Nervous System Post-transplant Lymphoproliferative Disorder Research Articles

A disease warranting attention from neurosurgeons: primary central nervous system post-transplant lymphoproliferative disorder.

Primary central nervous system post-transplant lymphoproliferative disorder (PCNS-PTLD) is a rare condition, posing diagnostic and treatment challenges, with histological biopsy essential for diagnosis. Standardized treatment protocols are lacking. This disease requires urgent attention due to the increasing number of organ transplant surgeries and the use of immunosuppressive agents. From 2020 to 2023, our center diagnosed five patients with PCNS-PTLD. We reviewed their clinical records and conducted a comprehensive analysis of 22 literatures on PCNS-PTLD cases following renal transplantation or allogeneic hematopoietic stem cell transplantation (HSCT). Four patients had previously received a kidney transplant, one had undergone allogeneic HSCT. The median time from the last transplant surgery to the diagnosis of PCNS-PTLD differs between kidney transplant (21.5 years) and allogeneic HSCT (9 months). Common symptoms included motor weakness (n = 4), headache (n = 2), confusion (n = 2), and nausea (n = 2), with ring-enhancing (n = 5), typically solitary (n = 3) and supratentorial (n = 3) lesions on imaging. Diagnosis involved robot-assisted stereotactic brain biopsy (n = 4) or craniotomy (n = 1), all showing Epstein-Barr virus and CD20 positivity. Most cases (n = 4) were monomorphic diffuse large B-cell lymphoma. Treatment included rituximab (n = 3), surgical resection (n = 2), zanubrutinib (n = 1), whole-brain radiation (n = 1), and methotrexate (n = 1). At the last follow-up, the median duration of follow-up for all patients was 19 months. During this time, 3 patients had died and 2 patients were still alive. In patients with a history of kidney transplantation or allogeneic HSCT who are on long-term immunosuppressive therapy, any neurological symptoms, particularly the presence of supratentorial ring-enhancing masses in the brain on imaging, whether solitary or multiple, should raise high suspicion for this disease, warranting a timely brain biopsy. Additionally, we found that besides reducing immunosuppressants, zanubrutinib may be a potential, safe, and effective treatment for this condition. Moreover, post-surgical administration of rituximab in conjunction with whole-brain radiotherapy also appears to be a potentially safe and effective approach.

Treatment of Central Nervous System Post-Transplant Lymphoproliferative Disorder in Immunocompromised Patients with Pancreas Transplant– Between the Rock and a Hard Place (P2-13.002)

<h3>Objective:</h3> To describe the clinical presentation and management of two patients who developed pancreatic transplant rejection during treatment of post-transplant CNS lymphoma (PT-CNSL). <h3>Background:</h3> PT-CNSL is a rare neoplasm developing after immunosuppressive therapy following solid-organ transplantation. Treatment involves reducing immunosuppression, which risks graft rejection. In pancreas transplant recipients, this is associated with increased mortality rates with limited therapeutic alternatives. <h3>Design/Methods:</h3> NA <h3>Results:</h3> <h3>Case Description:</h3> <h3>Case 1:</h3> a 43-year-old female status post pancreas-kidney transplant was diagnosed with PT-CNSL in 2022, initially managed by withholding tacrolimus and initiating rituximab therapy at 375 mg/m2 IV (starting weekly for 3 months, then monthly). The lymphoma regressed with treatment until the patient experienced pancreatic graft rejection (lipase peak 1,124 U/L). This was treated by adding on low-dose tacrolimus which resulted in an improvement in graft rejection and allowed ongoing therapy with rituximab, yielding a complete response of the PT-CNSL. <h3>Case 2:</h3> A 55-year-old female status post pancreas-kidney transplant in 2010, was diagnosed with PT-CNSL in 2021. Treatment involved discontinuation of mycophenolate and tacrolimus and initiation of rituximab at 375 mg/m2 IV (starting weekly for six months, then monthly). Although the lymphoma regressed, the patient experienced acute epigastric pain with a lipase peak of 2,715 U/L with CT of the abdomen illustrating acute pancreatitis. Due to concern for transplant rejection, low-dose tacrolimus was initiated along with rituximab, resulting in resolution of elevated lipase. Continued serial neuroimaging studies demonstrated a complete response. <h3>Conclusions:</h3> PT-CNSL increases morbidity and mortality in pancreas transplant patients with limited treatment options. Treatment should balance maintaining CNS response with careful re-initiation of immunosuppression in the setting of graft rejection; however, there is limited knowledge regarding ideal doses of immunosuppression. We demonstrate that low-dose tacrolimus to prevent graft rejection was safe and effective in treating two patients with PT-CNSL, highlighting the need for further investigation into optimal management strategies. <b>Disclosure:</b> Mrs. Haque has nothing to disclose. Prof. ORLANDO has nothing to disclose. Glenn Lesser has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Cancer Expert Now. Glenn Lesser has received personal compensation in the range of $500-$4,999 for serving as a Consultant for SDP Oncology. Glenn Lesser has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Agios. Glenn Lesser has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Incysus . Glenn Lesser has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for ONO Pharma. Glenn Lesser has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer. The institution of Glenn Lesser has received research support from Denovo Biopharma. The institution of Glenn Lesser has received research support from Oblato . The institution of Glenn Lesser has received research support from Novocure. The institution of Glenn Lesser has received research support from GBM Agile - GCAR. Dr. Strowd has received personal compensation for serving as an employee of Kaplan. Dr. Strowd has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Monteris Medical, Inc. Dr. Strowd has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novocure. Dr. Strowd has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for American Academy of Neurology. The institution of Dr. Strowd has received research support from Southeastern Brain Tumor Foundation. The institution of Dr. Strowd has received research support from Jazz Pharmaceuticals. The institution of Dr. Strowd has received research support from National Institutes of Health. The institution of Dr. Strowd has received research support from Alpha Omega Alpha. The institution of Dr. Strowd has received research support from American Board of Psychiatry and Neurology. Dr. Strowd has received publishing royalties from a publication relating to health care. Dr. Strowd has received publishing royalties from a publication relating to health care.

Frequent intrathecal production of antibodies to the viral capsid antigen of Epstein-Barr virus in patients with central nervous system post-transplant lymphoproliferative disorder

Primary central nervous system post-transplant lymphoproliferative disorder (PCNS-PTLD) is strongly associated with Epstein-Barr virus (EBV). We analysed intrathecal production of EBV viral capsid antigen (VCA) immunoglobulin (Ig)G and IgA and Epstein-Barr nuclear antigen-1 (EBNA-1) IgG in nine patients with PNCS-PTLD and 20 patients with non-inflammatory neurological diseases (NINDs). Intrathecally produced VCA-IgG was detected in 7/9 (78%), VCA-IgA in 6/9 (67%) and EBNA-1-IgG in 2/9 (22%) patients with PCNS-PTLD, but not in NINDs. This exploratory study suggests that intrathecal EBV antibody production might be frequent in PCNS-PTLD. Detecting intrathecally produced VCA-IgG and VCA-IgA could thus potentially be helpful for diagnosing PCNS-PTLD.

The spectrum of Epstein-Barr virus infections of the central nervous system after organ transplantation

BackgroundEpstein-Barr virus (EBV)-related neurologic complications have a diverse presentation in transplant recipients, creating diagnostic and therapeutic challenges for clinicians. In this case series, we report unique manifestations of EBV related neurologic complications following solid organ transplant and highlight pitfalls in management.Case presentationsA retrospective search of the electronic medical record of all patients from January 2015 to December 2020 who underwent solid organ transplantation and had central nervous system complications as determined by ICD-10 codes were included. Three patients with unique manifestation of EBV-related neurologic complications after liver transplantation were identified. The first was a 52-year-old man with a live-donor liver transplant 11 years prior for Budd-Chiari syndrome presented with several weeks of headache and several lesions on brain MRI; he was diagnosed with primary central nervous system post-transplant lymphoproliferative disorder. The second patient was a 63-year-old man with a deceased-donor liver transplant 16 years prior for alpha-1-antitrypsin deficiency and was found to have a stroke; he was diagnosed with EBV encephalitis. The final patient was a 75-year-old woman with a deceased-donor liver transplant six years prior for primary biliary cirrhosis who presented with four months of gait instability; she was diagnosed with EBV myelitis. A review of the literature was performed to supplement description of the different diseases.ConclusionsEBV-related central nervous infection in post-transplant patients can manifest in a variety of neurologic syndromes, which can be challenging to diagnose. Careful correlation of clinical, pathologic, and radiologic findings and a high index of suspicion are crucial in identification and appropriate management.

Late Primary B Cell Cerebral Lymphoma After Kidney Transplant: A Case Report and Literature Review

Background: Primary central nervous system post-transplant lymphoproliferative disorder (PCNS-PTLD) is a serious and uncommon complication which can be developed months or years after a Kidney transplant. Immunosuppressive agents administered before and after transplantation to minimize the chances of allograft rejection has proved to be a double-edged sword that puts the host at risk of infectious, neoplastic and vascular diseases, including PCNS-PTLD. The immunosuppressive therapy leads to decreased innate malignant and viral immune surveillance and this has been shown to play a role in lymphoproliferative diseases after transplantation. In most cases, PCNS-PTLD is Epstein–Barr virus related. Case Description: A 60-year-old female with history of kidney transplant presented to the emergency room with history of low fever, dizziness nausea and vomiting for 1 month. MRI and CT scans showed a mass cerebellar lesion and a biopsy revealed Primary central nervous system post-transplant lymphoproliferative disorder (PCNS-PTLD). Conclusion: This case highlights the need for a careful long-term follow up of patients with kidney transplant. PCNS-PTLD represents a continuing long-term risk after transplantation, although less common. This case report supports observational data that suggests that peripheral blood screening for EBV DNA does not seem helpful for identification of PCNS-PTLD. Suspicion of PCNS PTLD should be considered when patients with long-term history of kidney transplant present neurological complaints.

Reduction of immunosuppression combined with whole-brain radiotherapy and concurrent systemic rituximab is an effective yet toxic treatment of primary central nervous system post-transplant lymphoproliferative disorder (pCNS-PTLD): 14 cases from the prospective German PTLD registry.

Post-transplant lymphoproliferative disorders (PTLD) exclusively affecting the central nervous system-primary CNS-PTLD (pCNS-PTLD)-are rare. There is no standard therapy, and previous case series have included heterogeneous treatment approaches. We performed a retrospective, multi-centre analysis of 14 patients with pCNS-PTLD after solid organ transplantation (SOT) treated in the prospective German PTLD registry with reduction of immunosuppression (RI), whole-brain radiotherapy (WBRT), and concurrent systemic rituximab between 2001 and 2018. Twelve of fourteen patients were kidney transplant recipients and median age at diagnosis was 65years. Thirteen of fourteen cases (93%) were monomorphic PTLD of the diffuse large B-cell lymphoma type, and 12/13 were EBV-associated. The median dose of WBRT administered was 40Gy with a median fraction of 2Gy. The median number of administered doses of rituximab (375mg/m2) IV was four. All ten patients evaluated responded to treatment (100%). Median OS was 2.5years with a 2-year Kaplan-Meier estimate of 63% (95% confidence interval 30-83%) without any recorded relapses after a median follow-up of 2.6years. Seven of fourteen patients (50%) suffered grade III/IV infections under therapy (fatal in two cases, 14%). During follow-up, imaging demonstrated grey matter changes interpreted as radiation toxicity in 7/10 evaluated patients (70%). The combination of RI, WBRT, and rituximab was an effective yet toxic treatment of pCNS-PTLD in this series of 14 patients. Future treatment approaches in pCNS-PTLD should take into account the significant risk of infections as well as radiation-induced neurotoxicity.

Intracranial peripherally enhancing lesions in cardiac transplant recipients: A rare case series and literature review

Intracranial peripherally enhancing lesions in immunosuppressed solid organ transplant recipients represent a unique diagnostic and management dilemma due to the vast array of differentials that demand consideration. Diagnosis of the underlying pathology is often guided by the use of magnetic resonance imaging (MRI). We present the first published case series of three cardiac transplant recipients with significantly atypical neuroradiological findings contrary to the tenets of contemporary literature. Our rare case series consists of: (1) A sterile Mycobacterium pyogenic abscess mimicking glioblastoma multiforme due to an immunosuppressed state (2) Epstein Barr Virus encephalitis masquerading as Central Nervous System Post-Transplant Lymphoproliferative Disorder (3) An unusual case of partially treated disseminated Nocardiosis warning of the need to consider the immunosuppressed state and partial treatment response obfuscating classical MRI appearances. We utilise these unprecedented cases as the basis of a literature review to understand the pathophysiology behind the peculiar imaging findings in this rarefied cohort of transplant recipients, and rationalise why the MRI findings in each instance contradicts the accepted imaging patterns. In the setting of potential unreliability of neuroradiology in this immunosuppressed unique subgroup, we hope to impart to clinicians that definitive diagnosis obtained by emergent neurosurgical intervention may be necessary to accurately and expediently guide further medical management.

Isolated B cell central nervous system posttransplant lymphoproliferative disorder: Role of magnetic resonance imaging in the diagnosis and management in the absence of neurological signs - a case report

A 29-year-old female who received a kidney from her mother 9 months ago, on minimal triple immunosuppression presented with short duration vertigo. There were no focal neurological deficits. Magnetic resonance imaging of the brain revealed peripherally enhancing periventricular lesions, predominantly in the bilateral frontal lobes. Positron-emission tomography showed increased uptake in the brain lesions. A stereotactic biopsy revealed CD20+ monomorphic B cell posttransplant lymphoproliferative disorder. The donor mother and daughter were Epstein–Barr virus (EBV) immunoglobulin G (IgG+)/IgG−. The cerebrospinal fluid and brain biopsy were positive for EBV. Treatment consisted of discontinuing prednisolone and MMF and reducing tacrolimus to 0.5 mg od. Rituximab, zidovudine, ganciclovir, and dexamethasone are being used. She has stable renal function.

Event-Free Survival at 24 Months Following Autologous Stem Cell Transplant in Diffuse Large B-Cell Lymphoma

Introduction: Front-line immunochemotherapy (IC) with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is expected to cure 60-70% of newly diagnosed DLBCL. Up to one third of newly diagnosed DLBCL patients will have relapsed or refractory (r/r) disease.1 Current standard of care for these patients is salvage chemotherapy and, if chemosensitive, to be followed by high dose chemotherapy with hematopoietic cell rescue (autoHCT).2,3 Event-free survival at 24 months (EFS24) after frontline IC is associated with excellent long-term outcomes with overall survival (OS) similar to that of age- and sex-matched controls.4 In comparison, those achieving EFS24 following autoHCT for relapsed or refractory disease may have increased risk for late-mortality compared to the general population with advanced age and intensive salvage therapy contributing to the risk of late complications.5 We sought to better characterize EFS24 after autoHCT to determine the utility of this end-point for informed clinical decisions, patient management, and future clinical trials. Methods: Patients were prospectively enrolled onto the Molecular Epidemiology Resource (MER) of the University of Iowa/ Mayo Clinic Specialized Program of Research Excellence (SPORE). Patients were followed for relapse, retreatment, and death; all events were validated by medical record review. For this analysis patients were included if they were consented within 9 months of initial diagnosis of DLBCL between 2002-2012, had received anthracycline-based IC (R-CHOP, or similar), and eventually had undergone autoHCT for r/r DLBCL. Patients with primary central nervous system (CNS) lymphoma or post-transplant lymphoproliferative disorders (PTLD) were excluded. Overall survival (OS) was defined as time from autoHCT until death due to any cause. Event-free survival (EFS) was defined as time from autoHCT until progression, relapse, retreatment, or death due to any cause. OS from achieving EFS24 after autoHCT was compared to age- and sex-matched general US population. Results: 108 patients underwent autoHCT for relapsed DLBCL between 2002 and 2017. Median age at autoHCT of the patients was 60 years (range 20-78) and 72 (67%) were male. The most common transplant conditioning regimen was BEAM (82%). At a median follow-up after autoHCT of 85 months (range 1-171), 72 patients (67%) had an event and 64 patients (59%) had died. Kaplan-Meier estimates for EFS and OS at 24 months from the time of autoHCT were 49% (95% CI: 40-59) and 61% (95% CI: 52-71), respectively. 52 patients had a progression within 24 months of autoHCT; OS from progression was poor (median OS=2.8 months, 95% CI: 1.8-6.0; 5 year OS = 9%, 95% CI: 2-22). 48 patients achieved EFS24 after autoHCT; median OS from achieving EFS24 was 136 months (95% CI: 92-NE) and 5 year OS was 79% (95% CI: 68-93). This was inferior to the background population (Figure 1, SMR=3.64, 95% CI: 2.11-6.27, p&lt;0.0001). Eight patients had a progression after achieving EFS24 from autoHCT. OS from progression in these 8 patients (median OS=27.3 months, 95% CI: 14.4-NE; 5 year OS = 16%, 95% CI: 3-93) was improved compared to progression within 24 months of autoHCT (p=0.072, figure B). Cause of death (COD) in EFS24 achievers was progression of lymphoma (n=6), infection (n=1), secondary malignancy related to therapy (n=3), heart disease (n=1), and unknown (n=1). Conclusions: Patients achieving EFS24 after salvage chemotherapy and autoHCT have a favorable long-term prognosis; however, overall survival remained inferior to the general population. Most common COD after achieving EFS24 was progression of lymphoma. In spite of this, EFS24 remains a valuable end-point for informed clinical decisions, patient management, and future clinical trials. Figure 1 Disclosures Maurer: Morphosys: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Nanostring: Research Funding. Ansell:Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Trillium: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; LAM Therapeutics: Research Funding. Cerhan:Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding. Farooq:Celgene: Honoraria; Kite Pharma: Research Funding.

Non-Diffuse Large B-Cell Primary Central Nervous System Lymphoma

Background: The majority of subjects with a diagnosis of primary central nervous system lymphoma (PCSNL) have diffuse large B-cell lymphoma (DLBCL) as their histology. However, there are a sub-set of PCSNL patients who present with other histologies. This retrospective study was conducted to evaluate histological morphology, risk factors and clinical course in subjects with non-diffuse large B-cell primary CNS lymphoma.Methods: We used the Mayo Clinic Lymphoma Database to search for patients with PCSNL during the time period from January 1995 to June 2018. One hundred and fifty nine patients met the criteria and underwent record review. One hundred and nine patients were excluded as they had PCSNL with DLBCL histology (N=47, 43%), secondary central nervous system lymphoma (N=56, 51%) and post-transplant lymphoproliferative disorders (PTLD) with DLBCL morphology (N=6, 5%). We identified fifty patients with PCSNL Non-DLBCL histology, by evaluating the biopsy reports. We abstracted clinical data and outcomes for these groups through medical chart review. Kaplan-Meier analysis was used to estimate survival.Results: The mean age of the study population was 70 ± 11.3 years and 66% were male. Of the 50 patients, the most common histology was low grade CNS lymphoma (N=14, 28%) while Hodgkin's lymphoma (N= 1, 2%), Burkitt's lymphoma (N= 1, 2%) and histiocytic lymphoma (N= 1, 2%) were the least common. The frequencies of other PCSNL Non-DLBCL histology are demonstrated in Table1. Most patients showed good ECOG performance status of 0-2 and four patients had ECOG performance status of grade 3 (N=4, 8%). Six of the patients were immunocompromised (N=6, 12%), PPD positive tuberculosis; corticosteroids and PTLD with DLBCL histology were the causes for the immunocompromised state. The location of the CNS lymphoma included brain (N=24, 50%); spinal cord (N=9, 18%); orbits (N=5, 10%); deep structures which included brainstem, cerebellum, cerebellopontine angle and cauda equina (N=5, 10%); leptomeninges (N=4, 8%) and neural involvement which included sciatic, peroneal and facial nerve (N=3, 6%). CSF examination revealed increased protein levels (N=10, 20%), malignant cells (N=11, 22%), negative cytology (N=14, 28%) and unknown or not done (N=15, 30%). Most patients presented with neurological symptoms such as seizures, peripheral neuropathy (numbness/weakness/tingling), headache, confusion & cognitive disturbances (memory changes), gait disturbances (difficulty with balance/ataxia), visual disturbances (blurry vision) and paraplegia, but none of them presented with B-cell symptoms such as fever, night sweats and weight loss. Treatment modalities included chemotherapy, radiation and surgery. Fourteen patients underwent radiation therapy (N=14, 28%); three of the patients had undergone surgery of which the patient with peripheral T-cell lymphoma had undergone a complete excision, the patient with marginal zone lymphoma had undergone debulking with subtotal craniotomy and the patient with MALT lymphoma had undergone resection with gamma knife. Table 2 demonstrates the various chemotherapy drugs used and the distribution of frequency of biopsy, radiation and surgical treatment in the different pathology of PCSNL Non-DLBCL.The median overall survival period using Kaplan-Meier analysis showed that Burkitt's Lymphoma had the least median time survival of less than a month and PTLD had the highest median survival of 146.25 months (p=0.0017). Table 3 shows the median survival time for all the different pathology's of PCSNL Non-DLBCL.Conclusion: This retrospective study reinforces the critical need for a histologic diagnosis when a patient is diagnosed with PCNSL. PCSNL is considered to be DLBCL but there are other histology's that could potentially be PCSNL and the treatment should be tailored to the individual patient's histology. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Complete and Durable Responses in Primary Central Nervous System Posttransplant Lymphoproliferative Disorder with Zidovudine, Ganciclovir, Rituximab, and Dexamethasone

Purpose: Primary central nervous system posttransplant lymphoproliferative disorder (PCNS-PTLD) is a complication of solid organ transplantation with a poor prognosis and typically associated with Epstein-Barr virus (EBV). We hypothesized EBV lytic-phase protein expression would allow successful treatment with antiviral therapy.Patients and Methods: Thirteen patients were treated with zidovudine (AZT), ganciclovir (GCV), dexamethasone, and rituximab in EBV+ PCNS-PTLD. Twice-daily, intravenous AZT 1,500 mg, GCV 5 mg/kg, and dexamethasone 10 mg were given for 14 days. Weekly rituximab 375 mg/m2 was delivered for the first 4 weeks. Twice-daily valganciclovir 450 mg and AZT 300 mg started day 15. Lytic and latent protein expression was assessed using in situ hybridization and immunohistochemistry. Immunoblot assay assessed lytic gene activation. Cells transfected with lytic kinase vectors were assessed for sensitivity to our therapy using MTS tetrazolium and flow cytometry.Results: The median time to response was 2 months. Median therapy duration was 26.5 months. Median follow-up was 52 months. The estimated 2-year overall survival (OS) was 76.9% (95% CI, 44.2%-91.9%). Overall response rate (ORR) was 92% (95% CI, 64%-100%). BXLF1/vTK and BGLF4 expression was found in the seven tumor biopsies evaluated. Lytic gene expression was induced in vitro using the four-drug regimen. Transfection with viral kinase cDNA increased cellular sensitivity to antiviral therapy.Conclusions: EBV+ PCNS-PTLD expressed lytic kinases and therapy with AZT, GCV, rituximab and dexamethasone provided durable responses. Induction of the lytic protein expression and increased cellular sensitivity to antiviral therapy after transfection with viral kinase cDNA provides a mechanistic rationale for our approach. Clin Cancer Res; 24(14); 3273-81. ©2018 AACR.

Isolated central nervous system post-transplant lymphoproliferative disorder in a pediatric patient: a case report with pathobiological perspective

Isolated central nervous system post-transplant lymphoproliferative disorder (ICNS-PTLD) in pediatric patients is a distinctly rare entity without accepted diagnostic criteria or treatment recommendations. We present a case of an 8-year-old male with a prior history of a kidney transplant who developed and ICNS-PTLD. We highlight the pathobiology and diagnostic features with a brief review of the literature on these rare cases. There is a complex interplay between CD30, Epstein Barr Virus and MYC as part of lymphocyte transformation leading to PTLD. In the appropriate clinical setting, CD30 and EBV positivity along with normal MYC expression are highly predictive of CNS-PTLD over a Primary CNS lymphoma. ICNS-PTLD has only been rarely reported in children. The faithful diagnosis is necessary for prognostication and to accrue data for treatment recommendations.

Primary central nervous system posttransplant lymphoproliferative disorder after solid organ transplantation: report of four cases with distinct clinical characteristics (P3.162)

Primary central nervous system posttransplant lymphoproliferative disorder after solid organ transplantation: report of four cases with distinct clinical characteristics (P3.162)

Prognosis of Patients with Primary Central Nervous System Post-Transplant Lymphoproliferative Disorder (PTLD-CNS) Treated with Immunossupression Reduction, Intrathecal Chemotherapy and Whole-Brain Radiotherapy: An Analysis of 23 Patients in a Brazilian Cohort

Introduction: Post-transplant lymphoproliferative disorders are a rare heterogenous group of diseases occurring in the setting of post-transplant immunossupression (IS). Clinically, extranodal involvement is common, and it occurs in the central nervous system (CNS) in approximately 7-15% of cases. Most data on PTLD-CNS are based on case series/reports and due to paucity of data no treatment algorithms have been established. In our series, we retrospectively analyzed 23 consecutively cases of PTLD-CNS in Hospital do Rim, Sao Paulo, Brazil.Methods: We retrospectively reviewed all cases of PTLD-CNS diagnosed between 2001 and 2014 at Hospital do Rim (HRim), a school hospital from the Federal University of 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.Results: From 2001 to 2014, from a total of 98 PTLD patients, 23 patients (23%) were diagnosed with PTLD-CNS. Median age at time of diagnosis was 36, with a male:female ratio of 0.9:1. Fifteen (65%) patients received anti-thymocyte globulin (ATG) at the time of transplant and 17 (74%) had at least one episode of acute rejection. The most common immunossupressive regimen (IR) consisted of cyclosporine or tacrolimus associated with prednisone and azathioprine (15, 65%). Median time from transplant to PTLD diagnosis was 31 months (ranging from 8.4 to 153). EBV was positive in tumor lymphocytes by in situ hybridization in 21 cases (91%). Monomorphic cases were diagnosed in 21 (91%) patients. All patients had their IR reduced, usually with suspension of azathioprine and calcineurin inhibitors and change from prednisone to dexamethasone, 19 (82%) patients underwent WBRt (from 25 to 40 Gy) together with intra-thecal (IT) chemotherapy with methotrexate (MTX) 12mg and dexamethasone 2mg. Only 1 patient received high dose MTX and died due to treatment-related toxicities 1 month after diagnosis and 2 patients died before starting WBRt due to disease progression and poor performance status (PS). For those patients who received WBRt together with IT chemotherapy, fourteen patients (74%) had CR, 2 patients (10%) had refractory disease and 3 patients (16%) had relapsed disease within 2 years. Overall Survival (OS) for the group treated with WBRt and IT chemotherapy was 62% in 5 years (CI95% 69-82%). In our series, induction therapy with ATG and acute rejection were associated with increased risk of PTLD-CNS. Age and PS at diagnosis were the only 2 factors predictive of survival. No serious cognitive impairment was identified among the survivors.Conclusions: The current study demonstrated that PTLD-CNS is a serious late EBV-induced B-cell lymphoma, mostly monomorphic with an incidence of 23%, higher than previously described in the post renal transplant setting. Treatment with immunossupression reduction, intrathecal chemotherapy and whole-brain radiotherapy showed a high CR rate with favorable survival in many cases. DisclosuresNo relevant conflicts of interest to declare.

Susceptibility-weighted imaging and diffusion-weighted imaging findings in central nervous system monomorphic B cell post-transplant lymphoproliferative disorder before and after treatment and comparison with primary B cell central nervous system lymphoma.

The purpose of this article is to review the MRI features of monomorphic central nervous system post-transplant lymphoproliferative disorder (CNS PTLD), including diffusion-weighted and susceptibility-weighted sequences before and after treatment and to compare the imaging findings with those of primary central nervous system B cell lymphoma (PCNS BCL). Retrospective review of the brain MRI characteristics in patients with pathology proven monomorphic CNS PTLD and PCNS BCL was performed. In particular, the enhancement, diffusion-weighted, susceptibility-weighted MRI characteristics of the lesions were evaluated. In addition, the diffusion-weighted, susceptibility-weighted MRI features after treatment for CNS PTLD were evaluated. A total of 12 lesions in six patients with CNS PTLD and 12 lesions in nine patients with PCNS BCL were identified on MRI. Among the CNS PTLD lesions with post-contrast images, 80 % demonstrated peripheral enhancement. All of the CNS PTLD lesions contained foci of intratumoral susceptibility signal (ITSS) and the average mean ADC values and ratios were 0.892 × 10(-3) mm(2)/s (standard deviation: 0.082 × 10(-3) mm(2)/s) and 1.19 (standard deviation: 0.15), respectively. On the other hand, 75 % of the PCNS BCL displayed diffuse enhancement, two cases (16.7 %) contained ITSS, and the mean ADC values and ratios were 0.721 × 10(-3) mm(2)/s (standard deviation: 0.093 × 10(-3) mm(2)/s), and 0.99 (standard deviation: 0.17), respectively. Thus, the presence of heterogeneous lesions with ITSS that do not necessarily have as extensive restricted diffusion as PCNS BCL is suggestive of CNS PTLD in the appropriate clinical setting. The preliminary data in this series suggests that diffusion-weighted imaging may serve as a useful biomarker for monitoring treatment response, in which successful treatment of CNS PTLD may result in increased ADC values. In addition, foci of susceptibility effect in CNS PTLD tend to persist or increase over the course of treatment.

Epstein-Barr Virus Kinase-Targeted Therapy for Primary Central Nervous System Post-Transplant Lymphoproliferative Disorder

Abstract BACKGROUND: Primary central nervous system post-transplant lymphoproliferative disorder (PCNS-PTLD) is a rare complication of solid organ transplant, with no standard therapy. Epstein-Barr virus (EBV) is ubiquitous making the virus a candidate therapeutic target. For virus targeted therapy to be effective, antiviral agents must be phosphorylated by lytic-phase kinases BXLF1 and BGLF4. We hypothesized that lytic kinases would be constitutively expressed in PCNS-PTLD and that antiviral therapy would prove an attractive therapeutic alternative to high dose methotrexate-based regimens in patients who often have impaired organ function and poor performance status. METHODS: We investigated the safety and efficacy of EBV-kinase targeted therapy with zidovudine (AZT), ganciclovir (GCV), rituximab, and dexamethasone in patients with PCNS-PTLD. Patients with biopsy-proven PCNS-PTLD following solid organ transplantation were eligible for treatment. Immune suppression was reduced in all patients prior to treatment. Induction therapy consisted of 14 days of AZT 1500 mg IV BID, GCV 5 mg/kg IV BID, dexamethasone 10 mg IV BID and rituximab 375 mg/m2 once weekly for four weeks. Maintenance antiviral therapy was initiated on day 15 with valganciclovir 450 mg and AZT 300 mg, both twice daily. Responses were evaluated by serial brain MRIs beginning 4 weeks after initiation of treatment. Brain biopsy specimens were evaluated for expression of BGLF4 and BXLF1 by in situ hybridization or immunohistochemistry. To test the hypothesis that expression of EBV kinases conferred sensitivity to antiviral therapy, 293T cells were transfected with cDNAs (or control vectors) encoding for full length BXLF1 and/or BGLF4. Transiently transfected cells were tested for expression by immunoblot and drug sensitivity to AZT/GCV was performed by MTS and flow cytometry assays. RESULTS: Twelve patients (7 M, 5 F) with a median age of 49 were treated from 1998-2014. Transplant history included kidney (N=11), pancreas (N=2), and liver (N=1). Histology data included diffuse large B-cell lymphoma (N=7) and grade III lymphomatoid granulomatosis (N=5). EBV positivity (EBER-ISH) and CD20 expression were documented in all cases. All patients completed induction therapy. Median follow-up time and median duration of maintenance therapy were 28 months (range 2 - 143). The mean progression free survival (PFS) was 33.8 months. Overall response rate (ORR) was 83.3%. Eight patients achieved a complete response (CR) within a median time of 2 months (range 0.75 – 6 months). Two patients had a partial response (PR) with an average time to response of 1.25 months. Two patients (2/12) had progressive disease (PD). Causes of death included septic shock (n=3), pulmonary embolism (n=1), and poor functional status requiring hospice (n=1). One patient had PD at the time of death. Median overall survival (OS) was 29 months (range 2 – 143 months). Grade 3-4 toxicity was primarily hematologic, including anemia (N=4), thrombocytopenia (N=2), and neutropenia (N=5). Toxicity in the maintenance phase was generally reversible with holding therapy. Three patients required discontinuation of AZT during maintenance treatment for transfusion-dependent anemia persisting after holding AZT for 7 days or neutropenia coinciding with systemic infection. One patient had AZT discontinued due to nausea and vomiting that led to acute kidney injury. Evaluation of BXLF1, BGLF4 and LMP1 was completed in 7 patients and found to be positive in all cases. LMP1 and kinase expression occurred in mutually exclusive regions of the tumor. Expression of BXLF1 and BGLF4 led to enhanced sensitization of 293T cells to antiviral-induced growth inhibition and apoptosis. CONCLUSIONS: EBV-kinase targeted therapy with AZT, GCV, rituximab and dexamethasone appears to be effective treatment for patients with EBV+ PCNS-PTLD. We demonstrated durable responses without disease recurrence and minimal toxicity. Expression of BXLF1 and BGLF4 kinases provides a mechanistic rationale for an antiviral approach to this disease and an attractive option to replace high dose chemotherapeutic regimens with less toxic targeted therapy in patients with compromised transplant organ function. A multi-center phase II trial is in development to further investigate this regimen in patients with immune deficiency-related CNS EBV-LPD. Figure 1 Figure 1. Disclosures Porcu: Infinity: Research Funding; Seattle genetics: Research Funding; Actelion: Honoraria; Celgene: Honoraria; United States Cutaneous Lymphoma Consortium: Membership on an entity's Board of Directors or advisory committees; Cutaneous Lymphoma Foundation: Membership on an entity's Board of Directors or advisory committees.

A Comprehensive Analysis of the Cellular and EBV-Specific MicroRNAome in Primary CNS PTLD Identifies Different Patterns Among EBV-Associated Tumors

Primary central nervous system (pCNS) posttransplant lymphoproliferative disorder (PTLD) is a complication of solid organ transplantation characterized by poor outcome. In contrast to systemic PTLD, Epstein-Barr virus (EBV)-association of pCNS PTLD is almost universal, yet viral and cellular data are limited. To identify differences in the pattern of EBV-association of pCNS and systemic PTLD, we analyzed the expression of latent and lytic EBV transcripts and the viral and cellular microRNAome in nine pCNS (eight EBV-associated) and in 16 systemic PTLD samples (eight EBV-associated). Notably although 15/16 EBV-associated samples exhibited a viral type III latency pattern, lytic transcripts were also strongly expressed. Members of the ebv-miR-BHRF1 and ebv-miR-BART clusters were expressed in virtually all EBV-associated PTLD samples. There were 28 cellular microRNAs differentially expressed between systemic and pCNS PTLD. pCNS PTLD expressed lower hsa-miR-199a-5p/3p and hsa-miR-143/145 (implicated in nuclear factor kappa beta and c-myc signaling) as compared to systemic PTLD. Unsupervised nonhierarchical clustering of the viral and cellular microRNAome distinguished non-EBV-associated from EBV-associated samples and identified a separate group of EBV-associated pCNS PTLD that displayed reduced levels of B cell lymphoma associated oncomiRs such as hsa-miR-155, -21, -221 and the hsa-miR-17-92 cluster. EBV has a major impact on viral and cellular microRNA expression in EBV-associated pCNS PTLD.

Successful treatment of central nervous system PTLD with rituximab and cranial radiotherapy

Primary central nervous system (PCNS) post-transplant lymphoproliferative disorder (PTLD) is a rare complication of solid organ transplantation and is typically an Epstein-Barr virus (EBV)-induced B-cell CD20+ lymphoma. The modalities of treatment include reduction in immunosuppression, cranial radiotherapy (CRT), intravenous and intrathecal rituximab when CD20 is expressed on B-lymphocytes and PTLD cells, and chemotherapy. We report the successful treatment of EBV-driven PCNS PTLD by reduction in immunosuppression (RI), CRT, and intravenous rituximab. Our patient was an 11-year-old boy with a living-related renal transplant for end-stage renal failure (ESRF) secondary to posterior urethral valves (PUV) and bilateral renal dysplasia (BRD) and on triple immunosuppression with prednisolone, tacrolimus, and azathioprine who had a rising EBV load, which was managed with reduction in tacrolimus dose, withdrawal of azathioprine, and introduction of mycophenolate mofetil (MMF). The patient presented 7 years post-transplant with a seizure and abnormal neurology secondary to polymorphous hyperplastic lesions in the brain, which responded to rituximab and CRT.

Neurological symptoms in a post-transplant patient: a cautionary tale

Primary central nervous system (CNS) post-transplant lymphoproliferative disorder (PTLD) is a rare complication of organ transplantation affecting about 1 % of transplant recipients [1, 2]. The median time from transplantation to diagnosis ranges from 12.6 months to 52 months [1, 3]. We herein describe an unusual case of Epstein barr virus (EBV) positive primary CNS PTLD, presenting after a very long delay of 12 years after renal transplant. A 50-year-old woman presented with a 12-week history of gradual onset, constant, throbbing generalised headache of moderate intensity. She also reported progressive vertigo, difficulty in walking, nausea and vomiting. She was a nonsmoker and denied use of alcohol or other illicit drugs. Twelve years previously, she had a renal transplant for endstage renal disease secondary to chronic pyelonephritis. Her routine medications included cyclosporin 50 mg twice daily, azathioprine 100 mg once daily and prednisolone 5 mg once daily. Clinical examination demonstrated broken pursuit eye movements, mild appendicular ataxia and right extensor plantar response. She walked with a slightly broadbased ataxic gait. Systemic examination was unremarkable. Laboratory studies including inflammatory markers and autoimmune screen were unremarkable. Magnetic resonance imaging (MRI) of the brain with gadolinium showed scattered nodular enhancing lesions involving bilateral cerebellar hemispheres, splenium of corpus callosum and right peritrigonal white matter (Fig. 1). Cerebrospinal fluid (CSF) analysis revealed a white cell count of 7 (100 % lymphocytes), protein 0.39 g/L and normal glucose. Stains and culture results for bacteria, mycobacteria and fungi were negative. However, CSF polymerase chain reaction for EBV was positive at 1,000 copies/ml; BK and JC virus were negative. Computed tomography scan of chest, abdomen, and pelvis was unremarkable. A biopsy of the posterior fossa lesion showed a polymorphic population of lymphoid cells, in keeping with polymorphic type PTLD (Fig. 2). Azathioprine was discontinued and cyclosporin was initially reduced to 25 mg twice daily. She was also treated with 4 cycles of methotrexate (3000 mg/m on day 1) and cytarabine (1600 mg/m every 12 h on day 2 and 3) at 3 weekly intervals, with complete clinical and radiological response. The dose of cytarabine was reduced by 20 percent from the standard dose (2000 mg/m), given the reduced baseline creatinine clearance rate of 53 mL/min/ 1.73 m. She is currently on prednisolone 5 mg daily and cyclosporin 35 mg twice daily. There has been no recurrence to date over a period of 18 months. She also retains good renal graft function. Post-transplant lymphoproliferative disorders represent a spectrum ranging from EBV-driven infectious mononucleosis type polyclonal proliferations, to EBV positive or S. K. Chhetri R. Dayanandan H. C. A. Emsley (&) Department of Neurology, Royal Preston Hospital, Preston PR2 9HT, UK e-mail: h.emsley@liv.ac.uk; hedley.emsley@manchester.ac.uk

Successful Treatment of Primary Central Nervous System Post-Transplant Lymphoproliferative Disorder (PCNS-PTLD) with Zidovudine (AZT), Ganciclovir (GCV), Rituximab and Dexamethasone: A Single-Institution Case Series

Abstract 3067 BACKGROUND:Primary central nervous system post-transplant lymphoproliferative disorder (PCNS PTLD) is a rare complication of solid organ transplantation, with no standard therapy. Most PCNS PTLDs are associated with Epstein-Barr virus (EBV) infection, thus EBV could serve as a potentially attractive therapeutic target. For EBV-targeted antiviral therapy to be effective, antiviral agents must be phosphorylated by lytic-phase EBV kinases BXLF1/vTK and BGLF4. We hypothesized that PCNS-PTLDs would express viral kinases and that antiviral therapy would prove an attractive therapeutic alternative to high dose methotrexate-based chemotherapy for patients who often have impaired organ function and poor performance status. METHODS:We investigated the safety and efficacy of EBV-targeted therapy with zidovudine (AZT), ganciclovir (GCV), rituximab, and dexamethasone in patients with PCNS PTLD, as well as the relationship of viral protein kinase expression with response to therapy. Patients with biopsy-proven PCNS PTLD following solid organ transplantation were eligible for treatment. Induction therapy consisted of AZT 1500 mg IV, and GCV 5 mg/kg IV, dexamethasone 10 mg IV, twice daily on days 1–14 and 4 weekly doses of rituximab 375 mg/m2 on days 1, 8, 15, and 22. Maintenance therapy was initiated on day 15 with valganciclovir 500 mg twice daily, and AZT 300 mg twice daily until disease progression or intolerable toxicity. Treatment was adjusted for hematologic toxicity and impaired liver and kidney function. Responses were evaluated by serial brain MRIs beginning 4 weeks after initiation of treatment. Brain biopsy specimens were evaluated for expression of viral kinases BGLF4 and BXLF1/vTK by in situ hybridization. RESULTS:Eight patients (5 M, 3 F) with a median age of 49 were treated at our institution from 1999–2011. Transplant history included kidney (N=7), and kidney + pancreas (N=1). Pathology data was available for all patients and included diffuse-large B-cell lymphoma (N=4), grade III lymphomatoid granulomatosis (N=2), and B-cell lymphoma, not further classifiable (N=2). EBV positivity (EBER) and CD20 expression was documented in all cases. Evaluation of BXLF1/vTK and BGLF4 was completed in 4 patients and found to be positive. Areas of tumor expressing viral kinases did not express LMP1. Immune suppression was reduced in all patients prior to treatment. All patients completed induction therapy. Median duration of maintenance therapy was 16.6 months. At the time of analysis, 6 patients were still alive and disease free (median duration of follow-up = 19.6 months, inter-quartile range = 10.6 – 28.3). All 8 patients achieved a complete response by MRI criteria with a median duration to response of 2 months (inter-quartile range = 1.5 – 4 months). Two patients died with survival times of 3 and 143 months after diagnosis. No patients had documented disease progression. Thus far, median duration of progression free survival has been 17.1 months (inter-quartile range = 7 – 31 months). Patient 1 was disease-free for 141 months but developed and died from complications of colon cancer. Patient 8 died of multi-organ failure related to pneumonia and septic shock, which was considered non-treatment-related, 3 months after initiation of therapy. At that time, a brain MRI showed evidence of complete response. Grade 3–4 toxicity was primarily hematologic, including anemia (N=4), thrombocytopenia (N=3), leukopenia (N=5) and neutropenia (N=4). Toxicity in the maintenance phase was generally reversible within 7 days of holding therapy. One patient required discontinuation of AZT during maintenance treatment for persistent, transfusion-dependent anemia. CONCLUSIONS:EBV-targeted therapy with AZT, GCV, rituximab and dexamethasone appears to be safe for the treatment of EBV+ PCNS PTLD, with promising evidence of activity. Responses were generally rapid and durable. Expression of BXLF1/vTK and BGLF4 kinases provides mechanistic rationale for an antiviral approach for this disease. Given the lack of effective standard therapy for these patients, this regimen deserves further investigation. Unanswered questions include the optimum length of maintenance therapy that is still effective while minimizing toxicity, and whether rituximab is necessary to achieve the responses observed. A multi-center phase II trial is in development to further investigate this regimen. Disclosures:Off Label Use: We will discuss the use of zidovudine and ganciclovir to treat primary CNS lymphoma in transplant patients.