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Primary cutaneous B-cell lymphomas represent a type of non-Hodgkin's lymphoma of the skin without evidence of extracutaneous involvement at the time of diagnosis. According to the 2018 World Health Organization-the European Organization for Research and Treatment of Cancer classification, primary cutaneous B-cell lymphomas include primary cutaneous marginal zone lymphoma, primary cutaneous follicle center lymphoma, primary cutaneous diffuse large B-cell lymphoma, leg type, intravascular large B-cell lymphoma, and Epstein-Barr virus+ mucocutaneous ulcer (provisional). Herein, we provide a comprehensive review of the updated literature on these entities, including clinical presentation, histopathology, immunophenotype, molecular genetics, prognosis, and treatment., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Immunoglobulin (IG) gene remodeling by V(D)J recombination plays a central role in the generation of normal B cells, and somatic hypermutation and class switching of IG genes are key processes during antigen-driven B cell differentiation in the germinal center reaction. However, errors of these processes are involved in the development of B cell lymphomas. IG locus-associated translocations of proto-oncogenes are a hallmark of many B cell malignancies. Additional transforming events include inactivating mutations in various tumor suppressor genes and also latent infection of B cells with viruses, such as Epstein-Barr virus. Most B cell lymphomas require B cell antigen receptor expression, and in several instances chronic antigenic stimulation plays a role in lymphoma development and/or sustaining tumor growth. Often, survival and proliferation signals provided by other cells in the microenvironment are a further critical factor in lymphoma development and pathophysiology. Most B cell malignancies derive from germinal center B cells, most likely due to the high proliferative activity of these B cells and aberrant mutations caused by their naturally active mutagenic processes., (© 2025. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: To summarize the clinical characteristics, prognostic factors and treatment outcomes of childhood aggressive mature B-cell lymphoma after liver transplantation. Methods: This retrospective study included 18 children with newly diagnosed aggressive mature B-cell lymphoma after liver transplantation and treated from June 2018 to June 2022 in the Department of Hematology and Oncology of Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine. Clinical characteristics, treatment and outcomes of patients at last evaluation were analyzed. Overall survival (OS) and event free survival (EFS) rates were calculated by Kaplan-Meier method and Log-Rank analysis was performed to find factors of poor prognosis. Results: Among all 18 patients, there were 6 males and 12 females, and the age of onset was 40 (35, 54) months. The interval from transplant to tumor diagnosis was 21 (17, 35) months and 5 patients had early onset disease (<1 year since transplant). Seventeen patients had abdominal lesions. Diarrhea, vomiting and abdominal masses were the main clinical manifestations. All patients were Epstein-Barr virus (EBV) related posttransplant lymphoproliferative disorders (PTLD). One patient received individualized therapy due to critical sick at diagnosis, and the remaining 17 patients received CP (cyclophosphamide, methylprednisolone plus rituximab) and (or) modified EPOCH (prednisone, etoposide, doxorubicin, vincristine, cyclophosphamide plus rituximab) regimens. Of all 18 patients, 15 cases got complete response, 2 cases got partial response, 1 patient died of severe infection. The 2-year OS and EFS rates of 18 patients were (94±5)% and (83±8)%, respectively. None of age, gender or early onset disease had effect on OS and EFS rates in univariate analysis (all P >0.05). Conclusions: The symptoms of PTLD were atypical. Close surveillance of EBV-DNA for patients after liver transplantation was crucial to early stage PTLD diagnosis. CP or modified EPOCH regimen was efficient for pediatric patients with aggressive mature B cell lymphoma after liver transplantation.

Chimeric antigen receptor T cells (CAR-T) has emerged as a promising therapy, over 60% of patients fail to sustain a long-term response. The underlying factors that leads to the effectiveness of this therapy are not completely understood, CAR-T cell persistence and monitoring seems to be pivotal for ensuring a successful response. Various monitoring methods such as multiparametric flow cytometry (MFC) or quantitative PCR (qPCR) have been applied. Our objective is to develop digital PCR (dPCR) assays for detection and quantification of CAR-T cells, comparing them with MFC and qPCR. Samples taken at different follow-up times from 45 patients treated with CAR-T therapy were analyzed to assess the correlation between the different methodologies. dPCR presented a high correlation with MFC and qPCR (r = 0.97 and r = 0.87, respectively), while offering a higher sensitivity (0.01%) compared to MFC (0.1%) and qPCR (1%). dPCR emerged as an alternative and highly sensitivity method for monitoring CAR-T cell dynamics. This technique is well-suited for implementation in clinical practice as a complementary technique to MFC., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Introduction: Although anti-CD19 chimeric antigen receptor (CAR) T cell therapy was approved as a very effective salvage strategy in relapsed/refractory (R/R) B cell lymphoma, the experience in R/R gastrointestinal (GI) lymphoma is still insufficient., Methods: We summarized the efficacy and side effects of anti-CD19 CAR T-cell therapy in 12 patients with R/R GI lymphoma. Based on literature, the R/R GI lymphoma patients were divided into subgroups with different characteristics: Bulky/No bulky disease, Gastric/Gastrointestinal involvement, Gastrointestinal/Combined extra-gastrointestinal lesions, Ulcer/Lumps or nodules type, With/without gastrointestinal bleeding., Results: The objective response rate (ORR) was 66.67% in these 12 patients. The ORR was 83.33% in no bulky disease group, 80.00% in gastric involvement group, 100.00% in ulcer type group, and 80.00% in no gastrointestinal bleeding group. The CR rate was 33.33% in these 12 patients. The CR was 50.0% in no bulky disease group, 60.00% in gastric involvement group, and 80.00% in ulcer type group. The PFS and OS rate of the 12 patients at 6 months after infusion were 54.55% and 58.33%, respectively. The overall survival (OS) at 6 months was higher in no bulky disease group. There was no difference of the OS or the progression free survival (PFS) at 6 months between the other groups. The mean peak of CAR-T cells and Cytokine Release Syndrome (CRS) grade were higher in gastrointestinal lesions group. The mean peak of IFN-γ and CRS grade were higher in gastrointestinal bleeding group. Four out of six patients in group of gastrointestinal lesions group were patient with high tumor burden. Patients with gastrointestinal involvement only were at higher risk for gastrointestinal bleeding., Conclusions: The ORR and CR of high tumor load, gastrointestinal involvement, lumps or nodules type and gastrointestinal bleeding group were lower. The CRS grade was higher in gastrointestinal lesions group and in gastrointestinal bleeding group. Patients with gastrointestinal involvement only were at higher risk for gastrointestinal bleeding., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Relapse is the major cause of failure of high-dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) for B cell non-Hodgkin lymphomas (B-NHL). Improvement strategies include use in combination with effective immunotherapies. We hypothesized that the combination of rituximab/HDC/ASCT with expanded cord blood (CB)-derived natural killer (NK) cells is safe and active in B-NHL. Patients with B-NHL age 15 to 70 years and appropriate ASCT candidates were eligible for the study. The CB units were selected without considering HLA match with the recipient. The CB NK cells were expanded from day -19 to day -5. Treatment included rituximab on days -13 and -7, BEAM (carmustine/etoposide/cytarabine/melphalan) on days -13 to -7, lenalidomide on days -7 to -2, CB NK infusion (10 8 /kg) on day -5, and ASCT (day 0). The primary endpoint was 30-day treatment-related mortality (TRM); secondary endpoints included relapse-free survival (RFS), overall survival (OS), and persistence of CB NK cells. We enrolled 20 patients. CB NK cells were expanded a median of 1552-fold with >98% purity and >96% viability. We saw no adverse events attributable to the CB NK cells and 0% 30-day TRM. At median follow-up of 47 months, the RFS and OS rates were 53% and 74%, respectively. CB NK cells were detectable in blood for 2 weeks, independent of HLA-mismatch status. CD16 expression in donor NK cells was correlated favorably with outcome, and homozygosity for the high-affinity CD16 variant (158 V/V) in CB, but not recipient, NK cells was correlated with better outcomes. Our data indicate that the combination of expanded and highly purified CB-derived NK cells with HDC/ASCT for B-NHL is safe. CD16 expression in donor NK cells, particularly if homozygous for the high-affinity CD16 variant, was correlated with better outcomes., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Purpose: CAR T-cell therapy gives patients new hope, who are diagnosed with relapsed or refractory B-cell lymphoma or B-cell leukaemia. To date, there is no scientific knowledge about the experiences of patients with CAR T-cell therapy, their process of treatment decision making or how they handle potential side effects. The study aims at deepening the understanding of the patient's experiences, indicating how to improve nursing care for this patient population., Method: A qualitative study was carried out. Episodic guideline-based interviews were conducted with 14 patients who had received CAR T-cell therapy. The data analysis was performed according to the Grounded Theory. The study took place at a German university hospital., Results: Data analysis showed five sequential phases including the following concepts: 'living with cancer recurrence', 'deciding on CAR T-cell therapy', 'waiting for the reinfusion of the CAR T-cells', 'experiencing CAR T-cell therapy' and 'recovering and staying healthy'. The decision for CAR T-cell therapy was characterised by the lack of alternatives and uncertainty about the outcome and side effects., Conclusions: Before, during and after CAR T-cell therapy, patients are faced with major challenges for which they need nursing support and guidance. These include preparation for CAR T-cell therapy, handling of side effects and preparation for discharge home., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) is a challenging disease with low rates of remission and survival in adult patients. Anti-CD19 Chimeric Antigen Receptor T-cells (CAR-Ts) therapies have been approved for these patients. Dual-target CAR-Ts against CD19 and CD22 have recently been developed to improve the efficacy of the single-target therapy; however, extent of the improvement using this dual-target therapy has yet to be determined. We performed a meta-analysis of the outcome and safety of CAR-Ts, comparing anti-CD19 vs anti-CD22 vs dual-target anti-CD19/CD22 CAR-Ts, to elucidate the differences and limitations of these therapies in adult patients with R/R B-ALL. Although the limitations of our study derived from heterogeneity in the included publications, our results suggest that anti-CD19/CD22 CAR-Ts generate lower incidence of relapse and neurotoxicity, but similar results were obtained regarding complete remission, minimal residual disease, overall survival, and cytokine release syndrome compared with single-target anti-CD19 and anti-CD22 CAR-Ts.

Bendamustine has a potent immunosuppressive effect because it causes T-cell lymphopenia, which might lead to a second primary malignancy (SPM) and would increase the risk of infection. Using the Medical Data Vision administrative claims database, we compared the cumulative incidence of SPM, infections within 6 months, and overall survival (OS) among untreated patients with indolent B-cell lymphomas (iBCL) who received rituximab-based chemotherapy between 2009 and 2020. Patients with grade 3b follicular lymphoma or a previous history of malignancy were excluded. Eligible 5234 patients were assigned to three cohorts: rituximab monotherapy (N = 780), RCHOP/RCVP/RTHPCOP (doxorubicin replaced with pirarubicin) (N = 2298), or bendamustine/rituximab (BR) (N = 2156). There were 589 recorded SPMs, of which myelodysplastic syndromes were the most common (1.7%). The cumulative incidence of SPM was significantly higher in patients treated with BR than in those treated with rituximab monotherapy (p < 0.01) or RCHOP/RCVP/RTHPCOP (p < 0.0001): the 5-year cumulative incidence function was 18.1%, 12.5%, and 12.9%, respectively. In the Fine-Gray subdistribution hazards model, BR showed a significantly higher cumulative incidence of SPM than RCHOP/RCVP/RTHPCOP (subhazard ratio, 1.33; 95% confidence interval [CI], 1.10-1.61). Furthermore, in sensitivity analysis, a nested case-control study using an entire cohort showed consistent results: the SPM odds ratios (95% CI) of first-line bendamustine, bendamustine after first-line, and any-line bendamustine were 1.43 (1.14-1.78), 1.26 (0.96-1.64), and 1.33 (1.09-1.62), respectively. Regarding infections, adjusted odds ratios (95% CI) of BR compared to RCHOP/RCVP/RTHPCOP were as follows: cytomegalovirus infection, 13.7 (4.88-38.4); bacterial pneumonia, 0.63 (0.50-0.78); and pneumocystis pneumonia, 0.24 (0.11-0.53). There was no significant difference in OS between RCHOP/RCVP/RTHPCOP and BR in patients with follicular, mantle cell, marginal zone, or lymphoplasmacytic lymphomas. In conclusion, treatment strategies that consider the risk of SPM and infections after chemotherapy are warranted in patients with iBCL., (© 2023 The Authors. Hematological Oncology published by John Wiley & Sons Ltd.)

Purpose: Chimeric antigen receptor (CAR)-T cells are a viable treatment option for patients with relapsed or refractory (r/r) aggressive B-cell lymphomas. The prognosis of patients who relapse after CAR-T cell treatment is dismal and factors predicting outcomes need to be identified. Our aim was to assess the value of FDG-PET/CT in terms of predicting patient outcomes., Methods: Twenty-two patients with r/r B-cell lymphoma who received CAR-T cell treatment with tisagenlecleucel (n = 17) or axicabtagene ciloleucel (n = 5) underwent quantitative FDG-PET/CT before (PET-0) and 1 month after infusion of CAR-T cells (PET-1). PET-1 was classified as complete metabolic response (CMR, Deauville score 1-3) or non-CMR (Deauville score 4-5)., Results: At the time of PET-1, 12/22 (55%) patients showed CMR, ten (45%) patients non-CMR. 7/12 (58%) CMR patients relapsed after a median of 223 days, three of them (25%) died. 9/10 (90%) non-CMR patients developed relapse or progressive disease after a median of 91 days, eight of them (80%) died. CMR patients demonstrated a significantly lower median total metabolic tumor volume (TMTV) in PET-0 (1 ml) than non-CMR patients (225 ml)., Conclusion: Our results confirm the prognostic value of PET-1. 42% of all CMR patients are still in remission 1 year after CAR T-cell treatment. 90% of the non-CMR patients relapsed, indicating the need for early intervention. Higher TMTV before CAR-T cell infusion was associated with lower chances of CMR., (© 2023. The Author(s).)

Purpose: A barrier to widespread adoption of chimeric antigen receptor (CAR) T-cell therapy is toxicity. To address this, we recently developed a novel antibody-T-cell receptor (AbTCR) platform (trademarked as ARTEMIS ® ) which was designed to leverage natural immune receptor signaling and regulation. The AbTCR platform includes a gamma/delta (γδ) TCR-based AbTCR construct and a separate co-stimulatory molecule, both engineered to be tumor-specific. Here, we aim to assess the safety and preliminary efficacy of a CD19-directed AbTCR T-cell therapy., Methods: We generated ET019003 T cells, which are autologous CD19-directed AbTCR T cells. We then conducted an early phase I study to evaluate the safety and preliminary efficacy of ET019003 T cells for the treatment of CD19-positive relapsed/refractory (r/r) B-cell lymphoma., Results: Sixteen patients enrolled in this study and 12 patients were treated. Of the 12 patients treated, 6 patients (50%) achieved a complete response (CR), and 4 (33%) achieved a partial response (PR) (best objective response rate [ORR] of 83%). CRs were durable, including 2 patients with ongoing CRs for 22.7 months and 23.2 months. ET019003 was well-tolerated with an attractive safety profile. No patients experienced severe (grade ≥ 3) cytokine release syndrome (CRS) and only 1 patient experienced immune effector cell-associated neurotoxicity syndrome (ICANS) of any grade. Significant elevations of cytokine levels were not seen, even in patients with marked expansion of ET019003 T cells., Conclusion: This study provides initial clinical validation of the AbTCR platform as a novel cancer treatment with the potential to provide durable clinical benefit with low toxicity., Trial Registration: NCT03642496; Date of registration: August 22, 2018., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

GABRIELL was a phase II single-arm study to evaluate the efficacy and safety of obinutuzumab plus bendamustine for relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Seventy-two patients with active disease received treatment for up to six 28-day cycles. Overall response rate was 78.6% with a median progression-free survival (PFS) of 26 months, and overall survival (OS) not reached at the end of follow-up (36 months). Undetectable measurable residual disease (≤0.01%; 36.4% in bone marrow and 53.4% in peripheral blood) correlated with a significantly longer PFS and OS (vs. >0.01). Common grade ≥3 adverse events (76.4%) were neutropenia (58.3%), thrombocytopenia (26.4%) and febrile neutropenia (11.1%). TP53 disruption was the only independent predictive factor for response (Hazard ratio; HR: 0.228). Unmutated immunoglobulin heavy chain variable region (HR: 16.061) was a negative prognostic factor for PFS. In conclusion, the combination of obinutuzumab plus bendamustine is an active and generally adequately-tolerated treatment for R/R CLL.

The tick-borne pathogen Neoehrlichia (N.) mikurensis is implicated in persistent infection of the vascular endothelium. B cells are crucial for the host defence to this infection. Chronic stimulation of B cells may result in B-cell transformation and lymphoma. Five patients with malignant B-cell lymphoma and concomitant N. mikurensis infection were investigated regarding clinical picture, lymphoma subtype, B-cell lymphoma immunophenotype and IGHV (variable region of the immunoglobulin heavy) gene repertoire. Three of the five patients improved markedly and ceased lymphoma treatment after doxycycline treatment to eliminate N. mikurensis. Sequencing the B-cell lymphoma IGHV genes revealed preferred usage of the IGHV1 (IGHV1-2, and -69) and IGHV3 (IGHV3-15, -21, -23) families. In conclusion, N. mikurensis infection may drive the development of malignant B-cell lymphomas. Eradication of the pathogen appears to induce remission with apparent curing of the lymphoma in some cases., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

The prognosis of non-Hodgkin lymphoma (NHL) remains poor, with an unmet need for novel therapies. MG4101, an ex vivo-expanded allogeneic natural killer (NK) cell, can enhance rituximab antibody-dependent cytotoxicity in relapsed/refractory (r/r) B cell non-Hodgkin lymphoma. This study assessed the safety and efficacy of MG4101 plus rituximab for patients with r/r NHL. Patients received escalating doses of i.v. MG4101 plus rituximab every 2 weeks. IL-2 was administered s.c. after MG4101 treatment. Fludarabine plus cyclophosphamide was administered i.v. before rituximab treatment in cycles 1, 3, and 5. A 3+3 design was used to determine the maximum tolerated dose (MTD) and maximum feasible dose. Assessments were performed over a 6-cycle period, with an extended maintenance period of up to 8 cycles. Nine patients received 3 different doses of MG4101 and rituximab. MTD could not be determined because of the absence of dose-limiting toxicity. Treatment-related adverse events, mostly grade 1 or 2, occurred in 89% of patients. Only 1 patient experienced grade 1 cytokine release syndrome. MG4101 persisted for at least 7 days in 7 patients. Four patients achieved a partial response and 1 patient attained a complete response, for an overall response rate of 55.6%. Two patients showed prolonged responses and low exhaustion marker levels in T cells. For allogeneic NK cell therapy, strategies including the use of the high-affinity hFcγRIIIaV158 variant of the KIR B/x haplotype with lymphodepleting chemotherapy may be promising options for improving clinical efficacy in the antibody combination therapeutic setting as an off-the-shelf product. MG4101 plus rituximab presented a favorable safety profile and overall response rate in patients with r/r NHL., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Chimeric antigen receptor (CAR) T-cell therapy has led to profound and durable tumor responses in a relevant subset of patients with relapsed/refractory (r/r) B-cell lymphomas. Still, some patients show insufficient benefit or relapse after CAR T-cell therapy. We performed a retrospective study to investigate the correlation between CAR T-cell persistence in the peripheral blood (PB) at 6 months, assessed by droplet digital PCR (ddPCR), with CAR T-cell treatment outcome. 92 patients with r/r B-cell lymphomas were treated with CD19-targeting CAR T-cell therapies at our institution between 01/2019-08/2022. Six months post-treatment, 15 (16%) patients had no detectable circulating CAR-T constructs by ddPCR. Patients with CAR T-cell persistence had a significantly higher CAR T-cell peak (5432 vs. 620 copies/ug cfDNA, p = 0.0096), as well as higher incidence of immune effector cell-associated neurotoxicity syndrome (37% vs. 7%, p = 0.0182). After a median follow-up of 8.5 months, 31 (34%) patients relapsed. Lymphoma relapses were less frequent among patients with CAR T-cell persistence (29% vs. 60%, p = 0.0336), and CAR T-cell persistence in the PB at 6 months was associated with longer progression-free survival (PFS) (HR 2.79, 95% CI: 1.09-7.11, p = 0.0319). Moreover, we observed a trend towards improved overall survival (OS) (HR 1.99, 95% CI: 0.68-5.82, p = 0.2092) for these patients. In our cohort of 92 B-cell lymphomas, CAR T-cell persistence at 6 months was associated with lower relapse rates and longer PFS. Moreover, our data confirm that 4-1BB-CAR T-cells have a longer persistence as compared to CD-28-based CAR T-cells.

Purpose: We aimed to analyze the safety and efficacy of a radiation bridging regimen with or without chemotherapy compared with chemotherapy alone prior to CAR T-cell treatment for relapsed/refractory aggressive B-cell lymphoma (r/r ABL)., Methods and Materials: In this study, 45 out of 105 patients enrolled in CD19/22 CAR T-cell "cocktail" clinical trial were excluded, including 34 patients without bridging treatment. Total 60 patients receiving CAR T-cell therapies with bridging regimens as chemotherapy alone (C-CAR-T group, n = 31), and radiotherapy with or without chemotherapy (R-CAR-T group, n = 29) between February 2017 and October 2020 were retrospectively analyzed., Results: No significant toxicities were identified in the R-CAR-T group, and no patients in either group experienced CAR-T-related deaths. However, the R-CAR-T group showed a lower incidence of cytokine release syndrome (CRS) of grade ≥ 3 relative to the C-CAR-T group (0% vs 19.4%, P = 0.036). The incidence of neurological toxicity was 9.9% and 6.9% in the C-CAR-T group and R-CAR-T group, respectively (P = 0.697). The R-CAR-T group achieved a higher overall response rate (ORR) at the day 30 assessment (82.8% vs 45.2%, P = 0.0025). Further analyzing the outcomes, the R-CAR-T group presented a better 1-year progression-free survival (PFS) rate than the C-CAR-T group (46.9% vs 22.6%, P = 0.0356). Intriguingly, the bridging radiation regimen extremely improved the 6-month PFS (50.8% vs 16. 7%, P = 0.0369) and 1-year overall survival (OS) (56.3% vs 33.3%, P = 0.0236) rates in patients with bulky disease. The study also found that conducting radiotherapy as a bridging regimen was an independent factor that predicted better PFS (HR: 0.534, 95% CI: 0.289-0.987, P = 0.045)., Conclusions: Our results provide and strengthen novel insights that the use of radiotherapy as a bridging strategy was demonstrated to reduce the incidence of severe CRS and improve the PFS of patients. In subgroup analysis, it was confirmed that radiotherapy can improve PFS and OS in patients with bulky disease. These findings open new avenues to improve the efficacy and safety of CAR T-cell therapy., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Autologous T cells expressing the Chimeric Antigen Receptor (CAR) have been approved as advanced therapy medicinal products (ATMPs) against several hematological malignancies. However, the generation of patient-specific CAR-T products delays treatment and precludes standardization. Allogeneic off-the-shelf CAR-T cells are an alternative to simplify this complex and time-consuming process. Here we investigated safety and efficacy of knocking out the TCR molecule in ARI-0001 CAR-T cells, a second generation αCD19 CAR approved by the Spanish Agency of Medicines and Medical Devices (AEMPS) under the Hospital Exemption for treatment of patients older than 25 years with Relapsed/Refractory acute B cell lymphoblastic leukemia (B-ALL). We first analyzed the efficacy and safety issues that arise during disruption of the TCR gene using CRISPR/Cas9. We have shown that edition of TRAC locus in T cells using CRISPR as ribonuleorproteins allows a highly efficient TCR disruption (over 80%) without significant alterations on T cells phenotype and with an increased percentage of energetic mitochondria. However, we also found that efficient TCRKO can lead to on-target large and medium size deletions, indicating a potential safety risk of this procedure that needs monitoring. Importantly, TCR edition of ARI-0001 efficiently prevented allogeneic responses and did not detectably alter their phenotype, while maintaining a similar anti-tumor activity ex vivo and in vivo compared to unedited ARI-0001 CAR-T cells. In summary, we showed here that, although there are still some risks of genotoxicity due to genome editing, disruption of the TCR is a feasible strategy for the generation of functional allogeneic ARI-0001 CAR-T cells. We propose to further validate this protocol for the treatment of patients that do not fit the requirements for standard autologous CAR-T cells administration., Competing Interests: Authors MT-M, PJ-L, and CB-B were employed by LentiStem Biotech. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Maldonado-Pérez, Tristán-Manzano, Justicia-Lirio, Martínez-Planes, Muñoz, Pavlovic, Cortijo-Gutiérrez, Blanco-Benítez, Castella, Juan, Wenes, Romero, Molina-Estévez, Marañón, Herrera, Benabdellah and Martin.)

Bruton tyrosine kinase inhibitors (BTKi) and venetoclax are currently used to treat newly diagnosed and relapsed/refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). However, most patients eventually develop resistance to these therapies, underscoring the need for effective new therapies. We report results of the phase 1 dose-escalation portion of the multicenter, open-label, phase 1/2 TRANSCEND CLL 004 (NCT03331198) study of lisocabtagene maraleucel (liso-cel), an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy, in patients with relapsed/refractory CLL/SLL. Patients with standard- or high-risk features treated with ≥3 or ≥2 prior therapies, respectively, including a BTKi, received liso-cel at 1 of 2 dose levels (50 × 106 or 100 × 106 CAR+ T cells). Primary objectives included safety and determining recommended dose; antitumor activity by 2018 International Workshop on CLL guidelines was exploratory. Minimal residual disease (MRD) was assessed in blood and marrow. Twenty-three of 25 enrolled patients received liso-cel and were evaluable for safety. Patients had a median of 4 (range, 2-11) prior therapies (100% had ibrutinib; 65% had venetoclax) and 83% had high-risk features including mutated TP53 and del(17p). Seventy-four percent of patients had cytokine release syndrome (9% grade 3) and 39% had neurological events (22% grade 3/4). Of 22 efficacy-evaluable patients, 82% and 45% achieved overall and complete responses, respectively. Of 20 MRD-evaluable patients, 75% and 65% achieved undetectable MRD in blood and marrow, respectively. Safety and efficacy were similar between dose levels. The phase 2 portion of the study is ongoing at 100 × 106 CAR+ T cells. This trial was registered at clinicaltrials.gov as NCT03331198., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

The generation of high-affinity antibodies against pathogens and vaccines requires the germinal center (GC) reaction, which relies on a complex interplay between specialized effector B and CD4 T lymphocytes, the GC B cells and T follicular helper (TFH) cells. Intriguingly, several positive key regulators of the GC reaction are common for both cell types. Here, we report that the transcription factor Bhlhe40 is a crucial cell-intrinsic negative regulator affecting both the B and T cell sides of the GC reaction. In activated CD4 T cells, Bhlhe40 was required to restrain proliferation, thus limiting the number of TFH cells. In B cells, Bhlhe40 executed its function in the first days after immunization by selectively restricting the generation of the earliest GC B cells but not of early memory B cells or plasmablasts. Bhlhe40-deficient mice with progressing age succumbed to a B cell lymphoma characterized by the accumulation of monoclonal GC B-like cells and polyclonal TFH cells in various tissues., Competing Interests: Disclosures: The authors declare no competing interests exist., (© 2021 Rauschmeier et al.)

HCV has been shown to induce many B-cell lymphoproliferative disorders. B lymphocytes specialise in producing immunoglobulins and, during chronic HCV infection, they can cause manifestations ranging from polyclonal hypergammaglobulinaemia without clinical repercussions, through mixed cryoglobulinaemic vasculitis to B-cell non-Hodgkin lymphoma. This spectrum is supported by substantial epidemiological, pathophysiological and therapeutic data. Many, although not all, of the pathogenic pathways leading from one extreme to another have been decrypted. Chronic viral antigen stimulation of B lymphocytes has a central role until the final steps before overt malignancy. This has direct implications for treatment strategies, which always include the use of direct-acting antivirals sometimes alongside immunosuppressants. The role of direct-acting antivirals has been well established in patients with cryoglobulinaemia vasculitis. However, their positive impact on B-cell non-Hodgkin lymphoma needs to be confirmed in larger studies with longer follow-up., Competing Interests: Conflict of interest Patrice Cacoub declares consultancies, honoraria, advisory board, or speakers’ fees with Abbvie, Alnylam, Bayer, Boehringer Ingelheim, Bristol Myer Squibb, Gilead, Glaxo Smith Kline, Innotech, Mylan, Pfizer, Servier, and Vifor. David Saadoun, Cloé Comarmond, Matheus Vieira, and Paul Régnier have nothing to disclose. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Epstein-Barr virus (EBV) is closely related to the development of several malignancies, such as B-cell lymphoma (B-CL), by the mechanism through which these malignancies develop remains largely unknown. We previously observed downregulation of the long noncoding RNA (lncRNA) IGFBP7-AS1 in response to EBV infection. However, the role of IGFBP7-AS1 in EBV-associated cancers has not been clarified. Here, we found that expression of IGFBP7-AS1, as well as its sense gene IGFBP7, is decreased in EBV-positive B-CL cells and clinical tissues. IGFBP7-AS1 stabilizes IGFBP7 mRNA by forming a duplex based on their overlapping regions. The tumour suppressor p53 transcriptionally activates IGFBP7-AS1 expression by binding to the promoter region of the lncRNA gene. The IGFBP7-AS1 expression is able to be rescued in EBV-positive cells in wild-type (wt) p53-dependent manner. IGFBP7-AS1 inhibits the proliferation and promotes the apoptosis of B-CL cells. Moreover, tumorigenic properties due to the depletion of IGFBP7-AS1 were restored by exogenous expression of IGFBP7 or wt-p53. Furthermore, the functional p53/IGFBP7-AS1/IGFBP7 axis facilitates apoptosis by suppressing the production and secretion of the NPPB signal peptide and further regulating the cGMP-PKG signalling pathway. This study demonstrates that EBV promotes tumorigenesis, particularly in B-CL progression, by downregulating the novel p53-responsive lncRNA IGFBP7-AS1., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Lymphoma survivors have a significantly higher risk of developing second primary lymphoma than the general population; however, bidirectional risks of developing B- and T-cell lymphomas (BCLs and TCLs) specifically are less well understood. We used population-based cancer registry data to estimate the subtype-specific risks of second primary lymphoma among patients with first BCL (n = 288 478) or TCL (n = 23 747). We observed nearly fivefold increased bidirectional risk between BCL and TCL overall (TCL following BCL: standardized incidence ratio [SIR] = 4.7, 95% confidence interval [CI] = 4.2-5.2; BCL following TCL: SIR = 4.7, 95% CI = 4.1-5.2), but the risk varied substantially by lymphoma subtype. The highest SIRs were observed between Hodgkin lymphoma (HL) and peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) (PTCL-NOS following HL: SIR = 27.5; HL following PTCL-NOS: SIR = 31.6). Strikingly elevated risks also were notable for angioimmunoblastic T-cell lymphoma (AITL) and diffuse large B-cell lymphoma (DLBCL) (AITL following DLBCL: SIR = 9.7; DLBCL following AITL: SIR = 15.3). These increased risks were strongest within the first year following diagnosis but remained persistently elevated even at ≥5 years. In contrast, SIRs were <5 for all associations of TCL with chronic lymphocytic leukemia/small lymphocytic lymphoma and follicular lymphoma. These patterns support etiologic heterogeneity among lymphoma subtypes and provide further insights into lymphomagenesis.

Background: The most common B-cell cancers, chronic lymphocytic leukemia/lymphoma (CLL), follicular and diffuse large B-cell (FL, DLBCL) lymphomas, have distinct clinical courses, yet overlapping "cell-of-origin". Dynamic changes to the epigenome are essential regulators of B-cell differentiation. Therefore, we reasoned that these distinct cancers may be driven by shared mechanisms of disruption in transcriptional circuitry., Methods: We compared purified malignant B-cells from 52 patients with normal B-cell subsets (germinal center centrocytes and centroblasts, naïve and memory B-cells) from 36 donor tonsils using >325 high-resolution molecular profiling assays for histone modifications, open chromatin (ChIP-, FAIRE-seq), transcriptome (RNA-seq), transcription factor (TF) binding, and genome copy number (microarrays)., Findings: From the resulting data, we identified gains in active chromatin in enhancers/super-enhancers that likely promote unchecked B-cell receptor signaling, including one we validated near the immunoglobulin superfamily receptors FCMR and PIGR. More striking and pervasive was the profound loss of key B-cell identity TFs, tumor suppressors and their super-enhancers, including EBF1, OCT2(POU2F2), and RUNX3. Using a novel approach to identify transcriptional feedback, we showed that these core transcriptional circuitries are self-regulating. Their selective gain and loss form a complex, iterative, and interactive process that likely curbs B-cell maturation and spurs proliferation., Interpretation: Our study is the first to map the transcriptional circuitry of the most common blood cancers. We demonstrate that a critical subset of B-cell TFs and their cognate enhancers form self-regulatory transcriptional feedback loops whose disruption is a shared mechanism underlying these diverse subtypes of B-cell lymphoma., Funding: National Institute of Health, Siteman Cancer Center, Barnes-Jewish Hospital Foundation, Doris Duke Foundation., Competing Interests: Declaration of Competing Interest The authors declare no potential conflicts of interest., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Over the last decades, the revolution in DNA sequencing has changed the way we understand the genetics and biology of B-cell lymphomas by uncovering a large number of recurrently mutated genes, whose aberrant function is likely to play an important role in the initiation and/or maintenance of these cancers. Dissecting how the involved genes contribute to the physiology and pathology of germinal center (GC) B cells -the origin of most B-cell lymphomas- will be key to advance our ability to diagnose and treat these patients. Genetically engineered mouse models (GEMM) that faithfully recapitulate lymphoma-associated genetic alterations offer a valuable platform to investigate the pathogenic roles of candidate oncogenes and tumor suppressors in vivo , and to pre-clinically develop new therapeutic principles in the context of an intact tumor immune microenvironment. In this review, we provide a summary of state-of-the art GEMMs obtained by accurately modelling the most common genetic alterations found in human GC B cell malignancies, with a focus on Burkitt lymphoma, follicular lymphoma, and diffuse large B-cell lymphoma, and we discuss how lessons learned from these models can help guide the design of novel therapeutic approaches for this disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Meyer, Koul and Pasqualucci.)

Lymphomas are cancers deriving from lymphocytes, arising preferentially in secondary lymphoid organs, and represent the 6th cancer worldwide and the most frequent blood cancer. The majority of B cell Non-Hodgkin lymphomas (B-NHL) develop from germinal center (GC) experienced mature B cells. GCs are transient structures that form in lymphoid organs in response to antigen exposure of naive B cells, and where B cell receptor (BCR) affinity maturation occurs to promote B cell differentiation into memory B and plasma cells producing high-affinity antibodies. Genomic instability associated with the somatic hypermutation (SHM) and class-switch recombination (CSR) processes during GC transit enhance susceptibility to malignant transformation. Most B cell differentiation steps in the GC are at the origin of frequent B cell malignant entities, namely Follicular Lymphoma (FL) and GCB diffuse large B cell lymphomas (GCB-DLBCL). Over the past decade, large sequencing efforts have provided a great boost in the identification of candidate oncogenes and tumor suppressors involved in FL and DLBCL oncogenesis. Mouse models have been instrumental to accurately mimic in vivo lymphoma-specific mutations and interrogate their normal function in the GC context and their oncogenic function leading to lymphoma onset. The limited access of biopsies during the initiating steps of the disease, the cellular and (epi)genetic heterogeneity of individual tumors across and within patients linked to perturbed dynamics of GC ecosystems make the development of genetically engineered mouse models crucial to decipher lymphomagenesis and disease progression and eventually to test the effects of novel targeted therapies. In this review, we provide an overview of some of the important genetically engineered mouse models that have been developed to recapitulate lymphoma-associated (epi)genetic alterations of two frequent GC-derived lymphoma entities: FL and GCB-DLCBL and describe how those mouse models have improved our knowledge of the molecular processes supporting GC B cell transformation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Mossadegh-Keller, Brisou, Beyou, Nadel and Roulland.)

90 Y-Ibritumomab tiuxetan (IT) therapy is a radioimmunotherapy for indolent B-cell lymphoma. Several predictors of insufficient therapeutic effects have been reported. We performed a retrospective study at a single institute to investigate whether 111 In SPECT/CT can predict the therapeutic effects and grade of cytopenia due to 90 Y-IT therapy. We enrolled 16 consecutive patients who underwent 90 Y-IT therapy, including 15 who underwent 111 In-IT SPECT/CT. After 90 Y-IT therapy, there were 4 patients in complete remission in whom the lesion SUV max on 111 In-IT SPECT/CT and soluble IL-2 receptor were significantly lower than those of the other patients (P<0.05 and P<0.05, respectively). Based on the log-rank test of factors associated with the progression-free survival (PFS), ≥2 previous treatment regimens was significantly associated with a poor prognosis (P<0.05). The SUV on 111 In-IT SPECT/CT may be a good predictor of the clinical response to 90 Y-IT therapy.

Central nervous system (CNS) lymphoma is an extranodal non-Hodgkin B-cell lymphoma characterized by malignant lymph tissue arising in the brain or spinal cord, associated with inflammation and blood-brain barrier (BBB) disruption. Although BBB disruption is known to occur in patients with CNS lymphoma, a direct link between these two has not been shown. Herein, abundant deposition of the blood coagulation protein fibrinogen around B-cell lymphoma was detected in CNS lymphoma patients and in the CNS parenchyma in an orthotopic mouse model. Functional enrichment analysis of unbiased cerebrospinal fluid proteomics of CNS B-cell lymphoma patients showed that coagulation protein networks were highly connected with tumor-associated biological signaling pathways. In vivo two-photon imaging demonstrated that lymphoma growth was associated with BBB disruption, and in vitro experiments identified a role for fibrinogen in promoting lymphoma cell adhesion. Overall, these results identify perivascular lymphoma clustering at sites of fibrinogen deposition, and suggest that fibrinogen may be a target for pharmacologic intervention in metastatic B-cell lymphoma associated with BBB disruption., (Copyright © 2021 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Efficacy of conventional chemoimmunotherapy is limited in patients with Richter syndrome (RS) with anticipated median overall survival (OS) of less than 10 months. Allogeneic hematopoietic cell transplantation (allo-HCT) is commonly offered as a consolidative treatment option in RS. To our knowledge, there are no randomized controlled studies that have compared allo-HCT against other therapies in RS; available allo-HCT data are limited to small case series from single-institution or registry studies. We performed a systematic review and meta-analysis to assess the totality of evidence regarding the efficacy (or lack thereof) of allo-HCT for RS. We extracted data on post-allograft outcomes related to benefits (overall response rate [ORR], complete remission [CR], OS, and progression-free survival [PFS]). For harms, data were extracted on non-relapse mortality (NRM) and relapse post-allografting. Our search strategy identified 240 studies, but only four studies (n = 72 patients) met our inclusion criteria. Pooled ORR, CR, OS, and PFS rates were 79%, 33%, 49%, and 30%, respectively. Pooled NRM and relapse rates were 24% and 28%, respectively. Results of this systematic review and meta-analysis indicate that allo-HCT yields encouraging OS in RS, thus remaining a reasonable treatment option in fit patients whose disease demonstrates a chemosensitive response to pre-transplant salvage therapies. Novel strategies are certainly needed to reduce the risk of relapse to further improve outcomes in these patients., (Copyright © 2020 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. All rights reserved.)

The IRE-1 kinase/RNase splices the mRNA of the XBP-1 gene, resulting in the spliced XBP-1 (XBP-1s) mRNA that encodes the functional XBP-1s transcription factor that is critically important for the growth and survival of B-cell leukemia, lymphoma, and multiple myeloma (MM). Several inhibitors targeting the expression of XBP-1s have been reported; however, the cytotoxicity exerted by each inhibitor against cancer cells is highly variable. To design better therapeutic strategies for B-cell cancer, we systematically compared the ability of these compounds to inhibit the RNase activity of IRE-1 in vitro and to suppress the expression of XBP-1s in mouse and human MM cell lines. Tricyclic chromenone-based inhibitors B-I09 and D-F07, prodrugs harboring an aldehyde-masking group, emerged as the most reliable inhibitors for potent suppression of XBP-1s expression in MM cells. The cytotoxicity of B-I09 and D-F07 against MM as well as chronic lymphocytic leukemia and mantle cell lymphoma could be further enhanced by combination with inhibitors of the PI3K/AKT pathway. Because chemical modifications of the salicylaldehyde hydroxy group could be used to tune 1,3-dioxane prodrug stability, we installed reactive oxygen species-sensitive structural cage groups onto these inhibitors to achieve stimuli-responsive activities and improve tumor-targeting efficiency., (©2020 American Association for Cancer Research.)

Congenital defects of the immune system called primary immunodeficiency disorders (PID) describe a group of diseases characterized by a decrease, an absence, or a malfunction of at least one part of the immune system. As a result, PID patients are more prone to develop life-threatening complications, including cancer. PID currently include over 400 different disorders, however, the variety of PID-related cancers is narrow. We discuss here reasons for this clinical phenotype. Namely, PID can lead to cell intrinsic failure to control cell transformation, failure to activate tumor surveillance by cytotoxic cells or both. As the most frequent tumors seen among PID patients stem from faulty lymphocyte development leading to leukemia and lymphoma, we focus on the extensive genomic alterations needed to create the vast diversity of B and T lymphocytes with potential to recognize any pathogen and why defects in these processes lead to malignancies in the immunodeficient environment of PID patients. In the second part of the review, we discuss PID affecting tumor surveillance and especially membrane trafficking defects caused by altered exocytosis and regulation of the actin cytoskeleton. As an impairment of these membrane trafficking pathways often results in dysfunctional effector immune cells, tumor cell immune evasion is elevated in PID. By considering new anti-cancer treatment concepts, such as transfer of genetically engineered immune cells, restoration of anti-tumor immunity in PID patients could be an approach to complement standard therapies., (Copyright © 2020 Mastio, Saeed, Wurzer, Krecke, Westerberg and Thomas.)

High plasma lactate is emerging as a critical regulator in development and progression of many human malignancies. Small RNAs derived from cleavage of mature tRNAs have been implicated in many cellular stresses, but the detailed mechanisms that respond to lactic acid (LA; acidic lactate) are not well defined. Here, using an Epstein-Barr virus (EBV)-immortalized B lymphoblastic cell line (LCL) as a model, we report that LA induces cleavage of mature tRNA at the anticodon loop, particularly production of three 5'-tRNA halves (5'-HisGUG, 5'-ValAAC, and 5'-GlyGCC), along with increased expression of RNA polymerase III and angiogenin (ANG). Of these, only the 5'-HisGUG half binds to the chromatin regulator argonaute-2 (AGO2) instead of the AGO1 protein for stability. Notably, the levels of ANG and 5'-HisGUG half expression in peripheral blood mononuclear cells from B cell lymphoma patients are tightly correlated with lactate dehydrogenase (LDH; a lactate indicator) in plasma. Silencing production of the 5'-HisGUG half by small interfering RNA or inhibition of ANG significantly reduces colony formation and growth of LA-induced tumor cells in vitro and in vivo using a murine xenograft model. Overall, our findings identify a novel molecular therapeutic target for the diagnosis and treatment of B cell lymphoma., (Copyright © 2020 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Primary nasopharyngeal lymphoma (NPL) is a very rare tumor of Waldeyer ring (WR) lymphoid tissue. It is challenging to differentiate lymphoma infiltration of pituitary from a pituitary adenoma, meningioma infiltration, and other sellar lesions to plan a suitable treatment strategy. We presented for the first time a unique case of NPL with an unusual presentation of oculomotor nerve palsy associated with pan-pituitary involvement in a diabetic patient., Case Presentation: A 64-year old diabetic woman with no previous history of malignancy presented with intermittent diplopia for about the last nine months. Severe headache, left eye ptosis and hypoglycemic episodes were added to her symptoms after a while. Further complaints include generalized weakness, loss of appetite, generalized musculoskeletal pain, and 6-7 kg weight loss within six months. Her family history was unremarkable. Physical examinations of eyes indicated left eye 3rd, 4th, and 6th nerve palsy. But, she was not anisocoric, and the pupillary reflexes were normal on both eyes. No lymphadenopathy, organomegaly and other abnormalities were found. Magnetic resonance imaging (MRI) showed a heterogeneous enhancement in the seller and suprasellar regions, enlargement of the stalk, parasellar dural enhancement and thickening of the sphenoid sinus without bone erosion. Also, both cavernous sinuses were infiltrated and both internal carotid arteries were encased by the neoplastic lesion. It suggested an infiltrative neoplastic lesion which compressed the cranial nerves. Pituitary hormone levels assessment indicated a pan-hypopituitarism. Following nasopharyngeal mucosal biopsy, the immunohistochemistry (IHC) findings revealed a low-grade non-Hodgkin's B-cell lymphoma. Systemic workup, including cerebrospinal fluid (CSF) studies, bone marrow aspiration, chest and abdominopelvic high-resolution computed tomography (HRCT) indicated no other involvement by the lymphoma. After chemotherapy courses, central adrenal insufficiency, partial central diabetes incipidious (CDI) and central hypothyroidism have been resolved. To our best knowledge, we found 17 cases of NPL with cranial nerve palsy, 1 case of NPL with pan-hypopituitarism and no NPL case with both cranial nerve palsy and pituitary dysfunction., Conclusions: The incidence of cranial neuropathy in patients with diabetes should not merely be attributed to diabetic neuropathy without further evaluation.

Chimeric antigen receptor (CAR) T cells targeting CD19 have achieved breakthroughs in the treatment of hematological malignancies, such as relapsed/refractory non-Hodgkin lymphoma (r/rNHL); however, high rates of treatment failure and recurrence after CAR T-cell therapy are considerable obstacles to overcome. In this study, we designed a series of tandem CARs (TanCARs) and found that TanCAR7 T cells showed dual antigen targeting of CD19 and CD20, as well as formed superior and stable immunological synapse (IS) structures, which may be related to their robust antitumor activity. In an open-label single-arm phase 1/2a trial (NCT03097770), we enrolled 33 patients with r/rNHL; 28 patients received an infusion after conditioning chemotherapy. The primary objective was to evaluate the safety and tolerability of TanCAR7 T cells. Efficacy, progression-free survival, and overall survival were evaluated as secondary objectives. Cytokine release syndrome occurred in 14 patients (50%): 36% had grade 1 or 2 and 14% had grade 3. No cases of CAR T-cell-related encephalopathy syndrome (CRES) of grade 3 or higher were confirmed in any patient. One patient died from a treatment-associated severe pulmonary infection. The overall response rate was 79% (95% confidence interval [CI], 60-92%), and the complete response rate was 71%. The progression-free survival rate at 12 months was 64% (95% CI, 43-79%). In this study, TanCAR7 T cells elicited a potent and durable antitumor response, but not grade 3 or higher CRES, in patients with r/rNHL., (© 2020 by The American Society of Hematology.)

B-cell malignancies are a heterogeneous group of hematological neoplasms derived from cells at different stages of B-cell development. Recent studies revealed that dysregulated redox metabolism is one of the factors contributing to the pathogenesis and progression of B-cell malignancies. Elevated levels of oxidative stress markers usually correlate with the advanced stage of various B-cell malignancies. In the complex tumor microenvironment, reactive oxygen species affect not only malignant cells but also bystander cells, including immune cells. Importantly, malignant cells, due to genetic dysregulation, are able to adapt to the increased demands for energy and reducing equivalents via metabolic reprogramming and upregulation of antioxidants. The immune cells, however, are more sensitive to oxidative imbalance. This may cause their dysfunction, leading to immune evasion and tumor progression. On the other hand, the already imbalanced redox homeostasis renders malignant B-cells particularly sensitive to further elevation of reactive oxygen species. Indeed, targeting antioxidant systems has already presented anti-leukemic efficacy in preclinical models. Moreover, the prooxidant treatment that triggers immunogenic cell death has been utilized to generate autologous anti-leukemic vaccines. In this article, we review novel research on the dual role of the reactive oxygen species in B-cell malignancies. We highlight the mechanisms of maintaining redox homeostasis by malignant B-cells along with the antioxidant shield provided by the microenvironment. We summarize current findings regarding therapeutic targeting of redox metabolism in B-cell malignancies. We also discuss how the oxidative stress affects antitumor immune response and how excessive reactive oxygens species influence anticancer prooxidant treatments and immunotherapies., (Copyright © 2020 Domka, Goral and Firczuk.)

Since the first reported case in 1997, over 600 women with breast implant-associated anaplastic large cell lymphoma (BI ALCL) have been reported. BI ALCL is a CD30-positive T-cell lymphoma that carries clonal T-cell receptor gene rearrangements, and a subset of cases harbors mutations in the JAK-STAT signaling pathway. Rarely, other histologic types of lymphoma have been reported in association with breast implants, including fewer than 10 cases of B-cell origin. Here, we describe three additional patients with B-cell lymphoma occurring around breast implants. Two of these patients developed extranodal marginal zone lymphoma in the peri-implant capsule, one of which had a concurrent ALCL within the superficial lining of the capsule. The third patient presented with diffuse large B-cell lymphoma inside the breast parenchyma surrounding her implant. Determining the etiology and risk factors for the development of B-cell lymphomas associated with breast implants remains challenging, given the wide spectrum of histologic features and the rarity of these neoplasms. Ultimately, we document three new cases of B-cell lymphoma arising around breast implants and highlight their clinical and pathologic features in order to expand our understanding of this rare disease presentation., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Primary Sjögren's syndrome (pSS) is an autoimmune disease characterised by an increased risk for non-Hodgkin lymphoma (NHL) development. Ectopic germinal centre (GC) in the salivary gland is associated with increased NHL risk in pSS, and the chemokine CXCL13 is implicated in B-cell migration and GC formation. Serum CXCL13 concentrations were quantified by ELISA in 48 healthy individuals, 273 pSS patients without NHL (pSS-nonL), and 38 pSS patients with NHL (pSS-NHL+) from the United Kingdom Primary Sjögren's Syndrome Registry cohort. PSS-nonL patients were stratified into low risk (LR), moderate risk (MR) and high risk (HR) groups according to the lymphoma risk score proposed by Fragkioudaki et al. Differences in serum CXCL13 levels among groups were analysed using the Wilcoxon method. Also, changes in serum CXCL13 over a time period of at least 1 year and a median 4 years were assessed for 200 pSS-nonL and 8 pSS-NHL+ patients. In addition, associations of serum CXCL13 with B-cell and inflammatory markers were investigated by correlation analyses and logistic regression. Serum CXCL13 levels were higher in all pSS groups compared to controls (p < 0.0001), and in pSS-NHL+ compared to pSS-nonL patients (p = 0.0204). LR patients had lower CXCL13 levels than MR patients (p < 0.0001) and pSS-NHL+ patients (p = 0.0008). CXCL13 levels remained stable over the study period for all pSS groups. CXCL13 was associated (p < 0.0005) with Immunoglobulin G (IgG), B-cell activating factor, β2 microglobulin, combined free light chains, κ and λ light chains, anti-Ro/SSA, anti-La/SSB, and erythrocyte sedimentation rate. IgG and C3 controlled for age and gender were significantly associated with NHL risk in pSS. Serum CXCL13 levels were elevated in pSS-NHL+ and MR patients compared to LR patients and remained stable over time. Further study is required to investigate the role of CXCL13 in pSS-associated NHL risk.

Lineage commitment and differentiation of hematopoietic cells takes place in well-defined microenvironmental surroundings. Communication with other cell types is a vital prerequisite for the normal functions of the immune system, while disturbances in this communication support the development and progression of neoplastic disease. Integrins such as the integrin very late antigen-4 (VLA-4; CD49d/CD29) control the localization of healthy as well as malignant B cells within the tissue, and thus determine the patterns of organ infiltration. Malignant B cells retain some key characteristics of their normal counterparts, with B cell receptor (BCR) signaling and integrin-mediated adhesion being essential mediators of tumor cell homing, survival and proliferation. It is thus not surprising that targeting the BCR pathway using small molecule inhibitors has proved highly effective in the treatment of B cell malignancies. Attenuation of BCR-dependent lymphoma-microenvironment interactions was, in this regard, described as a main mechanism critically contributing to the efficacy of these agents. Here, we review the contribution of VLA-4 to normal B cell differentiation on the one hand, and to the pathophysiology of B cell malignancies on the other hand. We describe its impact as a prognostic marker, its interplay with BCR signaling and its predictive role for novel BCR-targeting therapies, in chronic lymphocytic leukemia and beyond.

CD19-targeted immunotherapies have drastically improved outcomes for relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (ALL) patients. Such therapies, including blinatumomab and CD19 chimeric antigen receptor (CD19CAR) T cells, yield high remission rates and can bridge to more definitive consolidation therapy with curative intent. Both treatments are approved by the US Food and Drug Administration (FDA) for r/r ALL (CD19CAR T-cell approval is restricted to patients ≤25 years old). Although availability of blinatumomab and CD19CAR T cells has extended options for the treatment of r/r ALL, prioritizing the sequence of these agents on an individual-patient basis may be difficult for the treating physician. Considering each therapy's advantages, limitations, and challenges is necessary when choosing between them. Although patients may receive both blinatumomab and CD19CAR T cells sequentially in cases that fail to respond or subsequently relapse, a proportion of patients treated with CD19-targeted immunotherapy will lose expression of CD19 and will be excluded from receiving the alternative CD19-targeted therapy. Thus, weighing all considerations for each patient before selecting a CD19-targeted immunotherapy is crucial. Here, we discuss real-life scenarios of adults with r/r ALL, in which we selected either blinatumomab or CD19CAR T-cell therapy, and the rationale behind each decision., (© 2020 by The American Society of Hematology.)

Activated phosphatidylinositol 3-kinase-δ (PI3K-δ) syndrome (APDS) is a rare primary combined immunodeficiency caused by either dominant gain-of-function mutations in the PIK3CD gene encoding the catalytic subunit p110δ of PI3K-δ (referred to as type 1 APDS) or dominant loss-of-function mutations in the PIK3R1 gene encoding the p85α, p55α, and p50α regulatory subunits (type 2 APDS). In types 1 and 2 APDS, the PI3K-δ hyperactivity resulting from the gene mutations leads to similar clinical presentations, characterized by increased susceptibility to bacterial and viral infections and (to a lesser extent) autoimmune manifestations. A hallmark of this disease is lymphoproliferation, which may even be life threatening and require repeated surgical treatment. A major complication of APDS is malignancy (especially B-cell lymphomas), which greatly worsens the prognosis. Here, we review the different neoplastic conditions observed in patients with APDS and discuss the uncontrolled PI3K-δ activity in B and T cells that leads to malignant transformation., (© 2020 by The American Society of Hematology.)

Background: DuoBody®-CD3xCD20 (GEN3013) is a full-length human IgG1 bispecific antibody (bsAb) recognizing CD3 and CD20, generated by controlled Fab-arm exchange. Its Fc domain was silenced by introduction of mutations L234F L235E D265A., Methods: T-cell activation and T-cell-mediated cytotoxicity were measured by flow cytometry following co-culture with tumour cells. Anti-tumour activity of DuoBody-CD3xCD20 was assessed in humanized mouse models in vivo. Non-clinical safety studies were performed in cynomolgus monkeys., Findings: DuoBody-CD3xCD20 induced highly potent T-cell activation and T-cell-mediated cytotoxicity towards malignant B cells in vitro. Comparison of DuoBody-CD3xCD20 to CD3 bsAb targeting alternative B-cell antigens, or to CD3xCD20 bsAb generated using alternative CD20 Ab, emphasized its exceptional potency. In vitro comparison with other CD3xCD20 bsAb in clinical development showed that DuoBody-CD3xCD20 was significantly more potent than three other bsAb with single CD3 and CD20 binding regions and equally potent as a bsAb with a single CD3 and two CD20 binding regions. DuoBody-CD3xCD20 showed promising anti-tumour activity in vivo, also in the presence of excess levels of a CD20 Ab that competes for binding. In cynomolgus monkeys, DuoBody-CD3xCD20 demonstrated profound and long-lasting B-cell depletion from peripheral blood and lymphoid organs, which was comparable after subcutaneous and intravenous administration. Peak plasma levels of DuoBody-CD3xCD20 were lower and delayed after subcutaneous administration, which was associated with a reduction in plasma cytokine levels compared to intravenous administration, while bioavailability was comparable., Interpretation: Based on these preclinical studies, a clinical trial was initiated to assess the clinical safety of subcutaneous DuoBody-CD3xCD20 in patients with B-cell malignancies., Funding: Genmab., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Lymphomas associated with implants are predominantly of T-cell type-with anaplastic large cell lymphoma (ALCL) being most reported. That said, to date, 6 cases of B-cell lymphoma associated with breast implants have been reported. All cases exhibited unilateral breast involvement. Here, the authors report a case of low-grade B-cell lymphoma occurring bilaterally in a 34-year-old woman with a history of Poly Implant Prosthese silicone implants at age 20, T-cell angioimmunoblastic lymphoma, and subsequent myeloablative double cord blood transplantation. Lymphoma cells were positive for CD20, CD5, BCL-2, CD21, CD23, IgD, IgM, with very low Ki-67 of 1%. Nevertheless, cases of ALCL associated with breast implants are rare but much more documented in the literature than B-cell lymphomas associated with breast implants, as in this patient. Identification of a relationship between breast cancer and silicone is still ongoing in the literature, with long-term clinical follow up required. More research will be necessary to fully characterize the occurrence, course, and association of this disease with breast implants in order to properly guide diagnosis and management., (© 2018 The Aesthetic Society. Reprints and permission: journals.permissions@oup.com.)

Background: Heterogeneous nuclear ribonucleoprotein K (hnRNP K) is an RNA-binding protein that is aberrantly expressed in cancers. We and others have previously shown that reduced hnRNP K expression downmodulates tumor-suppressive programs. However, overexpression of hnRNP K is the more commonly observed clinical phenomenon, yet its functional consequences and clinical significance remain unknown., Methods: Clinical implications of hnRNP K overexpression were examined through immunohistochemistry on samples from patients with diffuse large B-cell lymphoma who did not harbor MYC alterations (n = 75). A novel transgenic mouse model that overexpresses hnRNP K specifically in B cells was generated to directly examine the role of hnRNP K overexpression in mice (three transgenic lines). Molecular consequences of hnRNP K overexpression were determined through proteomics, formaldehyde-RNA-immunoprecipitation sequencing, and biochemical assays. Therapeutic response to BET-bromodomain inhibition in the context of hnRNP K overexpression was evaluated in vitro and in vivo (n = 3 per group). All statistical tests were two-sided., Results: hnRNP K is overexpressed in diffuse large B-cell lymphoma patients without MYC genomic alterations. This overexpression is associated with dismal overall survival and progression-free survival (P < .001). Overexpression of hnRNP K in transgenic mice resulted in the development of lymphomas and reduced survival (P < .001 for all transgenic lines; Line 171[n = 30]: hazard ratio [HR] = 64.23, 95% confidence interval [CI] = 26.1 to 158.0; Line 173 [n = 31]: HR = 25.27, 95% CI = 10.3 to 62.1; Line 177 [n = 25]: HR = 119.5, 95% CI = 42.7 to 334.2, compared with wild-type mice). Clinical samples, mouse models, global screening assays, and biochemical studies revealed that hnRNP K's oncogenic potential stems from its ability to posttranscriptionally and translationally regulate MYC. Consequently, Hnrnpk overexpression renders cells sensitive to BET-bromodomain-inhibition in both in vitro and transplantation models, which represents a strategy for mitigating hnRNP K-mediated c-Myc activation in patients., Conclusion: Our findings indicate that hnRNP K is a bona fide oncogene when overexpressed and represents a novel mechanism for c-Myc activation in the absence of MYC lesions., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The approval of tisagenlecleucel and axicabtagene ciloleucel represents a breakthrough in the field of immune and cellular therapy for hematologic malignancies. These anti-CD19 chimeric antigen receptor-T cells (CAR) proved to be highly effective in the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) and specific histologic subtypes of B-cell non-Hodgkin lymphomas. This expert review aims to summarize the current available research evidence in this field, with a special focus on the different challenges faced by treating physicians, and we also provide future perspectives.