Impact of T-Cell Engagers on COVID-19-Related Mortality in B-Cell Lymphoma Patients Receiving B-Cell Depleting Therapy.

PURPOSE: B-cell depleting therapies, including T-cell engager (TCE), are increasingly used for patients with hematologic malignancies, including during the coronavirus disease 2019 (COVID-19) pandemic. We aimed to evaluate the relationship between TCE therapy and COVID-19-related outcomes among patients with COVID-19 and B-cell lymphomas receiving B-cell depleting therapy. MATERIALS AND METHODS: This retrospective cohort study included patients with B-cell lymphoma, who were admitted to Seoul Natio-nal University Hospital with COVID-19 between September 2021 and February 2023, and received B-cell depleting therapy before COVID-19 diagnosis. Multivariable logistic regression was used to identify factors associated with severe to critical COVID-19 and COVID-19-related mortality. RESULTS: Of 54 patients with B-cell lymphomas and COVID-19 who received B-cell depleting therapy, 14 were treated with TCE (TCE group) and 40 with rituximab (RTX group). COVID-19-related mortality was higher in the TCE group than in the RTX group (57.1% vs. 12.5%, p=0.002). In multivariable analyses, TCE therapy (adjusted odds ratio [aOR], 7.08; 95% confidence interval [CI], 1.29 to 38.76; p=0.024) and older age (aOR, 1.06; 95% CI, 1.00 to 1.13; p=0.035) were associated with severe to critical COVID-19. TCE therapy (aOR, 8.98; 95% CI, 1.48 to 54.40; p=0.017), older age (aOR, 1.13; 95% CI, 1.02 to 1.26; p=0.022), and prior bendamustine therapy (aOR, 7.78; 95% CI, 1.17 to 51.65; p=0.034) were independent risk factors for COVID-19-related mortality. CONCLUSION: B-cell lymphoma patients treated with TCE had significantly worse outcomes from COVID-19 than those treated with RTX. TCE therapy should be used with caution in B-cell lymphoma patients during the COVID-19 epidemic.

Dissemination and genome characterization of a human adenovirus F41 in a patient with B-Cell lymphoma.

Adenovirus (HAdV) F41 is a common cause of gastroenteritis and has rarely been reported associated with disseminated disease. In this report, an adult patient with a history of ulcerative colitis, cryptogenic cirrhosis, stage III adenocarcinoma, high-grade diffuse large B-cell lymphoma on chemotherapy was diagnosed with disseminated adenovirus infection. HAdV DNA was quantified in stool, plasma, and urine with viral loads of 7, 4, and 3 log10 copies/mL, respectively. The patient's course was rapidly progressive and he passed away 2 days after initiation of antiviral therapy. The patient's infecting virus was characterized as HAdV-F41 by whole genome sequencing.

Trimethoprim-sulfamethoxazole prevents interstitial pneumonitis in B-cell lymphoma patients receiving chemotherapy: a propensity score matching analysis.

B-cell lymphoma is the most prevalent type of non-Hodgkin lymphoma, for which the standard treatment regimen includes rituximab combined with CHOP. However, some patients may develop interstitial pneumonitis (IP), which can be caused by various factors; one of the most important factors is Pneumocystis jirovecii. It is crucial to investigate the pathophysiology of IP and implement preventive measures since IP can be fatal for some people. The data were collected from the First Affiliated Hospital, Zhejiang University School of Medicine, where patients with B-cell lymphoma received the R-CHOP/R-CDOP regimen with or without prophylactic use of trimethoprim-sulfamethoxazole (TMP-SMX). Multivariable logistic regression and propensity score matching (PSM) were used to investigate any potential association. Eight hundred thirty-one patients with B-cell lymphoma were classified into two groups: the non-prophylaxis group without TMP-SMX (n=699) and the prophylaxis group with TMP-SMX (n = 132). IP occurred in 66 patients (9.4%, all in the non-prophylaxis group), with an onset median of three cycles of chemotherapy. Multiple logistic regression analysis demonstrated that IP incidence was associated with pegylated liposome doxorubicin (OR=3.29, 95% CI 1.84-5.90, P<0.001). After utilizing a 1:1 matching algorithm for PSM, 90 patients from each group were obtained. There was a statistical difference between the two cohorts in the IP incidence (non-prophylaxis 12.2% vs prophylaxis 0.0%, P <0.001). The prophylactic use of TMP-SMX could prevent the occurrence of IP whose risk factor was pegylated liposome doxorubicin after chemotherapy for B-cell lymphoma.

COVID-19 associated Bell's Palsy and lumbosacral neurolymphomatosis in a patient with B-cell lymphoma-Case Report.

This is a case of acute onset unilateral Bell's Palsy during COVID-19 illness, coinciding with development of progressive leg pain, weakness, and sensation change. The patient was ultimately found to have a large B-cell lymphoma mass invading the sciatic nerve, lumbosacral plexus and the spinal canal with compression of cauda equina consistent with neurolymphomatosis. Although COVID-19 infection has been associated with Bell's palsy, Bell's palsy has also been reported with lymphoid malignancy. We review current literature on the association of Bell's palsy with COVID-19 infection and lymphoid malignancy, as well as review the diagnostic challenges of neurolymphomatosis. Providers should be aware of the possible association of Bell's palsy as harbinger of lymphoid malignancy.

An Unusual Cause of Femoral Nerve Paresis in a Horse: Disseminated B Cell Lymphoma With Plasmacytoid Differentiation and Direct Neuronal Invasion.

A 21-year-old Quarter Horse mare presented with a chronic, progressively worsening left pelvic limb lameness of 3 weeks duration. The initial examination identified a consistent lameness at a walk. Neurological examination showed sensory and gait abnormalities consistent with left femoral nerve dysfunction. The horse minimally advanced the leg cranially and had a shortened stride length at the walk. During the stance phase, the heels of the left hind foot did not contact the ground and the horse quickly took weight off of the limb. Diagnostic imaging (ultrasound and nuclear scintigraphy) examinations did not reveal a cause. Severe lymphocytosis was identified on complete blood cell count (69,600 cells /uL; reference range: 1,500-4,000 cells/uL), suggestive of lymphoma. Postmortem examination revealed focal swelling of the left femoral nerve. Multiple masses were found in the stomach, large colon, adrenal gland, mesentery, heart, and meninges. The entire left pelvic limb was dissected and did not reveal other causes of the gait deficit. Histologic evaluation of the left femoral nerve revealed disseminated intermediate cell size B cell lymphoma, with an immunophenotype suggestive of plasmacytoid differentiation. These lymphocytes infiltrated the femoral nerve at the location of the focal nerve swelling, in addition to other peripheral nerves. This case highlights a horse with an atypical diagnosis of femoral nerve paresis caused by direct neoplastic lymphocyte infiltration, deriving from disseminated B cell lymphoma with plasmacytoid differentiation (neurolymphomatosis). Though rare, disseminated lymphoma with direct nerve infiltration should be considered in horses with peripheral neuropathies.

B-cell Lymphoma Presenting as Nasal Septal Perforation.

Sinonasal lymphoma is a rare clinical entity. Three main subtypes exhibit different clinical patterns and treatment outcomes. We report the first case of a B-cell lymphoma in a patient without any previous history of nasal surgery, trauma or drug use, who presented to our center with a nasal septal perforation. Laryngoscope, 133:2871-2873, 2023.

Migratory Pneumonia in Prolonged SARS-CoV-2 Infection in Patients Treated With B-cell Depletion Therapies for B-cell Lymphoma.

OBJECTIVE: To report the clinical and radiological characteristics of patients with underlying B-cell lymphoma and coronavirus disease 2019 (COVID-19) showing migratory airspace opacities on serial chest computed tomography (CT) with persistent COVID-19 symptoms. MATERIALS AND METHODS: From January 2020 to June 2022, of the 56 patients with underlying hematologic malignancy who had undergone chest CT more than once at our hospital after acquiring COVID-19, seven adult patients (5 female; age range, 37-71 years; median age, 45 years) who showed migratory airspace opacities on chest CT were selected for the analysis of clinical and CT features. RESULTS: All patients had been diagnosed with B-cell lymphoma (three diffuse large B-cell lymphoma and four follicular lymphoma) and had received B-cell depleting chemotherapy, including rituximab, within three months prior to COVID-19 diagnosis. The patients underwent a median of 3 CT scans during the follow-up period (median 124 days). All patients showed multifocal patchy peripheral ground glass opacities (GGOs) with basal predominance in the baseline CTs. In all patients, follow-up CTs demonstrated clearing of previous airspace opacities with the development of new peripheral and peribronchial GGO and consolidation in different locations. Throughout the follow-up period, all patients demonstrated prolonged COVID-19 symptoms accompanied by positive polymerase chain reaction results from nasopharyngeal swabs, with cycle threshold values of less than 25. CONCLUSION: COVID-19 patients with B-cell lymphoma who had received B-cell depleting therapy and are experiencing prolonged SARS-CoV-2 infection and persistent symptoms may demonstrate migratory airspace opacities on serial CT, which could be interpreted as ongoing COVID-19 pneumonia.

Mature B-cell lymphoma with acute myelitis as the first presentation: a case report and literature review.

BACKGROUND: Lymphomas are malignant tumors of the immune system that arise in lymphoid organs and can impact the central nervous system. However, lymphomas with acute myelitis as the first manifestation are exceedingly rare, and most of them are symptoms of spinal cord damage due to the lack of specificity in their clinical manifestations. The rate of early misdiagnosis is exceedingly high, and the prognosis is dire. Here, we report a case of mature B-cell lymphoma with acute myelitis as the first presentation and review the related literature. CASE PRESENTATION: In this study, We report a case of a 70-year-old male patient with bilateral lower extremity weakness, bowel and bladder dysfunction, and recurrent fever. A paraureteral mass was seen beneath the right kidney on imaging, and the final pathological biopsy revealed: CD20 ( +), mature B-cell tumor, The patient refused to undergo additional tests to ascertain the type of lymphoma and subsequent therapy and asked to be discharged. In mid-November 2020, the patient died. CONCLUSIONS: This case report shows that patients with lymphoma can present with acute myelitis as the first symptom, especially if they have recurrent fever, that conventional treatment for myelitis is ineffective, and that tumors are considered after other causes of myelitis have been ruled out. Furthermore, a focused search for tumor-related evidence, as well as early identification and therapy, may help patients live longer lives.

B-cell lymphoma-extra large is a promising drug target in Merkel cell carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive skin tumour with neuroendocrine differentiation. Immunotherapies are effective in the treatment of patients with advanced-stage MCC, but for patients whose tumours cannot be controlled by the immune system, alternative approaches are urgently needed. OBJECTIVES: To identify overexpressed oncogenes as potential drug targets for MCC. METHODS: NanoString platform, digital droplet polymerase chain reaction (ddPCR) and fluorescence in situ hybridization (FISH) assays were used to determine copy number variations (CNVs); BCL2L1 and PARP1 mRNA expression levels were determined by quantitative real-time polymerase chain reaction (qRT-PCR), B-cell lymphoma extra-large (Bcl-xL) and poly (ADP-ribose) polymerase 1 (PARP1) protein by immuno-blot. Specific Bcl-xL inhibitors and a PARP1 inhibitor were used alone or in combination to test their antitumour effect. RESULTS: Screening for CNVs in 13 classic Merkel cell polyomavirus (MCPyV)-positive and MCPyV-negative MCC cell lines revealed BCL2L1 gains and amplifications, confirmed by ddPCR in 10 cell lines. By ddPCR and FISH, we demonstrated that BCL2L1 gains are present in tumour tissue. BCL2L1 copy number gains were associated with increased Bcl-xL mRNA and protein expression. However, high Bcl-xL expression was not restricted to MCC cells harbouring a BCL2L1 gain/amplification, suggesting additional epigenetic means of regulation. The functional relevance of Bcl-xL in MCC cells was demonstrated by the fact that specific Bcl-xL inhibitors (A1331852 and WEHI-539) led to the induction of apoptosis. Owing to the strong expression and activation of PARP1 in MCC cell lines, we next tested the combination of Bcl-xL inhibitors with the PARP1 inhibitor olaparib, which showed synergistic antitumour effects. CONCLUSIONS: Bcl-xL, which is highly expressed in MCC, appears to be an attractive therapeutic target for the treatment of this tumour, especially as the effect of specific Bcl-xL inhibitors is synergistically enhanced by simultaneous PARP inhibition.

Targeting the immune microenvironment in Waldenström macroglobulinemia via halting the CD40/CD40-ligand axis.

Recent investigations have improved our understanding of the molecular aberrations supporting Waldenström macroglobulinemia (WM) biology; however, whether the immune microenvironment contributes to WM pathogenesis remains unanswered. First, we showed how a transgenic murine model of human-like lymphoplasmacytic lymphoma/WM exhibits an increased number of regulatory T cells (Tregs) relative to control mice. These findings were translated into the WM clinical setting, in which the transcriptomic profiling of Tregs derived from patients with WM unveiled a peculiar WM-devoted messenger RNA signature, with significant enrichment for genes related to nuclear factor κB-mediated tumor necrosis factor α signaling, MAPK, and PI3K/AKT, which was paralleled by a different Treg functional phenotype. We demonstrated significantly higher Treg induction, expansion, and proliferation triggered by WM cells, compared with their normal cellular counterpart; with a more profound effect within the context of CXCR4C1013G-mutated WM cells. By investigating the B-cell-to-T-cell cross talk at single-cell level, we identified the CD40/CD40-ligand as a potentially relevant axis that supports WM cell-Tregs interaction. Our findings demonstrate the existence of a Treg-mediated immunosuppressive phenotype in WM, which can be therapeutically reversed by blocking the CD40L/CD40 axis to inhibit WM cell growth.

Epstein-Barr Virus-Positive Lymphomas Exploit Ectonucleotidase Activity To Limit Immune Responses and Prevent Cell Death.

Epstein-Barr virus (EBV) is a cancer-associated virus that infects more than 90% of adults. Unfortunately, many EBV-driven malignancies, including numerous B cell lymphomas, are highly aggressive and lack acceptable therapeutic outcomes. The concentrations of extracellular purines, namely, ATP and adenosine, are highly dysregulated in the tumor microenvironment and significantly impact the degree of immune responses to the tumor. Additionally, many tumor cells adapt to this dysregulation by overexpressing one or more ectonucleotidases, enzymes that degrade extracellular nucleotides to nucleosides. The degradation of immunostimulatory extracellular ATP to immunosuppressive adenosine through ectonucleotidase activity is one example of tumor cell exploitation of the purinergic signaling pathway. As such, preclinical studies targeting the purinergic signaling pathway have found it to be a promising immunotherapeutic target for the treatment of solid tumors; however, the extent to which purinergic signaling impacts the development and survival of EBV+ B cell lymphoma remains unstudied. Here, we demonstrate robust ectonucleotidase expression on multiple types of EBV-positive B cell non-Hodgkin lymphoma (NHL). Furthermore, the presence of high concentrations of extracellular ATP resulted in the expression of lytic viral proteins and exhibited cytotoxicity toward EBV+ B cell lines, particularly when CD39 was inhibited. Inhibition of CD39 also significantly prolonged survival in an aggressive cord blood humanized mouse model of EBV-driven lymphomagenesis and was correlated with an enhanced inflammatory immune response and reduced tumor burden. Taken together, these data suggest that EBV+ B cell lymphomas exploit ectonucleotidase activity to circumvent ATP-mediated inflammation and cell death. IMPORTANCE EBV is a ubiquitous pathogen responsible for significant global lymphoma burden, including Hodgkin lymphoma, numerous non-Hodgkin B, T, and NK cell lymphomas, and lymphoproliferative disorders. EBV is also associated with epithelial cancers and autoimmune diseases, such as multiple sclerosis. Many of these diseases are highly aggressive and exhibit poor outcomes. As such, new treatments for EBV-driven cancers have the potential to benefit a large number of patients. We use in vitro and in vivo models to demonstrate the therapeutic potential of targeting the purinergic signaling pathway in the context of EBV-driven B cell lymphoma. These findings lend credence to the manipulation of purinergic signaling as a viable therapeutic approach to EBV+ malignancies and support the feasibility of immunotherapeutic treatments for viral lymphoma.

Waldenstrom Macroglobulinemia Arising During Maintenance Therapy of Plasma Cell Myeloma.

BACKGROUND: Both plasma cell myeloma (PCM) and Waldenstrom's macroglobulinemia (WM) are mature B-cell neoplasms commonly involving bone marrow and usually related to paraproteinemia. METHODS: Secondary WM in a patient with PCM during maintenance therapy has not been previously reported. We herein report the first case of WM arising during maintenance therapy of PCM. RESULTS: The diagnosis of secondary WM during maintenance therapy of PCM was based on combination of medical history, morphology, flow cytometry, immunofixation electrophoresis, and molecular genetics. CONCLUSIONS: This case highlights the importance of an integrated diagnostic work-up, with an interesting role for morphology and flow immunotyping.

Second primary malignancies in non-Hodgkin lymphoma: epidemiology and risk factors.

With the advancements in therapeutics for non-Hodgkin lymphoma (NHL), the long-term survival of patients with NHL has markedly increased. Second primary malignancies (SPMs) have become an increasingly relevant long-term concern for NHL survivors. The etiology of SPMs is multifactorial and involves multiple steps. Germline alterations, immune dysregulation, and clonal hematopoiesis contribute to the accumulation of intrinsic adverse factors, and external factors such as lifestyle; exposure to infectious factors; and late effects of radiotherapy, chemotherapy, high-dose therapy, and autologous hematopoietic stem cell transplantation further increase SPM risk. Therapy-related myeloid neoplasms (t-MNs) are a devastating complication of cytotoxic chemotherapeutic agents. However, as targeted therapies begin to replace cytotoxic chemotherapy, the incidence of t-MNs is likely to decline, particularly for indolent B-cell NHL.

Pathology review identifies frequent misdiagnoses in recurrent classic Hodgkin lymphoma in a nationwide cohort: implications for clinical and epidemiological studies.

Patients treated for classic Hodgkin lymphoma (CHL) have a reported 13-fold increased risk of developing subsequent non-Hodgkin lymphoma (NHL). In light of the growing awareness of CHL mimickers, this study re-assesses this risk based on an in-depth pathology review of a nationwide cohort of patients diagnosed with CHL in the Netherlands (2006-2013) and explores the spectrum of CHL mimickers. Among 2,669 patients with biopsy-proven CHL, 54 were registered with secondary NHL. On review, CHL was confirmed in 25/54 patients. In six of these, the subsequent lymphoma was a primary mediastinal B-cell lymphoma/mediastinal gray zone lymphoma, biologically related to CHL and 19/25 were apparently unrelated B-cell NHL. In 29/54 patients, CHL was reclassified as NHL, including T-cell lymphomas with secondary Hodgkin-like B-blasts (n=15), Epstein Barr virus-positive diffuse large B-cell lymphoma (n=8), CD30+ T-cell lymphoma (n=3) and indolent B-cell proliferations (n=3). Higher age, disseminated disease at presentation, extensive B-cell marker expression and association with Epstein-Barr virus were identified as markers to alert for CHL mimickers. Based on these data, the risk of developing NHL after CHL treatment was re-calculated to 3.6-fold (standardized incidence ratio 3.61; confidence interval: 2.29-5.42). In addition, this study highlights the clinicopathological pitfalls leading to misinterpretation of CHL and consequences for the care of individual patients, interpretation of trials and epidemiological assessments.

Recognizing a Mediastinal Mass: A Case of Primary Mediastinal Large B-Cell Lymphoma With Pruritus in a 23-Year-Old Adult Male Sailor.

Primary mediastinal large B-cell lymphoma (PMBCL) is a rare, non-Hodgkin, B-cell lymphoma thought to originate from thymic B cells, which occurs primarily in young adults such as in the active duty population. Primary mediastinal large B-cell lymphoma (PMBCL) presents as a large mediastinal mass, posing risks to the cardiopulmonary safety of patients and challenging the routine approach to diagnosis. We describe a case of a 23-year-old male sailor who presented to sick call on his ship while in port with shortness of breath, night sweats, 50-pound weight loss, and pruritic punched-out lesions on all extremities. An initial chest X-ray showed a large consolidation. After being seen in the pulmonary medicine clinic 5 weeks after his initial presentation, the patient was admitted to the intensive care unit after computed tomography of his chest revealed a mediastinal mass, causing compression of both the right bronchus and superior vena cava with a large pericardial effusion. Empiric high-dose dexamethasone was initiated before a formal diagnosis due to his significant risk for cardiopulmonary compromise. Following diagnosis and two cycles of chemotherapy, the patient was transferred to a medical oncology facility in the continental USA. This case demonstrates the need to educate all military providers to recognize the presentation of mediastinal masses in active duty service members and the importance of urgently escalating these patients to higher levels of care in order to avoid life-threatening complications.

Impact of Cytomegalovirus Replication in Patients with Aggressive B Cell Lymphoma Treated with Chimeric Antigen Receptor T Cell Therapy.

Data are scarce on cytomegalovirus (CMV) replication in patients receiving CD19-directed chimeric antigen receptor (CAR) T cell treatment. Here we describe the incidence, severity, and management of CMV infection in patients with aggressive B cell lymphoma treated with CAR T cell therapy. In this retrospective observational study, we analyzed CMV viral load and its clinical impact in patients with aggressive B cell lymphoma receiving CAR T cell therapy between July 2018 and December 2021 at a single center. Patients with a negative baseline CMV IgG or a previous allogeneic stem cell transplantation were excluded. CMV replication was determined in whole blood. Overall, 105 patients met the study's inclusion criteria. Ten patients presented with CMV replication before CAR T cell infusion and were analyzed separately. Forty-two of the remaining 95 patients (44%) had at least 1 positive CMV determination, with a viral load ≥1000 IU/mL in 21 patients (22%). Four patients in the main cohort (N = 95) and 4 patients in the preinfusion replication group (N = 10) achieved a viral load >10,000 IU/mL. Only 7 patients received preemptive antiviral treatment. No CMV end-organ disease was reported. The sole independent risk factor associated with CMV viremia ≥1000 IU/mL was dexamethasone treatment (odds ratio, 8.4; 95% confidence interval, 2.4 to 36.6; P = .002). Based on our findings, we designed an algorithm for CMV management in this setting. CMV replication is relatively frequent in patients with aggressive B cell lymphoma receiving CAR T cell therapy. It is usually self-limited and not associated with end-organ disease. Patients receiving dexamethasone or harboring CMV replication before infusion might benefit from active surveillance and preemptive treatment strategies.