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Shpilberg, Ofer, John Wilson, Theresa L. Whiteside, and Ronald B. Herberman. "Pre-Transplant Immunological Profile and Risk Factor Analysis of Post-Transplant Lymphoproliferative Disease Development: The Results of a Nested Matched Case-Control Study." Leukemia & Lymphoma 36, no. 1-2 (1999): 109–21. http://dx.doi.org/10.3109/10428199909145954.
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Pearse, William B., Chetan V. Vakkalagadda, Irene Helenowski, et al. "Prognosis and Outcomes of Patients with Post-Transplant Lymphoproliferative Disorder: A Single Center Retrospective Review." Blood 136, Supplement 1 (2020): 9–10. http://dx.doi.org/10.1182/blood-2020-141286.
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Background Patients treated with chronic immunosuppression face a six-fold increase in their cumulative lifetime risk of lymphoma relative to age-matched immunocompetent counterparts. These malignances represent a spectrum of lymphoid and plasmacytic histologies collectively referred to as post-transplant lymphoproliferative disorders (PTLD). Accurate risk-stratification and optimal treatment strategies are unclear given wide histologic and clinical heterogeneity. Current standard-of-care models include immunosuppression reduction and sequential, response-adapted chemoimmunotherapy platforms, however 80% of patients will require chemotherapy exposure. Overall response rates (ORR) are >90%, however relapse is common and serious treatment-related toxicities including infection and allograft rejection pose significant challenges. Several risk-stratification schemes have been proposed to direct initial therapy and predict clinical outcomes, however their external validity has been inconsistent across patient populations. We report here the results of a single-center retrospective study assessing the treatment patterns and outcomes of patients diagnosed with PTLD and provide a risk-assessment profile that may help improve clinical outcomes. Methods Patients 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. ORR is defined as complete or partial response. Progression-free survival (PFS) is defined as time from diagnosis to disease progression; patients who died before restaging or who were lost to follow-up were censored. Overall survival (OS) is defined as time from diagnosis to death from any cause; patients who were alive at last follow-up were censored. Results A total of 182 patients were identified by database query and 111 patients met our inclusion criteria. Demographics data are provided (Figure 1A). Five-year PFS and OS were 55.7% and 87.2%, respectively (Figure 1B). 92.6% of patients treated with immunosuppression agents underwent dose reduction and 16.8% experienced graft rejection, of which 27.8% required re-transplantation. Exploratory univariate analyses were performed on the following clinical factors: age, LDH, Ann-Arbor Stage, presence of extranodal disease, histologic EBER positivity, ECOG PS, comorbid conditions (type II diabetes, obesity, and coronary artery disease), CNS involvement, transplant type, presence of EBV viremia, and PTLD subtype. Established risk stratification models, including the IPI, R-IPI, Leblond score, Ghobrial score, and PTLD prognostic index, were applied to this cohort. We identified elevated LDH (p=0.04) and IPI score >3 (p=0.015) as predictors of PFS (Figure 1C); elevated LDH (p=0.02) and thoracic allograft transplantation (p=0.03) were predictors of OS (Figure 1D). The PTLD prognostic index significantly predicted PFS (p=0.03) and OS (p=0.013) (Figure 1E). 50.4% received Rituximab monotherapy prior to risk-stratification for combination chemoimmunotherapy; ORR and CR rates with Rituximab monotherapy were 67.9% and 41.1%, respectively. Overall response to Rituximab monotherapy was found to be a significant predictor of PFS (p<0.0001) but not OS (p=0.14) (Figure 1F). Conclusions This study represents one of the largest retrospective cohorts of PTLD patients to date. We show that the PTLD prognostic index is the most accurate risk stratification tool in predicting PFS and OS in this patient population and may have utility in guiding therapeutic approaches in PTLD patients. LDH, IPI score, and type of allograft transplantation are significant clinical variables in predicting clinical outcomes. Furthermore, response to Rituximab monotherapy was a significant predictor of PFS; improving frontline outcomes to high-risk patients remains a critical unmet need. Figure Disclosures Winter: Epizyme: Other: DSMB; Delta Fly Pharma: Consultancy; Amgen: Consultancy; CVS/Caremark: Consultancy; Ariad/Takeda: Consultancy; Norvartis: Consultancy, Other: DSMB; Merck: Membership on an entity's Board of Directors or advisory committees, Other: advisory board; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: advisory board. Gordon:Zylem Biosciences: Patents & Royalties: Patents, No Royalties. Karmali:BeiGene: Speakers Bureau; BMS/Celgene/Juno: Honoraria, Other, Research Funding, Speakers Bureau; Gilead/Kite: Honoraria, Other, Research Funding, Speakers Bureau; Takeda: Research Funding; Karyopharm: Honoraria; AstraZeneca: Speakers Bureau. Ma:AbbVie: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; BeiGene: Honoraria, Research Funding, Speakers Bureau; Bioverativ: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Kite: Consultancy, Honoraria; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Juno: Research Funding; Novartis: Research Funding; TG Therapeutics: Research Funding. Ganger:Mallinkrodt: Consultancy; Gilead: Speakers Bureau. Pro:Verastem Oncology: Research Funding.
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Crane, Genevieve Marie, Helen Powell, Rumen Kostadinov, et al. "Lymphoproliferative Disease Risk in Patients with Autoimmune Disease: Clustering of Primary CNS Lymphoma with Drug Regimen and Disease Process." Blood 126, no. 23 (2015): 1490. http://dx.doi.org/10.1182/blood.v126.23.1490.1490.
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Abstract Introduction: While immunosuppression for solid organ transplant is associated with an increased risk of lymphoproliferative disease (LPD), this has been more difficult to establish in autoimmune disorders, even though patients are often treated with similar agents. One reason is that autoimmune disease may elevate baseline LPD risk. However, associations have been shown with certain rare types of LPD; most strikingly hepatosplenic lymphoma, now known to occur as a consequence of anti-TNF-alpha therapy in young men with inflammatory bowel disease (IBD) (J Ped Gast Nutr. 2007; 44:265-7). We have noticed a rise in the incidence of another rare lymphoma in autoimmune disease patients: primary central nervous system (PCNS) LPD. Six cases have been diagnosed at our institution since 2010, with none before that dating back to onset of electronic records in 1986. All of these patients were taking mycophenolate mofetil (MMF) and/or thiopurines. A similar rise in reported cases has been seen in the literature (Fig 1) with suggestion of but no direct association with drug treatment shown. We systematically investigated this trend. Methods: We searched our pathology database to identify all LPD cases diagnosed over a 28-year period in patients treated for autoimmune disease as well as all similar cases involving the CNS reported in the literature over the past 40 years. Statistical analyses were performed using the Fisher's exact test. Results: We identified 44 cases of LPD arising in patients treated for autoimmune disease, including 6 with PCNS disease (Table 1). Of LPDs in patients on anti-TNF-alpha agents, 4/5 had a T-cell phenotype, and 3 had IBD. By contrast, in patients who developed LPD while taking methotrexate, the majority for rheumatoid arthritis, only 1/18 had a T-cell phenotype. Instead they were categorized as polymorphous, Hodgkin or large B-cell morphologies, which were frequently EBV-positive (67%), but never involved the brain (0/18). The LPDs arising in patients on MMF and/or thiopurines showed a similar morphologic profile but were more likely to involve the CNS. In particular, MMF was significantly associated with PCNS compared to non-CNS disease (p<0.001), and the only patient on MMF that developed an LPD outside the CNS was taking MMF in combination with cyclosporine. The most common underlying disorders in PCNS disease were myasthenia gravis (MG) and IBD. We reviewed all cases of CNS LPD in patients treated for autoimmune disease reported in the literature (34 reports, 40 patients), including 32 with PCNS LPD and 8 with secondary CNS involvement. The vast majority of PCNS cases arose in patients taking MMF and/or thiopurines (29/32), but only MMF was significantly associated with primary compared to secondary CNS involvement (p<0.05). The most common underlying disease in PCNS patients was systemic lupus erythematosus (SLE) (10/32), followed by IBD and MG. No patients with secondary CNS involvement had SLE. Conclusions: While the overall risk of LPD in the context of autoimmune disease treatment has been controversial, the interaction between drug type and individual patient characteristics may dramatically increase risk for certain lymphomas. We now demonstrate a significant association between use of MMF and PCNS LPD, which appears to cluster in patients with a history of SLE, MG or IBD. Of interest, all 3 autoimmune patients in the JHH database who developed PCNS LPD following solid organ transplant (not shown) also had SLE. While methotrexate never produced a PCNS LPD in our series, it has been infrequently found in the literature. There is no evidence of an increased baseline risk of PCNS LPD in autoimmune patients; indeed, only one reported case in an untreated patient could be identified in the literature (J Rheum 1978; 5:75-78). In addition, EBV-associated PCNS lymphoma is virtually always seen in the context of immunosuppression. Further investigation into the increased risk of specific types of LPD with immunosuppressive treatment is warranted with significant implications for tailoring treatment options. Table 1. Demographics of JHH and Reported CNS Cases ('*' p<0.05). JHH All Reported CNS Cases (Literature) PCNS Non-CNS PCNS 2o CNS No. Cases 6 38 32 8 Age (range) 69(27-77) 61(18-77) 57(27-88) 62(15-71) % Male 50% 50% 32% 25% Deceased 17% 37% 45% 40% EBV 100% 69% 95% 100% MMF 80%* 3% 41%* 0 Thiopurines 40% 23% 72% 75% Methotrexate 0 58% 13% 38% SLE 0 9% 31%* 0 MG 33% 3% 19% 0 IBD 33% 24% 19% 38% Disclosures Borowitz: Becton Dickinson Biosciences, Medimmune: Research Funding.
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Faridi, Rehan Mujeeb, Taylor J. Kemp, Poonam Dharmani, et al. "Copies of Donor Killer Immunoglobulin-like Receptor Genes and Motifs Titrate Natural Killer (NK) Cells' Functional Response to Epstein - Barr Virus Infections and Influence the Risk of Developing Post-Transplant Lymphoproliferative Disease (PTLD) after Allogeneic Hematopoietic Cell Transplantation." Blood 126, no. 23 (2015): 741. http://dx.doi.org/10.1182/blood.v126.23.741.741.
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Abstract BACKGROUND: Recipientsof allogeneic HCT remain vulnerable to a heightened risk of reactivation of otherwise latent viral infections owing to a compromised immune system early after transplantation. Uncontrolled reactivation of Epstein-Barr virus (EBV) leading to post-transplant lymphoproliferative disorder (PTLD) is one of such major complications after T-cell depleted HCT. Recovering within weeks after transplantation and being first in line of defense against viral infections, natural killer (NK) cells are deemed important in the immunopathogenesis of EBV complications. Their role however remains elusive. NK cell responses are regulated by a series of activating and inhibitory cell surface receptors, central to which are the Killer Immunoglobulin-like Receptors (KIR). Through these receptors NK cells discriminate healthy cells from 'altered' self-cells by scaling the perturbations in HLA expression after viral transformation of the target cell. Here, we set out to determine whether and how KIR gene and motifs' content of HCT donors and/or recipients influences the development of PTLD after allo-HCT. STUDY DESIGN: Hypothesizing that diverse NK cell receptor repertoires can titrate NK cell functional responses to EBV infections/reactivation and can potentially modify the risk of developing PTLD, we determined the KIR gene repertoires of 356 HLA-matched donor-recipient pairs of first allo-HCT and 50 healthy donors through Next Generation Sequencing of the KIR locus on the Illumina MiSeq platform. Based on the presence/absence and number of copies of individual genes, the KIR genotypes were determined and classified into four common centromeric (cA01, cB01, cB02 and cB03) and two telomeric (tA01 and tB01) motifs along with their variants. PBMNCs from KIR typed healthy volunteers were stimulated with EBV-transformed target cells to enumerate NK cell response to EBV (degranulation and/or IFNγ production) as a function of KIR gene content and motifs' distribution using a multicolor flow cytometry-based assay. Effect of KIR gene profile on development of PTLD was analyzed using binomial competing risks regression statistics. Distribution of NK cell functional response across various KIR characterized groups was analyzed using Mann-Whitney U statistics. RESULTS: Donor telomeric A motifs (tA01, KIR3DL1+ve KIR2DS4+ve; KIR3DS1/2DS1+/-ve), strongly protected against PTLD (p=0.0001, SHR=0.17; Figure 1). An increased protection against PTLD with increasing number of tA01 was noted with at least one copy required for a significant protective effect (Figure 1B). Copy number analysis of tA01 gene contents yielded similar associations. Further, the number of EBV induced functional NK cell subsets were significantly higher in individuals with than without KIR genotypes containing tA01 motifs (Figure 2 A-C) and was found to be increasing with an increasing number of tA01 copies (Figure 2 A'-C'). There was no influence of recipients' KIR repertoire on the risk of developing PTLD CONCLUSIONS: NK cell responsiveness, a function of KIR gene repertoire has a profound effect on the development of PTLD. Appropriately characterized KIR gene profile based identification of HCT recipients at high risk of developing PTLD will enable closer monitoring of EBV DNAemia and facilitate prompt therapy. Figure 1. Donor KIR telomeric A motif (tA01) protects against the risk of developing PTLD (A). Presence of at least one copy of donor KIR tA01 motif confers significant protection from PTLD (B) Figure 1. Donor KIR telomeric A motif (tA01) protects against the risk of developing PTLD (A). Presence of at least one copy of donor KIR tA01 motif confers significant protection from PTLD (B) Figure 2. KIR telomeric A motifs (tA01) titrate NK cells' functional response to Epstein-Barr virus infected cells (A-C), with and increasing %functional NK cells and subsets (measures as expressing CD107a, IFN-γ, or both) are observed with increasing tA01 motifs' copies (A'-C') Figure 2. KIR telomeric A motifs (tA01) titrate NK cells' functional response to Epstein-Barr virus infected cells (A-C), with and increasing %functional NK cells and subsets (measures as expressing CD107a, IFN-γ, or both) are observed with increasing tA01 motifs' copies (A'-C') Disclosures No relevant conflicts of interest to declare.
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Prockop, Susan, Ran Reshef, Donald E. Tsai, et al. "Long-Term Outcomes of Subjects with Epstein-Barr Virus-Driven Post-Transplant Lymphoproliferative Disorder (EBV+PTLD) Following Solid Organ (SOT) or Allogeneic Hematopoietic Cell Transplants (HCT) Treated with Tabelecleucel on an Expanded Access Program." Blood 134, Supplement_1 (2019): 4071. http://dx.doi.org/10.1182/blood-2019-124904.
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Background: Patients (pts) undergoing solid organ (SOT) or allogeneic hematopoietic cell transplants (HCT) are at risk for developing Epstein-Barr (EBV) virus-driven post-transplant lymphoproliferative disorder (PTLD). Pts with EBV+PTLD not responding to rituximab ± chemotherapy after SOT or HCT have poor outcomes. Many SOT and HCT recipients are also not good candidates for aggressive chemotherapy regimens. There is an unmet need for effective and well tolerated therapies in this patient population. Tabelecleucel (tab-cel®) is an investigational, off-the-shelf, allogeneic, EBV-specific, T-cell immunotherapy generated from healthy donors, which functions through native, endogenous T-cell receptors (TCRs) and HLA restrictions. Tabelecleucel is selected for an individual patient from an existing library, based on HLA restriction and matching. Here, we report long-term study results from US centers using tabelecleucel for subjects with EBV+PTLD following HCT or SOT. Methods: Subjects with EBV+PTLD after HCT (n=14) or SOT (n=12) were treated with tabelecleucel on Atara's expanded access program (EAP; ATA129-EBV-201, NCT02822495, ongoing). Subjects received tabelecleucel matched by ≥ 2/10 HLA alleles, including ≥1 HLA allele through which tabelecleucel exerts cytotoxicity (HLA restriction). Key inclusion criteria were: presence of biopsy-proven EBV+PTLD, adequate organ function (ANC ≥ 500/µL +/- cytokine support; platelets ≥ 20,000/µL +/- transfusion support if no ≥ grade 2 bleed in prior 6 months; ALT, AST, T. Bili < 3X ULN; Creatinine < 3X ULN) and performance status (ECOG ≤ 4 or Lansky ≥ 20), and lack of approved alternative therapies. Non-PTLD-related vasopressor or ventilatory support, pregnancy, concomitant need for T-cell inhibiting medications were exclusionary. Tabelecleucel was given at 1.6-2 x 106 cells/kg/dose on days 1, 8, and 15 of every 5-week cycle with imaging-based response assessment at ~d28 of each cycle. Subjects were treated to maximal response with up to 4 tabelecleucel products (cell lines) with different HLA restrictions, occurrence of an adverse event leading to tabelecleucel discontinuation, or withdrawal of consent. The results presented herein reflect a data snapshot from 3th June 2019. Results: All subjects had received prior rituximab and 7/12 SOT subjects received prior chemotherapy. Intermediate/high risk PTLD-prognostic index (PTLD-IPI; Choquet et al, Ann Hematol 2007) was noted in 79% and 42% of HCT and SOT subjects, respectively. The results are presented in table 1. While the median follow-up time in HCT subjects is short, 3 subjects were followed for over 12 months including 2 who were followed for more than 24 months. In subjects responding to tabelecleucel, 1-year OS was 85.7% in HCT and 100% in SOT, and no deaths were attributable to PTLD progression. In a subset of study subjects (HCT: n=11; SOT: n=11) with adequate ECOG, no CNS disease, and no PTLD-related ventilatory support, who would have likely been eligible for Atara's ongoing phase-3 trials, the ORR was 55% (HCT) and 82% (SOT), with a 2-yr OS of 79% (HCT) and 81% (SOT). The safety profile of tabelecleucel was consistent with previously published data. At the data snapshot for this abstract, no tabelecleucel-related adverse events led to treatment discontinuation or death. In addition, no cytokine release syndrome, organ rejection or tumor flare adverse events were reported in the PTLD subjects treated with tabelecleucel on this EAP. Conclusions: The data demonstrate a high response rate for tabelecleucel in PTLD in both HCT and SOT after initial treatment failure. Longer term follow-up shows a favorable 2-year OS in this predominantly high-risk population for whom there are no approved alternative therapies. Similar outcomes were observed in the subset of subjects potentially eligible for ongoing phase 3 studies of tabelecleucel in relapsed/refractory EBV+PTLD following SOT (NCT03394365) or HCT (NCT03392142). Tabelecleucel appears to be an effective and well-tolerated option in the subset of subjects with EBV+PTLD treated on this EAP. Disclosures Prockop: Atara Biotherapeutics: Other: Support for industry sponsored trails ; Mesoblast: Other: Support for industry sponsored trails . Reshef:Atara: Consultancy, Research Funding; BMS: Consultancy; Shire: Research Funding; Incyte: Consultancy, Research Funding; Magenta: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; Pharmacyclics: Consultancy, Research Funding; Celgene: Research Funding. Tsai:Eli Lilly and Company: Employment. Bunin:PRA Health Sciences: Other: Immediate family member employed. Mahadeo:PI for ATARA EBV CTL Trials: Other: Other ; Recipient of unrestricted medical education grant from Jazz: Research Funding. Van Besien:Miltenyi Biotec: Research Funding. Dwivedy Nasta:Debiopharm: Research Funding; Millenium/takeda: Research Funding; Merck: Consultancy, Other: data safety monitorin; 47 (Forty Seven): Research Funding; Roche: Research Funding; Rafael: Research Funding; Aileron: Research Funding; ATARA: Research Funding; Pharmacyclics: Research Funding; Celgene: Honoraria. Hiremath:Atara Biotherapeutics: Employment, Equity Ownership. Yue:Atara Biotherapeutics: Employment, Equity Ownership. Sun:Atara Biotherapeutics: Employment, Equity Ownership. Navarro:GE: Equity Ownership; Pfizer: Equity Ownership; Atara Biotherapeutics: Employment, Equity Ownership, Patents & Royalties; Bluebird Bio: Equity Ownership.
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Stréhn, Anita, László Szőnyi, Gergely Kriván, et al. "Post-transplant lymphoproliferative disorder in childhood." Orvosi Hetilap 155, no. 8 (2014): 313–18. http://dx.doi.org/10.1556/oh.2014.29796.
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Introduction: Among possible complications of transplantation the post-transplant lymphoproliferative disease due to immunosuppressive therapy is of paramount importance. In most cases the direct modulating effect of Epstein–Barr virus on immune cells can be documented. Aim: The aim of the authors was to evaluate the incidence os post-transplant lymphoproliferative diseases in pediatric transplant patients in Hungary. Method: The study group included kidney, liver and lung transplant children followed up at the 1st Department of Pediatrics, Semmelweis University, Budapest and stem cell transplant children at Szent László Hospital, Budapest. Data were collected from 78 kidney, 109 liver and 17 lung transplant children as well as from 243 children who underwent allogenic stem cell transplantation. Results: Between 1998 and 2012, 13 children developed post-transplant lymphoproliferative disorder (8 solid organ transplanted and 5 stem cell transplanted children). The diagnosis was based on histological findings in all cases. Mortality was 3 out of the 8 solid organ transplant children and 4 out of the 5 stem cell transplant children. The highest incidence was observed among lung transplant children (17.6%). Conclusions: These data indicate that post-transplant lymphoproliferative disease is a rare but devastating complication of transplantation in children. The most important therapeutic approaches are reduction of immunosuppressive therapy, chemotherapy and rituximab. Early diagnosis may improve clinical outcome and, therefore, routine polymerase chain reaction screening for Epstein–Barr virus of high risk patients is recommended. Orv. Hetil., 2014, 155(8), 313–318.
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Ekman-Joelsson, Britt-Marie, Håkan Wåhlander, Mats Synnergren, Madeleine Sager, and Karin Mellgren. "Post-transplant lymphoproliferative disease is associated with early sternotomy and left ventricular hypoplasia during infancy: a population-based retrospective review." Cardiology in the Young 27, no. 9 (2017): 1823–31. http://dx.doi.org/10.1017/s104795111700155x.
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AbstractBackgroundHeart transplantation has been an option for children in Sweden since 1989. As our unit faced an increased rate of post-transplant lymphoproliferative disorder, the objective of the study was to identify possible risk factors.MethodsThis is a retrospective study of all children aged 0–18 years who underwent heart transplantation in Gothenburg from 1989 to 2014.ResultsA total of 71 children underwent heart transplantation. The overall incidence of post-transplant lymphoproliferative disorder was 14% (10/71); however, 17% (6/36) of those undergoing transplantation after 2007 developed lymphoma, compared with only 10% (4/35) of transplantation cases before 2007 (p=0.85). The mean age at transplantation was 9 years (0–17). The mean post-transplant follow-up time was 5.5 years (0.5–21.9) in the group that developed post-transplant lymphoproliferative disorder, compared with 10.2 years (0.02–25.2) in those who did not. In our study group, risk factors for post-transplant lymphoproliferative disorder were surgically palliated CHD (p=0.0005), sternotomy during infancy (p⩽0.0001), hypoplastic left ventricle (p=0.0001), number of surgical events (p=0.0022), mismatch concerning Epstein–Barr virus infection – that is, a positive donor–negative recipient (p⩽0.0001) – and immunosuppressive treatment with tacrolimus compared with ciclosporine (p=0.028).DiscussionThis study has three major findings. First, post-transplant lymphoproliferative disorder only developed in subjects born with CHD. Second, the vast majority (9/10) of the subjects developing the disorder had undergone sternotomy as infants. Third, the number of surgical events correlated with a higher risk for developing post-transplant lymphoproliferative disorder.
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Skrabs, Cathri n. C., Alexander Hauswirth, Karin Eigenberger, et al. "Liposome-Encapsulated Doxorubicin Is Highly Active in Patients with B- as Well as T/NK-Cell Lymphomas and Cardiac Comorbidity or Older Age." Blood 112, no. 11 (2008): 3587. http://dx.doi.org/10.1182/blood.v112.11.3587.3587.
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Abstract Conventional anthracyclines may have severe dose-limiting side effects in patients with pre-existing cardiac comorbidity, particularly if they are elderly. In routine practice, this will lead to dose reductions or preclude the use of anthracyclines. This may result in lower remission and shorter lymphoma-free or overall survival rates. Non-pegylated liposome-encapsulated doxorubicin (Myocet®) in combination with Rituximab, cyclophosphamide, vincristine and prednisone (R-COMP) has been shown to be effective with a low cardiotoxicity profile in patients with diffuse large B-cell lymphoma (DLBCL) (Rigacci et al., Hematol Oncol.2007;25:198–203). We have treated 37 lymphoma patients with pre-existing cardiac disorders or elderly patients with reduced general condition who were considered ineligible or high risk for anthracycline containing therapy. Thirty seven patients with various histologies were included: 20 DLBCL, 9 T-/NK cell lymphomas, 3 follicular lymphomas, 2 post-transplant lymphoproliferative disease (PTLD), 2 chronic lymphocytic leukemia (CLL) and 1 multiple myeloma (MM). Reasons for the use of liposome-encapsulated doxorubicin were: pre-existing cardiac disorders (N=19) including myocardial infarction, cardiomyopathy, reduced left ventricular ejection fraction LVEF (N=6), elevated B-type natriuretic peptide (BNP) levels (N=10, median 680 pg/ml), aortic valve problems, or heart transplantation; older age (N=12; median age 78 years); previous therapy with anthracyclines (N=3); other comorbity or reduced general condition (N=4). Twenty-nine patients (78%) were previously untreated. The following combination regimens were given: R-COMP (N=25), COMP (N=11), and BMD (N=1). The median number of Myocet® containing cycles administered was 5. For various reasons, liposome encapsulated doxorubicin was reduced to a dose of less than 50mg/m2 in 19 patients. High remission rates were observed for this poor risk population: Complete remission rates were 70% (14/20) for DLBCL and 57% (4/7 evaluable patients) for T-/NK cell lymphomas. 31 patients (83%) are still alive at 2–9 months after the end of therapy. Five patients died from progressive disease, one of unknown reasons. Thirteen patients with DLBCL are in continuous CR 3 months after the end of therapy (range 1–8 months). No major cardiac or gastrointestinal toxicity was observed. Of note, paravasation of liposome-encapsulated doxorubicin occurred in 2 patients, but resulted in mild inflammation only without tissue damage. Hematologic toxicity was comparable to that of conventional anthracycline containing regimens: CTC Grade 3 or 4 toxicity for leukocytopenia/neutropenia occurred in 22 patients (59%). Nineteen patients (51%) received G-CSF for primary or secondary prophylaxis in at least one cycle of treatment. We conclude that liposome-encapsulated doxorubicine is highly active in combination chemotherapy for B-cell lymphomas with low cardiac toxicity in patients with pre-existing cardiac disorders or older age. Moreover, we herewith report for the first time efficacy in T/NK-cell lymphomas in this high-risk population. A randomized study evaluating cardiac effects of substitution of conventional doxorubicin by liposome-encapsulated doxorubicin in combination chemotherapy (R-CHOP vs. R-COMP) is currently being conducted by the Austrian Cooperative Group on Cancer Drug Therapy (AGMT).
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Saueressig, Maurício G., Veronique Boussaud, Catherine Amrein, Romain Guillemain, Jihane Souilamas, and Redha Souilamas. "Risk factors for post-transplant lymphoproliferative disease in patients with cystic fibrosis." Clinical Transplantation 25, no. 4 (2011): E430—E436. http://dx.doi.org/10.1111/j.1399-0012.2011.01464.x.
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Al-Mansour, Zeina, Beverly P. Nelson, and Andrew M. Evens. "Post-Transplant Lymphoproliferative Disease (PTLD): Risk Factors, Diagnosis, and Current Treatment Strategies." Current Hematologic Malignancy Reports 8, no. 3 (2013): 173–83. http://dx.doi.org/10.1007/s11899-013-0162-5.
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Lustberg, Mark E., Ronald Pelletier, Pierluigi Porcu, Stanley Martin, and Robert A. Baiocchi. "Risk Factors for Post-Transplant Lymphoproliferative Disorder in Solid Organ Transplant Recipients." Blood 118, no. 21 (2011): 4465. http://dx.doi.org/10.1182/blood.v118.21.4465.4465.
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Abstract Abstract 4465 Introduction: Solid organ transplant recipients are profoundly immune suppressed and are at risk for post-transplant lymphoproliferative disorder (PTLD). PTLD is associated with substantial morbidity and mortality. With limited treatment options, earlier detection of disease and earlier initiation of therapy may be essential for optimizing therapeutic outcomes. Thus, identifying at risk groups is critical. Methods: We conducted an IRB-approved retrospective study of 1,496 solid organ transplant recipients treated at our institution to identify risk factors for the development of PTLD. We identified 104 cases of PTLD going back over the past 20 years, through 1991. A cross-sectional sample of solid organ transplants evaluated at our institution was used as controls (N = 1,392). Charts were reviewed for relevant demographic variables, reason for transplantation, Epstein-Barr virus (EBV) serostatus pre-transplant, and Human Leukocyte Antigen (HLA)-type. Information on outcomes, such as organ rejection over follow up and death was also recorded. In individuals with PTLD, date of diagnosis, tumor characteristics (i.e., EBV status), tumor pathology, and PTLD treatment was recorded. Survival analysis (Kaplan-Meier plots and Cox proportional hazards regression) was conducted on collected data, to determine risk factors for the development of PTLD. Results: In the cohort as a whole, 86/1,496 (5.8%) of individuals were EBV seronegative at baseline, and 20.9% (312/1496) did not have an available documented baseline EBV serology. EBV serostatus was the major risk factor for EBV-associated PTLD (N=74, or 71% of PTLD cases): EBV-seronegative individuals had a Hazard Ratio (HR) =7.70 [95% CI = 3.8 – 15.5, p < 0.001] for EBV-associated PTLD compared to seropositive individuals. Thus, further analyses were stratified by EBV serostatus, to examine the effect of HLA-type on risk of development of PTLD. In an exploratory data analysis, we found that HLA-B40 was a major risk factor for the development of EBV-associated PTLD in EBV-seronegative individuals, while HLA-B8 was a risk factor for the development of EBV-associated PTLD in EBV-seropositive individuals. In baseline seronegative individuals HLA-B40 was associated with a HR=5.99 [95% CI = 1.95 – 18.4, p=0.002] for PTLD (see figure below for Kaplan Meier curves). In baseline seropositive individuals HLA-B8 was associated with a HR = 3.65 [95% CI = 1.52 – 8.76, p= 0.004] for PTLD. In EBV seropositive individuals, receipt of either a liver, cardiac, lung or pancreas transplant (compared to a kidney transplant alone) was associated with an increased risk of PTLD as well, HR = 6.72 [95% CI = 2.78 – 16.24, p < 0.001. Conclusions: While the relation of HLA-type and EBV-associated PTLD seen in the study are novel, we recommend future studies to test these observations. These results demonstrate that risk factors for EBV-associated PTLD may verify substantially with baseline EBV-serostatus. We recommend future studies consider stratifying analyses by baseline EBV-serostatus, as EBV-associated PTLD resulting from primary EBV-infection may represent a distinct pathology than EBV-associated PTLD arising in individuals who are known to be EBV-seropositive. Disclosures: No relevant conflicts of interest to declare.
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Duarte, Fernando Barroso, and Eduardo José Alencar Paton. "Maintenance Treatment Post-transplant." JOURNAL OF BONE MARROW TRANSPLANTATION AND CELLULAR THERAPY 2, no. 2 (2021): p89. http://dx.doi.org/10.46765/2675-374x.2021v2n2p89.
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Disease recurrence is the most common cause of HCT failure in patients with AML,ALL and SMD and factors such as the presence of measurable residual disease before and after transplantation, stage of the disease before transplantation and the cytogenetic and molecular risk profile are factors associated with increased risk of recurrence.
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Stefanovic, Alexandra, Daniel Dammrich, Andreas Tzakis, and Izidore S. Lossos. "Post-Transplant Lymphoproliferative Disease In Liver Transplant Recipients: A Single Institution Experience." Blood 116, no. 21 (2010): 1752. http://dx.doi.org/10.1182/blood.v116.21.1752.1752.
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Abstract Abstract 1752 Background: Post-transplant lymphoproliferative disease (PTLD) represents a major complication after solid organ transplantation, associated with high morbidity and mortality. Few, mostly small retrospective case series have reported on the clinical features, treatment and outcome of PTLD after liver transplantation, and the optimal treatment approach remains controversial. At our institution, the management of PTLD was not standardized until 2006, when a dedicated lymphoma team for PTLD treatment was formed and adopted a uniform approach based on histologic phenotype. In this approach, monoclonal diffuse large B-cell lymphoma (DLBCL) occurring post transplant was treated aggressively with immunochemotherapy. Methods: We retrospectively analyzed the clinical data of all adult patients who developed PTLD following liver transplantation at our institution between 1988 and 2010. We also compared the outcomes of patients with the most common PTLD histology - DLBCL - treated before 2006 (era 1) and thereafter (era 2). Results: We identified 26 patients (m=18, f=8) with median age of 60 (range 15–80). Underlying liver diseases included hepatitis C (n=9), non-alcoholic steatohepatitis (n=3), alcoholic cirrhosis (n=3), biliary atresia (n=3), autoimmune hepatitis (n=3), cryptogenic cirrhosis (n=2), hepatitis B (n=1), fulminant hepatic failure (n=1) and congenital syndrome (n=1). Acute transplant rejection that required additional immunosuppressive therapy was observed in 16 (62%). Median latency of PTLD after liver transplantation was 39 (range 1–192) months. Eight patients (31%) presented with early PTLD, i.e. within one year after transplantation. Histologic entities included DLBCL (n=16), polymorphic lymphoplasmacytic infiltrate (n=4), marginal zone lymphoma (n=1), Burkitt lymphoma (n=1), Hodgkin lymphoma (n=1) and plasmacytoma (n=1). Tissue staining for EBER was positive in 4/21 evaluated cases (19%). The majority of patients (65%) presented with stage IV disease, and all but one (96%) manifested with extranodal disease. Median IPI score was 3. Initial treatment approaches in patients diagnosed and treated in era 1 (n=13) included reduction or discontinuation of immunosuppression alone (n=2) or in combination with antiviral agents (n=2) and Rituximab (n=7). Two patients died before initiation of therapy. Complete remission to first-line therapy was observed in 3 and partial remission in 4 patients evaluated for response. Six patients in this group died from progressive disease (n=1), infectious complications (n=3), hemorrhagic stroke (n=1) and unknown cause (n=1). Among patients diagnosed and treated in era 2 (n=13), eleven received chemotherapy with or without Rituximab without reduction of immunosppression, one patient was on “watch and wait” for asymptomatic splenic marginal zone lymphoma and another patient decided to seek treatment elsewhere and was lost to follow-up. Eleven patients in this group (1 patient with plasmacytoma of the liver and 10 with DLBCL, including 1 case of primary CNS lymphoma) were evaluable for response and all achieved a complete remission. After a median follow-up period of 28.5 months for surviving patients, the 3-year overall survival (OS) and progression-free survival (PFS) for all patients were 73% and 71%, respectively. One- and 3-year OS was 60% and 51%, respectively, for patients treated in era 1 and 100% for patients treated in era 2 (p=0.01), with 1- and 3-year PFS of 51% in era 1 and 91% in era 2, respectively (p=0.03). Patients with DLBCL histology treated in era 1 had 1- and 3-year OS of 40% and 20% (median 11 months), respectively, while those treated in era 2 had 1- and 3-year OS of 100% (p=0.001), with corresponding 1 and 3-year PFS of 20% (median 8 months) and 90%, respectively (p=0.004). Conclusion: Our study is one of the largest ever published on PTLD in adult liver transplant recipients. The majority of these patients present with aggressive histologies and high risk features. An aggressive immunochemotherapeutic approach by experienced and dedicated lymphoma and liver transplant teams may benefit post-transplant patients with DLBCL and lead to outcomes similar to those observed in the non-transplant setting. Disclosures: No relevant conflicts of interest to declare.
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&NA;. "RECOMBINANT HUMAN GROWTH HORMONE (rhGH) USE PRE-TRANSPLANT AND RISK OF LYMPHOPROLIFERATIVE DISEASE (LPD) POST-TRANSPLANT." Transplantation 82, Suppl 2 (2006): 100. http://dx.doi.org/10.1097/00007890-200607152-00100.
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Sinit, Ryan B., David M. Aboulafia, and Russell K. Dorer. "The First 100 Cases of Epstein-Barr Virus-Positive Mucocutaneous Ulcers." Blood 132, Supplement 1 (2018): 5340. http://dx.doi.org/10.1182/blood-2018-99-110278.
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Abstract In 2016, the World Health Organization provisionally classified Epstein-Barr virus (EBV)-positive mucocutaneous ulcer (EBVMCU) as a lymphoid neoplasm under the subcategory of mature B-cell neoplasms. Here we describe a 59-year-old Chinese woman with a long history of recurrent sinus and oropharyngeal infections and was diagnosed initially with EBVMCU and later, diffuse large B-cell lymphoma (DLBCL). She had sought medical attention after a particularly long bout of increased facial pressure and nasal obstruction. As a young adult she had undergone a tonsillectomy, adenoidectomy, and received innumerable treatments for bronchiectasis and recurrent sinopulmonary infections. A sinus computerized tomography (CT) scan showed mucosal thickening and swellings of the left frontal posterior sinus. A subsequent 18fludeoxyglucose (18FDG) positron emission tomography (PET)-CT scan showed a large hypermetabolic mass (standardized uptake value [SUV] 30.6) centered in the left half of the nasopharynx and sinus processes and extending across the mid-line. She underwent an endoscopic turbinate reduction with removal of a polypoid soft-tissue mass. Immunohistochemical studies indicated large atypical lymphoid cells that stained positively for CD20, CD30, EBER-1, MUM-1, OCT-2, and PAX-5 and variably for BCL-6, CD15, CD45, and CD79a. The Ki-67 proliferation index was 100% in the atypical cells. Tissue blocks were reviewed locally and at the National Institute of Health and were felt to be most consistent with EBVMCU. She received 4000 cGy involved-field external-beam radiation therapy over 20 fractions. At completion of treatment, no residual abnormalities were identified and no additional adjuvant therapy was pursued. Three years later she presented to medical attention with shortness of breath and a non-productive cough. A PET-CT scan showed whiteout of the left lung and intense 18FDG uptake in a left perihilar nodule (SUV of 18). Bronchoscopy revealed many reactive polypoid bronchial wall masses and a complete collapse of the lower left lobe due to an obstructing mass. The left lower lobe intraluminal mass biopsies however showed EBV-positive DLBCL of non-germinal center phenotype. She received six cycles of conventional R-CHOP therapy (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone) and 36 months later she remains cancer free but with persistent bronchial inflammatory nodules and recurrent infections. Using the key words "EBV mucocutaneous ulcers," "EBV-associated lymphoproliferative disorders," and "lymphoproliferative disorders," we identified 100 cases of EBVMCU in the literature. EBVMCU is manifested as a well-circumscribed ulcer typically unifocal (90%) and of the oropharynx (58%), gastrointestinal (GI) tract (20%), and skin (20%). Immunohistochemical studies of the ulcers reveal monoclonal B-immunoblasts staining positively for CD20, CD30, EBER-1, MUM-1, OCT-2, and PAX-5 and staining variably for BCL-6, CD15, CD45, and CD79a. EBVMCU is most commonly associated with medication-induced (iatrogenic) immunosuppression (65%), advanced age-associated immunosenescence (27%), and primary (3%) and acquired (3%) immunodeficiencies. The median age for all EBVMCU cases is 68.5 (range, 16 -101) years. Of the 65 cases where medication-induced immunosuppression contributed to EBVMCU, 45 (69%) were in patients greater than 60 years-old. EBVMCU is a predominantly indolent disease reminiscent of post-transplant lymphoproliferative disorders in which conservative strategies are primarily employed with potential escalation to B-cell targeted therapy with or without cytotoxic chemotherapy, resection, and/or radiotherapy. Surveillance for EBVMCU should follow B-cell directed therapies and should be considered in the differential diagnosis in cases of suspected lymphoma relapse. Additionally, other LPDs, including lymphomas, should be monitored after resolution of EBVMCU. Due to overlap of the immunohistochemical profiles and risk factors associated with EBVMCU and other ulcerative LPDs of the oral and sinus cavities, nasopharynx, or GI tract, EBVMCU should be considered in the differential diagnosis to prevent under- or over-diagnosis and their associated potential repercussions. Disclosures No relevant conflicts of interest to declare.
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Spasojevic-Dimitrijeva, Brankica, Amira Peco-Antic, Dusan Paripovic, et al. "Post-transplant lymphoproliferative disorder: Case reports of three children with kidney transplant." Srpski arhiv za celokupno lekarstvo 142, no. 1-2 (2014): 83–88. http://dx.doi.org/10.2298/sarh1402083s.
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Introduction. Post-transplant lymphoproliferative disorder (PTLD) is a heterogeneous group of diseases, characterized by abnormal lymphoid proliferation following transplantation. It is a disease of the immunosuppressed state, and its occurrence is mostly associated with the use of T-cell depleting agents, and also intensification of immunosuppressive regimens. In the majority of cases, PTLD is a consequence of Epstein-Barr virus (EBV) infection and is a B-cell hyperplasia with CD-20 positive lymphocytes. The 2008 World Health Organization classification for lymphoid malignancies divides PTLD into four major categories: early lesions, polymorphic PTLD, monomorphic PTLD and Hodgkin PTLD. The treatment and prognosis depend on histology. The cornerstone of PTLD therapy includes reduction/withdrawal of immunosuppression, monoclonal anti CD-20 antibody (rituximab) and chemotherapy. Outline of Cases. We reported here our experiences with three patients, two girls aged 7.5 and 15 and a 16-year old boy. They had different organ involvement: brain, combined spleen-liver and intestines, respectively. Even though EBV was a trigger of lymphoid proliferation as it was confirmed by histopathology or in cerebrospinal fluid, qualitative EBV-PCR was positive only in one patient at disease presentation. Reduction of immunosuppression therapy was applied in treatment of all three patients, while two of them received rituximab and ganciclovir. They had an excellent outcome besides many difficulties in diagnosis and management of disease. Conclusion. Qualitative EBV-PCR is not useful marker in pediatric transplant recipients. Our suggestion is that patients with the risk factors like T-cell depleting agents, immunosuppressant protocol or increasing immunosuppressive therapy and EBV miss-match with donor must be more accurately monitored with quantitative EBV PCR.
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Kikuta, Atsushi, Hideki Sano, Shogo Kobayashi, Mitsuko Akaihata, and Masaki Ito. "Efficacy and Toxicity of Non-T-Cell Depleted Haploidentical Stem Cell Transplantation in Children with Refractory or Relapsed Acute Leukemia." Blood 118, no. 21 (2011): 3063. http://dx.doi.org/10.1182/blood.v118.21.3063.3063.
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Abstract Abstract 3063 Background: The efficacy of allogeneic hematopoietic stem celltransplantation(SCT) is primarily attributed to a T/NK- cell-mediatedresponse to HLA disparity between donor and tumor cell. Non-T-cell depleted (non-TCD) HLA-haploidentical SCT (haplo-SCT) is a form of adoptive cellular therapy that has a high degree of efficacy in hematologic malignancies. The major problems of non-TCD haplo-SCT are lethal graft-versus-host disease (GVHD), graft failure (GF) and high-risk of early death. Previously we reported the safety profile from the retrospective study assessing GVHD prophylaxis that was conducted with anti-human thymocyte immunoglobulin(ATG), tacrolimus, methotrexate and prednisolone in non-TCD haplo-SCT (Mochizuki, Kikuta, Clin Transplant, 2010 DOI :10.1111/j.1399–0012.2010.01352.x). We evaluated efficacy and toxicity of non-TCD haplo-SCT in children with very high risk refractory/relapsed acute leukemia (VHR-R/R AL). Methods: VHR-R/R AL was defined by the 1-year survival rate less than 30%. From Aug 2000 to April 2011, consecutive 16 patients (pts) with VHR-R/R AL who underwent non-TCD-haplo-SCT were included. The median age of patients was 7.7(0.5–17.9) years old. The diagnosis included ALL (10), AML (3), M/NKL (3). The disease status at non-TCD-haplo-SCT were 4 in CR2 (MLL rearrangement: 1 pt, Ph positive: 1 pt, after SCT: 2 pts), 12 in non-CR (after SCT: 5 pts, after chemotherapy: 7 pts). HLA disparities were 3/8 in 1 pt, 4/8 in 15 pts. Donors included fathers (9), mothers (5), and siblings (2). Fifteen pts received myeloablative conditioning (TBI based: 11 pts, Bu based: 4 pts) and 1 pt received reduced intensity conditioning, and 12 pts of them received ATG (rabbit, thymoglobulin 2.5mg/kg) containing regimen. The GVHD prophylaxis was conducted with tacrolimus (0.03mg/kg/day, start on day-1), methotrexate (10mg/m2, 7mg/m2, 7mg/m2 on day+1, +3, +6) and prednisolone (1mg/kg/day, day0–29, taper on day30 without GVHD). Thirteen pts received peripheral blood stem cells and 3 pts received bone marrow. Results: All patients achieved engraftment (median 14 days for neutrophils[range: 11–15]). All patients achieved CR in non-remission at non-TCD-haplo-SCT and full donor chimerism by day +30. Acute GVHD grade2–4 and grade 3–4 occurred in 12/16 pts(75%) and 2/16(13%), respectively, all of which were controllable by steroids. Chronic GVHD occurred in 8/13(62%). The treatment-related non-hematologicalcomplications observed within day+100 included: viral reactivations (14 pts [CMV: 8, EBV: 3, VZV; 1, BKV: 1, HHV6: 1]), Candida sepsis(2 pts), Aspergillus(1 pt), Bacterial sepsis(2 pts), hemorrhagic cystitis(2 pts), thrombotic microangiopathy(1 pt), and posterior reversible encephalopathy syndrome(1 pt). Non-relapsed mortality occurred in 3 pts and the causes of death were CMV-peumonia(1 pt) and EBV-lymphoproliferative disease(2 pts) which occurred day+48, day+71 and day+439, respectively. Relapse occurred in 2 pts. With the median follow-up of 12(6–133) months, 1-year and 2-year event free survival (EFS) were 73% and 61%. Conclusions: These data suggest that non-TCD haplo-SCT combined with our GVHD prophylaxis is well tolerated, facilitate engraftment, and has significant anti-tumor activity, particularly in pediatric patients with non-remission acute leukemia. The safety profile is acceptable in this refractory/ relapsed population. Disclosures: No relevant conflicts of interest to declare.
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Kumarasinghe, G., O. Lavee, A. Parker, et al. "Risk Factors and Response to Therapy in Heart and Lung Transplant Recipients with Post-Transplant Lymphoproliferative Disease." Journal of Heart and Lung Transplantation 32, no. 4 (2013): S254. http://dx.doi.org/10.1016/j.healun.2013.01.657.
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Uhlin, M., M. M. Norström, J. Mattsson, and M. Remberger. "Splenectomy prior to allogeneic hematopoietic SCT increases the risk of post-transplant lymphoproliferative disease." Bone Marrow Transplantation 49, no. 3 (2013): 463–64. http://dx.doi.org/10.1038/bmt.2013.201.
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Kumarasinghe, Gayathri, Orly Lavee, Andrew Parker, et al. "Post-transplant lymphoproliferative disease in heart and lung transplantation: Defining risk and prognostic factors." Journal of Heart and Lung Transplantation 34, no. 11 (2015): 1406–14. http://dx.doi.org/10.1016/j.healun.2015.05.021.
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Haider, Mobeen Zaka, Zarlakhta Zamani, Hafsa Shahid, et al. "Post-Transplant Lymphoproliferative Disorder after Liver Transplant: A Systematic Review." Blood 136, Supplement 1 (2020): 34–35. http://dx.doi.org/10.1182/blood-2020-142843.
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Background: Post-transplant lymphoproliferative disease (PTLD), a group of lymphoid disorders ranging from indolent polyclonal proliferation to aggressive lymphomas is a known complication following solid organ transplantation. The aim is to study the incidence, characteristics, predictive factors, management, and outcomes of PTLD after liver transplantation in particular. Methods: Following the PRISMA guideline, we performed a comprehensive literature search on PubMed, Cochrane Library, Embase, and clinicaltrials.gov from the past ten years on May 04, 2020. We used the MeSH terms of organ transplantation and lymphoproliferative disorders. The initial search revealed 1741 articles. We excluded all case reports, case series, pre-clinical trials, review articles, and meta-analysis. We found fifteen studies including retrospective observational and cohort studies. We extracted the data for baseline characteristics, the reason for transplantation, recipient & donor EBV status, immunosuppression used, type & stage of PTLD, organ system involved, duration between transplant and PTLD diagnosis, treatment, response to therapy, adverse effects of therapy and mortality. Results: We included 15 studies with a total (n) of 10706 post-liver transplant patients. 294 (2.74%) patients developed PTLD as a complication, out of which 104 (35.3%) were males, 106 (36%) females, and 84 unknowns. Table 1. The incidence of PTLD in the pediatric group was 135/3116 (4.3%) whereas in the adult population it was 115/7545 (1.5%). Data from eleven studies show that out of 202 participants, 67 recipients were positive, 39 negative, and 18 donors positive for EBV infection at the time of transplant. Data on the EBV serostatus for the remaining 106 recipients was not known at the time of transplant. Data from two studies showed that 25/29 patients who later developed PTLD were seronegative for EBV prior to the transplant and 26/29 were reported to undergo seroconversion partly due to transplantation with EBV positive donors (7/13). Post-transplant immunosuppression was achieved with cyclosporine, tacrolimus, azathioprine, mycophenolate mofetil, sirolimus, prednisone, OKT3 for acute cellular rejection and induction with monoclonal antibodies. Data from four studies conclude the median age at the time of PTLD diagnosis is 47.6 months in the pediatric population while 54 years in adults, overall ranging from 1 year to 73 years. Ten studies show the overall median duration from organ transplant to the diagnosis of PTLD is 23.5 months. The median duration for the pediatric population was 11.6 months from the data collected from 55 patients whereas five studies with 166 adult liver transplant recipients showed a median duration of 35.5 months. Histopathological types were diagnosed via biopsy samples, with monomorphic in 76 (25.8%), early lesions in 22 (7.4%), polymorphic in 19 (6.4%), and classic Hodgkin lymphoma like PTLD in 8 (2.7%) of the samples. Among the monomorphic type, Diffuse Large B-Cell Lymphoma (DLBCL) was the most commonly reported i.e. 10/50 (20%) of patients with monomorphic type in two studies. Treatment of PTLD consisted of reduction or cessation of the post-transplant immunosuppressive drugs, anti-CD20 antibody (rituximab), antiviral treatment with ganciclovir, and lymphoma treated with chemotherapy, radiotherapy, and surgical resection. Data from eight studies show a mortality rate of 61/214 (28.5%) with Huang, et al. reporting ¾(75%) of total deaths due to PTLD progression. Two studies report an overall survival rate of 26/32 (81.3%) and five-year survival of 15/41 (36.6%). Conclusions: Our analysis shows the incidence of PTLD after liver transplant is low with no significant gender predominance but a difference in the incidence was observed with significantly higher rates in the pediatric group as compared to the adult population. The most common biopsy proved histopathological type was monomorphic, with the least common type being Hodgkin lymphoma like PTLD. Among the monomorphic, DLBCL was the most common subtype. After liver transplantation, the development of PTLD is observed earlier in pediatric patients in comparison to adult recipients. EBV naive patients prior to liver transplantation are at higher risk for seroconversion post-transplant if transplanted with EBV positive donors and hence at increased risk of PTLD development. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.
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Colorio, Cecilia, Dolores Puente, Andrea Rossi, et al. "Post Transplant Lymphoproliferative Disorders (PTLD): Prevalence, Clinical Features and Outcome." Blood 110, no. 11 (2007): 5029. http://dx.doi.org/10.1182/blood.v110.11.5029.5029.
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Abstract PTLD is a life threatening complication developing in 1–5% of transplant (Tx) recipients. Epstein Barr (EBV), Cytomegalovirus (CMV) and immunosuppression (IS) were identified as risk factors. Aggressive evolution and therapy related toxicity generate poor prognosis. We retrospectively analyzed data from 18 PTLD patients (pts) diagnosed at our hospital between March 1994- June 2007. All of them were at least one graft recipient and were under IS. RESULTS: Out of 1206 adult Tx recipients, 18 (1,5%) developed PTLD. Ninety-four percent were men, mean age 42,9 years (range: 18–72). Our study comprises 10 heart, 2 kidney, 2 lung, 1 heart-lung, 1 liver and 2 non related allogeneic bone marrow (BM) recipients. IS protocols included Cyclosporin A (16 pts), Azathioprine (8), Mycophenolate mofetil (7), Tacrolimus (4) and antitymocyte globulin (2). Pretx recipients serology for EBV and CMV were positive in 87 and 94% respectively. Sixty-six percent (12/18) disclosed late onset PTLD (median 49 months), all of them were solid organ (SO) recipients. BM recipients developed the disease within the first 6 months after Tx. Fifty percent presented extranodal involvement, 3/18 with BM infiltration and 3/18 showed lymphoma in the graft. Histologycal findings: 15/18 B cell lymphoma (8/15 large cell lymphoma), 1 peripheral T cell lymphoma, 1 early lesion infectious mononucleosis-like PTLD, 1 polymorphic hyperplasia PTLD. Immunophenotype: 89% were CD20+. Fifty percent of the group achieved response, 7/9 with complete response(CR). Three/9 pts obtained CR with reduction of IS alone.Treatment included Rituximab (63% pts), CHOP (56%) and radiotherapy (25%). Eleven/18 pts died, 4 due to disease progression, 6 by sepsis and 1 because of underlying hematological disease relapse. CONCLUSIONS: In our experience, PTLD was an uncommon complication. The late onset of the disease was the most frequent form of presentation among SO recipients. B cell lymphoma was the main diagnosis (83%). Fifty percent (9/18) achieved response and 78% of them showed CR. Disease progression and sepsis were the most important causes of death.
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Wong, J. Y., B. Tait, B. Levvey, et al. "EBV mismatching and HLA matching post lung transplantation: key risk factors for post transplant lymphoproliferative disease(PTLD)." Journal of Heart and Lung Transplantation 20, no. 2 (2001): 199. http://dx.doi.org/10.1016/s1053-2498(00)00422-8.
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Penna, Adriana M. Damasco, Joao Garibaldi Junior, Guilherme Fleury Perini, et al. "Clinical Outcome of 96 Post-Transplant Lymphoproliferative Disease Patients in a Renal Transplant Cohort." Blood 126, no. 23 (2015): 5054. http://dx.doi.org/10.1182/blood.v126.23.5054.5054.
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Abstract Introduction: Post-Transplant Lymphoproliferative Disease (PTLD) is a rarewell-recognized group of lymphoid and or plasmacytic proliferations that occur following both solid organ (SOT) and allogenic hematopoietic stem cell transplantation (HSCT) as a result of immunossupression. A continuum of disease has been described, including early lesions, polymorphic PTLD and monomorphic PTLD. Epstein-bar virus (EBV) is considered the most important causative factor, with EBV positivity observed within up 90% of tumor lymphocytes. Optimal risk stratifications specific to kidney transplantation are still lacking. Patient and Methods: In our series, we retrospectively analyzed 98 consecutively cases of PTLD diagnosed between 2001 and 2014 at Hospital do Rim (HRim), a school hospital from the Federal University of São Paulo, São Paulo, Brazil. HRim is considered the leading renal transplant hospital in the world for the past 15 years. For this study, only PTLD patients with tumors whose histology could be confirmed by hemopathologist review, EBV-association established and whose clinical, epidemiological and laboratorial parameters could be retrieved were included in this study. Response was defined as complete (CR) or less than CR (partial response or refractory disease). Event was defined as treatment related mortality, progression (defined as time for initiation of second-line therapy) or relapse. Patients with conflicted data or loss of follow up were excluded. Results: A total of 98 patients were diagnosed with PTLD from 7665 renal transplants performed in this period, with a incidence of 1,3%. Two patients were excluded from the analysis due to conflicting clinical data. Median age at diagnosis was 41.4 years (range from 4-74), with a 0,6:1 Female:Male ratio. Median time of transplant to PTLD diagnosis was 56 months (range 1-967). Thirty-six patients (37.5%) received anti-thymocyte globulin (ATG), and the most common immunossupressive regimen (IR) consisted of cyclosporine or tacrolimus associated with prednisone and azathioprine (66, 69%). Monomorphic PTLD was observed in 75 (78%) patients, and two patients presented with HL. EBV positivity was seen in 67 patients (70.5%), being more frequent within PTLD cases diagnosed during the first 3 years of transplantation (90%). All patients had their IR reduced after PTLD diagnosis. The incidence of loss of engraftment following IR reduction was 19% (20 patients). Overall responses were: CR in 67% (n=64) and Partial response/Refractory disease in 33% (n=32); 30 patients died due to treatment-related toxicity and/or disease progression. Overall Survival (OS) for the entire group was 63% in 5 years (CI95% 73-83%), with a progression free survival (PFS) of 58% (CI95% 91-97%). EBV positivity was seen in 67 patients (70.5%). Median number of extra nodal sites involved was 1,2. The median overall survival time was 97 months. Patient survival following diagnosis was 77% at 1 year, 63% at 5 years and 38% at 10 years. The most common extra-nodal sites involved were: Gastro-intestinal Tract (43, 45%) followed by Central Nervous System (23, 24%). Extra nodal involvement was correlated with poorer outcome (p 0.014) as was the loss of engraftment (p<0.0001). Conclusions: PTLD is a rare complication of immunossupression, usually related to EBV, specially for PTLD diagnosed within the first 3 years of transplantation. Basically, the initial treatment consists of reduction or withdrawal of the immunossupressive regimen followed by specific imuno-chemotherapy as needed. In our cohort, the incidence of loss of engraftment was low, although it was correlated with inferior outcome, together with extranodal involvement. To date this is the largest cohort of post-renal transplant lymphoproliferative disease ever reported. Disclosures No relevant conflicts of interest to declare.
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Peters, Anthea C., Segun M. Akinwumi, Marco Iafolla, Curtis Mabilangan, Karen Doucette, and Jutta Preiksaitis. "Epidemiology Of Post-Transplant Lymphoproliferative Disorders Following Solid Organ Transplant In a Major Canadian Transplant Centre." Blood 122, no. 21 (2013): 4281. http://dx.doi.org/10.1182/blood.v122.21.4281.4281.
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Abstract 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.
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Francis, Anna, Eric Au, Wai H. Lim, and Germaine Wong. "Post-transplant cancer: An epidemiological evaluation." Journal of Onco-Nephrology 4, no. 3 (2020): 145–52. http://dx.doi.org/10.1177/2399369320953869.
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Kidney transplantation is a lifechanging event for patients with end-stage kidney disease (ESKD) because it improves the quality of life and survival of these patients. However, it is not a cure and is not without complications. Transplant recipients have an excess risk of premature death (largely from cancer and cardiovascular disease (CVD)) by at least 10-times compared to the general population. Published work has identified cancer as one of the most important and feared outcomes in transplant recipients and is a key research priority recognised by both patients and health professionals. There is also convincing epidemiological evidence, suggesting the overall risk of developing cancer in the transplant population is approximately 2 to 3-fold higher compared to the age-matched general population. Unlike CVD, where the death rates have fallen considerably over the past decade in this population in response to better screening, preventative and intervention approaches, the excess risk of cancer-related deaths in transplant recipients remains at least 10-fold higher compared to cancer patients in the general population. The causes of the increased risk of death are unknown but may be a consequence of possible differences in tumour biology under the influence of immunosuppression. In this review, we will discuss the epidemiology of overall and site-specific cancer risk and death across different countries. We will also focus on the current evidence on the prevention and screening in our at-risk transplant candidates. Finally, management strategies of common cancers such as skin, post-transplant lymphoproliferative disease and solid organ cancers such as colorectal, breast and lung cancer will be evaluated.
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McLaughlin, K., S. Wajstaub, M. Block, et al. "Increased Risk Of Post-Transplant Lymphoproliferative Disease In Recipients Of Liver Transplants With Hepatitis C." Transplantation 65, Supplement (1998): 123. http://dx.doi.org/10.1097/00007890-199805131-00180.
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McLaughlin, K., S. Wajstaub, M. Block, et al. "Increased Risk Of Post-Transplant Lymphoproliferative Disease In Recipients Of Liver Transplants With Hepatitis C." Transplantation 65, no. 12 (1998): S47. http://dx.doi.org/10.1097/00007890-199806270-00199.
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Jagadeesh, Deepa, Sharjeel Hooda, Kathleen B. Fenner, et al. "Post Transplant Lymphoproliferative Disorders (PTLD) after Solid Organ Transplant: Cleveland Clinic Experience." Blood 124, no. 21 (2014): 3008. http://dx.doi.org/10.1182/blood.v124.21.3008.3008.
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Abstract Background: Post transplant lymphoproliferative disorders (PTLD) are rare pathologically and clinically heterogeneous diseases arising in the setting of immunosuppression following hematopoietic stem cell and solid organ transplants (SOT). Our understanding of PTLD is restricted by its low incidence and heterogeneous treatment approaches, resulting in paucity of data. We sought to further describe characteristics and outcomes in PTLD patients who underwent treatment at our institution. Methods and Patients: We performed a retrospective study to describe our institutional experience in a relatively large cohort of PTLD patients after SOT. Patient and disease characteristics were examined and prognostic factors for survival were determined using univariate and multivariate Cox analysis. Results: Between May 1987 to January 2014, 98 patients with a confirmed diagnosis of PTLD underwent treatment at our institution. Median time from SOT to PTLD diagnosis was 60 months with median follow of 68 months from PTLD diagnosis. Baseline characteristics include male gender 77%, ECOG performance status (PS) 0-1 in 61%, and stage III-IV 69% with a median age at diagnosis of 47 years. Most common transplanted organ included heart 30%, lung 24%, kidney 20% and liver 19% and median time from SOT to PTLD diagnosis was 60 months. Most cases had monomorphic histology (81%) and were EBV+ (82%). Graft involvement and rejection were observed in 32% and 43% respectively. Of the 84% with extranodal (EN) involvement, gastrointestinal tract (37%) and lung (27%) were the common sites, while 3.2% had bone marrow (BM) involvement. Central nervous system (CNS) was involved in 11% of the cases. Only 58% received rituximab as part of the initial therapy, as significant part of our cohort was treated prior to rituximab era. Reduction in immunosuppression (73%), chemotherapy (40%), radiation (11%) and surgery (8%) were utilized either as single modality or in combination for treatment. Of the 66 patients with response data, 59% had complete response (CR) and 14% had progressive disease (PD). Relapse occurred in 23% of cases. Median overall survival (OS) from diagnosis of PTLD was 6 years (Figure 1), but in rituximab treated patients it was 8 years. On univariate analysis, higher age at diagnosis (HR 1.19, 95% CI 1.01-1.40, p=0.033), lung transplant (HR 2.42, 95% CI 1.36-4.33, p=0.003), higher IPI (HR 1.83, 95% CI 1.40-2.39, p=<0.001), decreased PS (HR 2.43, 95% CI 1.70-3.48, p=<0.001), and platelet count <200,000 (HR 2.84, 95% CI 1.27-6.33, p=0.011) were associated with lower OS, whereas liver transplant (HR 0.24, 95% CI 0.09-0.68, p=0.007) and GI involvement (HR 0.47, 95% CI 0.24-0.95, p=0.036) predicted better OS. Rituximab treatment (Figure 2) and achieving CR were associated with better OS. Histology, EN involvement, and EBV status were not significant predictors for survival. On multivariate analysis only lung transplant, IPI, and PS were predictive for OS. Lung transplant patients had a higher risk of mortality compared to other SOT (HR 2.63, 95% CI 1.39-4.95, p=0.003). Both higher IPI (HR 1.66, 95% CI 1.18-2.32, p=0.003) and poor PS (HR 1.94, 95% CI 1.27-2.96, p=0.002) were associated with inferior OS. Conclusions: In this large cohort of PTLD patients after SOT, lung transplants, higher IPI and poor PS were identified as poor prognostic factors for OS on both univariate and multivariate analysis. Rituximab treatment was a favorable prognostic factor for OS that resulted in prolonged survival observed in this cohort. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Hill: Millenium: Research Funding; Novartis: Research Funding.
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Cacciarelli, Thomas V., Jorge Reyes, Ronald Jaffe, et al. "Primary tacrolimus (FK506) therapy and the long-term risk of post-transplant lymphoproliferative disease in pediatric liver transplant recipients." Pediatric Transplantation 5, no. 5 (2001): 359–64. http://dx.doi.org/10.1034/j.1399-3046.2001.00021.x.
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Cohen, Alan H., George B. Mallory, Charles B. Huddleston, et al. "Analysis of Risk Factors for Post-Transplant Lymphoproliferative Disease in Pediatric Lung Transplant Recipients with Cystic Fibrosis ♦ 753." Pediatric Research 43 (April 1998): 131. http://dx.doi.org/10.1203/00006450-199804001-00774.
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Antunes, H., C. Beguin, M. Bodeus, et al. "RISK FACTORS FOR THE INCREASED INCIDENCE OF POST-TRANSPLANT LYMPHOPROLIFERATIVE DISEASE IN PEDIATRIC LIVER TRANSPLANT RECIPIENTS TREATED WITH TACROLIMUS." Journal of Pediatric Gastroenterology & Nutrition 24, no. 4 (1997): 458. http://dx.doi.org/10.1097/00005176-199704000-00043.
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Haider, Mobeen Zaka, Zarlakhta Zamani, Muhammad Taqi, et al. "Post-Transplant Lymphoproliferative Disorder after Renal Transplant in the Pediatric Population: A Systematic Review." Blood 136, Supplement 1 (2020): 35–36. http://dx.doi.org/10.1182/blood-2020-143333.
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Background: Post-transplant lymphoproliferative disease (PTLD), is one of the major complications after organ transplantation. The aim of this study is to study the incidence, various risk factors especially EBV status, histopathological types, management, and outcomes of PTLD following kidney transplantation in the pediatric groups. Methods: Following the PRISMA guideline, we performed a comprehensive literature search on PubMed, Cochrane Library, Embase, and clinicaltrials.gov from the past ten years on May 04, 2020. We used the MeSH terms of organ transplantation and lymphoproliferative disorders. The initial search revealed 1741 articles. We excluded all case reports, case series, pre-clinical trials, review articles, and meta-analysis. We found five retrospectives observational, one retrospective questionnaire survey, one prospective observational, and one prospective trial study. We extracted the data for baseline characteristics, the reason for transplantation, recipient & donor EBV status, immunosuppression used, type & stage of PTLD, organ system involved, duration between transplant and PTLD diagnosis, treatment, response to therapy, adverse effects of therapy and mortality. Results: We included eight studies with a total (n) number of 1713 post-kidney transplant pediatric patients, out of which 148 (8.63%) patients who developed PTLD as a complication of transplantation were studied(table 1). Among the 148 patients diagnosed with PTLD, 96 (64.86%) were males, 49 (33.1%) female participants and 3 (2.2%) were unknown. 34/148 (22.97%) PTLD recipients were EBV (+), 86 (58.1%) EBV (-) and 28 (18.9%) unknown at the time of transplant. EBV status for donors was known in only 2 studies, showing 7/99 (7.1%) to be EBV (+) at the time of transplant. Höcker et al. have shown that antiviral prophylaxis with ganciclovir/valganciclovir in the first year post-renal transplant reduces the risk of EBV viremia. Post-transplant immunosuppressive drugs included tacrolimus, mycophenolate mofetil, azathioprine, sirolimus, cyclosporine, IL-2R antagonist, methylprednisolone, basiliximab, daclizumab, anti-thymocyte globulin/anti-lymphocyte globulin, OKT3. In some cohorts, rituximab and antiviral prophylaxis with ganciclovir or valganciclovir were also used in some patients. The median time from transplant to the diagnosis of PTLD from five studies with 125 patients was 16 months (0.9m-186m). Longmore et al. reported a bimodal distribution curve, with 50% presenting with early PTLD, i.e. after a median duration of 313 days and 50% presenting late after a median duration of 8 years. The histopathological types of PTLD were diagnosed via biopsy samples, showing predominance with polymorphic type 48 (32.4%), followed by monomorphic type 45 (30.4%), early lesion 4 (2.7%), Kaposi like PTLD 1 (0.67%) and Hodgkin lymphoma 1 (0.67%). The histological testing results from two of the studies also showed that 18/19 (94.7%) of diagnosed PTLD samples were EBV positive. PTLD was managed with reduction or cessation of the immunosuppressive drugs, anti-CD20 antibodies, chemotherapy for lymphoma, and in some cases mTOR inhibitors, intravenous immunoglobulins, and surgical resection. Data from 5 studies show the mortality rate of 12/51 (23.5%) among PTLD groups. The survival rate from 2 studies was 100% among 17 PTLD patients and 1 study showed a 5-year survival rate of 85% among 92 PTLD patients. Cleper et al. in their study concluded that the type of PTLD might have a significant effect on the outcome, as ¾ (75%) deaths in the PTLD group were attributed to anaplastic T-cell type. Conclusions: Our analysis shows the EBV infection is closely associated with a higher risk of PTLD development. Recipients' EBV seronegativity and positive EBV status of the donor have been shown to increase post-transplant EBV infection risk which is associated with a higher risk of PTLD development. Furthermore, our study shows that PTLD may occur in less than a month to more than 15 years of renal transplant. The polymorphic type was the most common and Hodgkin lymphoma-type, the least commonly reported PTLD type. The main therapeutic approach is the reduction or cessation of immunosuppression. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.
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Liu, Jiangyue, Xianhui Chen, Jason Karlen, et al. "98 ATA3271: an armored, next-generation off-the-shelf, allogeneic, mesothelin-CAR T cell therapy for solid tumors." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (2020): A109. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0098.
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BackgroundMesothelin (MSLN) is a glycosylphosphatidylinositol (GPI)-anchored membrane protein with high expression levels in an array of malignancies including mesothelioma, ovaria, non-small cell lung cancer, and pancreatic cancers and is an attractive target antigen for immune-based therapies. Early clinical evaluation of autologous MSLN-targeted chimeric antigen receptor (CAR)-T cell therapies for malignant pleural mesothelioma has shown promising acceptable safety1 and have recently evolved with incorporation of next-generation CAR co-stimulatory domains and armoring with intrinsic checkpoint inhibition via expression of a PD-1 dominant negative receptor (PD1DNR).2 Despite the promise that MSLN CAR-T therapies hold, manufacturing and commercial challenges using an autologous approach may prove difficult for widespread application. EBV T cells represent a unique, non-gene edited approach toward an off-the-shelf, allogeneic T cell platform. EBV-specific T cells are currently being evaluated in phase 3 trials [NCT03394365] and, to-date, have demonstrated a favorable safety profile including limited risks for GvHD and cytokine release syndrome.3 4 Clinical proof-of-principle studies for CAR transduced allogeneic EBV T cell therapies have also been associated with acceptable safety and durable response in association with CD19 targeting.5 Here we describe the first preclinical evaluation of ATA3271, a next-generation allogeneic CAR EBV T cell therapy targeting MSLN and incorporating PD1DNR, designed for the treatment of solid tumor indications.MethodsWe generated allogeneic MSLN CAR+ EBV T cells (ATA3271) using retroviral transduction of EBV T cells. ATA3271 includes a novel 1XX CAR signaling domain, previously associated with improved signaling and decreased CAR-mediated exhaustion. It is also armored with PD1DNR to provide intrinsic checkpoint blockade and is designed to retain functional persistence.ResultsIn this study, we characterized ATA3271 both in vitro and in vivo. ATA3271 show stable and proportional CAR and PD1DNR expression. Functional studies show potent antitumor activity of ATA3271 against MSLN-expressing cell lines, including PD-L1-high expressors. In an orthotopic mouse model of pleural mesothelioma, ATA3271 demonstrates potent antitumor activity and significant survival benefit (100% survival exceeding 50 days vs. 25 day median for control), without evident toxicities. ATA3271 maintains persistence and retains central memory phenotype in vivo through end-of-study. Additionally, ATA3271 retains endogenous EBV TCR function and reduced allotoxicity in the context of HLA mismatched targets. ConclusionsOverall, ATA3271 shows potent anti-tumor activity without evidence of allotoxicity, both in vitro and in vivo, suggesting that allogeneic MSLN-CAR-engineered EBV T cells are a promising approach for the treatment of MSLN-positive cancers and warrant further clinical investigation.ReferencesAdusumilli PS, Zauderer MG, Rusch VW, et al. Abstract CT036: A phase I clinical trial of malignant pleural disease treated with regionally delivered autologous mesothelin-targeted CAR T cells: Safety and efficacy. Cancer Research 2019;79:CT036-CT036.Kiesgen S, Linot C, Quach HT, et al. Abstract LB-378: Regional delivery of clinical-grade mesothelin-targeted CAR T cells with cell-intrinsic PD-1 checkpoint blockade: Translation to a phase I trial. Cancer Research 2020;80:LB-378-LB-378.Prockop S, Doubrovina E, Suser S, et al. Off-the-shelf EBV-specific T cell immunotherapy for rituximab-refractory EBV-associated lymphoma following transplantation. J Clin Invest 2020;130:733–747.Prockop S, Hiremath M, Ye W, et al. A Multicenter, Open Label, Phase 3 Study of Tabelecleucel for Solid Organ Transplant Subjects with Epstein-Barr Virus-Driven Post-Transplant Lymphoproliferative Disease (EBV+PTLD) after Failure of Rituximab or Rituximab and Chemotherapy. Blood 2019; 134: 5326–5326.Curran KJ, Sauter CS, Kernan NA, et al. Durable remission following ‘Off-the-Shelf’ chimeric antigen receptor (CAR) T-Cells in patients with relapse/refractory (R/R) B-Cell malignancies. Biology of Blood and Marrow Transplantation 2020;26:S89.
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&NA;. "Aciclovir and ganciclovir prophylaxis is effective in reducing the risk of post-transplant lymphoproliferative disease (PTLD)." Inpharma Weekly &NA;, no. 1524 (2006): 12. http://dx.doi.org/10.2165/00128413-200615240-00030.
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Crespo-Leiro, Maria G., Javier Muñiz, and Francisco Gonzalez-Vilchez. "Comment on: Post-transplant lymphoproliferative disease in heart and lung transplantation: Defining risk and prognostic factors." Journal of Heart and Lung Transplantation 35, no. 5 (2016): 693–94. http://dx.doi.org/10.1016/j.healun.2016.01.006.
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Crepin, T., E. Gaiffe, C. Courivaud, et al. "Pre-transplant end-stage renal disease-related immune risk profile in kidney transplant recipients predicts post-transplant infections." Transplant Infectious Disease 18, no. 3 (2016): 415–22. http://dx.doi.org/10.1111/tid.12534.
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Schroers-Martin, Joseph G., Andrea Garofalo, Joanne Soo, et al. "Lymphoma Virome Dynamics Revealed By Cell-Free DNA Sequencing." Blood 132, Supplement 1 (2018): 2861. http://dx.doi.org/10.1182/blood-2018-99-119905.
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Abstract Background : Infectious disease plays a central role in malignancy, with up to one in six cancers having a microbial association (Parkin Int. J. Cancer 2006). Lymphomas in particular are associated with multiple viral pathogens, including Epstein Barr virus (EBV), Kaposi Sarcoma herpesvirus (KSHV), and HIV. Sequencing of cell-free DNA (cfDNA) is an emerging technique in the diagnosis and surveillance of cancer. While studies to date have focused primarily on tumor-associated somatic variants, cfDNA may also provide insight into the infectious and immune state of cancer patients. We examined cfDNA from lymphoma patients of multiple histologic subtypes to characterize viral detection and dynamics. Methods: Plasma from 360 pre-treatment patients with various lymphoma histologies was analyzed along with that of 69 healthy adults. Multiple samples per patient were included when available. All samples underwent deep sequencing with error correction by CAPP-Seq (Newman Nat Biotech 2016). Reads were filtered for homology to the human genome and endogenous retroviruses, mapped to NCBI consensus genomes for human-hosted viral species, and filtered by breadth of genomic coverage. Viral read count was normalized by total sequencing depth to determine viral read fraction (VRF). EBV fragment size was assessed via single-read BLAST alignment length considering reads with expect value < 1E-5. Integration sites were assessed with the VirusClip package (Ho Oncotarget 2015). Results: Patients with most lymphoma histologic subtypes had viral loads not significantly different from those of healthy adults. However, post-transplant lymphoproliferative disorder (PTLD) patients receiving immunosuppression for solid organ transplants had significantly increased total viremia (Fig 1A) and EBV levels (Fig 1B) when compared to healthy adults and non-transplant DLBCL patients. EBER+ classical Hodgkin lymphoma (cHL) displayed no difference in total viremia but had significantly elevated EBV. In an EBV-positive PTLD patient, cfDNA viral levels tracked both clinical viral qPCR and circulating tumor DNA (ctDNA) levels in serial samples leading to diagnosis (Fig 1C). Elevated EBV levels were also present in a subset of non-transplant DLBCL. In a cohort of DLBCL patients treated with frontline R-CHOP-like chemotherapy (n=152), individuals with pre-treatment EBV frequency greater than VRF 1E-7 had significantly higher risk of disease progression at three years (HR 1.8, CI 1.0-3.4, p=0.013) (Fig 1D). Immunosuppression in transplant patients is associated with the expansion of the endogenous anellovirus family (De Vlaminck Cell 2013). Accordingly, anellovirus was detected significantly more often in PTLD patients (91% of samples) compared to DLBCL NOS (2.8%) and controls (1.4%) (Fig 1E, p < 0.0001). As the standard-of-care R-CHOP regimen for DLBCL has activity against both B- and T- lymphocytes, we hypothesized that an immunosuppressive effect might be observed. In non-transplant DLBCL patients receiving R-CHOP (n=31), we detected anellovirus in 6% of samples at the time of first chemotherapy infusion, 16% immediately before cycle 2, but in no samples from post-treatment patients in complete response (Fig 1F). Viral integration into the host genome is associated with malignant transformation. We profiled a cohort of EBER+ cHL (n=8) and found circulating EBV/human chimeric reads suggesting integration in all cases. Viral fragment size distribution also distinguishes integrated DNA from shorter free episomes and may increase cancer screening performance (Lam PNAS 2018). We profiled EBV fragment sizes in cHL and PTLD patients grouped by EBER positivity. Plasma from EBER+ cHL and PTLD patients was significantly enriched in longer fragments (Fig 1G), suggesting nucleosomal protection of EBV integrated within tumor genomes but not their benign episomal counterparts. Conclusions: Viral infection in lymphoma has diagnostic and prognostic significance: elevated circulating EBV levels are associated with active PTLD (Kanakry Blood 2016) and poor outcomes in advanced HL (Kanakry Blood 2013) and DLBCL (Tisi Leuk & Lymph 2015). Our work demonstrates the utility of cfDNA sequencing for simultaneous characterization of malignancy, infection, and immunosuppression. The integration of viral dynamics into cfDNA analysis may assist in risk stratification and treatment monitoring in lymphoma patients. Disclosures Dührsen: Amgen: Research Funding; Celgene: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Roche: Honoraria, Research Funding; Gilead: Consultancy, Honoraria; Janssen: Honoraria. Hüttmann:Celgene: Other: Travel expenses; Roche: Other: Travel expenses. Meignan:F. Hoffman-La Roche Ltd: Honoraria. Casasnovas:Janssen: Consultancy; Takeda: Honoraria; Janssen: Honoraria; MSD: Honoraria; Merck: Honoraria; Gilead Sciences: Honoraria; Celgene: Honoraria; Roche: Consultancy; Roche: Research Funding; takeda: Consultancy; Gilead Sciences: Consultancy; Roche: Honoraria; Gilead Sciences: Research Funding; merck: Consultancy; MSD: Consultancy. Westin:Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Apotex: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees; Celgen: Membership on an entity's Board of Directors or advisory committees. Gaidano:Amgen: Consultancy, Honoraria; Morphosys: Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Advani:Bayer: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Agensys: Research Funding; Infinity: Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Merck: Research Funding; Janssen: Research Funding; Cell Medica: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Kyowa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Research Funding; Celgene: Research Funding; Kura: Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Regeneron: Research Funding; Autolus: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Gilead/Kite: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Forty Seven Inc.: Research Funding; Celgene: Research Funding.
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Katz, B. Z., E. Pahl, S. E. Crawford, et al. "Case-control study of risk factors for the development of post-transplant lymphoproliferative disease in a pediatric heart transplant cohort." Pediatric Transplantation 11, no. 1 (2007): 58–65. http://dx.doi.org/10.1111/j.1399-3046.2006.00609.x.
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Mayer, Jiri, Marta Krejci, Michael Doubek, and Yvona Brychtova. "Pulse Cyclophosphamide in the Treatment of Liver GvHD Unresponsive to Steroids." Blood 106, no. 11 (2005): 5332. http://dx.doi.org/10.1182/blood.v106.11.5332.5332.
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Abstract Introduction: Steroids provide an active but inadequate therapy for acute GvHD. Corticosteroid-resistant acute GvHD is extremely difficult to manage and is associated with very high morbidity and mortality. Cyclophosphamide (Cy) has been used for a long time as an immunosuppressive drug for the treatment of many autoimmune disorders, as a cytotoxic drug, and Cy is also a part of both classical conditioning regimens, Cy+TBI and Cy+busulfan. Pulse Cy at a dose of 1 g/m2 is now an established mainstay in the treatment of lupus nephritis. Therefore, we hypothesized that this pulse treatment can be used also for steroid-refractory GvHD. In a previous work, we showed that intestinal GvHD responded poorly to pulse Cy, whilst liver, skin, and oral GvHD responded very well. Since steroid-refractory acute skin GvHD is not frequent, in this report, we analyzed our new data concerning liver GvHD. Patients (pts) and methods: This is a retrospective study of 17 pts: 11 pts had acute GvHD, 3 pts had chronic GvHD (albeit progressing from acute GvHD), and 4 pts developed liver GvHD upon DLI. Seven pts had hepatitic variant of liver GvHD (serum aminotransferase ALT or AST elevation &gt;10 times the upper normal limit). Seven pts had steroids plus another previous therapy before receiving Cy pulse. Results and Conclusions: There were 21 Cy administrations at the dose of about 1 g/m2 (460 mg/m2 – 1500 mg/m2, median dose: 1000 mg/m2). The dose was empirically decreased or increased because of fear of myelosuppression, or previous incomplete response, respectively. There were 47% CR (8/17), 18% (3/17) PR, and 35% (6/17) NR. However, in 4 pts with NR their clinical status stabilized and they responded to another treatment. Four pts died: 2 from intractable liver and intestinal GvHD, 1 from intestinal GvHD with liver GvHD in PR, and 1 from relapsing leukemia. All GvHD related deaths occurred in pts with acute GvHD, whereas all but one pts (relapsing AML) with post-DLI or chronic GvHD survived. Concomitant severe gut GvHD seems to be the risk factor for not reaching CR in liver GvHD, and death. On the other hand, however, 6/7 pts (86%) with hepatitic GvHD reached CR. Pulse Cy exerts a good toxicity profile, except for a manageable, short-term myelosuppression in some patients, and does not appear to increase the risk of opportunistic infections, mixed chimerism, relapses, or posttransplant lymphoproliferative disease. The cost of the drug is negligible.
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Haider, Mobeen Zaka, Zarlakhta Zamani, Muhammad Taqi, et al. "Post-Transplant Lymphoproliferative Disorder after Liver Transplant in the Pediatric Population: A Systematic Review." Blood 136, Supplement 1 (2020): 38–39. http://dx.doi.org/10.1182/blood-2020-142387.
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Background: Post-transplant lymphoproliferative disease (PTLD), a group of lymphoid disorders ranging from indolent polyclonal proliferation to aggressive lymphomas is a known complication following solid organ transplantation. The aim is to study the characteristics, predictive factors, management, and outcomes of PTLD among pediatric groups after liver transplantation in particular. Methods: Following the PRISMA guideline, we performed a comprehensive literature search on PubMed, Cochrane Library, Embase, and clinicaltrials.gov from the past ten years on May 04, 2020. We used the MeSH terms of organ transplantation and lymphoproliferative disorders. Initial search revealed 1741 articles. We excluded all case reports, case series, pre-clinical trials, review articles, and meta-analysis. We found five retrospectives observational, one observational cohort study, and one multicenter cohort in the pediatric population. We extracted the data for baseline characteristics, the reason for transplantation, recipient & donor EBV status, immunosuppression used, type & stage of PTLD, organ system involved, duration between transplant and PTLD diagnosis, treatment, response to therapy, adverse effects of therapy and mortality. Results: We included seven retrospective observational studies with a total (n) number of 3116 post-liver transplant pediatric patients, out of which 135 (4.33%) patients who developed PTLD as a complication of transplantation were studied. The male to female ratio was 41: 55 with the gender of 6 patients unknown. In five studies, with 118 PTLD patients, 34 recipients and 24 donors were positive for EBV at the time of liver transplantation. In addition to EBV, CMV status of patients in 5 studies showed 11/25 (44%) PTLD patients positive for CMV at the time of transplant. Post-transplant immunosuppression was achieved among these seven cohorts with cyclosporine, tacrolimus, OKT3, mycophenolate mofetil, prednisone, and basiliximab. The diagnosis was made via biopsy, showing all histopathological types including early lesions 14/46 (30.4%), polymorphic 13/46 (28.3%), monomorphic 18/46 (39.1%), and classic Hodgkin's lymphoma PTLD 1/46 (2.1%). Diffuse large B-cell lymphoma was the most common subtype in 6/18 (33.3%) of samples with monomorphic PTLD. Hsu, et al. in their study showed a five-year survival rate of 33.3% for St. Jude's classification stage IV lymphoma compared to 88.9% for stage I-III. The median age for 36 patients from three studies at the diagnosis of PTLD was 39.6 months (range 24-48 months). The median duration from transplantation to the diagnosis of PTLD was 13.48 months (range 8-24 months) in 54 patients from four studies. PTLD treatment was achieved with a combination of reduction or withdrawal of the immunosuppressive drugs with antiviral prophylaxis, chemotherapy, irradiation & the use of monoclonal antibodies in a total of 57 PTLD patients for which post-transplant immunosuppression data was available. Study by Hsu, et al. reported that 5/16 (31.3%) patients had acute graft rejection and 2 had a chronic rejection in a group of 16 PTLD patients undergoing treatment for PTLD with a reduction in immunosuppressive therapy. The overall mortality in patients who developed PTLD was 15/54 (27.8%) in four of the studies. Conclusions: Pre-transplant EBV-naive status in patients was associated with a higher incidence of PTLD. Advanced stage (Stage IV) lymphoma was associated with poor survival outcomes. Monomorphic histopathology may be most commonly associated with PTLD post-liver transplant. The main approach for the treatment of PTLD is the reduction or complete withdrawal of immunosuppressive drugs, administration of antiviral drugs (ganciclovir/valganciclovir),and lymphoma treatment with chemotherapy or irradiation, and monoclonal antibody therapy such as rituximab. Management of PTLD with reduction or withdrawal of post-transplant immunosuppressive drugs in one cohort was associated with an increased risk of graft rejection. Thus immunosuppressive therapy maintaining a fine balance between the risk of graft rejection and risk of developing PTLD may be associated with better patient outcomes post-liver transplant. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.
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Stubbins, Ryan J., Anthea C. Peters, Mabilang Curtis, et al. "Morphologic Evolution in Post-Transplant Lymphoproliferative Disorders (PTLD): A Clinicopathologic Case Series." Blood 126, no. 23 (2015): 5008. http://dx.doi.org/10.1182/blood.v126.23.5008.5008.
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Abstract Post-transplant lymphoproliferative disorders (PTLDs) are classified as early PTLDs (E-PTLD), polymorphic PTLDs (P-PTLD), monomorphic PTLDs (M-PTLD) and classical Hodgkin's Lymphoma PTLD (HL). These entities are felt to represent a disease continuum, with a precursor-product relationship, though they are morphologically and clinically distinct. However, this process remains poorly understood, and limited evidence exists to support this hypothesis. We report a series of nine cases extracted from a PTLD database, including both pediatric and adult solid organ transplant recipients, with recurrent disease episodes that evince an apparent evolution in their morphologic categorization between episodes. All patients identified were high risk for PTLD, with multiple identifiable predisposing factors. Presentations varied from isolated lymphadenopathy, to gastrointestinal involvement to pulmonary involvement. Four of the patients were deceased at the time of acquisition, though only one directly from PTLD. Eight of the nine identified patients developed E or P-PTLD lesions that preceded a subsequent M-PTLD or HL lesion at a similar tissue site. Two of the cases had metachronous P and M-PTLD lesions. The six M-PTLD subtypes were variable, including DLBCL, Burkitt, T-cell, and extramedullary plasmacytoma, in addition to the three cases of classical Hodgkin's lymphoma. These cases suggest that E and P-PTLD may act as common precursor lesions to the development of both the M-PTLD variants and HL type lesions, and that the PTLD classification schema represents different stages of a common underlying pathology. Disclosures Owen: Lundbeck: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Roche: Honoraria.
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Vase, Maja Ølholm, Eva Maksten, Knud Bendix, et al. "Tumor Microenvironmental Features and Outcome in Post-Transplant Lymphoproliferative Disorder." Blood 124, no. 21 (2014): 1617. http://dx.doi.org/10.1182/blood.v124.21.1617.1617.
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Abstract Background: PTLD comprises a diverse spectrum of hematological conditions, ranging from early lesions, characterized by reactive-like proliferations, to monomorphic lesions, resembling overt lymphoma. Â In most cases, the lesions are believed to arise as the result of reduced immune surveillance secondary to the use of immunosuppressive drugs post-transplant. This view is supported by the observation that PTLDs, particularly those characterized by early or polymorphic lesions, may regress spontaneously upon reduction of the immunosuppressive treatment. Studies in sporadic lymphomas have identified distinct microenvironmental characteristics, predictive of the clinical behavior, but data is scarce in the immunocompromised setting. Therefore, the aim of this study was to investigate the tumor microenvironment in a population-based cohort of PTLD. Methods: We identified 108 PTLD patients diagnosed in the period 1994-2011. Of these, 62 cases had adequate tissue for tissue microarray construction. All biopsies were reviewed and classified according to the WHO 2008 criteria. Immunohistochemically stained sections were digitally quantified using Tissuemorph (Visiopharm Integrator System 4.0.3.0, Visiopharm, Denmark). Determination of optimal cut-off values of the area fraction (AF) was established by a ROC-curve. ROC analyses were performed in every disease entity and used for endpoint analyses. Results: Themedian age was 45 yrs (range 2-77 yrs) with a M/F ratio of 3:1. The majority presented in stage I-II (61%), and B symptoms and extranodal disease were common features (40% and 42%, respectively). Most tissue samples were EBV-positive (85%). The EBV latency pattern was predominantly latency II (41%) or III (43%). The AF of galectin-1 (gal-1) positive cells was clearly correlated to latency type (p=0.0001), whereas FOXP3 and programmed death-1 (PD-1) did not show such correlation (fig 1). Overall survival (OS) was significantly higher in cases with high levels of PD-1 expression, with 5-yrs OS of 39% (23-55%) and 69% (47-83%) for low and high levels, respectively (p=0.01). Expression levels of FOXP3 and gal-1 had no impact on OS in the total cohort (fig 1). In the monomorphic setting, a low AF of FOXP3 positive cells was associated with an increased risk of progression (OR 6.1; 95% CI: 1.4-26.0). This did not, however, translate into an inferior OS (p=0.163). To specifically characterize the tumor microenvironmental features of DLBCL-type PTLD with respect to cell of origin (COO), 30 evaluable cases were analyzed according to the Hans classifier; 10 (33%) were germinal center (GC) type and 20 (67%) of non-GC type. Cases of non-GC subtype had a significantly shorter time to PTLD of 1.16 yrs (CI: 0.64- 2.11), than those of GC-subtype (3.66 yrs; CI: 1.64- 8.16) (p=0.023) and a lower AF of gal-1 positive cells (p=0.042). The 5-yrs OS was 58% (32-77%) and 0% for non-GC versus GC-tumors, respectively (p=0.075). High levels of FOXP3 expression were associated with superior OS in the non-GC sub-group (p=0.04); gal-1 and PD-1 had no influence in the COO setting. Conclusion: The present study is one of the few attempts to describe tumor microenvironmental features in PTLD and relate them to outcome. In a population-based PTLD cohort, we found that specific immune cell subsets were variably expressed in different PTLD subtypes, and that high expression of PD-1 (whole cohort) and FOXP3 (non-GC DLBCL only) correlated with significantly better outcome. Â N(%) pts in TMA Organ tx(%) Kidney Heart Lung 47(75.8) 9(14.5) 6(9.7) Type PTLD(%) Early/polymorphic lesions Monomorphic PTLD Diffuse large B-cell lymphomaPeripheral T-cel lymphomal, NOS*T-Anaplastic large cell lymphomaBurkitt lymphomaHodgkin lymphoma-type PTLD Marginal zone lymphoma 18(29.0) 38(61.2) 32(51.6) 1(1.6) 3(4.8) 2(3.2) 4(6.5) 2(3.2) Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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Tarella, Corrado, Ornella Perotto, Roberto Passera, Renato Romagnoli, Alessandro Franchello, and Mauro Salizzoni. "Low Incidence and Successful Treatment of Post-Transplant Lymphoproliferative Disorders (PTLD) among 1,513 Patients Undergoing Liver Transplant Procedures." Blood 110, no. 11 (2007): 513. http://dx.doi.org/10.1182/blood.v110.11.513.513.
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Abstract Introduction. Post-transplant lymphoproliferative disorder (PTLD) is a serious complication due to immunosuppression in solid organ transplant recipients. The incidence is quite variable and the outcome has been reported to be often fatal, although improvements have been observed since the introduction of Rituximab. Aim of the study. To evaluate: frequency, risk factors, and outcome of PTLD in a large series of Liver Transplant (LT). Patients and Methods. Data have been collected on 1,513 patients who underwent LT (127 had one to four re-LT, for a total of 1,648 procedures), over the last 15 yrs. PTLD were diagnosed by histology and immunophenotipical analysis on biopsy specimens. Several parameters were evaluated for possible association with PTLD occurrence, including age, sex, liver disease and HCV state of LT recipient, presence of hepatocellular carcinoma, time elapsed from LT to PTLD, main immunosuppressant therapy (cyclosporine vs. tacrolimus), other drugs for graft rejection. The cumulative incidence of PTLD was determined using the Fine and Gray competing risk regression model. Results. At a median follow-up of 62 mos., 1,224 out of 1,513 patients are alive, with a 5-yr Overall Survival (OS) projection of 80% (see Figure 1). So far, 18 PTLD have been recorded, with a cumulative incidence of 1.0, 1.9 and 4.2% at 5, 10 and 15 yrs respectively. Median time of PTLD occurrence was 32 mos. (range 2–155) since LT. On competing risk multivariate analysis, the use of tacrolimus vs. cyclosporine A was the only factor associated with increased risk of PTLD (SDHR: 2.79, p=0.032). Treatment for PTLD included: i. reduction or discontinuation (4 cases) of the immunosuppression; ii. chemotherapy (15 cases); in addition, Rituximab was delivered to 11 patients (combined with chemotherapy in 5); treatment resulted in Complete Remission in 14 patients, good Partial Remission (PR) in 4; one patient had a transient PR soon followed by disease progression; this was the only patient dying for PTLD; 2 more patients died for causes other than PTLD; at present, at a median follow up of 30 mos., 15 out of the 18 PTLD patients are alive, with a 5-yr OS projection of 88% (see Figure 2). Conclusions. The overall incidence of PTLD in this large series of LT is among the lowest reported so far in patients receiving solid organ transplant; the use of tacrolimus is confirmed as a significant risk factor for PTLD; the outcome of PTLD seems definitely improved; the availability of Rituximab is quite likely to have contributed to the prolonged survival observed. Based on the results of this study, the exclusion of patients with a previous history of lymphoproliferative disease from LT procedures seems questionable. Figure 1. Overall survival of 1,513 patients undergoing LT Figure 1. Overall survival of 1,513 patients undergoing LT Figure 2. Overall survival of 18 patients developing PTLD Figure 2. Overall survival of 18 patients developing PTLD
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Uhlin, M., H. Wikell, M. Sundin, et al. "Risk factors for Epstein-Barr virus-related post-transplant lymphoproliferative disease after allogeneic hematopoietic stem cell transplantation." Haematologica 99, no. 2 (2013): 346–52. http://dx.doi.org/10.3324/haematol.2013.087338.
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Dharnidharka, Vikas R., Lynya I. Talley, Karen L. Martz, Donald M. Stablein, and Richard N. Fine. "Recombinant growth hormone use pretransplant and risk for post-transplant lymphoproliferative disease - A report of the NAPRTCS." Pediatric Transplantation 12, no. 6 (2008): 689–95. http://dx.doi.org/10.1111/j.1399-3046.2007.00881.x.
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Aguayo-Hiraldo, Paibel, Reuben Arasaratnam, and Rayne H. Rouce. "Recent advances in the risk factors, diagnosis and management of Epstein-Barr virus post-transplant lymphoproliferative disease." Boletín Médico Del Hospital Infantil de México (English Edition) 73, no. 1 (2016): 31–40. http://dx.doi.org/10.1016/s2444-3409(16)30016-4.
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Wong, Jackson Y., Brian Tait, Bronwyn Levvey, et al. "Epstein-Barr Virus Primary Mismatching and HLA Matching: Key Risk Factors for Post Lung Transplant Lymphoproliferative Disease." Transplantation Journal 78, no. 2 (2004): 205–10. http://dx.doi.org/10.1097/01.tp.0000128611.71038.0c.
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Mouchli, Mohamad, Siddharth Singh, Edward V. Loftus, et al. "Rate, Risk Factors, and Outcomes of Post-transplant Lymphoproliferative Disease After Liver Transplantation for Primary Sclerosing Cholangitis." American Journal of Gastroenterology 111 (October 2016): S366. http://dx.doi.org/10.14309/00000434-201610001-00832.
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Aguayo-Hiraldo, Paibel, Reuben Arasaratnam, and Rayne H. Rouce. "Recent advances in the risk factors, diagnosis and management of Epstein-Barr virus post-transplant lymphoproliferative disease." Boletín Médico del Hospital Infantil de México 73, no. 1 (2016): 31–40. http://dx.doi.org/10.1016/j.bmhimx.2015.11.007.
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