Primary CNS Diffuse Large B-cell Research Articles

IDENTIFICATION OF GENOMIC BIOMARKERS OF DISEASE PROGRESSION AND SURVIVAL IN NEWLY‐DIAGNOSED PRIMARY CNS LYMPHOMA

Introduction: There is a significant unmet need for robust genomic biomarkers that identify patients with newly-diagnosed primary CNS lymphoma (PCNSL) at high risk of progression, both during standard methotrexate-based induction as well as after dose-intensive consolidation. Methods: We performed targeted next-generation sequencing of 529 cancer genes of formalin-fixed, paraffin-embedded tumors from 74 patients with newly diagnosed primary CNS diffuse large B-cell lymphoma using the UCSF500 Cancer Panel and the Institute for Human Genetics CLIA Laboratory. The assay detects structural variants including single nucleotide variants, small insertions and deletions, and copy-number alterations (CNAs). Sixty-four EBV-negative PCNSL patients treated with a standard methotrexate, temozolomide, rituximab (MTR) induction were available for complete analysis. Results: We identified frequent mutations involving MYD88 (77%), CD79B (41.9%), ETV6 (27%) and BTG1 (25.7%) as well as frequent CNA involving 6q loss (62.5%), 9p loss (34.4%) and 12 gain (31.3%). Three genomic alterations were most significantly associated with early disease progression in PCNSL: (1) Alterations at 6p21.3, predominantly copy neutral loss of heterozygosity (CN-LOH) at the HLA Class I (HLA-A, B, C) and Class II loci (HLA-DR, DP, DQ, TAP1) as well as homozygous deletion of HLA Class II; (2) Mutations of tumor suppressor genes BTG1 and ETV6. Overall, these genomic alterations were detected in 28 out of 31 progression events in the cohort. The subgroup with either CN-LOH or homozygous deletion at 6p had the earliest progression, followed by the subgroup with mutations at either BTG1/ETV6 and no 6p CN-LOH or homozygous deletion, compared to no alterations at these 3 loci. 10 of 18 tumors with these alterations at 6p also contained BTG1 and/or ETV6 mutations. Survival analysis demonstrates that the subgroup with 6p CN-LOH or homozygous deletion had the earliest progression, followed by the subgroup with BTG1/ETV6 mutations compared to no alterations at these 3 loci (PFS p = 3.7e-5, OS p = 0.0017, logrank test, Figure 1). Multivariate Cox proportional hazard analysis demonstrated a significant 3.24-fold increased risk of progression with 6p CN-LOH/homozygous deletion or BTG1/ETV6 mutations (p = 3.5e-5, adjusted by Age, KPS, IELSG, MSKCC, IOL, Maintenance, and Consolidation). The research was funded by: National Cancer Institute NIH R01CA139-83-01A1 Keywords: aggressive B-cell non-Hodgkin lymphoma, diagnostic and prognostic biomarkers, genomics, epigenomics, and other-omics No conflicts of interests pertinent to the abstract.

INNV-29. BILATERAL PARIETAL LYMPHOMA LESIONS RESPONDED DIFFERENTLY TO HD-MTX AND RITUXIMAB/TEMOZOLOMIDE THERAPY

Abstract INTRODUCTION Primary CNS lymphoma is a rare aggressive hematological malignancy. Current chemotherapy for induction phase is HD-MTX single agent or HD-MTX based combination regimen. We report a rare case whose left and right parietal lymphoma lesions in the brain responded to different induction therapy regimens during the induction phase. CASE REPORT A 43-year-old female presented with seizure and her brain MRI showed bilateral parietal brain lesions in January of 2020. Biopsy and work-up revealed primary CNS diffuse large B-cell lymphoma (DLBCL). The patient underwent HD-MTX therapy. Brain MRI showed clear progression of left parietal lymphoma but stable right parietal lymphoma after two cycles of HD-MTX at 8 g/m2. The treatment was switched to a rituximab 750 mg/m2 weekly and temozolomide 150 mg/m2 daily one-week-on and one-week-off regimen. After 8 weeks, her brain MRI showed nearly complete response of her left parietal lymphoma to rituximab/temozolomide but progression of her right parietal lymphoma. She was switched back to HD-MTX and completed total 8 cycles. Her right parietal lymphoma lesion showed complete response to HD-MTX. The patient is doing well and has been off the treatment over the past 10 months and is waiting for consolidation therapy with autologous stem cell transplantation that has been postponed due to the COVID pandemic. DISCUSSION Our case highlights the very rare heterogenous feature of primary CNS lymphoma responding to different treatment regimen. Biopsy of bilateral heterogeneous lesions may be indicated to compare the different molecular features of the lymphoma to find underlying mechanism if they respond to treatment differently. Specific treatment regimen should be selected based on the responsiveness of CNS lymphoma lesions or combination therapy is selected to cover the heterogeneous susceptibility to chemotherapy regimens.

SEVERE NONINFECTIOUS PNEUMONITIS ASSOCIATED WITH IBRUTINIB FOR DIFFUSE LARGE-B-CELL LYMPHOMA

TOPIC: Diffuse Lung Disease TYPE: Medical Student/Resident Case Reports INTRODUCTION: Ibrutinib is an oral Bruton's tyrosine kinase inhibitor that is indicated in treatment of certain lymphomas and is now being investigated for primary CNS diffuse large B-cell lymphoma (DLBCL). We present a case of severe non-infectious pneumonitis in a patient receiving ibrutinib for recurrent primary CNS DLBCL CASE PRESENTATION: A 51-year-old male with primary CNS DLBCL was treated with ibrutinib in a clinical trial after failure of first line and salvage therapies. Seven weeks after initiation of the drug, patient presented with dyspnea, tachypnea, tachycardia, and encephalopathy to the hospital. Shortly after admission, patient developed worsening hypoxia and encephalopathy requiring intubation and mechanical ventilation. Labs demonstrated mild anemia and elevated LDH without leukocytosis or thrombocytopenia. Blood cultures and nasopharyngeal PCR for SARS-CoV-2 were negative. CT chest showed non-specific upper lung predominant extensive bilateral ground glass opacities with patchy consolidation. Differential diagnosis included infectious and inflammatory etiologies. Bronchoalveolar lavage was negative for viral, mycobacterial, fungal or bacterial pathogens. Ibrutinib was discontinued and patient was treated with 60 mg intravenous methylprednisolone daily. Patient's was successfully extubated with resolving hypoxia. DISCUSSION: Common adverse effects from treatment with ibrutinib include diarrhea, hypertension, fatigue, infections, and atrial fibrillation. Although infectious pneumonias have been documented, only a few accounts of non-infectious pneumonitis have been reported in the extant medical literature. Both non-specific interstitial pneumonia and organizing pneumonia cases have been reported. Early recognition in appropriate clinical context, discontinuation of offending drug, and treatment with steroids is warranted. CONCLUSIONS: Patients on targeted therapy with Ibrutinib are at risk of developing severe hypoxic respiratory failure from non-infectious pneumonitis. Timely consideration, treatment with steroids and ventilatory support can help with recovery. REFERENCE #1: 1. Mato AR, Islam P, Daniel C, Strelec L, Kaye AH, Brooks S, et al. Ibrutinib-induced pneumonitis in patients with chronic lymphocytic leukemia. Blood. 2016;127(8):1064-7. REFERENCE #2: 2. Murthy V, Suh J, Bradshaw A-d, Sloance M. Ibrutinib-Induced Rapidly Progressive Inflammatory Pneumonitis. C51 TOXIC INGESTIONS AND EXPOSURES. p. A4584-A. REFERENCE #3: 3. Blackwell L, Cai D, Srinivas S, Lovoulos C, Kim J. Ibrutinib-Induced Organizing Pneumonia. CHEST. 2016;150(4):782A. DISCLOSURES: No relevant relationships by zainub ajmal, source=Web Response No relevant relationships by Gowthami Kobbari, source=Web Response No relevant relationships by Fatima Tuz Zahra, source=Web Response No relevant relationships by Gregory Wu, source=Web Response

GCB-type is a favorable prognostic factor in primary CNS diffuse large B-cell lymphomas

Primary CNS lymphomas (PCNSLs) are aggressive diffuse large B-cell lymphomas (DLBCLs) limited to the CNS that generally have a poor prognosis. Classification of DLBCL into germinal center B-cell (GCB) and activated B-cell (non-GCB) subtypes has prognostic value in systemic DLBCL, with GCB-type having a better prognosis. The aim of this study was to determine whether GCB versus non-GCB classification in PCNSLs has similar prognostic value. We analyzed clinical, radiological and histologic data from 24 patients with biopsy confirmed DLBCL of the CNS with classification into GCB versus non-GCB subtypes. We found that after a median follow-up of 15 months, only 39% of patients with non-GCB-type PCNS DLBCL were alive, whereas all patients with GCB-type were alive. Non-GCB-type had a median survival of 11 months, whereas all GCB-type patients were alive after a median follow-up of 22 months. As previously reported, we also found that patients younger than 70 years had longer survival (median 29 months) compared to older patients (median 8.8 months). There was no statistically significant difference between the ages, gender, focality, size or location of lesions, or treatment of non-GCB and GCB-type patients. Our findings suggest that classifying PCNSLs into GCB versus non-GCB subtype using the Hans algorithm may help stratify patients into two groups with different prognosis.

TMOD-34. PATIENT-DERIVED XENOGRAFT AND CELL LINE MODELS FACILITATE NOVEL TREATMENT DISCOVERY IN CENTRAL NERVOUS SYSTEM LYMPHOMAS

Abstract Lymphomas of the central nervous system (CNSL) are rare tumors with few treatment options; however, recent genomic studies have uncovered several druggable targets. To facilitate novel treatment discovery, we sought to establish patient-derived xenograft (PDX) models and cell lines from patients with newly diagnosed or recurrent CNSL. PDX models were attempted from fresh tumor samples from 18 consented patients for whom rich clinical annotation was available. Orthotopic intracranial injections were performed via stereotactic injection. Cell line generation was attempted from both primary tumors (PDCL) and PDX samples (PDXCL). Characterization included histopathology, targeted exome sequencing, low-pass whole-genome sequencing for copy number evaluation, and expression profiling of matched patient tumors and PDXs. Drug response testing was performed using CellTiterGlo. From 18 samples attempted, 8 PDX models were successfully generated: 2 primary CNS diffuse large B-cell lymphoma (DLBCL), 5 secondary CNS DLBCL, and 1 secondary cutaneous T-cell lymphoma (CTCL). Mean time to moribund was 66 days. All 8 PDXs grew successfully as orthotopic models, and 4 also grew in subrenal capsule. Additionally, 6 PDCL and 2 PDXCL were established (> P3). Models faithfully represented primaries, showing nearly identical histopathology, immunoprofiles, and genomic signatures. To support expanded and rapid preclinical use of these models in drug testing we documented that PDX could be explanted to create short-term cell preparations or long-term cell lines with a 100% and 40% success rate, respectively. Proof of principle testing showed that explanted DLBCL PDX cells and cell lines showed sensitivity to copanlisib and venetoclax, which were not efficacious in the CTCL PDX. These findings showcase a diverse collection of CNSL models demonstrating high fidelity to primary tumors at the genomic and phenotypic levels, emphasizing their utility for preclinical studies and as patient avatars to rapidly determine sensitivities to existing and novel regimens prior to initiation of therapy.

EPCO-38. PRIMARY CNS DIFFUSE LARGE B-CELL LYMPHOMA WITH CIC-REARRANGEMENT IDENTIFYING FROM PAN-CANCER PATIENTS EXCLUDING SARCOMAS

Abstract BACKGROUND CIC-rearrangements most commonly occur in patients with Ewing-like sarcomas, an emerging class of round cell sarcomas. CIC sarcoma has considered being a new entity in CNS tumors by cIMPACT-NOW conform classification of tumors of soft tissue and bone. However, not all patients harbor CIC fusion are sarcoma cases. Herein, we firstly report a case of primary CNS diffuse large B-cell lymphoma (DLBCL) harboring CIC-rearrangement with a novel partner. METHODS CIC fusions were screened in the tumor tissue or peripheral blood from 3,961 cases with different types of cancer excluded patients with sarcomas. Comprehensive genomic profiling with a 539 cancer-related genes panel was administrated based on next generation sequencing (NGS) which is adept in finding novel fusion mutations. The pathology diagnosis of every case was confirmed via hematoxylin and eosin (H&E) stained. RESULTS Among the whole 3,961 cases, 3 CIC-rearrangements were observed. One case has been reported yet, one was a patient with lung adenocarcinoma, the last one was a patient harboring POU2F2 (Exon5) -CIC (Exon 11) with CNS arisen tumor, primary DLBCL. Literature review revealed only CIC-LEUTX was reported not only in sarcomas, but also in anaplastic ganglioglioma and CNS embryonal tumors. The partners of CIC sarcomas included DUX4, NUTM1, NUTM2A, FOXO4 and LEUTX, and whether specific partner affected biology of CIC-rearrangement tumors. CONCLUSIONS CIC-rearrangement arises in another type of brain cancer besides glioma and embryonal tumor, primary CNS DLBCL. Observation of novel partner provides new basis for further study of biology function of them in CIC fusions. Our study also indicates the presence of a specific tumor type with distinct histopathology driven by CIC fusions can be classified via CIC molecular pathology.

Frequency of MYD88 and CD79B mutations, and MGMT methylation in primary central nervous system diffuse large B-cell lymphoma.

Primary CNS diffuse large B-cell lymphoma (PCNS-DLBCL) and systemic DLBCL harbor mutations in MYD88 and CD79B. DNA methyltransferase (MGMT) is methylated in some DLBCL. Our goal was to investigate the frequencies of these events, which have not been previously reported within the same series of patients with PCNS-DLBCL. Fifty-four cases of PCNS-DLBCL from two institutions were analyzed by Sanger sequencing for MYD88 and CD79B, and pyrosequencing for MGMT. MYD88 mutations were identified in 68.8% (35 of 51 cases), with L265P being the most frequent mutation. Mutations other than L265P were identified in 21.6% of cases, of which eight novel MYD88 mutations were identified. Of mutated cases, 17.6% had homozygous/hemizygous MYD88 mutations, which has not been previously reported in PCNS-DLBCL. CD79B mutations were found in six of 19 cases (31.6%), all in the Y196 mutation hotspot. MGMT methylation was observed in 37% (20 of 54 cases). There was no significant difference in median overall survival (OS) between the wild type and mutated MYD88 cases, or between methylated and unmethylated MGMT cases. However, a significant difference (P = 0.028) was noted in median OS between the wild type and mutated CD79B cases.

Relapse patterns in primary CNS diffuse large B-cell lymphoma (P3.147)

Relapse patterns in primary CNS diffuse large B-cell lymphoma (P3.147)

Findings at presentation in primary CNS diffuse large B-cell lymphoma of the brain: A comparison of immunocompetent and immunodeficient patients

Background/Objectives: Primary central nervous system lymphoma (PCNSL) is a rare tumour with poor prognosis. Due to the increased number of patients with PCNSL over the past two decades our purpose are to describe magnetic resonance imaging (MRI) and Computed Tomography (CT) findings in (PCNSL) of the brain, and to study the differences between immunocompetent and immunodeficient patients with PCNSL. Methods : A retrospective, descriptive study was performed with 59 patients diagnosed of PCNSL in two hospitals from 1997 to 2010. Immunocompetent (n=38) and immunodeficient (n=21) patients were compared and differences between both groups were analyzed. Patients were evaluated according to sex, age, median time from clinical symptoms presentation to pathologic diagnosis, clinical symptoms, location, number of lesions, size, MRI and CT characteristics. Significance was defined as p < 0.05. Results : MRI findings: 50% of lesions in immunocompetent and 52.4% in immunodeficient group were heterogeneous, 89.5% of lesions in immunocompetent and 85,7% in immunodeficient were hypo-isointense on T1WI; 63.2% of lesions in immunocompetent and 76.2% in immunodeficient group were hyperintense on T2WI. CT images: 48.39% of lesions in immunocompetent and 20% in immunodeficient group were hyperdense. Statistically significant differences between immunocompetent and immunodeficient patients were found when evaluating the age ( p < 0.000) and median time from clinical symptoms presentation to pathologic diagnosis ( p < 0.008). Conclusions: MRI and CT are able to define imaging characteristics of PCNSL, promoting a quick diagnosis. There are no significant differences between immunocompetent and immunodeficient patients for MR and CT features.

Primary CNS anaplastic diffuse large B-cell lymphoma mimicking undifferentiated metastatic tumors: a case report

Primary central nervous system lymphoma (PCNSL) is a rare intracranial tumor, with an annual incidence of six per million population. Anaplastic variant of primary CNS diffuse large B-cell lymphoma is less common; to our knowledge, there is only one other case report in the world literature. We describe a 71 year old immunocompetent female without significant past medical history who presented with confusion and a homogeneously enhancing midline mass. The patient underwent craniotomy for tumor biopsy, followed by high-dose methotrexate-based chemotherapy despite a remarkably low performance status. Histologically, this tumor was composed of undifferentiated polymorphic tumor cells, multi-nucleated giant cells, extensive necrosis, and conspicuous mitotic activity, mimicking undifferentiated metastatic tumors. Immunohistochemical stains demonstrated immunopositivity of tumor cells for CD20, MUM-1, and BCL-6, and negative staining for CD3, CD10, and CD30. The clinical course, diagnostic workup, pathologic correlates, and treatment outcomes are described.

Comparative clinicopathological study of primary CNS diffuse large B‐cell lymphoma and intravascular large B‐cell lymphoma

Primary CNS diffuse large B-cell lymphoma (CNS DLBCL) is confined to the CNS, and constitutes a distinct entity. In the present study a series of 40 Japanese patients with CNS DLBCL who presented with neurological, but not systemic symptoms, was reviewed. Median survival was 18.7 months. CD5, CD10, Bcl-6, MUM-1, and Bcl-2 were positive in 30%, 10%, 84%, 100%, and 93% of patients, respectively. All CD10-negative patients had non-germinal center B-cell type. There was no significant difference in survival among the immunophenotypic subgroups. CNS DLBCL appeared to be homogenous as a group, which prompted the comparison with another distinct extranodal entity, intravascular large B-cell lymphoma (IVLBCL) in Japanese patients. CNS DLBCL patients did not differ in age, sex, or immunophenotype, including CD5 positivity, from IVLBCL patients, but were significantly less likely to have poor prognostic parameters than IVLBCL patients: the international prognostic index score was low or low-intermediate in 86% of CNS DLBCL patients and high or high-intermediate in 98% of IVLBCL patients. Notably, despite this difference, their survival curves almost overlapped. The present study highlights the issue of clinical distinctiveness of aggressive extranodal lymphomas, the peculiar migration and localization of which should be further clarified.