Response to Comment on “Primary Central Nervous System (CNS) Lymphoma B Cell Receptors Recognize CNS Proteins”

Abstract INTRODUCTION: The pathobiology mediating the development of primary central nervous system lymphoma (PCNSL) and its exclusive manifestation in the brain and spinal cord is still poorly understood. The monoclonal B-cell receptor expressed in PCNSL cells have a germinal center typology, suggesting previous antigen contact and antigen-based selection during B-cell development. Furthermore, sequence analysis of B-cell receptors in various patients revealed a bias in the immunoglobulin repertoire in PCNSL, potentially indicating that distinct epitopes might elicit such an immune response. Nevertheless, the nature of potential antigens containing such epitopes is unknown. Here, we provide the first evidence that such antigens may be located within the central nervous system itself, which might contribute to the specific organ tropism of PCNSL. METHODS: Cryopreserved tissue of five randomly chosen PCNSL cases and three control cases with mantle cell lymphoma were used for this study. The variable heavy and light chains of the B-cell receptors were amplified from extracted RNA and cloned in IgG1 expression vectors. Recombinant B-cell receptors were expressed and purified as soluble human immunoglobulins. To explore the potential recognition of central nervous system antigens, murine cryo- and paraffin-embedded brain tissue sections were immunostained using these PCNSL or mantle cell lymphoma-derived immunoglobulins as primary antibodies. RESULTS: Four out of five recombinant B-cell receptors from PCNSL but none of the MCL-derived control immunoglobulins recognized distinct anatomical structures in the brain which resulted in unambiguous immunostaining especially in regions with high neuronal density. The staining of brain tissue was associated with neuronal cells in all four positive cases. Staining was stronger in the cerebellum and the hippocampus compared to other areas of the brain and staining intensity varied broadly among the four positive cases. In the cerebellum, all four positive B-cell receptors recognized the cytoplasm of Purkinje cells, the largest neurons in the brain (therefore, staining could be readily identified). Two of the B-cell receptors also recognized the Purkinje cell’s dendrites. Three of the PCNSL-derived immunoglobulins also stained the granule cells, the most frequent neuronal cell type in the brain. Two of those stained in the cytoplasm and one showed a patchy but strong staining pattern in the nucleus of these cells. All of these stainings including negative controls were reproduced multiple times in independent experiments. CONCLUSION: B-cell receptors of primary central nervous system lymphomas recognize neuronal structures in the brain in an individually case-dependent pattern. This might point towards an important role of antigen recognition in the pathobiology and specific organ tropism of this lymphoma. Disclosures No relevant conflicts of interest to declare.

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A Phase II Trial of Nivolumab and Ibrutinib for Patients with Relapsed or Refractory Central Nervous System Lymphoma

Blood ◽

10.1182/blood-2019-131463 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4086-4086

Author(s):

Jason R. Westin ◽

Nathan H. Fowler ◽

Loretta J. Nastoupil ◽

Sattva S Neelapu ◽

Hun Ju Lee ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Response Rate ◽

Single Agent ◽

Advisory Board ◽

Cns Lymphoma ◽

Advisory Committees

Background: Central Nervous System (CNS) lymphoma is a rare and distinct subtype of diffuse large B-cell lymphoma (DLBCL). CNS lymphoma has a unique genomic profile which has similarities to the activated B-cell (ABC) subtype of DLBCL, which may speak to potential targets for therapy. These aberrancies include near uniform reliance on Toll-Like Receptor signaling, mutations of MYD88, and frequent translocation or copy number alterations of 9p24 which codes for programmed death receptor ligand 1 (PD-L1). Mutations of MYD88 may predict for response to Bruton's tyrosine kinase (BTK) inhibitors in patients with systemic DLBCL. Expression of PD1 or PD-L1, which corresponds to response with PD-targeted therapy in solid tumors, has been found on up to 90% of CNS lymphoma cases, and 60% of specimens had tumor infiltrating lymphocytes which were PD1+ (Berghoff, Clin Neuropath 2014). In addition, the majority of CNS lymphoma cases have a copy gain of 9p24.1, associated with increased expression of PD-L1 (Chapuy, Blood 2016). This suggests a potential ongoing immune reaction against CNS lymphoma, but the microenvironment and tumor conspire to render the immune response ineffective. Ibrutinib is a BTK inhibitor which is FDA approved for multiple B-cell malignancies and is known to achieve therapeutic concentration in the cerebral spinal fluid (CSF), with activity in CNS lymphoma as a single agent and in combination with other agents. Nivolumab is a PD1 inhibitor which is FDA approved for multiple malignancies, with impressive anecdotal evidence of single agent activity in CNS lymphoma. Ibrutinib and nivolumab have been combined in other studies with modest toxicities. Study Design and Methods: We are conducting a phase II, open label, single center clinical trial combining ibrutinib with nivolumab to treat patients with relapsed CNS lymphoma (NCT03770416). Patients are eligible if they have CNS lymphoma relapsed after or were refractory to at least 1 prior line of therapy with adequate organ and bone marrow function, are aged 18y or greater, have not received prior ibrutinib or PD1 inhibitor, and do not require persistent high dose steroids. The trial has two cohorts which will be sequentially enrolled. Cohort A begins with ibrutinib 560mg oral daily for a single 28-day cycle, followed by ibrutinib combined with nivolumab 240mg IV every 14 days. Cohort B begins with the ibrutinib and nivolumab combination during the first cycle. Patients who have at least a partial response at the conclusion of the planned 6 cycles of combined ibrutinib and nivolumab may continue therapy for up to 2 years total or until progression of disease or unacceptable toxicity occurs. Neurocognitive assays and patient reported outcome instruments are being utilized. The primary objective is to determine the best overall response rate during the first 24 weeks of therapy. Secondary objectives will include the response rate of ibrutinib as a lead in prior to the combination, the complete response rate, landmark survival outcomes, and the safety of the combination. Exploratory analyses include assays of the blood and CSF for ctDNA and immune profiling. The first patient was treated in February 2019, with a planned total of 40 patients to be enrolled. Disclosures Westin: MorphoSys: Other: Advisory Board; Juno: Other: Advisory Board; Novartis: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board, Research Funding; 47 Inc: Research Funding; Genentech: Other: Advisory Board, Research Funding; Curis: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding; Unum: Research Funding. Fowler:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Nastoupil:TG Therapeutics: Honoraria, Research Funding; Novartis: Honoraria; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Celgene: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding; Spectrum: Honoraria; Bayer: Honoraria. Neelapu:Allogene: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Novartis: Consultancy; Karus: Research Funding; Celgene: Consultancy, Research Funding; Precision Biosciences: Consultancy; Cell Medica: Consultancy; Incyte: Consultancy; Acerta: Research Funding; Unum Therapeutics: Consultancy, Research Funding; Pfizer: Consultancy; BMS: Research Funding; Poseida: Research Funding; Merck: Consultancy, Research Funding; Cellectis: Research Funding. Parmar:Cellenkos Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: ibrutinib and nivolumab are not yet indicated for CNS lymphoma

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Molecular Subtypes and Genomic Profile of Primary Central Nervous System Lymphoma

Journal of Neuropathology & Experimental Neurology ◽

10.1093/jnen/nlz125 ◽

2019 ◽

Vol 79 (2) ◽

pp. 176-183

Author(s):

Csaba Bödör ◽

Donát Alpár ◽

Dóra Marosvári ◽

Bence Galik ◽

Hajnalka Rajnai ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

B Cell ◽

Target Genes ◽

Molecular Subtypes ◽

Molecular Subtype ◽

Central Nervous System Lymphoma ◽

Diagnostic Algorithm ◽

Molecular Classification ◽

Cns Lymphoma

Abstract Primary central nervous system lymphomas (PCNSL) are aggressive non-Hodgkin lymphomas affecting the central nervous system (CNS). Although immunophenotyping studies suggested an uniform activated B-cell (ABC) origin, more recently a spectrum of ABC and germinal center B-cell (GC) cases has been proposed, with the molecular subtypes of PCNSL still being a matter of debate. With the emergence of novel therapies demonstrating different efficacy between the ABC and GC patient groups, precise assignment of molecular subtype is becoming indispensable. To determine the molecular subtype of 77 PCNSL and 17 secondary CNS lymphoma patients, we used the NanoString Lymphoma Subtyping Test (LST), a gene expression-based assay representing a more accurate technique of subtyping compared with standard immunohistochemical (IHC) algorithms. Mutational landscapes of 14 target genes were determined using ultra-deep next-generation sequencing. Using the LST-assay, a significantly lower proportion (80% vs 95%) of PCNSL cases displayed ABC phenotype compared with the IHC-based characterization. The most frequently mutated genes included MYD88, PIM1, and KMT2D. In summary, we successfully applied the LST-assay for molecular classification of PCNSL, reporting higher proportion of cases with GC phenotype compared with IHC analyses, leading to a more precise patient stratification potentially applicable in the diagnostic algorithm of PCNSL.

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

Blood ◽

10.1182/blood-2018-99-119741 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4208-4208

Author(s):

Sangeetha Gandhi ◽

Grzegorz S. Nowakowski ◽

Thomas M. Habermann ◽

Kay M. Ristow ◽

Patrick Johnston

Keyword(s):

Central Nervous System ◽

Nervous System ◽

B Cell ◽

Cell Lymphoma ◽

Performance Status ◽

Central Nervous System Lymphoma ◽

Cns Lymphoma ◽

Ecog Performance Status ◽

Kaplan Meier ◽

Large B Cell

Abstract 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. Disclosures No relevant conflicts of interest to declare.

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ML-11 DETECTION OF MYD88 MUTATIONS FROM CELL FREE DNA AIDS IN THE DIAGNOSIS OF CENTRAL NERVOUS SYSTEM LYMPHOMAS

Neuro-Oncology Advances ◽

10.1093/noajnl/vdz039.153 ◽

2019 ◽

Vol 1 (Supplement_2) ◽

pp. ii34-ii34

Author(s):

Manabu Natsumeda ◽

Jun Watanabe ◽

Yu Kanemaru ◽

Yoshihiro Tsukamoto ◽

Masayasu Okada ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Pcr Analysis ◽

Cns Lymphoma ◽

Precision Oncology ◽

Cell Free Dna ◽

Free Dna

Abstract BACKGROUND Diagnosis of primary central nervous system lymphomas (PCNSL) can be challenging. We have shown that the detection of MYD88 mutation in cell free DNA (cfDNA) taken from cerebrospinal fluid (CSF) is reliable (JCO Precision Oncology, 2019; Leukemia and Lymphoma, 2019). We report four cases in which detection of MYD88 mutation aided in the diagnosis. CASE 1 A 67-year-old man with a history of systemic B-cell lymphoma, experienced right hemiparesis. MRI showed a slightly enhancing lesion located in the midbrain. MYD88 L265P mutation was found by digital droplet PCR analysis of cfDNA extracted from CSF. The patient underwent a needle biopsy, and was diagnosed as diffuse large B-cell lymphoma. CASE 2 A 32-year-old man was diagnosed as having a demyelinating lesion after experiencing severe headaches. A small enhancing lesion was found in the right frontal lobe, and the patient was treated with steroids. The lesions repeatedly disappeared and reappeared and finally, stopped responding to steroids. MYD88 mutation was detected. A biopsy was performed, and the diagnosis was PCNSL. CASE 3 A 49-year-old man underwent a biopsy for a right frontal lesion after experiencing memory loss; the pathology showed broad T-cell infiltration but only some perivascular B-cells with slight atypia. The patient was tapered off steroids, and the lesion spread rapidly. An open biopsy was performed, but the pathology was not typical for B-cell lymphoma. The patient’s symptoms rapidly worsened, and whole brain irradiation was performed. At recurrence, MYD88 mutation was detected. CASE 4 An 82-year-old man presented with blurred vision. Vitreous humor biopsy was inconclusive for ocular lymphoma. A head MRI showed an intracranial lesion which spontaneously regressed. MYD88 was detected, and the patient is being closely observed. CONCLUSION Detection of MYD88 mutation from cfDNA extracted from CSF can aid in the diagnosis of CNS lymphoma, especially in atypical cases.

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Review for "Templated Insertions at VD and DJ junctions Create Unique B‐Cell Receptors in the Healthy B‐Cell Repertoire"

10.1002/eji.202048828/v1/review2 ◽

2018 ◽

Keyword(s):

B Cell ◽

B Cell Receptors ◽

Cell Repertoire ◽

Cell Receptors ◽

B Cell Repertoire

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Evaluating Optical Coherence Tomography (OCT) Findings as Potential Biomarkers in Central Nervous System (CNS) Lymphoma with or Without Ocular Involvement

SSRN Electronic Journal ◽

10.2139/ssrn.3310621 ◽

2019 ◽

Author(s):

Muhammad Hassan ◽

Muhammad Sohail Halim ◽

Arash Maliki ◽

Rubbia Afridi ◽

Nam V. Nguyen ◽

...

Keyword(s):

Central Nervous System ◽

Optical Coherence Tomography ◽

Nervous System ◽

Cns Lymphoma ◽

Ocular Involvement ◽

Optical Coherence ◽

Potential Biomarkers

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Targeting the PI3K/AKT/mTOR Signaling Pathway in Primary Central Nervous System Lymphoma: Current Status and Future Prospects

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527319666200517112252 ◽

2020 ◽

Vol 19 (3) ◽

pp. 165-173

Author(s):

Xiaowei Zhang ◽

Yuanbo Liu

Keyword(s):

Central Nervous System ◽

Nervous System ◽

B Cell ◽

Signaling Pathway ◽

Central Nervous System Lymphoma ◽

B Cell Lymphoma ◽

Mtor Signaling ◽

Mtor Signaling Pathway ◽

Antitumor Effects ◽

Term Survival

Primary Central Nervous System Lymphoma (PCNSL) is a rare invasive extranodal non- Hodgkin lymphoma, a vast majority of which is Diffuse Large B-Cell Lymphoma (DLBCL). Although high-dose methotrexate-based immunochemotherapy achieves a high remission rate, the risk of relapse and related death remains a crucial obstruction to long-term survival. Novel agents for the treatment of lymphatic malignancies have significantly broadened the horizons of therapeutic options for PCNSL. The PI3K/AKT/mTOR signaling pathway is one of the most important pathways for Bcell malignancy growth and survival. Novel therapies that target key components of this pathway have shown antitumor effects in many B-cell malignancies, including DLBCL. This review will discuss the aberrant status of the PI3K/AKT/mTOR signaling pathways in PCNSL and the application prospects of inhibitors in hopes of providing alternative clinical therapeutic strategies and improving prognosis.

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