Late Posttransplant Lymphoproliferative Disorder Research Articles

Early- and late-onset posttransplant lymphoproliferative disorders among adult kidney and liver transplant recipients.

ObjectivesPosttransplant lymphoproliferative disorder (PTLD) in solid organ transplant recipients has a high mortality and may present early (<2 years) or late (≥2 years) posttransplantation. We investigated the clinical characteristics of early and late PTLD among kidney and liver transplant recipients.MethodsRecipients, transplanted at Rigshospitalet, with PTLD development as adults from January 2010 to August 2020, were included. Clinical characteristics, laboratory parameters, and pathology of early and late PTLD were compared.ResultsThirty‐one PTLD cases were detected where 10 (32%) were early and 21 (68%) were late PTLD. EBV DNA in plasma was detected in 78% versus 28% in early and late PTLD (p = .037). None of the recipients with early PTLD and nine recipients with late PTLD (47%) had Ann Arbor stage IV at the time of their diagnosis (p = .006). Cyclophosphamid–Hydroxyrubicin–Oncovin–Prednisolon was used for treatment in 10 (48%) recipients with late PTLD (p = 0.032) only. There was no difference in mortality between the two groups.ConclusionsRecipients with late PTLD had a lower prevalence of detectable EBV DNA in plasma, were diagnosed with more advanced disease, and were more frequently treated with chemotherapy compared to recipients with early PTLD.

Anaplastic large cell lymphoma as a posttransplant lymphoproliferative disorder in a renal transplant patient: A case report.

We report a case of a 45‐year‐old female who developed an ALK‐positive anaplastic large cell lymphoma (ALCL) 9 years after renal transplant. The patient underwent a cadaveric renal transplant for diabetic nephropathy, and presented 9 years later with fever and multiorgan dysfunction. The initial CT scans showed multiple enlarged supra‐ and infradiaphrgamatic lymph nodes. A CT‐guided core needle biopsy of a retroperitoneal lymph node revealed ALK positive ALCL. She received six cycles of cyclophosphamide, adriamycin, vincristine, etoposide, and prednisone, and has been in remission for over 3 years. Monomorphic T‐cell posttransplant lymphoproliferative disorder (PTLD) is an established but rare entity of PTLD and generally carries poor prognosis. This is a case report of a late PTLD with pathology reporting an aggressive T‐cell lymphoma that has been successfully treated with multiagent chemotherapy.

Idiopathic Pulmonary Fibrosis Lung Transplant Recipients are at Increased Risk for Epstein-Barr Virus-Associated Post-Transplant Lymphoproliferative Disorder

Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disorder (PTLD) is a serious complication in lung transplant recipients (LTRs) associated with significant mortality. We performed a single-center retrospective study to evaluate the risks for PTLD in LTRs over a seven-year period. All LTRs transplanted from 2010 to 2016 were included. LTRs who died within 3 months or were lost to follow-up were excluded. Sex, age, EBV serostatus, induction agent, indication agent, and survival were collected via chart review. The primary outcome was development of PTLD. Secondary endpoints were early and late PTLD and survival. Primary and secondary outcomes were assessed using Kaplan-Meier methods and Cox proportional hazards models. Of 611 evaluable LTRs, we identified 28 cases of PTLD, with an incidence of 4.6%. Kaplan-Meier analysis showed an increased rate of PTLD in idiopathic pulmonary fibrosis (IPF)-LTRs (p<0.02). Multivariable Cox proportional hazards modeling found IPF (HR 3.51, 95% CI 1.33-8.21, p=0.01), alemtuzumab induction therapy (HR 2.73, 95% CI 1.10-6.74, p=0.03), and EBV mismatch (HR: 34.43, 95% CI: 15.57-76.09, p<0.0001) as risk factors for PTLD. Early PTLD (first-year) was associated with alemtuzumab use (p=0.04), whereas IPF was a predictor for late PTLD (after first-year) (p=0.002), after controlling for age and sex. Kaplan-Meier analysis revealed a shorter time to death from PTLD in IPF-LTRs compared to other LTRs (p=0.04). The use of alemtuzumab in EBV-mismatch was found to particularly increase PTLD risk. IPF-LTRs are at increased susceptibility for PTLD compared to non-IPF LTRs. LTRs who received alemtuzumab induction were at increased risk for PTLD, particularly those who were EBV mismatches. Ongoing studies are being conducted to understand the mechanisms driving PTLD in IPF-LTRs and develop strategies to mitigate risk.

Single-institution Retrospective Analysis of Prognostic Factors Influencing Very Late-onset Post-transplant Lymphoproliferative Disorder.

BackgroundPost-transplant lymphoproliferative disorder (PTLD) is a rare complication following transplant (solid organ or allogeneic) due to the proliferation of lymphoid cells in the immunosuppressed state. The incidence of PTLD follows a bimodal distribution, with high incidence immediately after transplant (early-onset PTLD), followed by a decline and then a high-incidence again five years after transplantation (late-onset PTLD). This study exclusively aims to identify prognostic factors for the subgroup of PTLD, described as very late-onset PTLD, occurring after 10 years of transplant.MethodsThis study was conducted at the University of Florida, with the requisite study population identified through the cancer registry. Data were collected by individual chart review and analyzed. Survival estimates and univariate and multivariate analyses were performed to measure the effects of each variable on overall survival.ResultsA total of 33 patients were identified, with a median age at transplant of 42.3 years, while the median age at PTLD diagnosis was 54.7 years. Median time from transplant to PTLD diagnosis was 13.3 years. Kidney (30.3%), liver (27.3%), and heart (24.2%) transplants were the most common allografts associated with very late PTLD development. The most common pathology was diffuse large B-cell lymphoma (DLBCL) in 45.5% of patients. CHOP+/-R (cyclophosphamide, doxorubicin hydrochloride (hydroxydaunorubicin), vincristine sulfate (Oncovin), prednisone, rituximab) was the most common chemo regimen used as the initial choice in 36.4% of patients.Median survival was 5.4 years. Univariate analysis showed that age at diagnosis over 65, male gender, bone marrow involvement, past medical history (PMH) of malignancy, immunosuppression regimen at PTLD diagnosis, and initial and final best response to treatment were statistically significant (p <0.05) factors associated with survival. On multivariate analysis, bone marrow involvement was significantly associated with poor survival (p=0.008). Surprisingly, performance status, Epstein-Barr virus (EBV) status, pathology type, Ann-Arbor stage, and chemotherapy regimen were not significantly associated with survival. At the end of the study, 48.5% of patients achieved complete remission and the allograft survived in 84.8%.ConclusionsIn this retrospective study of very-late onset PTLD, we identified factors associated with survival different from early and late PTLD. These factors should be considered during the treatment of this subgroup of PTLD patients.

Characteristics, risks, and outcomes of post-transplant lymphoproliferative disease >3 years after pediatric heart transplant: A multicenter analysis.

Post-transplant lymphoproliferative disorder (PTLD) is a significant complication after pediatric heart transplantation (HT), occurring in 5%-15% of patients within 3years. Data >3years from HT are limited. We sought to describe the prevalence, risk factors, and outcomes of PTLD occurring late (>3years) after pediatric HT in the Pediatric Heart Transplant Study from 1993 to 2010. Among 3844 primary HT patients, 110 (3%) developed late, nonrecurrent PTLD. The hazard rate for late PTLD was constant at 0.01 events/year out to 20years after HT. Risk factors for late PTLD were younger age at HT (HR 1.06, P=0.003) and Epstein-Barr virus (EBV) naivety (HR 1.65, P=0.02). Survival after late PTLD was 86% and 68% at 1 and 5years, with nonwhite race (HR 2.27, P=0.03) and earlier year of HT (HR 1.03, P=0.04) independently associated with mortality. Acute rejection and infection were both common after late PTLD, occurring in 26% and 34% of patients. The constant late hazard and contribution of EBV to late PTLD suggest that vigilance for development of PTLD, including for EBV conversion, should persist indefinitely after pediatric HT. The reasons for elevated risk of death for nonwhites after late PTLD are unclear and warrant further investigation.

POST-TRANSPLANT LYMPHOPROLIFERATIVE DISORDERS IN PATIENTS WITH KIDNEY ALLOGRAFT

Post-transplant lymphoproliferative disorders (PTLD) are a serious complication after kidney transplantation, which negatively affects the survival of recipients and transplants. An important factor in the pathogenesis of early PTLD is an active infection caused by the Epstein-Barr virus (EBV), while late PTLD are often EBV-negative. The use of modern imaging research methods (computed tomography, positron emission tomography), as well as morphological study of the affected organs plays an important role in the diagnosis of PTLD. The article discusses the classification of PTLD, risk factors, features of pathogenesis, approaches to prevention and treatment.

The Changing Epidemiology of Posttransplant Lymphoproliferative Disorder in Adult Solid Organ Transplant Recipients Over 30 Years: A Single-center Experience.

Posttransplant lymphoproliferative disorders (PTLD) are a complication of solid organ transplantation (SOT) associated with Epstein-Barr virus (EBV). We analyzed the incidence of and risk factors for PTLD among adult SOT recipients at our center over 30 years (1984-2013). We also compared PTLD incidence before and after a prevention strategy of EBV viral load monitoring in EBV serology mismatched patients was adapted in 2001 (ie, transplant era 1 [1983-2001] vs era 2 [2002-2013]). Among 4171 SOT patients, 109 developed PTLD. Cumulative incidence at 1, 10, and 20 years posttransplant was 0.95, 2.3, and 3.5 per 100 person-years, respectively. Beyond the first year peak of almost exclusively EBV-positive PTLD, a lower incidence of PTLD, predominantly EBV negative, persisted for 20 years. Thoracic transplant (hazard ratio [HR], 2.1; P = 0.007) and negative EBV serology (HR, 7.7; P < 0.001) were independent risk factors for PTLD on multivariate Cox regression analysis. EBV seronegativity significantly increased risk of early (HR, 18.5) and EBV-positive PTLD (HR, 14.2), as well as late (HR, 4.9) and EBV-negative PTLD (HR, 3.6) on univariate analyses. Risk of early PTLD was significantly reduced in the recent transplant era (0.8% era 2 vs 1.9% era 1 at 5 years, P = 0.002); this reduction was seen in recent era EBV seropositive (P = 0.035 at 5 years) but not seronegative recipients (P = 0.90 year 5), suggesting lack of impact of viral load monitoring. Adult SOT recipients face a prolonged risk of late PTLD, whereas risk of early PTLD may have declined in recent years.

Posttransplant lymphoproliferative disorders in kidney transplant recipients: a retrospective cohort analysis over two decades in Hong Kong.

ObjectiveTo characterize the posttransplant lymphoproliferative disorders (PTLD) including the Epstein-Barr virus (EBV) status, histological subgroups, site of occurrence and the clinical outcome in the Chinese kidney transplant recipients.MethodsA retrospective cohort study of 1, 227 adult kidney transplant recipients who were followed up in two transplant centers in Hong Kong over two decades.Results23 (1.9%) patients developed PTLD. Median duration from transplant to PTLD was 104 (5-252) months. Six patients (26.1%) had early PTLD and 17 (73.9%) had late PTLD. Ten (43%) developed PTLD >10 years after transplant. All patients in early PTLD group were EBV-positive. In the late PTLD group, 60% were EBV-negative and 40% EBV-positive. More than 90% of cases were monomorphic PTLD with majority being diffuse large B cell lymphoma. Bone marrow was the most common extranodal site. The overall treatment response rate was 52.2 %. None of the patients developed rejection or relapse after PTLD. At a median follow-up of 9 (1-79) months after PTLD, 18 patients died. Patient survival was 48% at 1 year and 30% at 3 years and death-censored allograft survival was 82% at 1year and 73% at 3 years.ConclusionLate PTLD is common. Careful adjustment of immunosuppression, close monitoring of patients, increased awareness and early detection of the disease are essential.

Post-Transplant Diffuse Large B Cell Lymphoma with Non Germinal Center B-Cell Subtype Frequently Lacks Programmed Cell Death Ligand (PD-L1) Overexpression Which May Influence Overall Outcomes

Background : Post Transplant Lymphoproliferative disorder (PTLD) represents a distinct and rare complication following solid organ transplantation (SOT). Insight into the biology of this disorder is limited to retrospective reviews and case series. In one of the first reports for post-transplant Diffuse Large B cell Lymphoma (PT-DLBCL) cases, we demonstrated a higher incidence and improved outcomes in PT-DLBCL non-germinal center B-cell (non-GCB) subtype compared to PT-DLBCL germinal center B-cell (GCB) Subtype. Published data suggests immunocompetent DLBCL non-GCB subtypes are less common and fare worse than immunocompetent GCB DLBCL. The reason for this unexpected finding in our PT-DLBCL pts is not fully understood. Recently Kiyasu and colleagues demonstrated that PD-L1 overexpression was significantly associated with non-GCB DLBCL, EBV virus positivity and poor prognosis in immunocompetent DLBCL samples. Therefore based on this we hypothesized that PT-DLBCL non-GCB subtype may have negative PD-L1 overexpression thus possibly accounting for improved outcomes compared to their immunocompetent counterparts. Hence we sought to test PD-L1 expression in our samples with PT-DLBCL.Methods: With IRB approval, we retrospectively identified PT- DLBCL patients treated at the University of Colorado between Jan 1989 to April 2015. We retrieved formalin fixed paraffin embedded PT-DLBCL tissue specimens and determined cell of origin by the Hans Algorithm. We assessed PD-L1 expression by immunohistochemistry. PD-L1 positive PT-DLBCL was defined as 30% of more of the lymphoma cells showing distinct membranous and or cytoplasmic staining. In addition EBER-ISH was performed to assess EBV status.Results: 86 adult SOT pts with PTLD were treated at our institution. 75 of 86 pts (87%) had monomorphic histology. Among monomorphic PTLD, 64% (48 of 75) had DLBCL. The median age at transplantation was 49.5 yrs (5-74 yrs). Median time from SOT to PTLD was 37 mos (1.4-499). The most common transplanted organ included kidney (40%), liver (38%), lung (13%) and heart (9%). 31% had early PTLD (<12mos of SOT) and 69% had late PTLD (>12mos of SOT). 60% were EBV positive. 77% with early PTLD and 49% with late PTLD were EBV positive. Due to a paucity of archived tissue blocks, IHC staining was applied to 32/48 samples with DLBCL. Non-GCB subtype was identified in 75% (24/32) samples and GCB subtype in 25% (8/32) samples.Of the 48 pts with PT-DLBCL histology, PD-L1 stain was performed on 18 samples. Of the 18 PT-DLBCL samples, 77% (14/18) had non-GCB subtype and 16% (3/18) had GCB subtype. PD-L1 expression was negative in 78% (11/14) and positive in 22% (3/14) of non-GCB DLBCL samples. PD-L1 expression was negative in 100% (3/3) of GCB DLBCL samples. The sample size was too small to effectively describe the survival experience of pt subsets. Using Fisher's exact test we found no evidence to support an association between EBV Status and PDL1 expression (p-value 0.316).Conclusions: We previously reported in our consecutive series of PTLD after SOT an increased incidence and improved survival in pts with PT-DLBCL non-GCB subtype (ASH 2015) compared to PT-DLBCL GCB subtype. The reason for this is not fully understood. However, our limited series reveals that a majority of pts with PT- DLBCL non-GCB subtype was negative for PD-L1 overexpression. This might explain the improved outcomes in the PT-DLBCL non-GCB population. Despite a small sample size it is also interesting to note that 100% pts with PT-DLBCL GCB subtype were negative for PD-L1 overexpression. In the era of immunotherapy further studies in larger patient cohorts are warranted in order to understand the unique biology and outcomes of PT-DLBCL since it may have therapeutic implications. DisclosuresPollyea:Celgene: Other: advisory board, Research Funding; Ariad: Other: advisory board; Alexion: Other: advisory board; Pfizer: Other: advisory board, Research Funding; Glycomimetics: Other: DSMB member. Kamdar:Seattle Genetics: Speakers Bureau.

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

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

Epidemiology of Post-Transplant Lymphoproliferative Disorders in Solid Organ Transplant Recipients in a Single Canadian Centre.

Objective: Many epidemiologic studies of post-transplant lymphoproliferative disorder (PTLD) in solid organ transplant (SOT) populations have limited follow-up, incomplete pre-transplant viral serology and PTLD histology, and study only adults or children. We describe a single center study of the PTLD cases in all adult and pediatric (ped) SOT recipients from January 1, 1984 to June 30, 2013. Methods: Patients (n=4750, 475 age < 18, 4275 age ≥ 18) included 724 heart (15.2%), 551 lung or heart/lung (11.6%), 1298 liver (27.3%), 2099 kidney (44.2%), 66 pancreas or kidney/pancreas (1.4%), and 12 multivisceral or small bowel (.3%). Yearly cumulative incidence (CI) was calculated using the patient-year variant of the incidence definition: number of cases/amount of patient-time at risk each year. PTLD risk factors were analyzed using univariate Cox regression analyses, ped and adult patients were analyzed separately. Results: 134 cases of PTLD occurred over a median follow-up (FU) of 5.98 yrs (standard error (SE) 0.09, range 0-29.5 yrs). Ped SOT recipients developed more early lesions and polymorphic PTLD than adults (44 vs. 10%); adults had more monomorphic PTLD (68 vs. 38%). CI of PTLD was 1.31% PY at 1 year, 2.25% PY at 5 years, 3.04% at 10 years, and 3.93% PY at 20 years. Median overall survival (OS) of the entire cohort was 13.8 years (SE .36); PTLD adversely impacted OS in adult (p=.000, HR 1.3 (95% C.Int. 1.1-1.4), but not ped recipients (p=.23). Factors that significantly increased PTLD risk were: younger age at transplant, less time post-transplant, REBV -, and RCMV- (adult only). Risk of early (≤ 1 year) and late (> 1 year) PTLD, early/late EBER+ PTLD, and PTLD localized to CNS, GI, allograft and >1 extranodal (EN) site decreased with increased age at transplant. Risk of early PTLD and allograft PTLD in adults was higher from 1984-1991 compared to 2002-13. Being REBV- conferred significantly higher risk of early and late PTLD, early and late EBER+ PTLD, and PTLD localized in the CNS, GI tract, allograft, and over 1 EN site in adults. Conclusions: PTLD cases continued to arise 20 yrs post-transplant, and risk was increased by younger age, shorter duration post-transplant, and negative EBV serology. Negative EBV serostatus also increased risk of all PTLD subgroups in adults, including CNS involvement.

Epidemiology Of Post-Transplant Lymphoproliferative Disorders Following Solid Organ Transplant In a Major Canadian Transplant Centre

Post-transplant lymphoproliferative disorder (PTLD) is a consequence of organ transplantation with a high risk of mortality. We analyzed records of all patients who received a solid organ transplant at the University of Alberta between 1984 and 2011 (n=4525). 133 patients developed PTLD over the follow up period of January 1984 to November 2012, including 61 cases that occurred less than 2 years after transplant ( early), 33 cases between 2 and 7 years after transplant (late), and 39 cases more than 7 years after transplant (very late). We calculated the cumulative incidence rate for PTLD. We also used Cox regression analysis to determine whether variables year of transplant, age at transplant, organ, and EBV serology mismatch influenced the risk of development of any PTLD, early and very late PTLD, and central nervous system (CNS) PTLD (any PTLD and early PTLD shown in Table 1). The cumulative incidence of any PTLD occurrence was 1.4% at 1 year, 2.6% at 5 years, 4.3% at 10 years, 6.6% at 15 years, and 7.9% at 20 years. Univariate analyses showed that year of transplant (1984-92 vs. 1993-2001 vs. 2002-2011) was not predictive of PTLD development (p=0.27, HR 0.88, CI 0.68-1.12). Patients aged 0-5 years at transplant had significantly higher risk of PTLD development (mean freedom from disease (FFD) 18.90 yrs, 95% CI 17.52-20.28) followed by patients over 60 (mean FFD 25.49 yrs, 95% CI 24.97-26.0; p value 0.000, hazard ratio (HR) 0.57, 95% CI 0.49-0.68). Among organs transplanted, multivisceral transplant conferred the highest risk (mean FFD 5.94, 95% CI 4.19-7.69, n=12) followed by lung transplant (mean FFD 15.45 yrs, 95% CI 17.76-19.83), whereas kidney transplant conferred the lowest risk (mean FFD 27.52 yrs, 95% CI 27.15-27.88; p=0.000, HR 0.57, 95% CI 0.49-0.68). Patients with EBV serology recipient to donor mismatch (ie. recipient negative, donor positive) also had a higher risk of PTLD development (mean FFD 22.9 yrs, 95% CI 21.2-24.6 vs. mean FFD 27.2 yrs, 95% CI 26.90-27.54, p=0.000, HR 8.79, 95% CI 5.83-13.24). Variables associated with increased risk of early PTLD development were year of transplant, with the highest risk in patients transplanted between 1984-1991 (mean FFD 27.88 yrs, 95% CI 27.51-28.24) and the lowest risk in those transplanted in 2002-2011 (mean FFD 10.7 yrs, 95% CI 10.69-10.79, p=0.002, HR 0.68, 95% CI 0.49-0.94); age, with the highest risk in patients 0-5 yrs (mean FFD 20.66, 95% CI 19.68-21.63), followed by over 60 yrs (mean FFD 26.17 yrs, 95% CI 25.98-26.36, p=0.000, HR 0.55, 95% CI 0.45-0.68); organ, with the highest risk in lung transplant (mean FFD 16.50 yrs, 95% CI 16.21-16.80), and the lowest risk in kidney transplant (mean FFD 28.40 yrs, 95% CI 28.30-28.96; p=0.000, HR 0.58, 95% CI 0.46-0.74), and EBV serologic mismatch (p=0.000, HR 18.62, 95% CI 10.45-33.20). In contrast, only organ significantly predicted development of late PTLD, with lung conferring the highest risk (mean FFD 16.27 yrs, 95% CI 15.6-16.94; p= 0.002, HR 0.53, 95% CI 0.39-0.73). Risk of development of CNS PTLD (n=10, either primary or secondary) was greater in patients with EBV serology mismatch (p=0.000, HR 19.95, CI 4.98-79.92), but no other variables significantly predicted its development. In conclusion, the risk of PTLD after solid organ transplant is increased even 20 years after transplant, but the risk of early PTLD is declining over time. The risk of PTLD is highest in patients 0-5 years of age at transplant, patients receiving lung transplant, and patients with EBV serologic mismatch.Total n (%)PTLD Cases (n=133) (%)p valueHazard ratio95% CIEARLY PTLD Cases (n=61) (%)p valueHazard ratio95% CIYear of transplant0.270.880.68-1.120.020.680.49-0.941984-92655 (14.5)33 (24.8)14 (23.0)1993-20011558 (34.4)55 (41.3)24 (39.3)2002-20112312 (51.1)45 (33.8)23 (37.7)Age category0.0000.6450.55-0.750.0000.550.45-0.680-5231 (5.1)23 (17.3)13 (21.3)5-18225 (5.0)9 (6.8)7 (11.5)18-603242 (71.6)31 (23.3)34 (55.7)Over 60827 (18.3)16 (12.0)7 (11.5)Organ0.0000.570.49-0.680.0000.580.46-0.74Heart701 (15.5)35 (26.3)17 (26.9)Lung(18 Heart/Lung)512 (11.3)28 (21.0)16 (26.2)Kidney1983 (43.8)41 (30.8)12 (19.7)Liver1219 (26.9)28 (21.0)16 (26.2)Multivisceral (6 small bowel)12 (0.3)1 (0.75)0Pancreas98 (2.2)00EBV Serology Mismatch0.0008.795.83-13.240.00018.6210.45-33.20No3832 (84.7)75 (56.3)23 (37.7)Yes231 (5.1)33 (24.8)23 (37.7)Unknown460 (10.2)25 (18.8)15 (24.6) Disclosures:Peters:Lundbeck Canada: Honoraria; Hoffman LaRoche: Research Funding.

Posttransplant Lymphoproliferative Disorder in Pediatric Patients

Transplantation of solid organs and hematopoietic stem cells is accompanied by profound disturbance of immune function mediated by immunosuppressive drugs or delayed immune reconstitution. Disturbed T cell control of Epstein-Barr virus (EBV)-infected B cells leads to posttransplant lymphoproliferative disorder (PTLD) in up to 10% of patients. Children are at a higher risk because they are more often EBV-naïve before transplantation. Patients with PTLD often present with unspecific symptoms (pain and organ/graft dysfunction). Depending on the onset of PTLD, manifestations vary between mainly nodal (late PTLD) and extranodal sites (early PTLD). Histology, immunohistology, EBER in situ hybridization and molecular pathology are required for diagnosis and subclassification of PTLD. The three major types are early lesions (resembling reactive proliferations in immunocompetent patients), polymorphic PTLD (proliferation of B and T cells with effacement of histoarchitecture) and monomorphic PTLD (presenting as malignant lymphomas, mainly high-grade B cell lymphomas). In a subfraction of cases, including monomorphic PTLD, reduction of immunosuppressive medication alone is sufficient to induce remission. Surgical debulking of tumor mass and anti-CD20-antibody treatment with or without chemotherapy (usually at lower dosages than in immunocompetent patients) constitute the basis of additional therapy.

Early and Late Posttransplant Lymphoproliferative Disorder After Lung Transplantation—34 Cases From the European PTLD Network

Jaksch et al. (1) have recently reported a low incidence of posttransplant lymphoproliferative disorder (PTLD) of B-cell origin after lung transplantation (18 in a series of 1157 [1.6%] consecutive patients) in Vienna. Their findings show that posttransplantation management is crucial to PTLD prevention and document the effectiveness of the program in Vienna. The authors hypothesize that their use of anti-cytomegalovirus (CMV) immunoglobulin prophylaxis (Cytotect, 1 mL/kg intravenously on days 1, 7, 14, and 21 postoperatively) protects patients from Epstein-Barr virus (EBV)–associated PTLD. This hypothesis is based on the findings by Opelz et al. (2) who had observed no cases of PTLD within the first year after transplantation in 2103 kidney transplant recipients who had received anti-CMV immunoglobulin prophylaxis for 4 months after transplantation—significantly less than in an untreated control group. However, in the subsequent 5 years, new cases of PTLD developed at similar rates in the examined groups with and without CMV prophylaxis. We were intrigued by the low proportion of late PTLD reported (only 3 of 18 cases occurred >1 year after transplantation) and analyzed time-to-PTLD in lung transplant recipients in the PTLD-1 (3) and PTLD 1–3 (4) trials as well as those treated at Hopital Pitie-Salpêtriere, Paris, or reported to the German PTLD registry. Overall, 34 patients with PTLD after lung transplantation were included from centers in Australia, Austria, Belgium, France, and Germany. Twenty-two of 34 had received lung transplants and 12 of 34 had received combined heart/lung transplants between 1988 and 2011. Strikingly, in both groups, less than 40% of cases occurred in the first year after transplantation (early PTLD) (Table 1). We observed cases later than 2 years (16 of 34 [47%]), 5 years (10 of 34 [29%]), and 10 years (6 of 34 [18%]). Furthermore, 6 of 31 patients with PTLD after lung or heart/lung transplantation evaluated for EBV association had EBV-negative disease by EBV-encoded RNA in situ hybridization. These included two cases of diffuse large B-cell lymphoma (DLBCL)-PTLD and one case each of marginal-zone PTLD, plasmacytoma-like PTLD, plasmablastic PTLD, and lymphoplasmocytic PTLD (median time-to-PTLD, 7.6 years; range, 3.8–12.0 years).TABLE 1: Time to PTLD in lung transplant recipients reported to the European PTLD networkIn comparison with our cases and the data of Opelz et al. (2), the key observation of Jaksch et al. (1) is the low proportion of late (and EBV-negative) PTLD in their transplant cohort. It is therefore possible to speculate that this effect was achieved not only through early administration of CMV immunoglobulin but by optimized immunosuppression throughout follow-up, potentially aided by monitoring of CMV polymerase chain reaction. A reduction of PTLD incidence through viral load monitoring (of EBV viral load) and immunosuppression alteration has previously been demonstrated after heart (5) and pediatric liver (6) transplantation. The test of this hypothesis will be the future incidence of late PTLD in the Vienna cohort. We would like to note that the differences between our cases and the cohort presented by Jaksch et al. might to some extent reflect selection bias (patients referred to a hematologist for treatment). Furthermore, we did not control for PTLD risk factors such as EBV serostatus at transplantation. Median overall survival of PTLD after lung transplantation was 1.1 years in the 18 patients reported by Jaksch et al. (1). We observed a median survival of 1.2 years for both our entire cohort of 34 patients and the subgroup of 22 lung transplant recipients. In addition, the four lung transplant recipients treated with sequential therapy (rituximab and CHOP chemotherapy) in the PTLD-1 trial (3) achieved a similarly poor median overall survival of only 1.0 years compared with a median overall survival of 6.6 years for the entire trial cohort of 70 patients with PTLD. This reinforces the need for both effective prophylaxis of and improved treatment strategies for PTLD after lung transplantation. Heiner Zimmermann 1 Sylvain Choquet2 Daan Dierickx3 Martin H. Dreyling4 John Moore5 Angelika Valentin6 Jana K. Striefler7 Hanno Riess7 Veronique Leblond2 Ralf Ulrich Trappe1,7 1 Department of Internal Medicine II: Haematology and Oncology University Medical Center Schleswig-Holstein, Campus Kiel Kiel, Germany. 2 Département d’Hématologie Hopital Pitie-Salpêtriere Université Pierre et Marie Curie Paris, France. 3 Department of Haematology University Hospital Gasthuisberg Leuven Leuven, Belgium. 4 Department of Internal Medicine III University of Munich, Campus Groβhadern Munich, Germany. 5 Haematology Department, St. Vincent’s Hospital Darlinghurst, New South Wales Australia. 6 Division of Haematology Medical University of Graz Graz, Austria. 7 Department of Haematology Charité-Universitätsmedizin Berlin Campus Virchow-Klinikum Berlin, Germany; for the German PTLD Study Group and the European PTLD Network.

Interim analysis of the largest prospective trial to date in adult CD20-positive post-transplant lymphoproliferative disorder (PTLD): Introducing risk-stratified sequential treatment (RSST).

8030 Background: The prospective, multicenter international phase II PTLD-1 trial of sequential treatment (ST, 4 cycles of weekly rituximab followed by 4 cycles of CHOP-21 + G-CSF) in adult CD20-positive PTLD demonstrated excellent efficacy (90% overall response rate, ORR) and safety (11% treatment-related mortality, TRM). As the response to rituximab predicted overall survival (OS), the trial was amended in 2007 introducing risk-stratified sequential treatment (RSST) according to the response to rituximab (NCT00590447). Methods: Following rituximab on days 1, 8, 15 and 22, RSST consisted of 4 3-weekly courses of rituximab monotherapy for patients (pts) in complete remission (CR, low risk) while all others (high risk) received 4 cycles of R-CHOP-21 + G-CSF. Key exclusion criteria were CNS involvement, HIV infection, severe organ dysfunction not related to PTLD, and ECOG &gt; 2. Primary endpoint was ORR. This is an analysis of the first 91 patients treated with RSST. Results: 79/91 pts had monomorphic, 12 polymorphic PTLD. 41/91 pts were kidney, 27 liver, 12 heart, 7 lung or heart+lung, 3 heart+kidney and 1 kidney+pancreas transplant recipients. Median age at diagnosis was 60 years (range 20-82). 73/91 pts had late PTLD and 39/85 PTLDs were EBV-associated. 1 pt died before initiation of treatment; 5 pts discontinued treatment after 4 cycles rituximab. TRM of RSST was 7/90 (8%) including 5 deaths with unknown remission status. ORR was thus 74/80 (93%, 95%CI: 84-97%; CR: 62/80 [78%]). 24/90 pts (27%) achieved CR with 4 cycles of rituximab. After a median follow up of &gt;3 years, relapse rate in low risk pts was not increased by rituximab consolidation in RSST compared to CHOP consolidation in ST (3/23 vs. 5/14, p=0.104]). In patients in PD after rituximab, R-CHOP was more effective than CHOP in achieving CR (15/23 vs. 3/11, p=0.038). OS at 3 years was higher with RSST (70%, 95% CI: 60-82%) compared to ST (61%, 95%CI 49-72%) but this difference was not significant. Conclusions: With RSST 27% of pts were classified as low risk and achieved durable tumor control without chemotherapy while R-CHOP seems more efficient than CHOP in in high risk patients.

Plasmablastic Posttransplant Lymphoma

Plasmablastic posttransplant lymphoma is a rare subtype of monomorphic B-cell posttransplant lymphoproliferative disorder (PTLD). There is little published clinical data to guide treatment. The German prospective PTLD registry D2006-2012 records baseline features, treatment, and outcome of rare PTLD subtypes in adults after solid organ transplantation. Treatment is at the discretion of the local physician. Clinical data on the patients in the registry is collected before, during, and at least 4 weeks, 6 months, 12 and 24 months after treatment. Eight cases of plasmablastic posttransplant lymphoma were reported to the registry until 2011. The majority occurred as late PTLD in male heart transplant recipients. Extranodal manifestations were common in stage I and in stage IV disease. Histological Epstein-Barr virus (EBV) association was confirmed in five of eight cases. MYC/IGH rearrangement was present in two of six patients examined. Although five of eight patients died from early disease progression, we observed that long-term survival can be achieved in localized (2/3) and in disseminated disease (1/5) by immunosuppression reduction (IR) followed by immediate systemic chemotherapy. However, all patients with cytogenetic aberrations and patients with non-EBV-associated PTLD were refractory to IR and to chemotherapy. Chemotherapy parallel to IR was associated with a high rate of infectious complications. In this series, IR and local therapy were not sufficient to treat plasmablastic posttransplant lymphoma even in localized disease whereas IR and systemic chemotherapy (CHOP-21) could achieve lasting complete remissions. Cytogenetic aberrations and lack of EBV association were linked with poor outcome.

Lymphoproliferative Disorders After Solid Organ Transplantation—Classification, Incidence, Risk Factors, Early Detection and Treatment Options

Posttransplant lymphoproliferative disorder (PTLD) is a heterogeneous disease group of benign and malignant entities. The new World Health Organisation classification introduced in 2008 distinguishes early lesions, polymorphic, monomorphic and classical Hodgkin lymphoma-type PTLD. Based on the time of appearance, early and late forms can be identified.PTLDs are the second most frequent posttransplantation tumors in adulthood, and the most frequent ones in childhood. The incidence varies with the transplanted organ-from 1%-2% following kidney transplantation to as high as 10% following thoracic organ transplantation-due to different intensities in immunosuppression. Immunocompromised state and Epstein-Barr virus (EBV) infection are the two major risk factors.In Europe and the US approximately 85% of PTLDs are of B-cell origin, and the majority are EBV-associated. Symptoms are often unspecific; extranodal, organ manifestations and central nervous system involvement is common. Early lesions respond well to a decrease in immunosuppression. Malignant entities are treated with rituximab, chemotherapy, radiotherapy and surgical therapy. Adoptive T-cell transfer represents a promising therapeutic approach. The prognosis is favorable in early PTLD, and poor in late PTLD. Five-year survival is 30% for high-grade lymphomas. The prognosis of EBV-negative lymphomas is worse.Lowering the risk of PTLD may be achieved by low dose maintenance immunosuppression, immunosuppressive drugs inhibiting cell proliferation, and special immunotherapy (e.g. interleukin-2 inhibitors). Early detection is especially important for high risk-e.g. EBV-negative-patients, where the appearance of EBV-DNA and the increase in its titer may help.

Post Transplant Lymphoproliferative Disorders (PTLD) After Lung Transplantation: Comparison of Patients with Early Versus Late Disease.

Abstract 3947Poster Board III-883The incidence and natural history of post-transplant lymphoproliferative disorders (PTLD) vary considerably after different types of organ transplantation. Lung and heart-lung transplants pose a higher risk of PTLD than kidney, pancreas or liver transplantation, most likely due to higher intensity post transplant immunosuppression. While the number of lung transplants is growing, there are only a few studies that detail PTLD in this setting. We studied 33 PTLD patients identified among 639 lung transplant recipients (5.1%) seen at the University of Minnesota between January 1985 and December 2008. The median age at diagnosis was 52 years (20-67 years); 17 cases (51%) were male. The median interval from transplantation to PTLD was 95 months (3-242 months). The great majority (91%) presented with extranodal disease; bone marrow involvement was rare (6%). Eight patients (24%) developed PTLD within one year of transplantation (early group) and predominantly had PTLD involving the allograft or other intra-thoracic organs. These patients often presented with subacute respiratory symptoms and evidence of pulmonary infiltration, raising the question of infection or allograft rejection. Twenty five patients (76%) were diagnosed more than one year after transplantation (late group) with disease mainly affecting gastrointestinal organs. Their presentations predominantly included acute abdominal symptoms and GI bleeding. Patients in both the early and late groups had advanced stage disease and high International Prognostic Index scores at diagnosis. Thirteen percent of the early group and 44% of the late group had a poor performance status (PS > 2) (p=0.107). Median LDH was 1117 U/L in the early group and 1830 U/L in the late group (p=0.204). Monomorphic diffuse large B cell lymphoma was the most common pathological diagnosis (86%) in both early and late groups. Ebstein-Barr encoded RNA (EBER) stain was positive in 20 cases (61%) and was not different between the two groups (p=0.177). For management, 31 of the 33 patients (94%) had their immunosuppression reduced and 30 patients also underwent systemic treatment, including rituximab (31%), chemotherapy (36%) or both (33%). The 3 patients who did not receive systemic treatment had progressive disease and died. Eighty seven percent of the early group and 45% of the late group achieved remission. However, there was no statistical difference in treatment response in the two groups (p=0.137). A total of 25 patients (76%) died; median survival was 9 months (0-107 months). Again, there was no statistically significant difference in survival between early and late PTLD (p=0.230). Major causes of death were infection and PTLD. Univariate analysis using the Cox proportional hazards model revealed that treatment response (p<0.001), good performance status (p<0.001) and presence of CD20 (p=0.006) were significant predictors for survival. We conclude that the incidence of PTLD after lung transplantation is high. Although there are clinical differences between those who present early or late, pathologic subtype, treatment response and survival are similar. Patients developing PTLD after lung or heart-lung transplantation have a poor prognosis, with patients dying most commonly from PTLD or infection. Disclosures:No relevant conflicts of interest to declare.

Clinical and pathological prognostic markers for survival in adult patients with post-transplant lymphoproliferative disorders in solid transplant

We sought to determine the clinical and immunohistopathological prognostic factors for overall survival (OS) in adult patients with post-transplant lymphoproliferative disorders (PTLDs). Eighty-four patients diagnosed with PTLDs between 1980 and 2004 at the University of Pittsburgh Medical Center were identified. Immunohistochemical staining was performed on tumor tissue at the time of diagnosis for the following proteins: Bcl-2, Bcl-6, c-myc and p53. The median survival for all patients was 20.8 months, 95% CI: (7.4–77.6). On univariate analysis for OS, the following poor prognostic factors were identified: age at transplant >60 years (p = 0.024), multiorgan transplant (p = 0.019), ECOG > 2 (p < 0.0001), grafted organ involvement (p < 0.0001), extranodal disease (p = 0.011), early (<1 year) PTLDs (p < 0.0001), stage IV (p = 0.0017), EBV positive (p = 0.012) and elevated white blood count (p = 0.010). Good prognostic factors included ECOG<2 (p < 0.0001), late (>1 year) PTLDs (p = 0.002), early stage at diagnosis (stages I and II, p = 0.005), nodal disease (p = 0.0053), monomorphic disease (0.0034), initial immunosuppression reduction (p = 0.0015) and use of rituximab (p = 0.045). Bcl-2 but not Bcl-6, c-myc, or p53 correlated with poor survival, p = 0.0036. This study identifies new clinical and pathological markers for poor survival in PTLDs.

Salvage Chemotherapy for Refractory and Relapsed Posttransplant Lymphoproliferative Disorders (PTLD) After Treatment With Single-Agent Rituximab

Single-agent rituximab has demonstrated encouraging efficacy and tolerability in posttransplant lymphoproliferative disorders (PTLDs) failing to respond to immunosuppression reduction (IR). This retrospective analysis was undertaken to determine the efficacy and safety of salvage therapy in recipients of solid organ transplants with progression of PTLD after rituximab first-line therapy. Eleven patients who had received IR and single-agent rituximab were analyzed. Of these, 10 had received CHOP salvage chemotherapy. One patient with limited disease received tumor irradiation and further IR. Most patients (73%) had late PTLD (median onset of disease 145 months posttransplant), and most (83%) had monomorphic histology; 36% had EBV-association. IR and irradiation therapy re-induced complete remission (CR) and allowed long-term disease control in a patient with polymorphic PTLD relapse. CHOP therapy achieved CR in five (50%) and partial remission (PR) in two (20%) patients. Four of five (80%) patients achieving CR remained in CR at a median follow-up of 44.2 months. Of the patients achieving PR, one is currently alive, and the second died from transplant rejection after converting to CR after consolidative chemotherapy. Patients with stable disease (two) and progressive disease (one) have died from PTLD. There was one possible CHOP-associated death (acute cardiac event) and two patients had to be switched to less-toxic monotherapies. Median overall survival was 46.5 months (95% confidence interval: 23.6-49.1 months). CHOP salvage therapy achieved a favorable overall response rate of 70% in this setting, indicating that PTLD generally remains chemotherapy-sensitive after progression following first-line rituximab.