz, Iran

Background: This study aimed to determine the prevalence of post-transplant lymphoproliferative disorder (PTLD) based on the clinical and epidemiological characteristics of donors and pediatric transplant recipients. Methods: This cross-sectional study was conducted on the patients who had experienced liver transplantation at Shiraz Transplant Center, Shiraz, Iran, from April 2007 to March 2017. Data on the epidemiological characteristics, underlying diseases, dosage of immunosuppressive drugs, and duration of drug consumption from the time of liver transplantation until the onset of PTLD for transplant recipients, and donors’ age, sex, and family relationship with recipients were collected using a data-gathering form. Log rank test was employed to determine the variations in the distribution of survival in different sex and age groups. Results: The study findings indicated that 49 out of the 1207 children who had undergone liver transplantation developed PTLD, revealing a prevalence of 4%. The results showed no significant relationship between gender and the incidence of PTLD (P = 0.13). However, the mean age of the cases with PTLD was 4.93 ± 1.07 years at the time of transplantation, while non-PTLD patients showed a higher mean age at that time (7.80 ± 5.54). The mean dose of the immunosuppressive drugs (dose/kg) consumed by the recipients was as follows: Tacrolimus = 0.2753 ± 0.23435, prednisolone = 0.6761 ± 0.62218, cellcept = 0.0724 ± 0.12963, and sirolimus = 0.1078 ± 0.08813. The average consumption period of the above-mentioned drugs from the time of transplantation until the onset of PTLD was 14.7 ± 14.409 months. Based on the results, the five-year survival rate was much lower in the patients with PTLD compared to the non-PTLD patients (31% Vs. 72.7%). The survival distribution was significantly different based on sex and age groups (P = 0.59 and P = 0.06, respectively). Conclusions: The prevalence of the clinical and epidemiological features of the PTLD in the patients under the present investigation was similar to those of the patients in other hospitals. Recognizing the clinical and epidemiological characteristics of transplant recipients with and without PTLD and donors can provide a basis for managing these patients.

Risk Factors for the Incidence of and the Mortality due to Post-Transplant Lymphoproliferative Disorder after Hematopoietic Cell Transplantation

Post-transplant lymphoproliferative disorder (PTLD) is a potentially serious complication that occurs following hematopoietic cell transplantation (HCT), in which B cells transformed by Epstein-Barr virus (EBV) proliferate uncontrollably. It is unknown whether risk factors for the incidence of PTLD are identical to those for mortality due to PTLD, a clinically more important outcome. We sought to determine the risk factors influencing the incidence of PTLD and those influencing mortality due to PTLD in a cohort of 1184allogenic HCT recipients. All patients were predisposed to PTLD, because their graft-versus-host disease (GVHD) prophylaxis included antithymocyte globulin. The overall PTLD incidence was 9.0%, and mortality due to PTLD was1.1%. Inmultivariate analysis, risk factors for PTLD incidence include donor+/recipient- (D+/R-) EBVserostatus (subhazard ratio [SHR], 3.3; P=.002), use of a donor other than an HLA-matched sibling donor (non-MSD) (SHR, 1.7; P=.029), receipt of total body irradiation (TBI; SHR, 3.3; P=.008), and the absence of GVHD (SHR, 3.3; P < .001). The sole risk factor for mortality due to PTLD among all patients was D+/R- serostatus (SHR, 5.8; P=.022). Risk factors for mortality due to PTLD among patients who developed PTLD were use of a bone marrow (BM) graft (compared with peripheral blood stem cells [PBSCs]; SHR, 22.8; P < .001) and extralymphatic involvement (SHR, 14.6; P < .001). Interestingly, whereas the absence of GVHD was a risk factor for PTLD incidence, there was a trend toward the presence of GVHD as a risk factor for PTLD mortality (SHR, 4.2; P=.093). Likewise, whereas use of a BM graft was a risk factor for PTLD mortality, there was a trend toward use of a PBSC graft as a risk factor for PTLD incidence (SHR, 0.44; P=.179). Some risk factors for the incidence of PTLD are identical to the risk factors for mortality due to PTLD (ie, D+/R- serostatus), whereas other risk factors are disparate. Specifically, TBI was identified as a risk factor for PTLD incidence but not for PTLD mortality; the absence of GVHD was a risk factor for PTLD incidence, whereas the presence of GVHD was possibly a risk factor for PTLD mortality; and receipt of a PBSC graft was possibly a risk factor for PTLD incidence, whereas receipt of a BM graft was a risk factor for PTLD mortality.

Novel Risk Factors for Epstein-Barr Virus (EBV) Reactivation and Post-Transplant Lymphoproliferative Disorder (PTLD) after Allogeneic Hematopoietic Stem Cell Transplant

Background: Epstein-Barr virus (EBV) reactivation and EBV-positive post-transplant lymphoproliferative disorder (EBV+PTLD) are often fatal complications following allogeneic hematopoietic stem cell transplant (HSCT). Risk factors for the development of EBV+PTLD after HSCT include human leukocyte antigen (HLA) mismatches, T cell depletion (TCD) and older age, among others. It has been proposed that specific HLA haplotypes are associated with the development of EBV+PTLD after solid organ transplant (SOT) and that pre-emptive use of Rituximab can reduce the risk of EBV+PTLD. We present a retrospective analysis of patients who underwent HSCT in order to determine the impact of donor source, TCD, age, HLA-A1 haplotypes and use of Rituximab prior to HSCT on the development of EBV reactivation and EBV+PTLD after HSCT.Methods: We retrospectively reviewed patients who had undergone allogeneic HSCT at our Institution between January 2012 and December 2016. We analyzed the cumulative incidence of EBV reactivation and EBV+PTLD and the impact of known and novel risk factors.Results: Of 474 patients, 10% developed EBV reactivation and 6% were diagnosed with EBV+PTLD. The cumulative incidence of EBV reactivation and EBV+PTLD was 15% and 11%, respectively, after haplo-cord HSCT, compared to 3% and 2% after MRD HSCT and 8% and 5% after MUD HSCT (p=0.0004 and p=0.02, respectively). EBV reactivation was associated with receipt of ATG compared to Alemtuzumab (p=0.03) and age older than 60 years (p=0.004). The presence of HLA-A1 haplotype in the recipient did not affect the incidence of EBV reactivation and EBV+PTLD (p=0.2 and p=0.9, respectively). The cumulative incidence of EBV reactivation and EBV+PTLD was lower in patients with Rituximab exposure prior to HSCT, although this did not reach statistical significance (p=0.2 and p=0.15, respectively). In a multivariate analysis, donor source (haplo-cord vs HLA-matched) and age older than 60 were found to be independent risk factors for the development of EBV reactivation (HR 1.9; p=0.038 and HR 2.6; p=0.002, respectively) and EBV+PTLD (HR 1.9; p=0.020 and HR 3.5; p=0.004, respectively). PTLD was fatal in 8 of 27 patients (29%) with PTLD and 17% of all patients with EBV reactivation. One patient died of disseminated EBV disease without PTLD.Conclusions: The cumulative incidence of EBV viremia and PTLD after allogeneic HSCT was 10% and 6%, respectively, and led to death in 2% of the patients. Haplo-cord grafts and age older than 60 years were independent risk factors for EBV reactivation and EBV+PTLD. Rituximab use prior to HSCT may confer protection against EBV reactivation and its use in the conditioning regimen of patients undergoing HSCT, at high risk for EBV reactivation, should be studied prospectively. Further studies are needed to determine the impact of HLA haplotypes on the incidence of EBV reactivation in patients after HSCT. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Post-transplant Lymphoproliferative Disorders After Liver Transplantation: A Retrospective Cohort Study Including 1954 Transplants.

Post‐transplant lymphoproliferative disorders (PTLDs) are life‐threatening neoplasms after organ transplantation. Because of their rarity and multiple grades of malignancy, the incidence, outcomes, and clinicopathological features affecting patient survival after liver transplantation (LT) remain unclear. We reviewed 1954 LTs in 1849 recipients (1990‐2020), including 886 pediatric (<18 years of age) and 963 adult recipients. The following clinicopathological factors were studied: age, sex, liver etiologies, malignancy grades, Epstein‐Barr virus status, performance status (PS), Ann Arbor stage, international prognostic index, and histopathological diagnosis. Of 1849 recipients, 79 PTLD lesions (4.3%) were identified in 70 patients (3.8%). After excluding 3 autopsy cases incidentally found, 67 (45 pediatric [5.1%] and 22 adult [2.3%]) patients were finally enrolled. Comorbid PTLDs significantly worsened recipient survival compared with non‐complicated cases (P < 0.001). The 3‐year, 5‐year, and 10‐year overall survival rates after PTLD diagnosis were 74%, 66%, and 58%, respectively. The incidence of PTLDs after LT (LT‐PTLDs) was significantly higher (P < 0.001) with earlier onset (P = 0.002) in children, whereas patient survival was significantly worse in adults (P = 0.002). Univariate and multivariate analyses identified the following 3 prognostic factors: age at PTLD diagnosis ≥18 years (hazard ratio [HR], 11.2; 95% confidence interval [CI], 2.63‐47.4; P = 0.001), PS ≥2 at diagnosis (HR, 6.77; 95% CI, 1.56‐29.3; P = 0.01), and monomorphic type (HR, 6.78; 95% CI, 1.40‐32.9; P = 0.02). A prognostic index, the “LT‐PTLD score,” that consists of these 3 factors effectively stratified patient survival and progression‐free survival (P = 0.003 and <0.001, respectively). In conclusion, comorbid PTLDs significantly worsened patient survival after LT. Age ≥18 years and PS ≥2 at PTLD diagnosis, and monomorphic type are independent prognostic factors, and the LT‐PTLD score that consists of these 3 factors may distinguish high‐risk cases and guide adequate interventions.

Induction and Increased Risk of Infections in Pediatric Fontan Patients after Heart Transplantation

<h3>Purpose</h3> To understand whether patients who have undergone Fontan palliation may have a higher susceptibility to post-HT infections given thymectomy in infancy and known depletions of T-cell subsets. <h3>Methods</h3> This was a single-center, retrospective cohort analysis of pediatric patients undergoing HT for dilated cardiomyopathy (DCM) or Fontan failure, who underwent induction with anti-thymoglobulin (ATG). The primary endpoint was infection in the first 180 days post-HT, defined as (1) positive blood/urine/respiratory culture; (2) positive viral PCR (excluding CMV and EBV); (3) skin or wound infection; and/or (4) culture-negative infection if a full antibiotic course (>5 days) was completed. Secondary endpoints included (1) absolute lymphocyte (ALC) and CD3 counts after 3 and 5 doses of anti-thymocyte gammaglobulin (ATG); (2) the incidence of post-transplant lymphoproliferative disorder (PTLD); and (3) rejection (≥ Grade 2R ACR or pAMR2) in the first 180 days post-HT. <h3>Results</h3> From 2014 to 2019, 59 pts (26 Fontan, 33 DCM) underwent HT at a median age of 14.7 (IQR 10.6, 19.5) and 11.7 (IQR 1.4, 13.6) years, respectively. The median total ATG received was 7.4 (IQR 4.9, 7.7) vs 7.5 (IQR 7.3, 7.6) mg/kg (p=NS). The median CD3 [8 (IQR 5, 14) vs 16 (IQR 10, 39); p=0.01] after 3 doses of ATG and ALC [172 (IQR 98, 400) vs 427 (IQR 205, 824); p=0.014] after 5 doses of ATG was lower in Fontan vs DCM patients (<b>A,B</b>). Twenty-three patients (39%) developed ≥1 infection within 180 days post-HT, with a higher rate of infection in Fontan patients (54% vs 27%, p=0.03; <b>C, D</b>). Adjusted for pre-transplant ALC, the risk for infection within 30 days post-HT for Fontan patients was OR 7.62, 95% CI 1.13-51.48, p=0.037. There was no difference in the incidence of PTLD (12% vs 0%; p=0.08) or rejection (12% vs 21%; p=0.49) between Fontan vs DCM patients. <h3>Conclusion</h3> Compared to DCM patients, Fontan patients have lower CD3 and ALC after induction, as well as a higher risk of infection. Modifications to induction therapy for Fontan patients may be considered.

Childhood post-transplant lymphoproliferative disorder

<h2>Abstract</h2> Post-transplant lymphoproliferative disorders (PTLDs) are a heterogeneous group of neoplasms that occur as a serious complication of haematopoetic stem cell or solid organ transplantation. They are Epstein Barr virus (EBV) driven in over 90% of the cases. Incidence of PTLD varies from 1 to 20 % depending on the organ transplanted, the intensity of immunosuppression and the recipient's pre transplant EBV status. The pathology of PTLD varies from polymorphic to monomorphic/monoclonal disease which is indistinguishable from a high-grade lymphoma. The clinical course varies from indolent to rapidly progressive, fulminant disease. Over two thirds to 90% of PTLDs are of B cell origin. The current standard of treatment involves reduction of immunosuppressive drugs and if that is not sufficient, use of anti CD20 monoclonal antibody (Rituximab) alone or in combination with conventional chemotherapy. This review offers an overview for healthcare professionals looking after children and young people who may be at risk of or have PTLD. It discusses the pathophysiology, the risk factors, classification and diagnosis of PTLD. It also summarises the current approach to management and monitoring strategies.