High-grade Large B-cell Lymphoma Research Articles

Abstract 3732: Peripheral pharmacodynamic activity of epcoritamab as monotherapy and in combination with rituximab + lenalidomide in patients with follicular lymphoma

Abstract Introduction: Epcoritamab (DuoBody®-CD3xCD20) is a subcutaneous IgG1 bispecific antibody that simultaneously binds to CD3 on T cells and CD20 on malignant B cells, inducing activation and cytotoxic activity of T cells to mediate killing of target lymphoma cells. Epcoritamab is approved in the US for the treatment of adults with relapsed/refractory (R/R) diffuse and high-grade large B-cell lymphoma after ≥2 lines of systemic therapy (also approved in Europe, the UK, Japan, and Canada). Here we present the pharmacodynamic effects of epcoritamab as monotherapy (EPCORE NHL-1: NCT03625037) or in combination with rituximab + lenalidomide (R2) (EPCORE NHL-2: NCT04663347) in peripheral blood of patients with follicular lymphoma (FL), a heterogeneous disease for which many patients have an unmet medical need for efficacious, well-tolerated, off-the-shelf therapies. Methods: In EPCORE NHL-1 expansion phase, adults with R/R FL received epcoritamab monotherapy; in EPCORE NHL-2, adults with R/R (arm 2) or newly diagnosed (ND) (arm 6) FL received epcoritamab combined with R2. B-cell markers and T-cell proliferation and activation markers in whole blood were assessed using validated flow cytometry assays. Cytokines in plasma were measured using a validated multiplex immunoassay. Results: Epcoritamab as monotherapy and in combination with R2 induced rapid depletion of circulating peripheral B cells (CD19+) in patients with detectable peripheral B cells at baseline. Additionally, within the first 2 cycles, epcoritamab monotherapy induced a transient elevation of peripheral CD8+ and CD4+ T cells expressing proliferation (Ki67+%) and activation (HLA-DR+% and PD-1+%) markers. R/R and ND patient groups treated with epcoritamab + R2 showed a trend for greater induction of proliferating and activated peripheral T cells. Likewise, elevation in T-cell absolute counts was observed from cycle 2 onward, with a trend of higher levels with epcoritamab + R2 vs epcoritamab monotherapy. In addition, a moderate but transient elevation of circulating cytokines including IFNγ, IL-6, and IL-10 during cycle 1 was observed with epcoritamab monotherapy and epcoritamab + R2. Importantly, IL-6 and IL-10 returned to approximate baseline levels prior to the subsequent dose. Compared with epcoritamab monotherapy, patients treated with epcoritamab + R2 showed a trend for lower median levels of IL-6 peaks 24 hours after the first full dose. Conclusion: The pharmacodynamic activity of epcoritamab combined with R2 in R/R and ND FL was consistent with epcoritamab’s mechanism of action as monotherapy. Epcoritamab + R2 showed a favorable pharmacodynamic profile with a trend toward increased T-cell activation and T-cell elevation, and lower IL-6 levels. These data support the ongoing phase 3 trial of epcoritamab + R2 compared with R2 alone in patients with R/R FL (EPCORE FL-1: NCT05409066). Citation Format: Han Si, Jimin Zhang, Monica Wielgos-Bonvallet, Lorenzo Falchi, Kim Linton, Wojciech Jurczak, David Belada, Işıl Altıntaş, Mariana Sacchi, Elena Favaro, Ali Rana, Daniela Hoehn, David Soong, Christopher W. Chiu, Maria Jure-Kunkel. Peripheral pharmacodynamic activity of epcoritamab as monotherapy and in combination with rituximab + lenalidomide in patients with follicular lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3732.

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.

Primary central nervous system lymphoma presenting as an isolated intramedullary spinal cord lesion: a case report

Intramedullary spinal cord lesions prove to be a diagnostic challenge due to their non-specific clinical and radiological presentation. There is a preference for empiric medical therapy, given the inherent risks of surgical intervention to the spine. These factors can lead to delay in diagnosis. Primary central nervous system lymphoma is a rare cause and presents with atypical features in the immunosuppressed patient, including a lack of response to steroid therapy. We present a 64-year-old male patient with underlying sarcoidosis who reported progressive neuropathy with imaging showing a spinal cord lesion. Based on the above, multiple courses of empiric therapy were employed, including systemic steroids, chemotherapy and immunotherapy. Despite this, there was further clinical deterioration and interim imaging showed disease progression. The decision was made to perform open biopsy of the spinal cord lesion to aid diagnosis. Histological analysis diagnosed Epstein-Barr virus (EBV)-positive high grade large B-cell lymphoma. The patient received rituximab and methotrexate with radiological response but no clinical benefit. He continued to suffer treatment-related complications including encephalopathy and recurrent infections which eventually lead to death. Primary central nervous system lymphoma is an aggressive disease and failure to respond to empiric treatment should prompt clinician's to consider biopsy for definitive diagnosis. A lack of response to steroids does not exclude lymphoma.

Comorbidities Associated with Early Mortality after CD19 CAR-T Cell Therapy

Objective: CD19 chimeric antigen receptor (CAR) T-cell therapy has changed the standard for treatment of relapsed and/or refractory (r/r) large b-cell lymphoma (LBCL). Currently, pre-treatment evaluation of patients and disease factors do not accurately predict outcomes. This study aims to identify risk factors associated with early mortality prior to day 100 after CAR-T infusion. Methods: We performed a single-centered retrospective adult patients (pts) with r/r LBCL who received CAR-T cell therapy between 2018-2021. CAR-T cell toxicities graded according to either CAR T-Cell Therapy-Associated Toxicity (CARTOX) grading system prior to May, 2019 or American Society of Transplantation and Cellular Therapy (ASTCT) consensus grading thereafter for cytokine release syndrome (CRS) and immune cell associated neurotoxicity syndrome (ICANS). Comorbidities defined as per Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI). (Sorror et al., 2009). Hepatic dysfunction defined as infection with hepatitis B or C or history of liver cirrhosis or elevated total bilirubin, AST, or ALT on at least two values on two different days from day -24 till day -10 prior to CAR-T. Cardiovascular (CV) comorbidity determined by presence of coronary heart disease, congestive heart failure or reduced ejection fraction detected by echocardiogram. Psychiatric disturbance defined as presence of depression and/or anxiety requiring treatment or consultation. Patient demographics, disease characteristics and clinical outcomes summarized through descriptive statistics. Wilcoxon rank sum test used to evaluate difference in a continuous variable between patient groups. Kaplan-Meier method used to estimate time-to-event endpoints including progression free survival (PFS), and overall survival (OS). Results: Two hundred and fifty patients included in analysis. Median age of 61years (range: 18-89) and 30.8% of patients were female (n=77). Histology was categorized as LBCL (65.9%) and included diffuse LBCL or high grade LBCL, transformed follicular lymphoma (26.9%), primary mediastinal b-cell lymphoma (6.4%) or follicular lymphoma (0.8%). Majority of pts received axicabtagene ciloleucel 95.6% (n=239) while 4.4% (n=11) received tisagenlecleucel and 52% (n=130) of pts received bridging therapy. CRS of any grade was 90.4% ; ICANS any grade was 57.2% while grade 3 CRS/ICANS occurred 6.4% and 38.4% respectively. Median follow-up 24.7 months (mo) (95% CI: 20.7 ~ 26.4 mo). One-hundred twenty-eight pts died during follow-up, 48 pts died within 100 days, and most common cause of death was progression of lymphoma (29.2%; n=73). Early 30-day mortality occurred in 4.8% pts and causes of death due to CAR-T related toxicity in 6 pts, disease progression in 3 pts, and infection in 1 pts. 100-day mortality rate was 24.6% (n=32) for pts >60 years old vs 13.3% (n=16) for <60 (p-value=0.02). 100-day mortality rate was 36.5% for ECOG 2-4 vs 14.9% for ECOG 0-1 (p-value=0.0005). In terms of non-relapsed mortality (NRM), risk stratification according to cumulative HCT-CI score was not associated with higher 100-day NRM (p=0.24). Pts with cardiac score of 1 had a higher NRM (26.9% vs. 8.1%; p-value=0.005). The 100-day NRM rates for hepatic score of 0, 1, and 3 were 8.9%, 14.3%, and 50% (p-value=0.04). Pts with psychiatric disturbance score of 1 had higher 100-day NRM (19.6% vs. 7.8%; p-value=0.03). Conclusion: This single center retrospective study observed an increase in 100-day mortality in correlation with pre-treatment performance status, and older age. Pts with cardiac comorbidity, hepatic dysfunction or psychiatric disturbance had a higher 100-day NRM. Similar to other studies, the combined HCT-CI score was not predictive of NRM, but individual variables were associated with higher non-CART related toxicity. These findings require validation with further studies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Case of Primary Dural Lymphoma Treated with Bendamustine and Rituxan

Background Primary CNS 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) arises from the dura mater of the brain. It differs biologically from other CNS lymphomas. It 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 who was treated with bendamustine and rituximab. Case Presentation A 38-year-old African American female patient presented with chronic intermittent headaches. MRI of the brain showed a dural-based homogeneously enhancing extra-axial mass along the left hemisphere with extension to the anterior interhemispheric falx and anterior right frontal lobe measuring up to 11 cm. This was found to have a significant mass effect and 1-2 cm left-to-right midline shift on the underlying brain parenchyma with vasogenic edema. The patient underwent an emergent craniotomy and debulking of the mass. The tumor was contained within the anterior and parietal dural matter. The malignant cells stained diffusely positive for CD19, CD20, and CD22 but negative for CD5, CD10, Cyclin D1, and CD56. Ki67 was 10-20%, consistent with extranodal marginal zone lymphoma. Given the location and pathology, the patient was diagnosed with PDL. She was started on treatment with bendamustine and rituximab. She completed six cycles, and post-therapy MRI brain showed complete remission. She continues to do well two years after finishing treatment. Discussion The Dura mater is devoid of lymphoid tissue; however, it is hypothesized that chronic inflammation of the dura due to chronic infection or autoimmune disorder may attract polyclonal lymphocytes from which monoclonal lymphoma could arise. PDL has not been definitively associated with any infectious or autoimmune disease, but patients with hepatitis C, scleroderma, Graves' disease, and Sjogren disease have been reported. Developmentally, the dura originates from the mesoderm. In contrast, the CNS originates from the ectoderm, which leads to the presence of the dura outside the blood-brain barrier and is easily exposed to systemic therapies. So, HDMTX regimens are excessive for PDL, where MZL is the most common pathology. Because of this and the known efficacy of bendamustine-rituximab in extranodal MZL, we decided to treat our patient with this regimen. Tsutsumi et al. reported 2 cases of dural MZL that were treated successfully with bendamustine-rituximab. However, those two cases also had evidence of systemic disease, not only dural disease like our patient. Because of its indolent pathology, surgery and/or radiation have also been used as treatment modalities, although complete resection of dural lymphomas can be technically difficult Conclusion Our case adds to the sparse literature about primary dural lymphoma. It emphasizes the importance of recognizing it as a separate entity from parenchymal PCNSL, an aggressive disease with a poor prognosis. Surgery, radiation, and/or chemoimmunotherapy used for other extranodal MZL are appropriate treatments for PDL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Association of a Giant Lymphoma Mass With Occupational Benzene Exposure

Benzene is a chemical widely used in industrial settings and known to have hematopoietic toxicity. Previous literature has been inconsistent regarding a direct association of benzene exposure with lymphoma. A young patient with a strong history of benzene exposure presented with a 17-cm chest wall lymphoma and purulent drainage from the mass. He underwent resection of the mass. Pathologic analysis revealed a high-grade diffuse large B-cell lymphoma. The wound ultimately healed well and the patient received adjuvant chemotherapy. Though the overall literature has been inconsistent regarding the association of benzene with lymphoma, our report highlights the possibility that a very extensive exposure history may be a risk factor for the development of lymphoma. J Med Cases. 2019;10(9):274-276 doi: https://doi.org/10.14740/jmc3364

ZUMA-12: A phase 2 multicenter study of axicabtagene ciloleucel (axi-cel) as a first-line therapy in patients (pts) with high-risk large B-cell lymphoma (LBCL).

TPS7574 Background: Pts with LBCL who have persistent disease assessed by dynamic PET after rituximab-based induction therapy have an increased risk of death (Casasnovas, et al. Blood. 2017). Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved for the treatment of pts with relapsed/refractory LBCL with ≥ 2 prior systemic therapies. In ZUMA-1, the registrational study of axi-cel in pts with refractory LBCL, the objective response rate (ORR) was 91% (70% complete response [CR] rate) in pts with double-expressor or high-grade LBCL with ongoing responses in 48% after a median follow-up of 27.1 mos (Locke FL, et al. Lancet Oncol 2019). Furthermore, pts with fewer prior lines of therapy and lower tumor burden had higher rates of ongoing responses and manageable safety (Locke et al. ASCO 2018. 3039). ZUMA-12 will investigate the efficacy and safety of axi-cel as a first-line therapy in newly diagnosed pts with high-risk LBCL who have PET-positive disease after 2 cycles of induction therapy. Methods: This Phase 2 study has a planned enrollment of ≈40 pts aged ≥ 18 y with high-risk LBCL, defined by the presence of MYC and BCL2 and/or BCL6 translocations by FISH or an IPI score ≥ 3 any time before enrollment, and an ECOG performance status of 0 – 1. Before enrollment, pts must have a Deauville score of 4 – 5 (Barrington SF et al. J Clin Oncol. 2014) after 2 cycles of chemoimmunotherapy that includes an anti-CD20 monoclonal antibody and anthracycline. After leukapheresis, pts with bulky or rapidly progressing disease may receive optional non-chemotherapy bridging therapy. Following conditioning therapy with cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) for 3 days, pts will receive a single infusion of axi-cel at a target dose of 2 × 106 CAR T cells/kg. The primary endpoint is investigator-assessed CR rate per the Lugano classification (Cheson et al. J Clin Oncol. 2014). Key secondary endpoints include ORR, duration of response, event-free survival, progression-free survival, overall response, safety, relapse with CNS disease and levels of blood CAR T cells and serum cytokines over time. Accrual is ongoing. Clinical trial information: NCT03761056.

Primary Diffuse Large B-cell Lymphoma of Dura and Cranial Vault

Primary central nervous system lymphoma (PCNSL) is an extranodal non-Hodgkin lymphoma that is deep seated and despite effective treatment regimens the prognosis is poor with a 5-year survival of 10%. Primary dural lymphoma a rare form of PCNSL, is usually a low-grade B-cell lymphoma of the mucosa-associated lymphoid tissue type or marginal zone B-cell lymphomas. Primary dural diffuse large B-cell lymphoma, as an aggressive form, is extremely rare with only 13 cases reported in literature. We present a short series of 3 cases of this rare variety of primary dural lymphomas along with the review of literature. They mimic meningiomas and involve the cranial vault, with scalp swelling being the most common presentation. They are staged as Ann-Arbor stage IE primary high-grade large B-cell lymphoma of the dura and, at present, owing to rarity of the disease, are treated as PCNSLs. Whether the high-grade dural lymphomas behave like aggressive PCNSLs and exact management in view of the fact that they appear to be outside blood-brain barrier will require the review of larger series and case reports.

High grade primary adrenal intravascular large B-cell lymphoma manifesting as Addison disease

We report a rare case of a 68 aged male who presented with adrenal failure and was diagnosed of high grade large B-cell lymphoma primarily arising in the adrenal glands. The patient was administrated with additional chemotherapy but he passed away 7 months later due to infection in the lungs. Intravascular lymphoma should be suspected in patients with bilateral adrenal masses who present with rapidly progressive adrenal insufficiency.

Genetic aberrations common in gastric high-grade large B-cell lymphoma

Genetic aberrations associated with the development of extranodal high-grade large B-cell lymphoma originating in the stomach have not been fully identified yet. We analyzed 31 such lymphomas using 73 microsatellite markers for allelic imbalance and microsatellite instability. The highest frequency (42%) of loss of heterozygosity (LOH) was found on the long arm of chromosome 6. We identified 2 LOH hot spots on 6q21-22.1 and 6q23.3-25, flanked by markers D6S246-D6S261 and D6S310-D6S441, respectively, containing putative tumor suppressor genes (TSGs). These 6q aberrations were found to be the sole allelic imbalance in 1 patient only; they were mostly accompanied by additional abnormalities. Several known TSGs, namely, the APC, p15/p16, p53, and DCC genes, were found to suffer frequent LOH during lymphomagenesis. LOH was also detected in regions containing putative TSGs on 7q and 13q14. Frequent amplification of genomic material was found in the 2p, 3q27 at the BCL-6 gene locus, 6p, 7q, 11q23-24 at the MLL gene locus, and 18q regions. Analysis of the pattern of occurrence of these aberrations revealed an association of the amplification of the MLL gene region with LOH at the p53 locus (P =.02). Only low frequency of microsatellite instability (MSI) was detected in these lymphomas and MSI incidence increased with age (P =.01). Karyotypic instability thus plays the main role in the development of gastric high-grade large B-cell lymphoma. Common genetic aberrations responsible for lymphomagenesis are deletions of 6q, loss of p53, and amplification of the 3q27 and the MLL gene regions. (Blood. 2000;95:1180-1187)

Lymphomas in Patients with Sjögren's Syndrome: Review of the Literature and Physiopathologic Hypothesis

The occurrence of non Hodgkin's lymphoma (NHL) is the most serious complication of Sjögren's syndrome (SS). Taking the opportunity to study 16 patients with lymphoma and an underlying SS, we performed a review of literature concerning SS and lymphoma and made an hypothesis on the physiopathology of lymphoproliferation in patients with SS.Lymphomas occurring in patients with SS are in most cases low grade marginal zone lymphomas (MZL). They arise frequently in mucosal extranodal sites, not only in the salivary glands but also the stomach and the lung. These lymphomas are not associated with viruses including hepatitis C virus (HCV), Epstein-Barr virus, human herpes virus 8 or human T lymphotropic virus-I, known to be present in other types of lymphomas. Some of the translocations or mutations of oncogenes or anti-oncogenes described in other lymphomas are also detected in SS-associated lymphomas.Lymphomas complicating SS share a number of characteristics with lymphomas complicating HCV infection. We make the asumption that, in both diseases, the first event of lymphomagenesis is the chronic stimulation, on the site of the disease, of polyclonal B-cells secreting rheumatoid factor (RF). Then, these RF B-cells may become monoclonal and disseminate in other organs. The monoclonal secreted RF complexed with polyclonal IgG may cryoprecipitate. The following step would be a chromosomal abnormality (e.g. trisomy 3) which would confer to these cells a low grade B-cell lymphoma compartment. A last event (e.g. mutation of p53) could transform this low grade B-cell lymphoma into a high grade large B-cell lymphoma. If this hypothesis was correct, most of B-cell lymphomas associated with SS should have a surface immunogiobulin with RF activity and should grow through an auto-antigen driven process.