Extranodal non-Hodgkin Lymphoma Research Articles

Gastric Mucosa-associated Lymphoid Tissue Lymphoma Mimicking Signet Ring Cell Carcinoma

Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is the most common type of extranodal non-Hodgkin lymphoma. Endoscopic findings are nonspecific and variable; therefore, differentiation of this malignancy from early gastric cancer is challenging during endoscopy. Although an endoscopic biopsy is the gold standard for diagnosis, a biopsy may not conclusively establish the diagnosis in all cases. Diagnostic confirmation requires interpretation of the biopsy specimen findings by an experienced histopathologist, and an additional immunoglobulin heavy chain (IgH) rearrangement test may aid with accurate diagnosis. We present a case of gastric MALT lymphoma that histopathologically mimicked signet ring cell carcinoma (SRCC) on evaluation of repeat endoscopic biopsies. Following endoscopic submucosal dissection (ESD), we confirmed the final diagnosis of gastric MALT lymphoma based on histopathological findings of prominent lymphoid infiltrates accompanied by lymphoepithelial lesions and results of the monoclonal IgH rearrangement test. Notably, a few carcinoma-like signet ring cells (SRCs) in the specimen were attributed to a reactive change. Clinicians should be mindful of possible SRCs in gastric MALT lymphoma specimens to avoid misdiagnosis of SRCC in patients with gastric MALT lymphoma. Confirmatory ESD may be useful for accurate diagnosis and appropriate management of such lesions.

Clinicopathological analysis and specific discriminating markers of interleukin detection in cerebrospinal fluid with primary central nervous system lymphoma: results from a retrospective study.

Primary central nervous system lymphoma (PCNSL) is special extranodal malignant non-Hodgkin lymphomas. This study analyzed clinical features and prognostic factors of PCNSL and evaluated the difference of interleukin (IL) concentrations incerebrospinal fluid (CSF) between PCNSL and systemic non-Hodgkin lymphoma (sNHL). Patients consecutive newly diagnosed with PCNSL were recruited, the demographic and clinicopathological data were retrospectively analyzed, and the potential prognostic factors for overall survival (OS) were identified with survival analysis. 27 patients with PCNSL and 21 patients with sNHL collected CSF IL-5, IL-6, and IL-10 concentrations at diagnosis. The difference in interleukin (IL) concentrations in two diseases was analyzed to evaluate the value of IL concentrations. A total of 64 patients with PCNSL were enrolled, the median age was 54.50years (range 16-85years); male: female ratio was 1.91. Headache was the most common complaint symptom involved in 42.19% (27/64) of patients. Diffuse large B-cell lymphoma (DLBCL) accounted for 89.06% (57/64) of patients; other uncommon types accounted for 3.13% (2/64). In prognostic analysis, multiple lesions and Ki67 ≥ 75% expression exhibited a worse prognosis(P = 0.041), and patients with autologous hematopoietic stem cell transplantation (auto-HSCT) treatment presented superior OS (P < 0.05). In multivariate analysis, BCL2 expression was revealed as an unfavorable prognostic marker, and auto-HSCT was revealed as a favorable prognostic marker. CSF IL-10 concentration in patients with PCNSL was significantly higher than sNHL (P = 0.000) and excluded other histopathology of NHL; IL-10 value was still significantly different between DLBCL of PCNSL and sDLBCL (P = 0.003). In ROC curve analysis, the cutoff value of IL-10 was 0.43pg/mL for the diagnosis value of PCNSL, sensitivity was 96.3%, specificity was 66.67%, and AUC was 0.84 (0.71-0.96). Although IL-6 concentration did not differ in the two groups, IL-10/IL-6 ratio was meaningful, with a cutoff value of 0.21, sensitivity of 81.48%, specificity of 80.95%, and AUC of 0.83 (0.71-0.95). This study highlights the characteristics of patients with PCNSL, potential prognostic makers also have been explained. CSF interleukin (IL) concentrations revealed IL-10 levels, and IL-10/IL-6 ratio may represent a useful biomarker in the differential diagnosis of PCNSL and sNHL.

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

Background: ENKTL is a highly aggressive NHL with a higher incidence in Asia. In 2020 ASH meeting, we reported Sintilimab(anti-PD-1 antibody) plus Chidamide(an oral subtype-selective HDACi) yielded effective antitumor activity, durable response with mild toxicity in patients with relapsed or refractory ENKTL. We then initiated this exploratory study to investigate the efficacy and safety of Sintilimab plus Chidamide(SC) for patients with newly diagnosed ENKTL. Methods: This trial enrolled eligible patients with newly diagnosed ENKTL(ND-ENKTL); ECOG score ≤2; at least one measurable or evaluable lesion. All patients received 2–3 cycles of Sintilimab (200 mg) plus Chidamide (30 mg, twice a week). For patients with early stage, 2 cycles of SC were given, subsequent 2–4 cycles of P-GemOx regimen administered and followed by involved field radiotherapy (IFRT). For advanced stage, patients were treated with 3 cycles of SC and 3–6 cycles of P-GemOx. The primary study endpoints are the ORR of SC and end of treatment assessed according to the lymphoma response to immunomodulatory therapy criteria (LYRIC). Key secondary endpoints included DOR, PFS, OS and safety. Results: From July 2019 to Nov 2021, 42 eligible patients were enrolled from Sun Yat-sen University Cancer Center. The median age was 47.5 (range, 20–81) years, 16(38%) patients with stage III-IV, 15(31%) patients with PINK-E score≥3. All patients were evaluated for efficacy. For stage I-II, 21(81%) patients achieved response, including 18(69%) CR patients with SC. After 2 cycles of SC, 17(94%) of 18 CR patients chosen to continue SC treatment. Only 1 (6%) PR patients accepted 2 cycles of P-GemOx and got CR after chemotherapy. Twenty-five (96%) patients obtained CR after IFRT. For stage III–IV, 9(56%) patients achieved response with 13%(2/16) CR, 3(33.3%) patients experienced rapid progression disease (RPD) in SC portion. Ten (63%) patients entered P-GemOx portion including 1 RPD patient. Thirteen (81%) patient got ORR with 69% (11/16) CR after whole treatment. The median follow-up time was 24.1(5.4–44.3) months. The 2-year PFS and OS rate were 76% and 78%, the prognosis of early stage is better than advanced stage (Fig. 1). Two RPD patients died within one month. Circulating EBV-DNA clearance after SC significantly correlated with superior outcome. Forty(95.2%) patients reported treatment-related adverse effects (TRAEs). The most common TRAEs (≥10%) were neutropenia (43%), thrombocytopenia (38%), elevated transaminase (29%), and anemia (24%). The most common grade 3 TRAEs (≥10%) was elevated transaminase (10%), no grade 4 TRAEs. Keywords: aggressive T-cell non-Hodgkin lymphoma, extranodal non-Hodgkin lymphoma, immunotherapy No conflicts of interests pertinent to the abstract.

Brincidofovir induces potent anti‐tumor activity in MYC‐driven Natural Killer/T‐cell Lymphoma with loss of transcriptional repressor TLE1

Introduction: Natural killer/T-cell lymphoma (NKTCL) is an aggressive Epstein-Barr virus (EBV)-associated malignancy which is prevalent in Asian countries. Brincidofovir (BCV), a lipid conjugated form of cidofovir, is a biologically-active acyclic nucleoside phosphonate recently shown to exhibit both antiviral and antitumor properties. Methods: We investigated BCV in NKTCL cell-lines (n = 11) and mouse xenograft models. Whole exome sequencing, bulk RNAseq and single cell RNAseq (scRNAseq) were employed to examine mechanisms of action, and validated using orthogonal assays. Results: BCV inhibited viability in all NKTCL cell-lines in a dose- and time-dependent manner. Highest sensitivity was demonstrated in four cell-lines KAI-3, NK-S1, NK-92 and KHYG-1 (IC50 36.0 to 303.6 ng/ml). Intraperitoneal BCV (40 mg/kg, 2X per week) inhibited tumor growth in NOD/SCID mice NK-S1 xenografts, compared with vehicle alone (p = 0.0005, two-tailed t-test). Whole exome sequencing of the cell-lines revealed widespread mutations in the JAK/STAT and DNA repair pathways, with no clear correlation observed with BCV sensitivity. RNAseq and Hallmark gene set enrichment analysis showed that MYC target pathways (FDR q < 0.001) were prominently upregulated in the four sensitive cell-lines compared to the rest. RNAseq of BCV-treated cell-lines (KAI-3 and NK-S1) revealed striking downregulation of MYC target pathways. scRNAseq revealed distinct temporal cell states evoked by BCV, including appearance of cell clusters enriched for p53 and apoptosis pathways, cell cycle and DNA repair pathways, as well as type I/II interferon and cytokine signaling. Western blot and quantitative PCR showed that markers of replication stress, DNA damage and STING signaling were potently upregulated, implicating an immunogenic form of cell death. Notably, TLE1, a known transcriptional repressor of the MYC oncogene, was the topmost downregulated gene (log2FoldChange -7.39, adjusted p = 3.51E-31) in the four BCV-sensitive cell-lines on RNAseq. This finding was verified on qPCR (p = 0.0061, Mann-Whitney test) and Western blot. In keeping with this result, RNAseq on NKTCL patient samples (n = 36) showed that TLE1-low tumors were enriched for MYC target pathways, which conferred worse progression-free survival (HR 3.44, 95% CI: 1.23–10.49, p = 0.0301). Conclusions: Taken together, these results suggest that BCV may play a novel role in the treatment of MYC-driven NKTCL. Loss of TLE1, a putative predictive biomarker, implies that BCV may favour patients in this poor prognostic subgroup. The research was funded by: Symbio Pharmaceuticals, Tanoto Foundation Professorship in Medical Oncology, New Century Foundation Limited, Ling Foundation, Singapore Ministry of Health’s National Medical Research Council Transition Award (TA21jun-0005), Research Training Fellowship Seed Fund (SEEDFD21jun-0002), Large Collaborative Grant (OFLCG18May-0028), and Collaborative Centre Grant (TETRAD II). Keywords: Diagnostic and Prognostic Biomarkers, Extranodal non-Hodgkin lymphoma, Molecular Targeted Therapies Conflicts of interests pertinent to the abstract. J. Y. Chan Consultant or advisory role: Symbio Pharmaceuticals Research funding: Symbio Pharmaceuticals M. Hazama Employment or leadership position: SymBio Pharmaceuticals Limited K. Fukushima Employment or leadership position: SymBio Pharmaceuticals Limited C. K. Ong Research funding: SymBio Pharmaceuticals Limited

TESTICULAR LARGE B‐CELL LYMPHOMA IS GENETICALLY SIMILAR TO PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA AND DISTINCT FROM NODAL DIFFUSE LARGE B‐CELL LYMPHOMA

Introduction: Testicular large B-cell lymphoma (TLBCL) is an infrequent and aggressive lymphoma presenting in an immune-privileged site, recently recognized as a distinct entity from diffuse large B-cell lymphoma (DLBCL). Here, we performed the genetic characterization of TLBCL and compare it with a published series of nodal DLBCL and primary central nervous system lymphoma (PCNSL). Patients and Methods: We collected 61 patients with TLBCL diagnosed between 2002 and 2021. Cell-of-origin was determined by immunochemistry and Lymph2Cx assay. To characterize the genomic profile of TLBCL we performed targeted next-generation sequencing, copy number arrays, and fluorescent in situ hybridization, and compared them to those of DLBCL and PCNSL. Results: The median age was 70 years and 30% of the patients had disseminated disease at diagnosis, including six cases with CNS involvement. Using Hans' algorithm, 83% (44/53) were identified as a non-germinal center while the Lymph2Cx assay categorized 71% (30/42) as activated B-cell phenotype and 12% (5/42) as unclassified. BCL6 rearrangements were detected in 36% (17/47) of cases, and no concomitant BCL2 and MYC rearrangements were found. Integrative analysis of 40 cases with single nucleotide variants, indels, and copy number alterations (CNA) data showed that the most frequent alterations (>50%) in TLBCL were PRDM1, CDKN2A/B, TNFAIP3, SGK1, ARID1B, MYD88L265P, SPIB, PIM1, and CD79B (Figure). Concomitant variants in MYD88L265P, CD79B, and PIM1 were detected in twelve (29%) cases. Using the LymphGen tool, 71% (30/42) of the cases could be classified into a molecular subgroup, with MCD being the most frequent group (66%, 20/30). Interestingly, patients with localized or disseminated disease displayed similar genomic complexity based on the number of CNAs and the number of mutated genes. Compared with nodal DLBCL, localized and disseminated TLBCL have less CNA complexity (P = 0.01 and P < 0.04, respectively) but showed a higher number of variants (P = 0.01 and P < 0.001, respectively). TLBCL also presented more frequently 18q21.32-q23 (BCL2) gains and 6q and 9p21.3 (CDKN2A/B) deletions. PIM1, MYD88L265P, CD79B, TBL1XR1, MEF2B, CIITA, EP300, and ETV6 variants were enriched in TLBCL, and BCL10 mutations in nodal DLBCL. There were no genetic differences between TLBCL and PCNSL. Encore Abstract - previously submitted to regional or national meetings (up to <1’000 attendees). The research was funded by: Asociación Española Contra el Cancer AECC/CIBER: PROYE18020BEA (SB); Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III Instituto de Salud Carlos III, “Cofinanciado por la Unión Europea” and Fondos FEDER: European Regional Development Fund “Una manera de hacer Europa”: PI17/01061 (SB), PI19/00887 (ALG and EG), and INT20/00050 (ALG); Marató TV3 TV3-Cancer/ 201904-30 (SB). ARD is supported by a grant from Sociedad Española de Hematología y Hemoterapia. CL is supported by postdoctoral Beatriu de Pinós grant from Secretaria d’Universitats i Recerca del Departament d’Empresa i Coneixement de la Generalitat de Catalunya and by Marie Sklodowska-Curie COFUND program from H2020 (2018-BP-00055). Keywords: Extranodal non-Hodgkin lymphoma, Pathology and Classification of Lymphomas Conflicts of interests pertinent to the abstract. F. Nadeu Honoraria: Janssen, AbbVie E. Campo Consultant or advisory role: Takeda, NanoString, AbbVie, Illumina Honoraria: Janssen, EUSPharma, Roche Research funding: AstraZeneca A. López-Guillermo Consultant or advisory role: Roche, Gilead, Kite Pharma, Celgene, Bristol Myers Squibb, Incyte, Takeda, Kern Pharma, Pfizer, Janssen Honoraria: Janssen, Roche, Kite Research funding: Gilead, Janssen, Celgene, Bristol Myers Squibb Educational grants: Roche, Kite/Gilead

A single‐center experience of low‐dose radiotherapy for primary extranodal marginal zone lymphoma of bronchus‐associated lymphoid tissue (BALT)

Introduction: Extranodal marginal zone lymphoma of bronchus-associated lymphoid tissue (BALT) is a rare cancer for which optimal treatment strategies are not well defined. Retrospective analyses show equivalent or superior outcomes with surgical resection compared to systemic therapy or active surveillance. Despite a well established role for radiotherapy in the management of other types of extranodal marginal zone lymphoma (MZL), its role in BALT lymphoma is underexplored. Methods: We screened 153 patients with a diagnosis of primary BALT lymphoma treated at a single institution from 1995 to 2022. Inclusion criteria comprised patients aged 18 years or older, histologically confirmed BALT lymphoma, and receipt of radiotherapy at initial presentation or disease progression/recurrence. We excluded patients with synchronous evidence of lymphoma involving non-thoracic extranodal sites and/or lymphadenopathy outside of the mediastinum and hilum, as these patients might represent MZL with secondary lung involvement as opposed to primary BALT lymphoma. All patients underwent baseline PET/CT staging. We extracted patient, tumor, imaging, and treatment characteristics from the electronic medical record. We defined active surveillance as at least 3 months of follow up prior to initiating active therapy combined with documentation of this plan in the medical record. We assessed treatment response using the RECIL 2017 criteria. Results: We report the largest to date single-center retrospective analysis of 13 patients (median age 67 years, range 33–84 years) with localized BALT lymphoma treated with radiotherapy. The median tumor size was 3.6 cm (range 0.8–8.2 cm) with a median SUV of 3.9 (range 1.3–11.4). Most patients (n = 8, 62%) received radiotherapy for BALT lymphoma after failing first-line treatment, including active surveillance (n = 3), surgical resection (n = 2), or systemic therapy (n = 3). Of 15 irradiated lesions, most (n = 10, 67%) received very low-dose radiotherapy (VLRDT) of 4 Gy (range 4–36 Gy). With a median follow-up of >50 months, only 3 patients experienced progression of disease, none within the irradiated field (1 following VLDRT and 2 following full-dose RT). Among all treated lesions, the overall response rate was 100% (n = 5, 33% partial response [PR] and n = 10, 67% complete response [CR]). Among 10 lesions treated with VLDRT, 6 (60%) achieved CR; among 5 lesions treated with full-dose RT, 4 (80%) achieved CR. There were no events of secondary lung cancers within or in proximity to the irradiated field. Conclusions: Radiotherapy, including VLDRT, is a feasible, well tolerated, non-invasive and effective treatment strategy for primary BALT lymphoma that can be considered in both the upfront and recurrent treatment settings. The research was funded by: National Cancer Institute (P30 CA008748) Keywords: Extranodal non-Hodgkin lymphoma, Indolent non-Hodgkin lymphoma No conflicts of interests pertinent to the abstract.

PRIMARY HEPATIC LYMPHOMA: ROLE OF LOW‐DOSE RADIOTHERAPY AND PAIRED LITERATURE REVIEW

Introduction: Primary hepatic lymphomas (PHL) are a rare form of non-Hodgkin lymphoma for which there are no established treatment guidelines. Available literature is largely comprised of small case reports and there are no reports on low-dose radiotherapy (RT) for indolent PHL. We report our institutional experience treating PHL within the context of existing literature to better understand the role of RT. We hypothesize that low-dose RT offers comparable outcomes to observation (obs), surgery and systemic therapy (ST) in select patients. Methods: We conducted a single-institution retrospective analysis of all biopsy-proven PHL patients (pts) diagnosed from 2000-2021 without other lymphomatous solid organ involvement. Subgroup analysis was performed for diffuse large B-cell lymphoma (DLBCL) and indolent lymphoma (IL). Univariable (UVA) and multivariable analysis (MVA) for overall survival (OS) was performed using the Cox proportional hazards model. Literature review was conducted using key words including “liver”, “lymphoma”, and “treatment” to identify all available reported cases of PHL. Results: We identified 30 PHL pts within our institution and 192 pts from literature review, with subgroup analysis of DLBCL and IL pts in the institutional cohort (n = 15, 9) and literature review (n = 78, 76), respectively (Table 1). Among the IL institutional cohort (n = 9), 3 pts underwent obs and 2 each received RT, ST and surgery. There were no recurrences among pts treated with RT, surgery or obs with median OS of 12.4 years, whereas both ST pts experienced either transformation to DLBCL or recurrence. Both RT patients received low-dose RT of 4Gy in 2 fractions. Literature review identified only 1 case report of RT use for IL with a dose of 41.4Gy. Conclusions: There is limited literature regarding use of RT in indolent PHLs. We present the first report of low-dose RT for indolent PHL with comparable outcomes to alternative modalities. PHL DLBCL is predominantly treated with ST in both our institutional experience and in the literature. Although our data is limited by the small cohort size reflective of the rarity of disease, our results are encouraging for the consideration of low-dose RT as a management option for appropriate patients with indolent PHL. Keywords: extranodal non-Hodgkin lymphoma, radiation therapy No conflicts of interests pertinent to the abstract.

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

Although previously characterized as a subtype of diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma (PMBCL) is a now recognized as a distinct subtype of NHL with unique clinical and biologic features, many of which overlap with classic Hodgkin lymphoma. PMBCL has a peak incidence in the adolescent and young adult (AYA) population and, unlike other subtypes of NHL, a higher incidence among females. Recent studies into the molecular biology of PMBCL have revealed frequent amplifications in 9p24.1 which includes the locus for PD-L1 and genomic alterations in CIITA, CD58, B2M, which likely further contribute to tumor immune evasion. Treatment for PMBCL varies across centers with no single standard of care. When treated on historic pediatric protocols designed for mature B-NHL, children and AYAs with PMBCL have inferior outcomes compared to patients with DLBCL treated on the same protocol. Recent clinical trials have sought to improve outcomes in PMBCL with the addition of rituximab with and modifications to pediatric regimens and/or the adoption of the dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) chemotherapy regimen. Despite this, outcomes in prospective multicenter trials remain suboptimal. There is strong rationale for immune checkpoint blockade in PMBCL including the key molecular features outlined above as well as data from phase II trials in adults showing efficacy of pembrolizumab and nivolumab in the relapsed setting. As such, we are now conducting a phase III trial evaluating the role of nivolumab in addition to chemotherapy for children and adults with previously untreated PMCBL. In this session we will review the current state of the science in PMBCL and provide an update on our ongoing phase III trial. Keywords: extranodal non-Hodgkin lymphoma, non-Hodgkin (pediatric, adolescent, and young adult) No conflicts of interests pertinent to the abstract.

Outcomes in primary gastrointestinal (GI) follicular lymphoma (FL): results from a multicenter analysis

Introduction: GI FL is a rare disease, accounting for less than 5% of GI non-Hodgkin’s lymphomas (NHL). We formed a consortium to clarify baseline features, common practices and survival outcomes in primary GI FL. Methods: A retrospective analysis of 182 patients (pts) with primary GI FL from 8 institutions was conducted. Overall survival (OS) and progression-free survival (PFS) were assessed. Cox regression models were used to estimate hazard ratios (HR) with 95% confidence intervals (CI). Results: Median age at diagnosis (dx) was 60 years (yrs) (IQR: 51–68). 89% (n = 141) of pts had low-grade FL by histology, and most presented with a low-risk score by FLIPI (68%, n = 111) or FLIPI-2 (76%, n = 103). At presentation, 18% (n = 32) of pts were asymptomatic, and 71% (n = 124) had at least one GI symptom, most commonly abdominal pain (40%, n = 70). 5% (n = 9) of pts presented with overt GI bleeding, and 9% (n = 15) with bowel obstruction. The most common first-line strategy was observation (33%, n = 59), of which 36% (n = 21) underwent surgical resection at dx. Other regimens included single-agent rituximab (R) (22%, n = 39), chemoimmunotherapy (CI) with R-bendamustine (18%, n = 32) or R-CHOP (11%, n = 19), and radiation therapy (5%, n = 9). The remainder received other CI combinations or R-lenalidomide. For those observed, median time to first treatment (tx) was 4.6 yrs. For those treated, overall response rate was 83% (95% CI, 76%–89%), and median time to second-line tx was 3.7 yrs. With median follow-up of 5.7 yrs, median OS was not reached. 5-yr PFS and OS were 71% (95% CI, 64%–79%) and 93% (95% CI, 89%–98%), respectively. Relevant factors that did not show a significant effect on PFS/OS included advanced disease by Paris and Ann Arbor staging systems, high-risk disease by FLIPI or FLIPI-2, B symptoms, GI symptoms, location of disease within the GI tract, and bone marrow involvement. Patients who were initially observed had similar OS to those who were treated up-front; PFS/OS did not improve significantly with use of maintenance rituximab. Factors that significantly impacted PFS and/or OS are outlined in Table 1. Conclusion: This multi-institutional analysis describes characteristics of the largest cohort of pts with GI FL to date. Observation or tx with rituximab ± chemotherapy were common initial approaches. Patients in this cohort had a good overall prognosis. While some factors including age, grade and BCL-2 expression by immunohistochemistry (IHC) predicted survival, traditional prognostic indices and staging systems did not. The research was funded by: No funding to disclose. Keyword: Extranodal non-Hodgkin lymphoma Conflicts of interests pertinent to the abstract. T. Alrifai Consultant or advisory role: Previous independent consultancy for MJH Life Sciences; completed in June of 2022. J. Kline Employment or leadership position: Speaker for Kite Pharma, Inc./Gilead. B.A.D Consultant or advisory role: Advisory boards for Merck, Kite Pharma, Inc./Gilead, Seattle Genetics, and Verastem Oncology Honoraria: Has received advisory board fees from Janssen, Sanofi, and consulting fees from COTA Healthcare. Research funding: Research support from Merck, iTeos, and Verastem Oncology R. Karmali Employment or leadership position: Speakers Bureau: AstraZeneca, BeiGene, Morphosys Consultant or advisory role: Advisory Board: BMS, Gilead Sciences/Kite Pharma, Janssen, Pharmacyclics, Morphosys, Epizyme, Genentech/Roche, Calithera, Miltenyi, Lilly Oncology Research funding: Grants/Research Support: BMS, Takeda, BeiGene, Gilead Sciences/Kite, Calithera

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.

MOLECULAR CHARACTERIZATION CONTRIBUTES TO DIAGNOSIS AND PREDICTS OUTCOME IN PRIMARY MEDIASTINAL LARGE B‐CELL LYMPHOMAS: A LYSA STUDY

Introduction: Primary mediastinal large B-cell lymphoma (PMBL) is a unique entity with an unusually good prognosis, except for ∼15% of refractory patients. Routine diagnosis relies on a clinicopathological confrontation. Tools to detect earlier refractory patients are lacking. Methods: We implemented a biological characterization of a multicenter retrospective LYSA cohort that previously reported clinical outcomes of 313 adult PMBL patients treated with first-line ACVBP or CHOP plus anti-CD20 between 2007 and 2017. We centrally reviewed 211 cases with available tumor material at diagnosis and then excluded 17 cases (misclassifications/inadequate material). Next, we applied Gene Expression Profiling (GEP) with a 137-genes RT-MLPA assay (LymphoSign signature) and Next-Generation Sequencing (NGS) with a 45-genes panel. Primary endpoints were progression-free survival (PFS) and overall survival (OS) according to molecular data. Results: We obtained GEP and NGS data for 139 (72%) and 131 (67.5%) cases, respectively. We observed a dominant expression of the PMBL-related driver genes IL4I1, B2M, PDL2, CD23, CD30, MAL, PDL1, and STAT6. Commonly mutated genes were SOCS1 (85.5%), B2M (61.1%), STAT6 (51.9%), IGLL5 (51.1%) and TNFAIP3 (51.1%). After integration of morphologic and available molecular data, 131/194 cases (67.5%) were considered as PMBL bona fide (with typical morphology and molecular profile). Within the PMBL bona fide group, we identified a cluster of 43 cases with overexpression of PDL1/2 genes (PDL1+/PDL2+, cutoff ≥median expression of each gene). As compared with others, PDL1+/PDL2+ cases were as follows: median [range] age of 34 [18–67] years (vs. 33.5 [19–64] years, p = 0.621), male sex: 53% (vs. 35%, p = 0.05), elevated LDH: 95% (vs. 76.3%, p = 0.008), PS 0–1: 79% (vs. 89.6%, p = 0.12), stage III–IV: 55.8% (vs. 39%, p = 0.08), IPI ≥ 3: 37.2% (vs. 18.4%, p = 0.027), extra-nodal involvements: 60% (vs. 45.5%, p = 0.12), metabolic tumor volume (MTV) ≥ 360 cm3: 53% (vs. 25.4%, p = 0.007). Treatments in the PDL1+/PDL2+ group did not differ from other patients: R-ACVBP: 69.8% (vs. 66.2%), R-CHOP14: 18.6% (vs. 20.8%) and R-CHOP21: 11.6% (vs. 14.3%) (p = 0.411). PDL1+/PDL2+ status was associated with poorer PFS (HR = 7, p < 0.001) and OS (HR = 15, p < 0.001, Figure 1). B2M mutations were inactivating and associated with lower PFS (p = 0.006). In a multivariate model including IPI ≥ 3, PDL1/2 status, MTV ≥ 360 and B2M mutations, only PDL1+/PDL2+ status was an independent prognostic factor of adverse PFS (HR = 7.1, 95% CI [1.5;33.1], p = 0.013). The research was funded by: This work was supported by grants from the Ligue Contre le Cancer (Comité de Seine-Maritime, AO_2020), the GIP Cancéropôle Nord-Ouest (N°2021/01 and N°2021/13), Force Hémato (N°02-2020) and CALYM (ANR-2020). Keywords: diagnostic and prognostic biomarkers, extranodal non-Hodgkin lymphoma No conflicts of interests pertinent to the abstract.

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

Background: Although clinical outcome of extranodal NK/T cell lymphoma (ENKTL) has been improved recently, some patients resistant to Asp-based chemotherapy suffered poorer survival. Therefore, reliable and convenient biomarkers become more important. Methods: We retrospectively analyzed 1017 ENKTL patients with available clinical data between December 2003 and August 2021. Demographics and serum lipid data of 500 healthy controls were reviewed. The median values at baseline were selected as the cutoff values for serum lipid. Results: The baseline serum levels of high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C) and apolipoprotein A1 (ApoA1) were lower, while the levels of triglyceride (TG) was higher in ENKTL patients than those in age- and gender-matched healthy controls (all p < 0.001). Besides conventional predictive factors, baseline serum TG (PFS: p = 0.017; OS: p = 0.018) and ApoA1 (PFS: p = 0.007; OS: p = 0.002) were identified as independent prognostic factors. Among patients with high levels of TG (or low levels of ApoA1) at baseline, those who exhibited objective responses had a significant serum TG decrease (or ApoA1 increase) after treatment (all p < 0.001) (Figure A-B). However, no significant change of TG or ApoA1 was observed in patients without satisfactory response. Compared with baseline levels, further increased levels of TG and decreased levels of ApoA1 after first-line treatment were associated with significantly shorter PFS and OS (all p < 0.001) (Figure C-D). We developed and validated a pre-treatment nomogram containing TG and ApoA1 at baseline and a post-treatment nomogram containing serum lipid at best response (Figure E-F). Compared with pre-treatment nomogram and PINK, the post-nomogram prognostic model was proved to possess a higher predictive power of survival for ENKTL with significantly higher concordance index and the area under the curve (AUC) and lower integrated Brier score (IBS) for 5-year OS. Subgroup analysis showed that Asp-containing regimens were associated with significant survival benefits among patients with low levels of LDL-C and high levels of HDL-C and ApoA1 at baseline (all p < 0.001). Furthermore, the comprehensive transcriptome analysis provided evidence for intratumoral lipid metabolic disorders and dysregulated classical tumor-related signaling pathways, including NOTCH and MAPK, among patients with high levels of TG (or low levels of ApoA1) at baseline (Figure G-H) Conclusion: This study suggests that ENKTL is accompanied by dyslipidemia. Baseline levels and change trends of TG and ApoA1 could contribute to risk stratification, disease status monitoring and treatment outcome prediction. Patients with dyslipidemia also have intratumoral lipid metabolic disorders and dysregulated classical tumor-related signaling pathway. Encore Abstract - previously submitted to EHA 2023 The research was funded by: The research was funded by grants from the National Key Research and Development Program (2022YFC2502602), the National Natural Science Foundation of China (82230001 and 82270199), the Sun Yat-Sen University Clinical Research 5010 Program (2020009), the Special Support Program of Sun Yat-sen University Cancer Center (PT19020401), and the Clinical Oncology Foundation of Chinese Society of Clinical Oncology (Y-XD2019-124 and Y-SY2021ZD-0110). Keyword: Extranodal non-Hodgkin lymphoma No conflicts of interests pertinent to the abstract.

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.

Locally advanced primary breast lymphoma: a rare case report

BackgroundPrimary Breast Lymphoma is a rare manifestation of extranodal non-Hodgkin lymphoma and accounts for less than 1% of all breast malignancies. It is defined by localized involvement of the mammary tissue by lymphomatous infiltrate in the absence of prior extramammary lymphoma and concomitant widespread disease.Case presentationA 46-year-old melanodermic woman was referred to our hospital due to an extensive ulcerated right breast lesion with signs of infection. Imaging studies revealed a large breast tumor invading the chest wall, with cortical disruption of adjacent ribs and associated pleural thickening. Later, it was complicated with a bronchopleural cutaneous fistula. Biopsy of the mass was performed and the histopathologic diagnosis was consistent with breast infiltration by diffuse large B-cell lymphoma. Concurrent widespread lymphomatous disease and preceding extramammary lymphoma were excluded. Firstly, antibiotic therapy was instituted and surgical debridement was performed in order to control the infection. Afterwards, she underwent chemotherapy and local radiotherapy, with radiologic complete response.ConclusionsThe diagnosis of primary breast lymphoma is challenging because this disease has non-specific symptoms and imaging features. Radio–pathological correlation and exclusion of systemic lymphoma are essential to establish the diagnosis and to minimize potential complications.

Primary Bone Lymphoma of the Knee: A Rare Entity

Introduction: The World Health Organization (WHO) defined primary bone lymphoma as a single bone lesion with or without regional lymph node involvement or multiple bone lesions without distant visceral or lymph node involvement. It is a rare entity; indeed, primary bone lymphomas represent 1-3% of non-Hodgkin's lymphomas, 5% of extra-nodal non-Hodgkin's lymphomas and 3% of primary bone tumors [2, 3]. Objective: The objective of our work is to clarify the imaging of a rare entity of primary bone lymphoma in a 6-year-old boy, who had been complaining for 1 month of pain in his right lower limb without functional impotence. Case Report: A 6 year old boy, who had been complaining for 1 month of pain in his right lower limb without functional impotence or other associated signs. The clinical examination revealed a child in good general condition, apyretic, with a limp when walking, limitation of all the articular amplitudes of the left he knee, a swelling of the homolateral thigh with discreet quadricipital amyotrophy. Examination of the lymph nodes did not identify any adenopathies. Standard radiographs of the left knee showed multiple lesions involving the lower extremities of the femur and the upper extremities of the tibia, with confluent intraspongiosa and areas of osteocondensation associated with localized cortical fracture without periosteal reaction. The biological workup revealed no abnormalities, including an LDH in the normal range. An MRI of the right thigh was requested for a better characterization of the lesion and to establish a locoregional extension assessment. It showed a large epiphyseal-metaphyseal lesion process of the lower end of the femur and epiphyseal-metaphyseal of the upper end of the left tibia in T1 hyposignal, locally infiltrating T2 heterogeneous hyper signal with vascular enclosure and popliteal ADPs. The CT scan was requested as part of the extension work-up and did not reveal any secondary lesion. The patient underwent a bone ........

Intravascular CNS Lymphoma: An elusive diagnosis (P2-5.016)

<h3>Objective:</h3> To report a rare case of intravascular CNS lymphoma presenting with subacute neuropsychiatric symptoms and multifocal cerebral infarcts and hemorrhages. <h3>Background:</h3> Intravascular lymphoma is a rare and aggressive subtype of extra-nodal non-Hodgkin lymphoma. It is characterized by proliferation of neoplastic B-lymphocytes within the lumen of small blood vessels, especially capillaries and post-capillary venules. Presentation is variable and depends on the organ dysfunction due to small vessel occlusion. Most common organs involved are CNS, skin and lungs. Given the rarity of the disease, variable presentation and absence of an extravascular tumor mass or peripheral blood abnormalities, the diagnosis can be extremely challenging and is often delayed. <h3>Design/Methods:</h3> NA <h3>Results:</h3> A 62-year old healthy woman presented with transient left hemiplegia and left facial numbness and was diagnosed with transient ischemic attack. In one month, she developed dysarthria and left hemibody clonic seizures without any systemic complaints. Over the next four months, she had a step-wise decline and developed severe apathy, decreased verbal fluency, diffuse hypertonia and worsening encephalopathy. Serial brain MRIs over four months showed acute-subacute infarcts and intracerebral hemorrhages involving both anterior and posterior circulation bilaterally with scattered micro-hemorrhages. Extensive work up, including CT-angiogram and PET-CT were unrevealing. CSF was notable for high protein level without pleocytosis and negative infectious and autoimmune workup. DSA was unrevealing. She did not respond to high dose steroids, intravenous immunoglobulin and cyclophosphamide. Brain biopsy revealed CNS intravascular large B-cell lymphoma. Patient was started on chemotherapy with HyperCVAD-R protocol with no improvement. <h3>Conclusions:</h3> Intravascular CNS lymphoma is a challenging diagnosis. It presents as subacute-chronic CNS vasculopathy with multifocal infarcts and hemorrhages and can mimic other CNS vasculopathies, including primary CNS angiitis and amyloid-related angiopathy. Tissue biopsy is the diagnostic gold standard and should be considered early if poor response to immunotherapy is noted. Despite high-dose chemotherapy, prognosis is poor. <b>Disclosure:</b> Dr. Ticku has nothing to disclose. Dr. Serra has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Biogen Idec. Dr. Serra has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Bristol Myers Squibb.

Deep learning-based overall survival prediction model in patients with rare cancer: a case study for primary central nervous system lymphoma

PurposePrimary central nervous system lymphoma (PCNSL) is a rare, aggressive form of extranodal non-Hodgkin lymphoma. To predict the overall survival (OS) in advance is of utmost importance as it has the potential to aid clinical decision-making. Though radiomics-based machine learning (ML) has demonstrated the promising performance in PCNSL, it demands large amounts of manual feature extraction efforts from magnetic resonance images beforehand. deep learning (DL) overcomes this limitation.MethodsIn this paper, we tailored the 3D ResNet to predict the OS of patients with PCNSL. To overcome the limitation of data sparsity, we introduced data augmentation and transfer learning, and we evaluated the results using r stratified k-fold cross-validation. To explain the results of our model, gradient-weighted class activation mapping was applied.ResultsWe obtained the best performance (the standard error) on post-contrast T1-weighted (T1Gd)—area under curve =0.81(0.03), accuracy =0.87(0.07), precision =0.88(0.07), recall =0.88(0.07) and F1-score =0.87(0.07), while compared with ML-based models on clinical data and radiomics data, respectively, further confirming the stability of our model. Also, we observed that PCNSL is a whole-brain disease and in the cases where the OS is less than 1 year, it is more difficult to distinguish the tumor boundary from the normal part of the brain, which is consistent with the clinical outcome.ConclusionsAll these findings indicate that T1Gd can improve prognosis predictions of patients with PCNSL. To the best of our knowledge, this is the first time to use DL to explain model patterns in OS classification of patients with PCNSL. Future work would involve collecting more data of patients with PCNSL, or additional retrospective studies on different patient populations with rare diseases, to further promote the clinical role of our model.

Intravascular Large B-Cell Lymphoma Identified by PET/CT.

Intravascular large B-cell lymphoma is a rare subtype of extranodal invasive non-Hodgkin lymphoma, and the diagnosis is challenging. Here we report findings of 18F-FDG PET/CT study in a case of intravascular large B-cell lymphoma invading bilateral lungs and kidneys in a 63-year-old woman. The PET/CT images showed diffuse increased FDG uptake in bilateral lungs and kidneys. Unexpectedly, there was no abnormal density on the CT images. The 18F-FDG PET/CT seems to be valuable and sensitive in the diagnosis of intravascular large B-cell lymphoma.

Whole-Exome Sequencing Revealed the Mutational Profiles of Primary Central Nervous System Lymphoma.

Primary central nervous system lymphoma (PCNSL) is a highly aggressive type of extranodal non-Hodgkin lymphoma, of which approximately 90% of the cases are diffuse large B-cell lymphoma (DLBCL). In recent years, the incidence of PCNSL has significantly increased in women and older men. Although advanced treatments such as high-dose methotrexate (HD-MTX) and targeted agents have been introduced, the prognosis of these patients remains poorer than those with other forms of non-Hodgkin's lymphoma. Twelve cases of Chinese PCNSL were analyzed to detect their genetic alterations using whole-exome sequencing (WES). We identified 448 potential somatic single nucleotide variants (SNVs) with a median of 12 SNVs per PCNSL sample and 35 small indels with potentially protein-changing features in 9 PCNSL samples. We found that myeloid differentiation factor 88 (MYD88) had the highest mutation frequency, which affected the activity of the nuclear factor-κB (NF-κB) pathway. PCNSL samples with low-density lipoprotein receptor-related protein 1B (LRP1B) mutations had a higher mutation rate than samples with wild-type LRP1B. Polycystic kidney and hepatic disease 1 (PKHD1), the causal gene of autosomal recessive polycystic kidney disease (ARPKD), was identified in 2 PCNSL cases and exhibited missense mutations. Pathway analysis revealed enrichment in pathways associated with central carbon metabolism in cancer, renal cell carcinoma, nicotine addiction, bladder cancer, and long-term depression. WES revealed significantly mutated genes associated with the molecular mechanisms of PCNSL, which could serve as therapeutic targets to improve patient outcomes.

A Meningioma Mimic and Distinct Subtype of Primary Central Nervous System Lymphoma: Primary Dural Lymphoma

Primary central nervous system lymphoma (PCNSL) is an aggressive form of extranodal non-Hodgkin lymphoma that arises in the brain parenchyma, eyes, meninges, or spinal cord in the absence of systemic disease. Primary dural lymphoma (PDL), in contrast, arises from the dura mater of the brain. PDL is usually a low-grade B-cell marginal zone lymphoma (MZL), whereas other types of PCNSL are usually high-grade large B-cell lymphoma. This specific pathological subtype has important therapeutic and prognostic implications, making PDL a distinct subtype of PCNSL. Herein, we report a case of PDL in an African American patient, in her late thirties, who presented to our emergency room with chronic headaches. An emergent magnetic resonance imaging (MRI) of the brain showed a dural-based homogeneously enhancing extra-axial mass along the left hemisphere, which was contained within the anterior and parietal dural mater. A surgical specimen was collected after an emergency debulking procedure. The flow cytometry, done on the surgical specimen obtained, was positive for CD19+, CD20+, and CD22+, but negative for CD5- and CD10-. These findings were consistent with a clonal B-lymphoproliferative disorder. The surgical pathology specimen immunohistochemistry was positive for CD20+ and CD45+, but negative for Bcl-6Cyclin D1- and CD56-. The Ki67 was 10-20%. These findings were consistent with extranodal MZL. Given the location and pathology, the patient was diagnosed with PDL. Due to MZL's indolent nature, location outside the blood-brain barrier, and known efficacy to bendamustine-rituximab (BR), we decided to treat our patient with BR. She completed six cycles without major complications, and her post-therapy brain MRI showed complete remission (CR). Our case adds to the sparse literature about PDL and highlights the efficacy of BR systemic chemotherapy on MZLs.