Secondary Lymphoma Research Articles

CAR T-cell therapy in large B cell lymphoma.

CD19-targeted chimeric antigen receptor (CAR) T-cells have revolutionized the treatment of lymphoid malignancies, including large B cell lymphoma (LBCL). Following seminal early phase multicenter clinical trials published between 2017 and 2020, three CD19-CAR T-cell products received FDA and EMA approval designations in lymphoma in the third-line setting, paving the way for follow-up studies in the second-line. Meanwhile, investigations into the applications of CAR T-cell therapy have further broadened to treating high-risk patients even prior to completion of first-line conventional chemo-immunotherapy. Furthermore, as early trials excluded patients with central nervous system involvement with lymphoma, several studies have recently shown promising efficacy of CD19-CAR T-cells in primary and secondary CNS lymphoma. Here we provide a detailed overview on clinical data supporting the use of CAR T-cells in patients withLBCL.

Neurotoxicity in patients with CNS lymphomas treated with CAR‐T cell therapy. A LOC network study

Introduction: CAR-T cell therapy represents one of the major progress of the last years in aggressive B-cell lymphomas. Its use in central nervous system (CNS) lymphomas has been limited due to the fear of neurotoxicity but several recent studies have showed promising efficacy in this setting. The aim of this study was to focus on neurotoxicity in CNS lymphoma patients treated with CAR-T cells. Methods: Patients with isolated CNS relapse of DLBCL treated with commercial CAR-T cells at Pitié-Salpêtrière hospital were retrospectively selected. We considered only neurological deterioration for which other causes than CAR-T cell toxicity had been reasonably ruled out. Results: Thirty patients (median age: 65, 17 women, 19 primary, 11 secondary CNS lymphomas, median of 3 previous lines) received CAR-T cells (Tisa-cel: N = 23, axi-cel, N = 7) between May 2020 and December 2022. At the time of CAR-T, 15 (50%) had stable or progressive disease, median Karnofsky Performance Status (KPS) was 70, median Montreal Cognitive Assessment (MoCA) score was 22 and median immune effector cell-associated encephalopathy (ICE) score was 10. Twelve (40%) patients didn’t experience any neurotoxicity after CAR-T, whereas 9 (30%), 3 (10%), 2 (7%), 4 (13%) patients experienced grade 1, 2, 3 or 4 toxicity according to ASTCT classification. The signs of neurotoxicity began at a median of 5 days after CAR-T. The most common symptoms were cognitive disorders (N = 18), motor deficit (N = 4), balance disorders (N = 8), consciousness disorders (N = 5), seizures (N = 3) and movement disorders (N = 3). Among cognitive symptoms, there was predominantly a worsening of pre-existing symptoms regarding memory impairment (12/15 patients) or dysexecutive syndrome (11/13), while dysgraphia or dyscalculia were most frequently new symptoms (in 14/15 and 7/11 patients). Brain MRI showed pseudo-progression in 4 cases. On lumbar puncture, median IL-6 level and median cellularity were higher in patients with grade 2 to 4 neurotoxicity compared to other patients (243 vs. 41 pg/ml, 15 vs. 3 cells/mm3). We found no association between risk of neurotoxicity and age, gender, pre-CART KPS, MoCA or ICE score, primary vs. secondary CNS lymphoma or type of CAR-T. Twelve patients (40%) received steroids, for a median of 10 days, leading to an improvement in a median of 5 days; one received anakinra. Median duration with neurological impairment was 13 days, but was >3 months in 3 patients, including one who finally died from neurotoxicity. Conclusions: The majority of CNS lymphoma patients didn’t experience severe neurotoxicity following CAR-T cells, so that this treatment shouldn’t be contraindicated in this population. However, the percentage of severe and prolonged neurotoxicity is probably higher than in systemic lymphomas and a close neurological follow-up is warranted in these complex situations. Further studies are needed to better predict severe neurotoxicity. Keyword: Cellular therapies Conflicts of interests pertinent to the abstract. S. Choquet Consultant or advisory role: Kite-Gilead, Novartis

Outcomes of stereotactic radiosurgery in central nervous system lymphoma: A single institution experience.

e14061 Background: Primary or systemic high-grade B-cell lymphoma with secondary central nervous system lymphoma (PCNSL or SCNSL) are currently treated with high-dose methotrexate (HD-MTx) based chemo-immunotherapy regimens with/without whole brain radiation therapy (WBRT). CNS relapse can occur in up to 50% of patients with PCNSL or SCNSL. WBRT has been used as a salvage therapy for those patients. However, long-term neurological toxicities significantly reduce its clinical benefit. Stereotactic radiosurgery (SRS) is the administration of a localized, high dose of ionizing radiation. Limited studies exist exploring SRS as a treatment modality in relapsed/refractory (r/r) PCNSL/SCNSL. Methods: We conducted a retrospective single-center study evaluating the clinical efficacy of SRS in r/r PCNSL/SCNSL. Demographic, clinical, pathological, and treatment characteristics were collected in 29 r/r PCNSL (N=17)/SCNSL (N=12) patients, age ≥ 18 years, who received SRS between 01/2000 and 01/2023. Progression-free survival (PFS) and overall survival (OS) were calculated and reported using Kaplan-Meier analyses and log-rank tests. Results: Baseline characteristics are summarized (Table). The median Karnofsky performance status and Charlson comorbidity index were 70 and 5 respectively. For patients with PCNSL (N=17), the most common prior chemotherapy regimen administered was rituximab (R) in combination with the DeAngelis regimen (N=12), followed by the MATRIX regimen (N=3). In patients with SCNSL, the most common systemic chemotherapy regimen used was R + CHOP (N=9). Few patients received temozolomide (N=2). 5/29 (17%) of patients received WBRT before SRS. The overall response rate (ORR) to SRS in r/r PCNSL was 60% (7 CR and 2 PR). The ORR in r/r SCNSL was 83% (7 CR and 3 PR). The median OS of the overall cohort was 7.0 months (95% CI 5.1-8.9), while the median PFS was 5.0 months (95% CI 1.2-8.7). For patients with PCNSL, the median OS was 10.0 months (95% CI 2.2-17.7), and only 7 months (95% CI 1.8-12.1) for patients with SCNSL. Prior WBRT was associated with worse survival outcomes. Of interest, WBRT was avoided in 24/24 patients (100%). Conclusions: Our data support that CNSL patients can benefit from SRS therapy, with acceptable OS and PFS. In addition, the disease control spared patients from WBRT and therefore, mitigated neurological complications associated with that modality. [Table: see text]

Radiotherapy as an effective bridge for chemo‐refractory or progressive secondary CNS lymphoma

Radiotherapy as an effective bridge for chemo‐refractory or progressive secondary CNS lymphoma

SALVAGE TREATMENTS FOR RELAPSED/REFRACTORY SECONDARY CNS LYMPHOMA IN THE CAR T ERA: A REAL‐WORLD COMPARISON

Introduction: Secondary central nervous system lymphoma (SCNSL) is a rare and aggressive subtype of non-Hodgkin lymphoma that involves the neuraxis. Patients with refractory or relapsed (r/r) disease have limited treatment options and poor outcomes. Chimeric antigen receptor T-cell therapy (CAR T) has shown promise in clinical trials but lacks mature data in the r/r SCNSL setting. In this retrospective, real-world review, we evaluated salvage treatment patterns and survival outcomes of patients with r/r SCNSL, comparing historic regimens to CAR T. Methods: We retrospectively reviewed medical records of SCNSL patients treated at our institution between 2008 and 2022. Patients were included if they had r/r disease and received salvage treatment. Progression-free (PFS) and overall survival (OS) from initiation of first salvage therapy were calculated using the Kaplan-Meier method. Results: We identified 28 r/r SCNSL patients, 11 with de novo CNS disease and 17 with CNS relapse. Initial treatments were based on intrathecal or high-dose methotrexate. Six patients underwent consolidative autologous stem cell transplant. Upon relapse, 7 patients received supportive care with steroids only with rapid disease progression and death within one month. The remaining 21 patients had a median age of 60 years (range, 34-77 years) and median Karnofsky performance status of 80. The most common histological subtype was diffuse large B-cell lymphoma (DLBCL) (n=19, 90%). CNS disease was mostly parenchymal (52%), followed by spinal cord (29%) and leptomeningeal (19%) involvement. Salvage regimens included combinations of radiation (RT, n = 14), immunologic, targeted and chemotherapies [(rituximab, ibrutinib, polatuzumab; n = 15), methotrexate (n = 11), temozolomide (n = 8)], and CAR T (n = 7). The overall response rate was 67% for initial salvage therapy, with 9 patients having a sustained response. Median OS was 23 months and median PFS was 10 months. Seven patients who underwent salvage anti-CD19 CAR T had improved PFS and OS compared to other salvage regimens (p = 0.0014, Figure 1). Four of these patients received bridging therapy, either with RT (n = 2) or chemo-immunotherapy (n = 2). The majority (6/7) remain alive, and 4/7 patients remain in complete remission past 1.5 years. 6/7 patients had grade 1-2 CRS and 4/7 had grade 2-3 ICANS that was successfully managed per institutional guidelines. Median OS for other salvage regimens was 6.2 months. The addition of radiation to systemic therapy trended to improve OS. Keywords: Aggressive B-cell non-Hodgkin lymphoma, Cellular therapies, Extranodal non-Hodgkin lymphoma This research was supported by the American Society of Hematology (ASH) HONORS Award. Conflicts of interests pertinent to the abstract G. Kaur Consultant or advisory role: SANOFI, BMS, Janssen, Cellectar, Arcellx Y. F. Madanat Consultant or advisory role: Sierra Oncology, Stemline Therapeutics, Blueprint Medicines, Morphosys, Taiho Oncology and Novartis. Honoraria: BluePrint Medicines, GERON, OncLive, and MD Education Travel grants: Blueprint Medicines and Morphosys P. Ramakrishnan Geethakumari Consultant or advisory role: PRG has provided consultancy services to Kite Pharma, Bristol Myers Squibb and Rafael Pharma and served on the advisory boards of Pharmacyclics LLC, ADC Therapeutics, Cellectar Biosciences and Ono Pharma.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: The prognosis of patients (pts) with diffuse large B-cell lymphoma (DLBCL) and involvement of the central nervous system (CNS) remains dismal. Anti-CD19 chimeric antigen receptor T-cells (CART) are considered standard treatment for pts with refractory or relapsed (r/r) DLBCL. Pts with involvement of the CNS were excluded from most CART trials; however, anecdotal reports suggest that CART might be an effective treatment option for such pts. This EBMT registry study aimed at compiling data of a larger cohort of pts with primary (PCNSL) or secondary CNS lymphoma (SCNCL) to better define the role of CART in these settings. Methods: All centres contributing to the EBMT database were asked for consecutive cases of PCNSL and SCNSL, which had been treated with any type of CART between January 2018 and December 2021. Reported pts were identified in the database and analysed for major patient characteristics, pre-treatment aspects, and major clinical endpoints. Kaplan Meier estimates were used to calculate overall survival (OS) and progression-free survival (PFS), whereas cumulative incidence was used for relapse incidence (RI), and non-relapse mortality (NRM). Results: 74 pts with PCNSL (n = 10) or SCNSL (n = 64) and complete information on major endpoints after CART and a median follow-up of 20.2 months [CI: 13.25–23.5] were analysed. Median age was 61.6 years (range 31–80), 31 pts were female. 37 of 57 pts (64.9%) had three or more prior treatment lines, 36.5% of pts had undergone autologous hematopoietic cell transplantation. 14 of 70 pts (20%) had ECOG ≥2. Disease-status at CART was complete (CR) or partial remission (PR) for 31.5% (6.8% and 24.7%, respectively) of pts, 68.5% of pts were in relapse, refractory, or had progressive disease. For one patient information on disease status was missing. 40 pts received axicabtagene ciloleucel (Yescarta®), 34 pts were treated with tisagenlecleucel (Kymriah®). OS- and PFS-rates at 12 months were 51.1% [CI: 40.2–64.8] and 33.7% [CI: 24.3–46.7] for the whole cohort. RI at 12 months was 59.4% [CI: 46.9–69.8]. NRM was 7% [CI: 2.5–14.5]. OS and PFS for pts in CR/PR were 53.0% [CI: 35.5–79.3] and 42.1% [CI: 25.9–68.7]. For the refractory cohort OS and PFS were 51.7% [CI: 38.7–69.0] and 30.6% [CI: 19.9–46.9], respectively. Conclusion: With a 51% OS-rate at 12 months CART seem to be a very effective therapeutic option in heavily pre-treated r/r PCNSL or SCNSL, particularly for pts being refractory to prior therapy. These results compare favourably with those of conventional treatment (including a minority of pts treated with autoSCT) in SCNSL with a median overall survival of 3.5 months (Schmitz et al., 2016) and 12-months OS-rate of 20% (Thieblemont et al., 2023). Pts with CNS involvement and r/r LBCL should be considered for treatment with CART. The research was funded by: Lymphoma Working Party of the EBMT GoCART coalition Keywords: Aggressive B-cell non-Hodgkin lymphoma, Cellular therapies Conflicts of interests pertinent to the abstract. S. Fuhrmann Consultant or advisory role: KiteGilead, BMS Celgene, Janssen D. Beauvais Honoraria: Merck & Co N. Kröger Consultant or advisory role: Takeda Honoraria: Takeda, Sanofi, Kite, Neovii, Amgen, BMS, Novartis, Jazz Research funding: Neovii, Riemser, DKMS, BMS, Novartis M. Stelljes Consultant or advisory role: MSD, Amgen, Novartis, Pfizer, Jazz, BMS, Kite Honoraria: MSD, Medac, Novartis, Pfizer, Jazz, BMS, Kite Research funding: Pfizer B. von Tresckow Consultant or advisory role: Allogene, BMS/Celgene, Cerus, Incyte, IQVIA, Gilead Kite, Miltenyi, Novartis, Noscendo, Pentixapharm, Roche, Amgen, Pfizer, Takeda, Merck Sharp & Dohme, Gilead Kite Honoraria: AstraZeneca, BMS, Incyte, Novartis, Roche Pharma AG, Takeda, Merck Sharp & Dohme Research funding: Novartis, Merck Sharp & Dohme, Takeda Educational grants: AbbVie, AstraZeneca, Gilead Kite, Merck Sharp & Dohme, Roche, Takeda, and Novartis P. Dreger Honoraria: Novartis, Kite, BMS, Miltenyi A. Sureda Consultant or advisory role: Takeda, BMS/Celgene, Novartis, Janssen, Gilead, Sanofi Honoraria: Takeda, BMS/Celgene, MSD, Janssen, Amgen, Novartis, Gilead, Kite, Sanofi, Roche, Alexion Research funding: Takeda, BMS/Celgene Other remuneration: Speaker’s bureau: Takeda, Non-profit organisations: Presidency of the GETH-TC, Presidency of the EBMT N. Schmitz Stock ownership: BMS Honoraria: Allogene Research funding: Astra Zeneca, Janssen, Roche Educational grants: Allogene, Miltenyi B. Glaß Honoraria: Novartis, JAZZ, Gilead, BMS, Roche, Abbvie, Miltenyi Research funding: Riemser, Roche

CLinicopathological characteristics of extranodal marginal zone B‐cell lymphoma of the intestine: a single center analysis

Extranodal marginal zone B-cell lymphoma of the mucosa associated lymphoid tissue (MALT-lymphoma) is mot commonly diagnosed in the stomach (30%–35%), but is exceedingly rare in the intestinal tract (2%). Consequently, data on this special subgroup are scarce. Out of 484 patients with MALt-lymphoma diagnosed and treated at our institution from 1999 to 2020, 42 (11%) had intestinal involvement (24 primary and 18 secondary) and were restrospectively analyzed. Out of 18 patients rated as secondary intestinal invlevement, 14 patients had gastric MALT-lymphoma as the primary origin. Median age at diagnosis was 67 years (interquartile range (IQR) 53–72) and the median follow-up time was 47 months (IQR 32–102). Patients presenting with lymphoma-associated symptoms were significantly more common in the group of primary versus secondary intestinal MALT lymphomas (52% vs. 20%, p = .047). Nine patients each, i.e. 9/18 secondary and 9/24 primary intestinal MALT lymphomas were found positive for Helicobacter pylori. Intestinal organs involved included the colon (n = 19), duodenum (n = 11), small intestine (n = 8) and rectum (n = 5). MALT-IPI could be calculated for 39 patients, with low MALT-IPI documented in 37/39 cases. Seven patients were found to be positive for translocation t(11;18)(q21;q21), 6 of whom had primary gastric MALT lymphoma, suggesting the presence of the translocation as highly suggestive for secondary involvement. Treatment data were available in 41 our of those 42 patients. Eleven patients (27%) received local therapy (ten surgery, and one radiotherapy, complete response rate 90%), 16 (38%) systemic therapy (overall response rate 87%) and 9 (22%) had only antibiotic therapy (complete response rate 38%). in 4/41 patients, only watchfuil waiting was applied. Eighteen patients progressed during follow-up; the median progression free survival following first line therapy was 50 mos (CI: 38.4–53.7 mos), with anumerical trend towards longer PFS in primary (134 mos) versus secondary MALT lmyphoma (35.5 mos). The estimated overall survival was 301 months, with 6 patients having died during follow up (two from lymphoma progression, the other 4 from unrelated conditions). A comparison in terms of PFS and Os with the cohort of 144 patients with gastric MALT-lmyphoma showed no significant difference in terms of outcome. Overall, patients with intestinal MALT-lymphoma appear to have a good prognosis irrespcetive of primary or secondary involvement, whichbappears to be comparable to our data obtined in gastric MALT-lymphoma. Keyword: Extranodal non-Hodgkin lymphoma No conflicts of interests pertinent to the abstract.

Spontaneous regression of secondary vitreoretinal lymphoma after diagnostic vitrectomy: case report

PurposeOur purpose is to report a patient with secondary intraocular mucosa-associated lymphoid tissue (MALT) who experienced spontaneous regression after diagnostic vitrectomy.MethodsWe retrospectively reviewed the clinical and imaging features of the case. Multimodal imaging, including fundus photograph, optical coherence tomography, fundus fluorescein angiography and ultrasound scan was presented.ResultsA 71-year-old female presented with a subretinal lesion temporal to macula and scattered multifocal creamy lesions deep to retina in her left eye. Optical coherence tomography of the left eye showed multifocal nodular hyper-reflective signals between the Bruch’s membrane and RPE. She had a history of gastric MALT lymphoma. Diagnostic vitrectomy was performed. IL-10 level of aqueous was 187.7pg/ml. Cytology, gene rearrangement and flow cytometry of the vitreous were inconclusive. Systemic evaluation was normal. Secondary vitreoretinal MALT lymphoma was considered. Interestingly, her subretinal lesions regressed gradually without any chemotherapy. And IL-10 level of aqueous declined to 64.3pg/ml.ConclusionsSecondary vitreoretinal MALT lymphoma is extremely rare. Spontaneous regression of intraocular lymphoma does occur.

CNS Aspergillosis Following BTK Inhibitors Mimicking Secondary CNS Lymphoma – A Case Series (P14-13.004)

<h3>Objective:</h3> NA <h3>Background:</h3> BTK inhibitors are commonly used in malignant B-cell lymphomas but can be associated with fungal infections, in part driven by altered platelet functions that diminish anti-fungal immune mechanisms. We describe four unique patients treated for B-cell malignancies (B-cell lymphoma, CLL, mantle cell lymphoma, and Waldenstrom’s disease) with progressive neurological deficits initially thought to represent secondary CNS lymphoma but on further diagnostic workup identified as CNS Aspergillosis. <h3>Design/Methods:</h3> Retrospective review of patients managed for B-cell hematological malignancies with BTK inhibitors associated with CNS Aspergillosis. <h3>Results:</h3> Four male patients (age 61–74) were treated with ibrutinib or zanubrutinib at a dose ranging from 160–560 mg daily (range 3–12 months) when developing new neurological symptoms and imaging findings were suggestive of recurrent lymphoma with CNS involvement. However, subsequent brain biopsies revealed invasive cerebral Aspergillosis in all cases with pulmonary involvement in three out of the four cases. Symptom presentation included headache and seizures (n=4), paresthesias (n=1) and expressive aphasia (n=1). Initial anti-fungal treatment consisted of voriconazole at a dose of 200–500 mg twice daily and subsequently posaconazole in three out of four patients. Additionally, three patients underwent surgical resection. Two patients remained stable without fungal disease progression for more than a year. One patient stopped taking voriconazole after 6 months due to side effects (decreased appetite, fatigue, lethargy, weight loss, and night sweats) and was eventually lost to follow-up. One patient had recurrent Aspergillosis and passed away following antifungal treatment for over two years. <h3>Conclusions:</h3> BTK inhibitors can be associated with fungal infections, including CNS involvement. These four cases illustrate the challenge in establishing a correct diagnosis and highlight the importance of considering atypical and fungal infections in individuals treated with BTK inhibitors. <b>Disclosure:</b> Ms. Murthy has nothing to disclose. The institution of Dr. Martinez-Lage has received research support from NIH. Jeremy Abramson has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Bristol-Myers Squibb. Jeremy Abramson has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Kite Pharma. Dr. Branagan has nothing to disclose. Dr. Ji has nothing to disclose. Yi-Bin Chen, 13609 has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Incyte. Yi-Bin Chen, 13609 has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Daiichi. Yi-Bin Chen, 13609 has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Abbvie. Yi-Bin Chen, 13609 has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Equilium. Yi-Bin Chen, 13609 has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Actinium. Yi-Bin Chen, 13609 has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Celularity. Dr. Letourneau has received research support from World Health Information Science Consultants, LLC. Dr. Letourneau has received publishing royalties from a publication relating to health care. Brian Nahed has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Robeaute. Brian Nahed has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BK Ultrasound. Brian Nahed has stock in React Neuro. Brian Nahed has received research support from NIH. Dr. Nelson has nothing to disclose. Dr. Arrillaga-Romany has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Boehringer Ingelheim. The institution of Dr. Arrillaga-Romany has received research support from Astex Pharmaceuticals. The institution of Dr. Arrillaga-Romany has received research support from Gsk. Dr. Wang has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Seattle Genetics. The institution of Dr. Wang has received research support from Merck. Dr. Wang has received publishing royalties from a publication relating to health care. Dr. Dietrich has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Amgen. Dr. Dietrich has received publishing royalties from a publication relating to health care.

Primary Lymphoproliferative Lung Diseases: Imaging and Multidisciplinary Approach.

Lymphoproliferative lung diseases are a heterogeneous group of disorders characterized by primary or secondary involvement of the lung. Primary pulmonary lymphomas are the most common type, representing 0.5-1% of all primary malignancies of the lung. The radiological presentation is often heterogeneous and non-specific: consolidations, masses, and nodules are the most common findings, followed by ground-glass opacities and interstitial involvement, more common in secondary lung lymphomas. These findings usually show a prevalent perilymphatic spread along bronchovascular bundles, without a prevalence in the upper or lower lung lobes. An ancillary sign, such as a "halo sign", "reverse halo sign", air bronchogram, or CT angiogram sign, may be present and can help rule out a differential diagnosis. Since a wide spectrum of pulmonary parenchymal diseases may mimic lymphoma, a correct clinical evaluation and a multidisciplinary approach are mandatory. In this sense, despite High-Resolution Computer Tomography (HRCT) representing the gold standard, a tissue sample is needed for a certain and definitive diagnosis. Cryobiopsy is a relatively new technique that permits the obtaining of a larger amount of tissue without significant artifacts, and is less invasive and more precise than surgical biopsy.

Patient-derived xenograft mouse models to investigate tropism to the central nervous system and retina of primary and secondary central nervous system lymphoma.

How and why lymphoma cells home to the central nervous system and vitreoretinal compartment in primary diffuse large B-cell lymphoma of the central nervous system remain unknown. Our aim was to create an in vivo model to study lymphoma cell tropism to the central nervous system. We established a patient-derived central nervous system lymphoma xenograft mouse model and characterised xenografts derived from four primary and four secondary central nervous system lymphoma patients using immunohistochemistry, flow cytometry and nucleic acid sequencing technology. In reimplantation experiments, we analysed dissemination patterns of orthotopic and heterotopic xenografts and performed RNA sequencing of different involved organs to detect differences at the transcriptome level. We found that xenografted primary central nervous system lymphoma cells home to the central nervous system and eye after intrasplenic transplantation, mimicking central nervous system and primary vitreoretinal lymphoma pathology, respectively. Transcriptomic analysis revealed distinct signatures for lymphoma cells in the brain in comparison to the spleen as well as a small overlap of commonly regulated genes in both primary and secondary central nervous system lymphoma. This in vivo tumour model preserves key features of primary and secondary central nervous system lymphoma and can be used to explore critical pathways for the central nervous system and retinal tropism with the goal to find new targets for novel therapeutic approaches.

Metastases to breast from primary lung cancer

BackgroundMetastatic involvement of the breast is relatively rare and has an incidence of 0.5–3%. Lesions that metastasize to the breast may produce changes that look similar to those of primary breast cancer on mammography, but they are more likely to be multiple and are frequently bilateral.Case presentationA 38-year-old female complaining of progressive proptosis with bilateral palpable breast lumps. She was referred to the breast imaging unit to evaluate the nature of those breast lesions, diagnostic mammography, and complementary ultrasound was done that revealed multiple variable-sized well-defined masses scattered all over their parenchyma. True cut biopsy was taken from one of them that show metastatic carcinoma of non-mammary origin. Immunophenotyping revealed neuroendocrine carcinoma of lung origin. A metastatic workup was done that revealed horrible metastatic deposits in multiple organs and the primary was found in the lung.ConclusionsMetastasis to the breast from extra-mammary carcinomas is extremely rare. The most common types are malignant melanoma, secondary lymphomas, and tumors of neuroendocrine origin like Small cell carcinoma. Histopathology and sometimes immunophenotyping can provide the diagnosis.

Usefulness of Serum Soluble Interleukin-2 Receptor Levels for Differentiating between PCNSL and SCNSL.

Serum soluble interleukin-2 receptor (sIL-2R) is a practical tumor marker that is elevated in hematogenous tumors. The purpose of this study was to determine the usefulness of serum sIL-2R for differentiating among malignant brain tumors, including primary central nervous system lymphoma (PCNSL) and secondary central nervous system lymphoma (SCNSL). This study retrospectively investigated the sIL-2R levels in 130 patients with various types of malignant brain tumors, including PCNSL patients (n = 48) and SCNSL (n = 8); metastatic brain tumors (MTs, n = 16); and glioblastoma (GBM, n = 58). The median sIL-2R level (U/mL) of the PCNSL, SCNSL, MTs, and GBM groups were 489.7, 1024.8, 413.3, and 332.7 respectively. The sIL-2R level was significantly higher in the SCNSL group than in the PCNSL or other groups. The area under the ROC curve generated from the sIL-2R level was 0.826 (sensitivity: 0.875, specificity: 0.667, cutoff value: 521 U/mL) for differentiating SCNSL from PCNSL and 0.685 (sensitivity: 0.667, specificity: 0.707, cutoff value: 342 U/mL) for differentiating PCNSL from GBM. Measurement of sIL-2R level was convenient and useful to differentiate between SCNSL and PCSNL, both of which demand different treatment strategies.

Breast MALT Lymphoma: A Clinical, Histomorphologic, and Immunophenotypic Evaluation.

Introduction. Primary breast extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) is rare and understudied. Embryonically, mammary glands are developed as specialized skin appendages. It is possible that overlapping features exist between breast MALT lymphoma and primary cutaneous marginal zone lymphoma. Methods. We studied 5 primary and 6 secondary breast MALT lymphomas diagnosed in our institution during a 20-year period. Clinical and pathologic features of these lymphomas were analyzed and compared. Results. Most primary and secondary breast MALT lymphomas had similar clinical presentations as unilateral breast lesions without axillary lymphadenopathy. However, primary lymphomas tended to be diagnosed in older patients (median: 77 years old) than secondary lymphomas (median: 60 years old). Thyroid abnormality was a common finding in both primary (3/5) and secondary (5/6) lymphomas. Hashimoto's thyroiditis was diagnosed in one primary lymphoma. No distinct histopathologic findings were found in primary lymphomas. Features for primary cutaneous marginal zone lymphoma, including overexpression of IgG and IgG4 and high IgG4/IgG ratio, were absent in all primary but present in one secondary lymphoma with cutaneous origin. This secondary lymphoma also had expansion of CD30-positive cells. Conclusion. Primary breast MALT lymphoma does not share the distinctive features of primary cutaneous marginal zone lymphoma that set it apart from other extranodal marginal zone lymphomas. Having increased IgG- and IgG4-positive cells with a high IgG/IgG4 ratio in breast MALT lymphoma may indicate cutaneous origin. CD30 overexpression may be a feature seen in marginal zone lymphoma of cutaneous origin, which needs further studies to prove.

Distribution and clinical features of lymphomas involving skin in Taiwan.

A wide variety of primary and secondary lymphoma types involves the skin. However, reports with comparisons between both groups are limited in Taiwan. We retrospectively enrolled all cutaneous lymphomas and evaluated their clinicopathologic features. There were 221 cases of lymphoma: 182 (82.3%) primary and 39 (17.7%) secondary. Mycosis fungoides was the most common primary T-cell lymphoma, 92 (41.7%) cases, followed by CD30-positive T-cell lymphoproliferative disorders including lymphomatoid papulosis (n=33, 14.9%) and cutaneous anaplastic large cell lymphoma (n=12, 5.4%). The most frequent primary B-cell lymphomas were marginal zone lymphoma (n=8, 3.6%) and diffuse large B-cell lymphoma (DLBCL), leg type (n=8, 3.6%). DLBCL including variants was the most common secondary lymphoma involving skin. Most primary lymphomas presented at low-stage (T-cell, 86%; B-cell, 75%), whereas the majority of secondary lymphomas presented at high-stage (T-cell, 94%; B-cell, 100%). Patients with secondary lymphomas had an older mean age, more frequent B symptoms, lower serum albumin and hemoglobin, and a higher frequency of atypical lymphocytes in blood than those with primary lymphomas. In primary lymphomas, older age, lymphoma types, decreased lymphocyte counts and atypical lymphocytes in blood were poorer prognostic factors. In secondary lymphoma patients, lymphoma types, high serum lactate dehydrogenase and low hemoglobin levels predicted poorer survival. We found that the distribution of primary cutaneous lymphomas in Taiwan mirrors that of other Asian countries but shows some differences as compared with Western countries. Primary cutaneous lymphomas have a better prognosis than secondary lymphomas. Histologic classification of lymphomas highly correlated with disease presentation and prognosis.

Clinical Analysis of Pulmonary Lymphoma

To study the clinical, imaging, and pathological features of pulmonary lymphoma. Patients with pulmonary lymphoma diagnosed by lung biopsy in Zhongda Hospital Affiliated to Southeast University from November 2013 to December 2020 were collected and divided into secondary pulmonary lymphoma (SPL) group and primary pulmonary lymphoma (PPL) group according to the primary site of lymphoma. The clinical characteristics, stages, imaging features, diagnostic methods and pathological types of the two groups were analyzed. A total of 22 patients were included, 10 cases were PPL and 12 cases were SPL. The main symptoms of the two groups were cough, dyspnea and chest pain. The proportion of stage III/IV patients and international prognostic index (IPI) in SPL group were significantly higher than those in PPL group (P<0.05). Chest high-resolution computed tomography (HRCT) mainly showed masses, nodules and consolidation in both groups. The proportions of single mass and air bronchial sign in PPL group were significantly higher than those in SPL group, while the proportions of multiple nodules, mediastinal/hilar lymphadenopathy and pleural effusion were significantly lower (P<0.05). The max standardized uptake value (SUVmax), peak standardized uptake value (SUVpeak), total lesion glycolysis (TLG) and metabolic tumor volume (MTV) of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in PPL group were lower than those in SPL group, but the differences were not statistically significant (P>0.05). In PPL group, 8 cases were diagnosed by transbronchial lung biopsy (TBLB) and 2 cases by percutaneous lung puncture. In SPL group, 4 cases were diagnosed by TBLB, 7 cases by percutaneous lung puncture, and 1 case by surgery. 95.5% patients were diagnosed by non-surgical methods. The main pathological type of PPL was mucosa-associated lymphoid tissue (MALT) lymphoma, while that of SPL was diffuse large B-cell lymphoma (P<0.05). The clinical symptoms of pulmonary lymphoma are nonspecific, but the chest HRCT has characteristic manifestations, which can also help to distinguish between SPL and PPL. 18F-FDG PET/CT is also a potential method to distinguish between SPL and PPL. TBLB and percutaneous lung puncture biopsy are reliable methods for the diagnosis of lung lymphoma. The main pathological type of PPL is MALT lymphoma, while that of SPL is diffuse large B-cell lymphoma.

Thiotepa, Busulfan, Cyclophosphamide: Effective but Toxic Conditioning Regimen Prior to Autologous Hematopoietic Stem Cell Transplantation in Central Nervous System Lymphoma.

In primary central nervous system lymphoma, two-year progression-free survival rates of up to 63 percent have been reported for first-line autologous stem cell transplantation after conditioning with the thiotepa busulfan cyclophosphamide regimen. However, 11 percent of the patients died due to toxicity. Besides conventional survival, progression-free survival and treatment related mortality analyses, a competing-risk analysis was applied to our cohort of twenty-four consecutive patients with primary or secondary central nervous system lymphoma who underwent autologous stem cell transplantation after thiotepa busulfan cyclophosphamide conditioning. The two-year overall survival and progression-free survival rates were 78 percent and 65 percent, respectively. The treatment-related mortality rate was 21 percent. The competing risks analysis demonstrate that age 60 or over and the infusion of less than 4.6 × 106/kg CD34+ stem cells were significant adverse prognostic factors for overall survival. Autologous stem cell transplantation with thiotepa busulfan cyclophosphamide conditioning was associated with sustained remission and survival. Nevertheless, the intensive thiotepa busulfan cyclophosphamide conditioning regimen was highly toxic, especially in older patients. Thus, our results suggest that future studies should aim at identifying the subgroup of patients who will really benefit of the procedure and/or to reduce the toxicity of future conditioning regimen.

Genomic Profiling Reveals Differences in Primary Central Nervous System Lymphoma and Large B-Cell Lymphoma, With Subtyping Suggesting Sensitivity to BTK Inhibition.

B-cell primary central nervous system (CNS) lymphoma (PCL) is diffuse large B-cell lymphoma (DLBCL) confined to the CNS. Less than 50% of patients with PCL achieve complete remission with current therapies. We describe the findings from comprehensive genomic profiling (CGP) of a cohort of 69 patients with PCL, 36 cases of secondary CNS lymphoma (SCL), and 969 cases of DLBCL to highlight their differences and characterize the PCL cohort. In addition, we highlight the differences in frequency of germinal center B-cell like (GCB) and non-GCB subtypes and molecular subtypes, particularly MCD and EZH subtypes, between PCL and DLBCL. Sixty-nine cases of B-cell PCL, 36 cases of secondary CNS lymphoma (SCL), and 969 cases of DLBCL were evaluated by CGP of 405 genes via DNAseq and 265 genes via RNAseq for fusions (FoundationOne Heme). Tumor mutational burden (TMB) was calculated from 1.23 Mb of sequenced DNA. Genomic alterations with significant differences between PCL and DLBCL included MYD88, ETV6, PIM1, PRDM1, CXCR4, TP53, and CREBBP, while only MYD88 was significantly different between SCL and DLBCL. PCL cases were significantly enriched for the MCD molecular subtypes, which have an excellent response to BTKi. We report a patient with a durable complete response to BTKi consistent with their genomic profile. EBV status, CD274 amplification, and TMB status suggest that 38% of PCL patients may benefit from ICPI; however further study is warranted. CGP of PCLs reveals biomarkers, genomic alterations, and molecular classifications predictive of BTKi efficacy and potential ICPI efficacy. Given the limitations of standard of care for PCL, CGP is critical to identify potential therapeutic approaches for patients in this rare form of lymphoma.

Clinical characteristics and prognosis of primary and secondary diffuse large B-cell lymphoma of the pancreas

Objective: To analyze the clinical characteristics and prognosis of primary and secondary pancreatic diffuse large B-cell lymphoma (DLBCL) . Methods: Clinical data of patients with pancreatic DLBCL admitted at Shanghai Rui Jin Hospital affiliated with Shanghai Jiao Tong University School of Medicine from April 2003 to June 2020 were analyzed. Gene mutation profiles were evaluated by targeted sequencing (55 lymphoma-related genes). Univariate and multivariate Cox regression models were used to evaluate the prognostic factors of overall survival (OS) and progression-free survival (PFS) . Results: Overall, 80 patients were included; 12 patients had primary pancreatic DLBCL (PPDLBCL), and 68 patients had secondary pancreatic DLBCL (SPDLBCL). Compared with those with PPDLBCL, patients with SPDLBCL had a higher number of affected extranodal sites (P<0.001) and had higher IPI scores (P=0.013). There was no significant difference in the OS (P=0.120) and PFS (P=0.067) between the two groups. Multivariate analysis indicated that IPI intermediate-high/high risk (P=0.025) and double expressor (DE) (P=0.017) were independent adverse prognostic factors of OS in patients with pancreatic DLBCL. IPI intermediate-high/high risk (P=0.021) was an independent adverse prognostic factor of PFS in patients with pancreatic DLBCL. Targeted sequencing of 29 patients showed that the mutation frequency of PIM1, SGK1, BTG2, FAS, MYC, and MYD88 in patients with pancreatic DLBCL were all >20%. PIM1 (P=0.006 for OS, P=0.032 for PFS) and MYD88 (P=0.001 for OS, P=0.017 for PFS) mutations were associated with poor OS and PFS in patients with SPDLBCL. Conclusion: There was no significant difference in the OS and PFS between patients with PPDLBCL and those with SPDLBCL. IPI intermediate-high/high risk and DE were adverse prognostic factors of pancreatic DLBCL. PIM1, SGK1, BTG2, FAS, MYC, and MYD88 were common mutations in pancreatic DLBCL. PIM1 and MYD88 mutations indicated worse prognosis.

Chimeric Antigen Receptor T-Cell (CAR T-Cell) Therapy for Primary and Secondary Central Nervous System Lymphoma: A Systematic Review of Literature.

Relapsed/refractory central nervous system (CNS) lymphoma, whether primary or secondary, is associated with poor prognosis with currently available treatment modalities, including high-dose chemotherapy-autologous stem cell transplantation. The pivotal ZUMA-1 and JULIET trials that led to FDA approval of Axicabtagene ciloleucel and Tisagenlecleucel for relapsed refractory large cell lymphoma excluded patients with CNS involvement due to concerns of increased toxicity. However, TRANSCEND study for Lisocabtagene maraleucel in relapsed refractory large cell lymphoma allowed patients with CNS involvement and reported manageable CNS toxicities in these patients. In the real-world experience, chimeric antigen receptor T-cell (CAR T) therapy has been deemed safe and effective for these patients with poor prognosis. In this systematic review, we analyzed available literature to evaluate the role of CAR T-cell therapy in both primary and secondary CNS lymphoma using Embase, Cochrane, and PubMed databases. A total of 14 studies, including 8 retrospective analyses and 6 prospective studies/clinical trials, were included in the qualitative synthesis to study the safety and efficacy of CAR T. Based on our analysis, CAR T-cell therapy appears to be associated with reasonable efficacy and a manageable safety for primary and secondary CNS lymphoma.