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Background: B-cell non-Hodgkin lymphoma (B-NHL) is the most common type of lymphoma and is significantly heterogeneous among various subtypes. Despite of considerable advancements in treatment strategies for B-NHL, the prognosis of relapsed/refractory patients remains poor. Main text: It has been indicated that epigenetic dysregulation is critically associated with the pathogenesis of most hematological malignancies, resulting in the clinical targeting of epigenetic modifications. Bromodomain (BRD) proteins are essential epigenetic regulators which contain eight subfamilies, including BRD and extra-terminal domain (BET) family, histone acetyltransferases (HATs) and HAT-related proteins, transcriptional coactivators, transcriptional mediators, methyltransferases, helicases, ATP-dependent chromatin-remodeling complexes, and nuclear-scaffolding proteins. Most pre-clinical and clinical studies on B-NHL have focused predominantly on the BET family and the use of BET inhibitors as mono-treatment or co-treatment with other anti-tumor drugs. Furthermore, preclinical models of B-NHL have revealed that BET degraders are more active than BET inhibitors. Moreover, with the development of BET inhibitors and degraders, non-BET BRD protein inhibitors have also been designed and have shown antitumor activities in B-NHL preclinical models. This review summarized the mechanism of BRD proteins and the recent progress of BRD protein-related drugs in B-NHL. This study aimed to collect the most recent evidences and summarize possibility on whether BRD proteins can serve as therapeutic targets for B-NHL. Conclusion: In summary, BRD proteins are critical epigenetic regulatory factors and may be potential therapeutic targets for B-NHL. [ABSTRACT FROM AUTHOR]

Previously, we reported the efficacy and safety of tazemetostat in Japanese patients with relapsed/refractory follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) harboring the EZH2 mutation in a multicenter, open-label, phase II study. Here, we present a follow-up analysis of tazemetostat at a long-term median follow-up of 35.0 months. Twenty patients were enrolled: 17 in the FL cohort and three in the DLBCL cohort. In the FL cohort, the objective response rate was 70.6%, consistent with the primary analysis, and the median progression-free survival (PFS) was not reached. The 24-month and 36-month PFS rates were 72.1% (95% confidence interval [CI] 41.5%–88.6%) and 64.1% (95% CI 33.7%–83.4%), respectively. The median duration of treatment was 30.2 months. After the primary analysis at a median follow-up of 12.9 months, grade 1–2 urinary tract infection, peripheral motor neuropathy, and hypogammaglobulinemia newly emerged, but the incidence of adverse events (AEs) did not increase notably during this follow-up period. No unexpected grade ≥ 3 treatment-related AEs were reported. Long-term oral monotherapy with tazemetostat showed favorable efficacy and safety profiles, indicating that it may be a useful third-line or later treatment option for patients with relapsed/refractory FL harboring the EZH2 mutation. Trial registration: ClinicalTrials.gov: NCT03456726. [ABSTRACT FROM AUTHOR]

Purpose: There is a lack of real-world data on the epidemiology, clinical manifestations, treatment effects, and prognosis of coronavirus disease 2019 (COVID-19) in patients with B-cell non-Hodgkin lymphoma (B-NHL). This study aimed to investigate the clinical features and prognostic factors of COVID-19 in patients with B-NHL. Patients and Methods: This study included individuals diagnosed with B-NHL who were also diagnosed with COVID-19 and hospitalized. A retrospective analysis was conducted, and univariate and multivariate logistic regression were used to identify independent factors affecting the duration of the positive-to-negative transition of COVID-19 nucleic acid test results and prognoses. Receiver operating characteristic curves were used to assess diagnostic accuracy and determine the optimal threshold. Results: Among 80 patients with COVID-19 and B-NHL, relapsed or refractory lymphoma and diffuse large B-cell lymphoma (DLBCL) accounted for 13.8% and 65% of cases, respectively. The mean age was 60.4 ± 13.0 years, and 50% of patients were women. The median duration of the positive-to-negative transition was 14 days (interquartile range [IQR], 17.2), and the median hospitalization duration was 12 days (IQR, 13). The rate of severe disease was 26.25%, and the 28-day mortality rate was 10.00%. Univariate and multivariate logistic regression analyses revealed that pathological classification of B-NHL, infection with COVID-19 within 3 months after the last dose of anti-CD20 monoclonal antibodies, and corticosteroid use were independent factors associated with a prolonged duration of the positive-to-negative transition. Compared with patients with DLBCL or FL and COVID-19, patients with B-NHL had longer nucleic acid test transition durations and higher rates of severe disease and mortality. Conclusion: In patients with B-NHL, infection with COVID-19 within 3 months after treatment with anti-CD20 monoclonal antibodies prolonged the positive-to-negative transition of nucleic acid test results and increased the risks of severe disease and 28-day mortality. Treatment with corticosteroids further prolonged this transition. [ABSTRACT FROM AUTHOR]

Abstract Background B-cell non-Hodgkin lymphoma (B-NHL) is the most common type of lymphoma and is significantly heterogeneous among various subtypes. Despite of considerable advancements in treatment strategies for B-NHL, the prognosis of relapsed/refractory patients remains poor. Main text It has been indicated that epigenetic dysregulation is critically associated with the pathogenesis of most hematological malignancies, resulting in the clinical targeting of epigenetic modifications. Bromodomain (BRD) proteins are essential epigenetic regulators which contain eight subfamilies, including BRD and extra-terminal domain (BET) family, histone acetyltransferases (HATs) and HAT-related proteins, transcriptional coactivators, transcriptional mediators, methyltransferases, helicases, ATP-dependent chromatin-remodeling complexes, and nuclear-scaffolding proteins. Most pre-clinical and clinical studies on B-NHL have focused predominantly on the BET family and the use of BET inhibitors as mono-treatment or co-treatment with other anti-tumor drugs. Furthermore, preclinical models of B-NHL have revealed that BET degraders are more active than BET inhibitors. Moreover, with the development of BET inhibitors and degraders, non-BET BRD protein inhibitors have also been designed and have shown antitumor activities in B-NHL preclinical models. This review summarized the mechanism of BRD proteins and the recent progress of BRD protein-related drugs in B-NHL. This study aimed to collect the most recent evidences and summarize possibility on whether BRD proteins can serve as therapeutic targets for B-NHL. Conclusion In summary, BRD proteins are critical epigenetic regulatory factors and may be potential therapeutic targets for B-NHL.

Introduction: Investigation on virus-host interaction may provide new clues for antitumor immunotherapy. Case Presentation: In this case report, we describe an unusual case of B-cell non-Hodgkin lymphoma in an aged woman who recovered following SARS-COV-2 infection. We discuss the case and suggest that virus induced cross-reactivity against tumor account for the remission. Conclusion: Mapping epitope characteristics on B cell non-Hodgkin lymphoma antigen and on SARS-COV-2 antigen may provide much needed information for antigen based antitumor immune therapy in the future.

Heart tumors are sporadic. Secondary heart tumors are 30 times more common than primary ones. Depending on the location and origin of the tumor, clinical pictures vary from asymptomatic to severe manifestations such as arrhythmia, heart failure, pericardial effusion, and cardiogenic shock. We report hereby a rare case who presented with faint clinical symptoms, rapidly progressing to right heart failure within a month. Echocardiography and computed tomography of the chest revealed a tumor in the right heart chamber of 72.0 × 43.0 mm, in addition to large mediastinal lymph and left supraclavicular lymph nodes, cardiogenic shock appeared 4 days after admission. Through examination, it was suspected that this was a cardiac lymphoma. The patient was treated with 2 mg methylprednisolone per kg body weight. Symptoms of cardiogenic shock improved significantly and disappeared after 6 hours of treatment. After supraclavicular lymph node biopsy and immunohistochemistry, the final result was diagnosed as diffuse large B-cell non-Hodgkin lymphoma with large lymphoma in the right heart. The patient received chemotherapy with the R-CHOP regimen (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisolone). Re-examination before the 5th chemotherapy cycle showed no signs of right heart failure, normal self-activity, and no dyspnea on exertion, and the tumor size in the heart on the echocardiogram was 23.8 × 19.1 mm. The report shows that a large right heart tumor with a clinical picture of cardiogenic shock in a patient with diffuse large B-cell non-Hodgkin's lymphoma was well-responded to initial treatment with methylprednisolone at a dose of 2 mg/kg body weight and R-CHOP chemotherapy. [ABSTRACT FROM AUTHOR]

Cell- and antibody-based CD19-directed therapies have demonstrated great potential for treating B-cell non-Hodgkin lymphoma (B-NHL). However, all these approaches suffer from limited response rates and considerable toxicity. Until now, therapy decisions have been routinely based on histopathological CD19 staining of a single lesion at initial diagnosis or relapse, disregarding heterogeneity and temporal alterations in antigen expression. To visualize in vivo CD19 expression noninvasively, we radiolabeled anti-human CD19 monoclonal antibodies with copper-64 (64Cu-αCD19) for positron emission tomography (CD19-immunoPET). 64Cu-αCD19 specifically bound to subcutaneous Daudi xenograft mouse models in vivo. Importantly, 64Cu-αCD19 did not affect the anti-lymphoma cytotoxicity of CD19 CAR-T cells in vitro. Following our preclinical validation, 64Cu-αCD19 was injected into four patients with follicular lymphoma, diffuse large B-cell lymphoma or mantle zone lymphoma. We observed varying 64Cu-αCD19 PET uptake patterns at different lymphoma sites, both within and among patients, correlating with ex vivo immunohistochemical CD19 expression. Moreover, one patient exhibited enhanced uptake in the spleen compared to that in patients with prior B-cell-depleting therapy, indicating that 64Cu-αCD19 is applicable for identifying B-cell-rich organs. In conclusion, we demonstrated the specific targeting and visualization of CD19+ B-NHL in mice and humans by CD19-immunoPET. The intra- and interindividual heterogeneous 64Cu-αCD19 uptake patterns of lymphoma lesions indicate variability in CD19 expression, suggesting the potential of CD19-immunoPET as a novel tool to guide CD19-directed therapies. [ABSTRACT FROM AUTHOR]

The presence of serum monoclonal components has been associated with poor outcomes in various hematological malignancies. The current study focused on exploring its prognostic role in B-cell non-Hodgkin lymphoma. Our study represented 314 patients with information on serum immunofixation electrophoresis at diagnosis that were available with B-cell non-Hodgkin lymphoma. IFE was positive in 61 patients (19%). Baseline features were comparable between pairs of groups, poor ECOG PS, B symptoms, advanced stage, and high-risk IPI score were significantly more frequent in the + IFE group. Shorter PFS and OS of B-NHL patients were observed in patients who presented at diagnosis with a + IFE, and IFE was the independent predictor of PFS and OS in multivariate analysis. Moreover, integrating IFE into the IPI-M1, IPI-M2, and IPI-M3 models improved the area under the curve for more accurate survival prediction and prognosis. Serum monoclonal proteins are significant prognostic indicators for newly diagnosed B-cell non-Hodgkin lymphoma that can early identify patients with poor prognosis and guide clinical treatment decisions. [ABSTRACT FROM AUTHOR]

Background: The primary cause of treatment failure in patients with refractory or relapsed B-cell non-Hodgkin lymphoma (r/r B-NHL) is resistance to current therapies, and therapy-induced senescence (TIS) stands out as a crucial mechanism contributing to tumor drug resistance. Here, we analyzed SENEX/Rho GTPase Activating Protein 18 (ARHGAP18) expression and prognostic significance in doxorubicin-induced B-NHL-TIS model and r/r B-NHL patients, investigating its target in B-NHL cell senescence and the effect of combining specific inhibitors on apoptosis resistance in B-NHL-TIS cells. Methods: Raji cells were transfected with the human SENEX shRNA recombinant lentiviral vector (Sh-SENEX) and the empty vector negative (NC) to construct a stable transfection cell line with knockdown of SENEX. Effect of SENEX-silencing on B-NHL-TIS formation, cell function and cell cycle-related pathways was analyzed. Using doxorubicin (DOX)-inducible senescent B-NHL cells combined with the specific cyclin dependent kinase 4/6 (CDK4/6) inhibitor Palbociclib to observe that blocking CDK4/6 effects on TIS formation. SENEX expression of 21 B-NHL patients and 8 healthy controls were analyzed by qRT-PCR, and the correlation between its expression and clinical indicators were evaluated. Results: The downregulation of SENEX expression promotes G1-S phase transition and apoptosis while inhibiting cell proliferation, collectively suppressing the formation of TIS in B-NHL. Blockade of CDK4/6 promotes the DOX-induced G1 phase arrest to enhance TIS formation in B-NHL cells which can reverse the regulatory effect of silencing SENEX on B-NHL cell cycle regulation and senescence. The expression levels of SENEX were notably elevated in B-NHL patients compared to healthy controls, and Elevated expression levels of SENEX were associated with poor prognosis of B-NHL patients. Conclusions: SENEX enhances apoptosis resistance in B-NHL by inhibiting CDK4/6, thereby preventing G1-S phase transition and promoting TIS formation. [ABSTRACT FROM AUTHOR]

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Simple Summary: We are entering an exciting new phase in the history of non-Hodgkin lymphoma treatment. Advances in monoclonal antibody-based therapies, which began with rituximab in the 1990s but have only recently started to show their full potential, along with the development of cellular therapies using chimeric antigen receptor constructs, are changing the way we tackle these cancers. Indeed, several of these non-chemotherapeutic agents, even when used as monotherapies, can confer robust and long-lasting remissions and, in some cases, even hold the promise of potential cures. This represents a truly remarkable opportunity, especially for patients who have undergone extensive prior treatments—a possibility that would have been inconceivable until just a short while ago. We are currently witnessing a dramatic shift in our approach to the treatment of B-cell non-Hodgkin lymphoma (B-NHL). In the evolving clinical landscape, novel treatments for this clinically heterogeneous disease span a wide range of interventions, encompassing targeted agents, cell therapy approaches, and novel monoclonal antibodies (NMABs). Among these, the latter are likely to exert the most profound impact due to their distinctive high efficacy and versatile applicability. NMABs represent a heterogeneous group of agents, including naked antibodies, immunotoxins, and T-cell-engaging molecules. In recent times, several NMABs have either gained regulatory approval or are on the verge of introduction into clinical practice, addressing multiple therapeutic indications and treatment regimens. Their anticipated impact is expected to be broad, initially in the context of relapsed/refractory (R/R) disease and subsequently extending to early treatment lines. The scope of this review is to provide a comprehensive overview of the biological characteristics, clinical properties, efficacy, and toxicity profiles of NMABs that have recently been introduced or are nearing integration into clinical practice. [ABSTRACT FROM AUTHOR]

Abstract Purpose SARS‐CoV‐2 vaccines cause acute ipsilateral lymph node swelling in an important proportion of vaccines. Thus far, no malignant lymphadenopathies have been reported in temporal context to vaccination in the ipsilateral draining lymph node areas. Experimental design Prompted by two cases with unilateral axillary lymphomas that occurred ipsilaterally to prior SARS‐CoV‐2 vaccination, we systematically retrieved all B‐cell non‐Hodgkin lymphomas at two German University Medical Centers diagnosed before and after introduction of SARS‐CoV‐2 vaccines in Germany. Available lymphoma tissue (n=19) was subjected to next‐generation immunosequencing of the IGH locus. Malignant clonotypes were mined in the CoVabDab database and published data sets from 342 uninfected individuals, 55 individuals 28 days after anti‐SARS‐CoV‐2 vaccination and 139 individuals with acute COVID‐19 together encompassing over 1 million CDR3 sequences in total. Results Of 313 newly diagnosed cases in the two centers and observation periods, 27 unilateral manifestations in the defined deltoid draining regions were identified. The majority thereof were diffuse large B‐cell lymphomas (18 of 27 cases). Eleven unilateral cases were diagnosed in the era of SARS‐CoV‐2 vaccination and 16 in the control period before introduction of such vaccines. Of the 11 unilateral lymphomas that occurred during the vaccination period, ten had received a SARS‐CoV‐2 vaccine prior to lymphoma diagnosis. These cases were further evaluated. While left‐sided were more frequent than right‐sided lymphomas (19 vs 8 cases), no statistically significant association of vaccination site and laterality of the lymphoma manifestation was found. The unilateral lymphomas showed a normal range of B‐cell receptors typically found in these lymphoma subtypes with no evidence for anti‐SARS‐CoV‐2 sequences in the malignant clonotype. Conclusions Together, we found no evidence that the current SARS‐CoV‐2 vaccines could serve as a trigger for lymphomagenesis in the draining lymph node areas of the deltoid region used for vaccination.

We report a case of an 88-year-old female who presented to us with dysphagia, change in voice, and stridor, the diagnosis of which turned out to be primary laryngeal lymphoma. It is a rare condition, and repeated biopsies are needed in most of the cases. It has a very good response to radiotherapy and chemotherapy. [ABSTRACT FROM AUTHOR]

The present study aimed to determine the clinical characteristics of cytopenia in patients with relapsed and refractory B-cell non-Hodgkin lymphoma (B-NHL) who were treated with chimeric antigen receptor T-cell (CAR-T) therapy. Thus, a total of 63 patients with relapsed and refractory B-NHL who underwent CAR-T therapy between March 2017 and October 2021 were retrospectively selected for analysis. Neutropenia, anemia and thrombocytopenia at grade =3 occurred in 48 (76.19%), 16 (25.39%) and 15 (23.80%) cases, respectively. The results of a multivariate analysis demonstrated that the baseline absolute neutrophil count (ANC) and hemoglobin concentration were independent risk factors for grade =3 cytopenia. A total of 3 patients died early and were therefore excluded from the present study. Furthermore, cell recovery was examined at day +28 after infusion; 21 patients (35%) did not recover from cytopenia and 39 patients (65%) recovered. A multivariate analysis demonstrated that the baseline ANC <2.29x109/l, baseline hemoglobin <114.50 g/l and baseline IL-6 >21.43 pg/l were independent risk factors affecting hemocyte recovery. In conclusion, patients with relapsed and refractory B-NHL exhibited an increased incidence of grade =3 hematologic toxicity following CAR-T cell therapy, while baseline blood cell and IL-6 levels are independent risk factors for hemocyte recovery. [ABSTRACT FROM AUTHOR]

Adoptive cellular immunotherapy with chimeric antigen receptor (CAR) T cells has emerged as a novel modality for treating relapsed and/or refractory B-cell non-Hodgkin lymphoma (B-NHL). With increasing approval of CAR T-cell products and advances in CAR T cell therapy, CAR T cells are expected to be used in a growing number of cases. However, CAR T-cell-associated toxicities can be severe or even fatal, thus compromising the survival benefit from this therapy. Standardizing and studying the clinical management of these toxicities are imperative. In contrast to other hematological malignancies, such as acute lymphoblastic leukemia and multiple myeloma, anti-CD19 CAR T-cell-associated toxicities in B-NHL have several distinctive features, most notably local cytokine-release syndrome (CRS). However, previously published guidelines have provided few specific recommendations for the grading and management of toxicities associated with CAR T-cell treatment for B-NHL. Consequently, we developed this consensus for the prevention, recognition, and management of these toxicities, on the basis of published literature regarding the management of anti-CD19 CAR T-cell-associated toxicities and the clinical experience of multiple Chinese institutions. This consensus refines a grading system and classification of CRS in B-NHL and corresponding measures for CRS management, and delineates comprehensive principles and exploratory recommendations for managing anti-CD19 CAR T-cell-associated toxicities in addition to CRS.

Abstract Background Mature B-cell non-Hodgkin lymphomas are one of the most common hematological malignancies with a divergent clinical presentation, phenotype, and course of disease regulated by underlying genetic mechanism. Main body Genetic and molecular alterations are not only critical for lymphomagenesis but also largely responsible for differing therapeutic response in these neoplasms. In recent years, advanced molecular tools have provided a deeper understanding regarding these oncogenic drives for predicting progression as well as refractory behavior in these diseases. The prognostic models based on gene expression profiling have also been proved effective in various clinical scenarios. However, considerable overlap does exist between the genotypes of individual lymphomas and at the same time where additional molecular lesions may be associated with each entity apart from the key genetic event. Therefore, genomics is one of the cornerstones in the multimodality approach essential for classification and risk stratification of B-cell non-Hodgkin lymphomas. Conclusion We hereby in this review discuss the wide range of genetic aberrancies associated with tumorigenesis, immune escape, and chemoresistance in major B-cell non-Hodgkin lymphomas.

Objective: We aimed to compare clinical and survival differences between B‐cell (B‐NHL) and NKT‐cell non‐Hodgkin lymphomas (NKT‐NHL) located in the nasal cavity (NC), nasopharynx, and paranasal sinuses, which are always categorized as one sinonasal type. Study Design: Patients diagnosed with primary B‐NHL and NKT‐NHL in the nasal cavity, nasopharynx, and paranasal sinuses from Surveillance, Epidemiology, and End Results (SEER) database were included (1975‐2017). Setting: Population‐based cohort study. Methods: We conducted univariate and multivariate Cox regressions and Kaplan‐Meier analysis to examine survival outcomes of B/NKT‐NHL in the nasal cavity, nasopharynx, and paranasal sinuses, respectively. Results: Overall, most B‐NHL cases originated from the nasopharynx, while the majority of NKT‐NHL cases occurred in the nasal cavity. Notably, the cancer‐special survival (CSS) outcomes improved significantly in all sinonasal B‐NHL cases over time, whereas no such improvement trend was observed in each sinonasal NKT‐NHL type. Additionally, increasing age was linked with an elevated risk of death in B‐NHL, particularly in the nasal cavity (Hazard ratio [HR]: 3.37), rather than in NKT‐NHL. Compared with B‐NHL, the adverse effect of a higher stage on CSS was more evident in NKT‐NHL, particularly in its nasopharynx site (HR: 5.12). Furthermore, radiotherapy was beneficial for survival in patients with sinonasal B‐NHL and NKT‐NHL, except in the nasopharynx NKT‐NHL. However, chemotherapy has only been beneficial for CSS in patients with paranasal sinuses B‐NHL (HR: 0.42) since 2010, rather than in other types of B/NKT‐NHL. Conclusion: Although B‐NHL and NKT‐NHL in the nasal cavity, nasopharynx and paranasal sinuses have similar anatomical locations, their clinicodemographics and prognoses are largely different and should be treated and studied as distinct diseases. [ABSTRACT FROM AUTHOR]

Purpose: SARS‐CoV‐2 vaccines cause acute ipsilateral lymph node swelling in an important proportion of vaccines. Thus far, no malignant lymphadenopathies have been reported in temporal context to vaccination in the ipsilateral draining lymph node areas. Experimental design: Prompted by two cases with unilateral axillary lymphomas that occurred ipsilaterally to prior SARS‐CoV‐2 vaccination, we systematically retrieved all B‐cell non‐Hodgkin lymphomas at two German University Medical Centers diagnosed before and after introduction of SARS‐CoV‐2 vaccines in Germany. Available lymphoma tissue (n=19) was subjected to next‐generation immunosequencing of the IGH locus. Malignant clonotypes were mined in the CoVabDab database and published data sets from 342 uninfected individuals, 55 individuals 28 days after anti‐SARS‐CoV‐2 vaccination and 139 individuals with acute COVID‐19 together encompassing over 1 million CDR3 sequences in total. Results: Of 313 newly diagnosed cases in the two centers and observation periods, 27 unilateral manifestations in the defined deltoid draining regions were identified. The majority thereof were diffuse large B‐cell lymphomas (18 of 27 cases). Eleven unilateral cases were diagnosed in the era of SARS‐CoV‐2 vaccination and 16 in the control period before introduction of such vaccines. Of the 11 unilateral lymphomas that occurred during the vaccination period, ten had received a SARS‐CoV‐2 vaccine prior to lymphoma diagnosis. These cases were further evaluated. While left‐sided were more frequent than right‐sided lymphomas (19 vs 8 cases), no statistically significant association of vaccination site and laterality of the lymphoma manifestation was found. The unilateral lymphomas showed a normal range of B‐cell receptors typically found in these lymphoma subtypes with no evidence for anti‐SARS‐CoV‐2 sequences in the malignant clonotype. Conclusions: Together, we found no evidence that the current SARS‐CoV‐2 vaccines could serve as a trigger for lymphomagenesis in the draining lymph node areas of the deltoid region used for vaccination. [ABSTRACT FROM AUTHOR]

Tirabrutinib is a Bruton's tyrosine kinase inhibitor for treating B-cell malignancies. We report the final results of a Phase I study of tirabrutinib in 17 Japanese patients with B-cell malignancies. Patients were administered tirabrutinib at a dose of 160 mg, 320 mg, or 480 mg once daily, or 300 mg twice daily (N = 3, 3, 4, and 7, respectively). Three patients continued tirabrutinib until study completion (November 30, 2020). Adverse events (AEs) occurred in all 17 patients, with Grade 3–4 AEs in 8 (47.1%), serious AEs in 7 (41.2%), drug-related AEs in 16 (94.1%), and Grade 3–4 drug-related AEs in 6 (35.3%). Drug-related AEs reported in 3 or more patients were rash, vomiting, neutropenia, arthralgia, and malaise. One additional serious AE (benign neoplasm of the lung, unrelated to tirabrutinib) occurred after the previous data cutoff (January 4, 2018). Tirabrutinib administration and response assessment were continued for over 4 years in 4 patients. The overall response rate was 76.5% (13/17 patients). The median (range) time to response and duration of response were 0.9 (0.9–5.9) months and 2.59 (0.08–5.45) years, respectively. These findings demonstrate the long-term safety and efficacy of tirabrutinib in Japanese patients with B-cell malignancies. Clinical trial registration: JapicCTI-142682 (http://www.clinicaltrials.jp/). [ABSTRACT FROM AUTHOR]

Purpose: New therapies are needed for relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma. This phase 1b, open-label trial evaluated two anti-CD20-based triplet combinations. Methods: Patients with R/R follicular lymphoma (FL; n = 13) were treated with obinutuzumab, atezolizumab, and polatuzumab vedotin (G-atezo-pola; 1.4 mg/kg/1.8 mg/kg) and patients with R/R diffuse large B-cell lymphoma (DLBCL; n = 23) received rituximab (R)-atezo-pola. The primary efficacy endpoint was complete response (CR) at end of induction (EOI) by PET-CT (investigator assessed; modified Lugano 2014 criteria). Safety endpoints were also assessed. Results: 13 FL patients were treated and evaluable for safety; 2/23 DLBCL patients did not receive treatment and were not included in the safety population. Median observation time was 23.3 and 5.7 months in the FL and DLBCL cohorts, respectively. At EOI, CR rates in FL patients treated with G-atezo-pola at pola doses of 1.4 mg/kg (N = 3) and 1.8 mg/kg (N = 7) were 33% and 14%, respectively. In DLBCL patients receiving R-atezo-pola, the CR rate at EOI was 13%. In the FL cohort, 62% of patients experienced a grade 3–5 adverse event (AE; including two deaths) and 31% developed a serious AE (SAE). In DLBCL patients, R-atezo-pola was associated with a lower incidence of grade 3–5 AEs (24%; one death) and SAEs (10%). In both cohorts, the most common grade 3–5 AEs were hematologic toxicities. Conclusion: Based on these safety issues, considered as related specifically to G-atezo-pola, and limited efficacy, no further development of either combination is planned. Trial registration: NCT02729896; Date of registration: April 6, 2016. [ABSTRACT FROM AUTHOR]

Monoclonal anti-CD20 antibodies in lymphomas therapy during the COVID-19 pandemic: pro and contraThe review presents the results of a combined analysis of literature data and own clinical observations regarding the safety and feasibility of using monoclonal anti-CD20 antibodies in the treatment of B-cell lymphoproliferative diseases during the COVID-19 pandemic. The main points of the pathogenesis of the influence of monoclonal anti-CD20 antibodies on the course of COVID-19 are described. The current trends in the modification of the accepted algorithms of lymphoproliferative diseases therapy with the inclusion of monoclonal anti-CD20 antibodies are summarized, and the possibilities of specific prevention by vaccination against COVID-19 are also considered.

Background: Mature B-cell non-Hodgkin lymphomas are one of the most common hematological malignancies with a divergent clinical presentation, phenotype, and course of disease regulated by underlying genetic mechanism. Main body: Genetic and molecular alterations are not only critical for lymphomagenesis but also largely responsible for differing therapeutic response in these neoplasms. In recent years, advanced molecular tools have provided a deeper understanding regarding these oncogenic drives for predicting progression as well as refractory behavior in these diseases. The prognostic models based on gene expression profiling have also been proved effective in various clinical scenarios. However, considerable overlap does exist between the genotypes of individual lymphomas and at the same time where additional molecular lesions may be associated with each entity apart from the key genetic event. Therefore, genomics is one of the cornerstones in the multimodality approach essential for classification and risk stratification of B-cell non-Hodgkin lymphomas. Conclusion: We hereby in this review discuss the wide range of genetic aberrancies associated with tumorigenesis, immune escape, and chemoresistance in major B-cell non-Hodgkin lymphomas. [ABSTRACT FROM AUTHOR]

Introduction: Investigation on virus-host interaction may provide new clues for antitumor immunotherapy., Case Presentation: In this case report, we describe an unusual case of B-cell non-Hodgkin lymphoma in an aged woman who recovered following SARS-COV-2 infection. We discuss the case and suggest that virus induced cross-reactivity against tumor account for the remission., Conclusion: Mapping epitope characteristics on B cell non-Hodgkin lymphoma antigen and on SARS-COV-2 antigen may provide much needed information for antigen based antitumor immune therapy in the future., Competing Interests: There was no conflict of interest declared., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Abstract Background Flow cytometry (FC) is a popular method to detect bone marrow (BM) involvement in patients with B-cell non-Hodgkin lymphoma (B-NHL). The majority of screen panels of FC still rely on finding monoclonal B-cells, e.g., B-cells with immunoglobin (Ig) light-chain restriction, which has many limitations. Therefore, exploring new markers is warranted. Methods A total of 52 cases of B-NHL with BM involvement were collected. The median age was 60 years. Out of these 52 cases, 34 were male, and 18 were female. A 10-color FC panel was used to detect the expression of CD54 on lymphoma cells. The expression of CD54 was calculated as the mean fluorescence index ratio (MFIR) and was described as the mean ± standard error of the mean (SEM). Results Up to 18/52 (34.62%) of BM specimens abnormally expressed an increased level of CD54, including 1/10 cases of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), 9/13 cases of mantle cell lymphoma (MCL), 2/14 cases of follicular lymphoma (FL), 5/9 cases of marginal zone lymphoma (MZL), and 1/3 cases of high-grade B-NHL (HG B-NHL). The expression level of CD54 was significantly increased in MCL cases (53.41 ± 11.04) compared with CLL/SLL cases (11.66 ± 2.79) and FL cases (13.49 ± 2.81). The lowest percentage of CD54-positive B-cells attained 0.13%. In 5/9 cases of MZL and 1/3 cases of HG B-NHL, increased expression of CD54 was the only abnormal immunophenotype detected besides Ig light-chain restriction. No aberrant CD54 expression was identified by FC in lymphoplasmacytic lymphoma (LPL) (0/2) and Burkitt lymphoma (BL) (0/1) cases. Aberrant expression of CD54 was not related to plasma cell differentiation. Conclusion Lymphoma cells, especially in MCL and MZL cases, frequently show increased expression of CD54. Such aberrant expression is not related to plasma cell differentiation. We highly recommend adding CD54 to the FC screening panel to detect BM involvement in patients with B-NHL.

Modulation of commensal gut microbiota is increasingly recognized as a promising strategy to reduce mortality in patients with malignant diseases, but monitoring for dysbiosis is generally not routine clinical practice due to equipment, expertise and funding required for sequencing analysis. A low-threshold alternative is microbial diversity profiling by single-cell flow cytometry (FCM), which we compared to 16S rRNA sequencing in human fecal samples and employed to characterize longitudinal changes in the microbiome composition of patients with aggressive B-cell non-Hodgkin lymphoma undergoing chemoimmunotherapy. Diversity measures obtained from both methods were correlated and captured identical trends in microbial community structures, finding no difference in patients’ pretreatment alpha or beta diversity compared to healthy controls and a significant and progressive loss of alpha diversity during chemoimmunotherapy. Our results highlight the potential of FCM-based microbiome profiling as a reliable and accessible diagnostic tool that can provide novel insights into cancer therapy-associated dysbiosis dynamics.

Limited data are available about the underlying causes of hemophagocytic lymphohistiocytosis (HLH) in adults. We collected and analyzed the data of 555 cases of adult HLH. HLH in 242 patients were malignancies-related and lymphoid malignancies (42.0%, 233/555) were the most common causes. Aggressive natural killer-cell leukemia, diffuse large B-cell lymphoma, and extranodal natural killer/T-cell lymphoma, nasal type were the most common specified pathological subtypes. Epstein-Barr virus (EBV) (69.0%, 100/145) was the most common pathogen among the cases of infectionsrelated HLH (26.1%, 145/555). Malignancies-related HLH showed male preponderance, more common splenomegaly, more severe anemia and thrombocytopenia, and significantly elevated soluble CD25. In patients with abnormal lymphoid cells in the bone marrow (BM) and increased EBV DNA copy number, 48.9% (45/92) of them were aggressive natural killer-cell leukemia. In patients with abnormal lymphoid cells in the BM and normal EBV DNA copy number, 66.2% (47/71) of them were B-cell non-Hodgkin lymphoma. In patients with elevated EBV DNA copy number but no abnormal lymphoid cells in the BM, 71.0% (98/138) of these cases were EBV infection. In conclusion, lymphoid malignancy is the most common underlying cause of adult HLH, followed by EBV infection. Based on the BM morphology and EBV load, we developed a diagnostic flow for rapid determination of the triggers for HLH. [ABSTRACT FROM AUTHOR]

Introduction: Myeloid‐derived suppressor cells (MDSCs) are a heterogeneous cell population with the ability to suppress immune responses. MDSCs usually cluster in cancer, inflammation, and autoimmune diseases. Although there have been some studies on MDSCs in non‐Hodgkin lymphoma (NHL), the correlation between the peripheral levels of MDSCs in patients with various subtypes of B cell NHL and clinical features and prognosis remains inconclusive. This study aimed at the issue. Methods: 101 patients with B cell NHL and 15 age‐matched healthy controls were included in this study. Flow cytometric detection of monocytic‐MDSCs (M‐MDSCs) and granulocytic‐MDSCs (G‐MDSCs) was done. Results: In this study, we found that counts of circulating M‐MDSCs and G‐MDSCs were significantly increased in different clinical statuses of B‐NHL patients compared to healthy controls. Similarly, a significant increase in the levels of M‐MDSCs and G‐MDSCs was found among the diverse types of B‐NHL compared with healthy donors. Stratification studies indicated MDSCs expansion was closely associated with disease progression (tumor stage, LDH levels and B syndromes). Moreover, the overall survival time of patients with G‐MDSCs (%) ≥ 98.70% was shorter than patients with G‐MDSCs (%) < 98.70% in newly diagnosed B‐NHL subgroup, meanwhile, there was a significant difference in survival of patients with M‐MDSCs (%) ≥ 7.19% compared to patients with M‐MDSCs (%) < 7.19% in relapsed B‐NHL subgroup. Conclusion: Our results suggested that M‐MDSCs and G‐MDSCs may be a potential and efficient index to evaluate the prognosis of B‐NHL patients. [ABSTRACT FROM AUTHOR]

Abstract Introduction Myeloid‐derived suppressor cells (MDSCs) are a heterogeneous cell population with the ability to suppress immune responses. MDSCs usually cluster in cancer, inflammation, and autoimmune diseases. Although there have been some studies on MDSCs in non‐Hodgkin lymphoma (NHL), the correlation between the peripheral levels of MDSCs in patients with various subtypes of B cell NHL and clinical features and prognosis remains inconclusive. This study aimed at the issue. Methods 101 patients with B cell NHL and 15 age‐matched healthy controls were included in this study. Flow cytometric detection of monocytic‐MDSCs (M‐MDSCs) and granulocytic‐MDSCs (G‐MDSCs) was done. Results In this study, we found that counts of circulating M‐MDSCs and G‐MDSCs were significantly increased in different clinical statuses of B‐NHL patients compared to healthy controls. Similarly, a significant increase in the levels of M‐MDSCs and G‐MDSCs was found among the diverse types of B‐NHL compared with healthy donors. Stratification studies indicated MDSCs expansion was closely associated with disease progression (tumor stage, LDH levels and B syndromes). Moreover, the overall survival time of patients with G‐MDSCs (%) ≥ 98.70% was shorter than patients with G‐MDSCs (%)

Summary: This prospective study evaluated seroconversion rates in response to BNT162b2 (Pfizer‐BioNTech) COVID‐19 vaccine booster in 44 B‐cell non‐Hodgkin lymphoma (B‐NHL) patients who failed to respond to two prior doses [42 previously exposed to anti‐CD20 monoclonal antibodies (moAbs) including 13 under maintenance treatment]. Seroconversion was obtained in 29.5% of the patients. Longer time from last anti‐CD20 moAb (>6 months) and diagnosis of aggressive lymphoma compared to other, incurable B‐NHLs were associated with increased seroconversion rates (47.8% vs.10.5%, p = 0.019 and 50% vs. 17.9%, p = 0.025 respectively). Thus, seronegative patients with B‐NHL that completed anti‐CD20 therapy more than 6 months prior to the booster have greater chances to achieve seroconversion. [ABSTRACT FROM AUTHOR]

Multicolor flow cytometry (MFC) is crucial in detecting occult or minimal bone marrow (BM) involvement by non-Hodgkin lymphomas (NHL), which may not be detected using trephine biopsy or imaging studies. Detection of low-level BM involvement can be challenging without definite immunophenotypic aberrancies. We studied the utility of CD305 in MFC detection of minimal BM involvement by B-NHL, especially in the absence of aberrancies by commonly used markers. The study included 1084 consecutive BM samples submitted for the staging of B-NHLs (excluding CLL) over two years. Samples were studied for morphological, immunophenotypic, and histopathological assessment. MFC studies were performed using 10-13 color MFC, including CD305-antibody (clone, DX26). Minimal BM involvement was defined with a cutoff of ≤10% lymphoma cells in viable cells on MFC assessment. Of 1084, 148 samples revealed overt morphological involvement by B-NHL and were excluded from analysis. BM samples of 172/936 patients were morphologically negative but revealed involvement using MFC independently. Corresponding trephine biopsy involvement was detected in only 79/172 (45.9%) patients. On MFC, 23/172 samples showed BM involvement with >10% lymphoma cells, and 149/172 (86.6%) samples revealed minimal involvement. In 54/149 (36.24%) samples, lymphoma cells were detected only with aberrant loss of CD305 expression. In 78 of the remaining 95 samples (82.1%), it provided an immunophenotypic aberrancy addition to other markers and supported the results. CD305 is a highly useful marker in the flow cytometric assessment of minimal BM involvement by B-NHL. MFC is a superior modality to trephine biopsy in detecting low-level BM involvement., (© 2024 The Author(s). Cytometry Part B: Clinical Cytometry published by Wiley Periodicals LLC on behalf of International Clinical Cytometry Society.)

Among patients receiving CD19 or B-cell maturation antigen (BCMA) CAR T therapy, inflammation pre- and post-CAR T infusion is implicated in the development of toxicities including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and likely contributes to prolonged cytopenias. Clonal hematopoiesis (CH), the clonal expansion of hematopoietic stem cells harboring somatic mutations, has been associated with inflammasome upregulation. Herein, we examined the prevalence of pre-CAR T CH in a predominantly transplant-naïve cohort of recipients with non-Hodgkin lymphoma (NHL) or multiple myeloma (MM), and assessed the relationship between the presence of CH mutations and CAR T-related outcomes including CRS, ICANS, prolonged cytopenia, progression-free survival (PFS), and overall survival (OS). This study included 62 patients with NHL or MM who underwent CD19 or BCMA CAR T therapy from 2017 to 2022 at City of Hope and had available pre-CAR T cryopreserved peripheral blood mononuclear cells (PBMCs). DNA was isolated with QIAamp DNA Mini Kit (Qiagen) from PBMC samples (94% collected <30d of CART infusion), on which we performed targeted exome sequencing (108 pre-defined gene panel with 1000x sequencing depth) to determine the presence of CH (variant allele frequency [VAF] ≥2%). Multivariable logistic regression was used to examine the association between CH and absolute neutrophil count (ANC) recovery at day +30 and +60, maximum grade CRS and ICANS, grade <2 versus 2+, and OS and PFS at 1y. Covariates considered were age at CART, baseline ANC, sex, race, CAR-HEMATOTOX, LDH, bridging therapy (Y/N), and number of prior lines of therapy. Fifteen (24%) patients had at least one pathogenic CH mutation; 2 (13%) had ≥2 CH mutations concurrently. DMT3A mutations were the most common; 29% of mutations had VAFs >10%. Patients with CH were significantly more likely to develop grade ≥2 CRS (60% versus 28%, p = .03) compared to those without CH (odds ratio [OR] 3.9, 95% CI 1.2-13.2; p = .027). Accounting for baseline ANC (which was higher among the CH cohort and associated with delayed ANC recovery, p = .02) patients with CH did not have a significantly different rate of delayed ANC recovery compared to those without CH (adjusted OR 0.37, 95% CI 0.09-1.5; p = .17). There was no association between CH and ICANS, nor with 1y PFS or OS. CH was frequent (24%) in this cohort of CAR T recipients and was associated with a higher risk of development of grade ≥2 CRS after CAR T. Additional validation studies are currently underway, which may set the stage for consideration of pre-CAR T CH as a biomarker for risk stratification towards more proactive CRS prophylaxis. Translational studies could aim to prove a direct relationship between CH-mutated myeloid cells and CRS., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Flow cytometry (FC) is a popular method to detect bone marrow (BM) involvement in patients with B-cell non-Hodgkin lymphoma (B-NHL). The majority of screen panels of FC still rely on finding monoclonal B-cells, e.g., B-cells with immunoglobin (Ig) light-chain restriction, which has many limitations. Therefore, exploring new markers is warranted.Methods: A total of 52 cases of B-NHL with BM involvement were collected. The median age was 60 years. Out of these 52 cases, 34 were male, and 18 were female. A 10-color FC panel was used to detect the expression of CD54 on lymphoma cells. The expression of CD54 was calculated as the mean fluorescence index ratio (MFIR) and was described as the mean ± standard error of the mean (SEM).Results: Up to 18/52 (34.62%) of BM specimens abnormally expressed an increased level of CD54, including 1/10 cases of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), 9/13 cases of mantle cell lymphoma (MCL), 2/14 cases of follicular lymphoma (FL), 5/9 cases of marginal zone lymphoma (MZL), and 1/3 cases of high-grade B-NHL (HG B-NHL). The expression level of CD54 was significantly increased in MCL cases (53.41 ± 11.04) compared with CLL/SLL cases (11.66 ± 2.79) and FL cases (13.49 ± 2.81). The lowest percentage of CD54-positive B-cells attained 0.13%. In 5/9 cases of MZL and 1/3 cases of HG B-NHL, increased expression of CD54 was the only abnormal immunophenotype detected besides Ig light-chain restriction. No aberrant CD54 expression was identified by FC in lymphoplasmacytic lymphoma (LPL) (0/2) and Burkitt lymphoma (BL) (0/1) cases. Aberrant expression of CD54 was not related to plasma cell differentiation.Conclusion: Lymphoma cells, especially in MCL and MZL cases, frequently show increased expression of CD54. Such aberrant expression is not related to plasma cell differentiation. We highly recommend adding CD54 to the FC screening panel to detect BM involvement in patients with B-NHL. [ABSTRACT FROM AUTHOR]

Background: Chronic lymphocytic leukemia (CLL) is a monoclonal disorder characterized by uncontrolled proliferation of mature B lymphocytes. CD26 is a multi-functional type II cell surface glycoprotein, which is expressed mainly by T lymphocyte and it has a regulatory role in progression and also in migration and metastasis of tumour. Objective: The aim of the work was to assess the regulatory role and expression of CD26 in patients with B-CLL and B-cell non-Hodgkin lymphoma (B-NHL) and the relation to disease staging and progression. Methods: This study was conducted on 6 patients with B-CLL and 5 patients with NHL who were attending at National Cancer Institute. We detected functional role and specificity of CD26 by flow cytometry during the period from December 2019 to March 2020. The ages of patients ranged from 42 to 79 years old. Besides, 5 healthy individuals worked as control group. Results: A significant difference was found as regards expression of CD26 in CLL cases in comparison to control cases (p.0001). Also there was a significant difference between the NHL group and control group in expression of CD26 (p.0001). But no significant difference was detected between the NHL groups and CLL groups in expression of CD26 (p.052). Conclusion: This study confirmed that CD26 expression in CLL and NHL is variable and didn't correlate with other prognostic factors. In addition, there was no significant difference between the NHL groups and CLL groups in expression of CD26. [ABSTRACT FROM AUTHOR]

B-cell non-Hodgkin lymphoma (NHL) is the most frequent hematologic malignancy. Despite the refinement of chemoimmunotherapy, a substantial number of patients experience chemorefractory disease. Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is considered the most promising and effective therapy to overcome chemorefractory B-cell NHL. Based on the promising results obtained from pivotal trials, the US Food and Drug Administration and European Medicines Agency approved anti-CD19 CAR T-cell therapy for relapsed/refractory diffuse large B-cell lymphoma. Nonetheless, there remain several controversial issues and problems awaiting solutions, including optimal management of toxicities, overcoming relapsed/refractory disease after CAR T-cell therapy, and improving CAR-T manufacturing platform. Definite unmet medical needs among patients with chemorefractory B-cell NHL still exist. CAR T-cell therapy might be a game changer that can defeat chemorefractory B-cell NHL, and further clinical development is warranted. In this review, we summarize the recent clinical developments, clinical implications, and perspectives of CAR T-cell therapy, focusing on B-cell NHL.

Abstract: Anti-CD19-directed chimeric antigen receptor (CAR) T-cell therapy yields durable remissions in up to 40% of patients with chemoresistant aggressive B-cell non-Hodgkin lymphoma (NHL), a group of patients expected only to survive on average 6 months. Although longer follow-up is needed to define durability, CD19 CAR T cells are demonstrating similar promise in other B-NHL subtypes such as mantle cell lymphoma and the indolent B-cell NHLs. This transformative therapy, however, remains hamstrung by its associated toxicities of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, as well as by mechanisms of resistance and relapse and accessibility. To address these limitations, studies are underway to investigate toxicity prevention and mitigation strategies and the development of safer CARs, combination strategies to overcome T-cell exhaustion and dual antigen targeting to combat antigen loss, and alternative cell sources to address cost and manufacturing inefficiencies and resolve issues surrounding T-cell fitness. [ABSTRACT FROM AUTHOR]

Lymphoproliferative lesions that have morphology between benign and malignant are difficult to diagnose even with immunohistochemical and clonality testing. The correct diagnosis is necessary for the prompt treatment. These lesions can also serve as instructive models of lymphomagenesis. FOXP1 plays an important role in B-cell development, has a potential oncogene in B-cell Non-Hodgkin lymphoma, and p53 protein has a crucial role in the regulation of cell cycle, DNA repair, apoptosis, and senescence tumor suppression activity. In this study, we analyze the role of FOXP1 and p53 expression in reactive lymphoid hyperplasia and B-cell Non-Hodgkin lymphoma, large cell type. 68 paraffin blocks samples from patients diagnosed as reactive lymphoid hyperplasia and B-cell Non-Hodgkin lymphoma, large cell type was sectioned and stained with immunohistochemistry for FOXP1 and p53, and the percentage of nuclear cells showing positive staining were evaluated. Expression of FOXP1 and p53 in B-cell Non-Hodgkin lymphoma, large cell type is higher than in reactive lymphoid hyperplasia with p=0.001 and cutoff point 45%(CI=95%) for FOXP1 and p=0.001 and cutoff point 7.5%(CI=95%) for p53. There is a significant correlation between the expression of FOXP1 and p53 in reactive lymphoid hyperplasia and B-cell Non-Hodgkin lymphoma, large cell type (p=0.001). Our findings suggest that high expression of FOXP1 and p53 in B-cell Non-Hodgkin lymphoma may demonstrate the role of FOXP1 and p53 in lymphomagenesis and these markers may help to distinguish benign and malignant lymphoproliferative lesions. [ABSTRACT FROM AUTHOR]

B lymphocytes play a critical role in humoral immunity. Abnormal B cell development and function cause a variety of hematological malignancies such as myeloma, B cell lymphoma, and leukemia. Histone deacetylase 6 (HDAC6) inhibitors alone or in combination with other drugs have shown efficacy in several hematological malignancies, including those resistant to targeted therapies. Mechanistically, HDAC6 inhibitors promote malignant tumor cell apoptosis by inhibiting protein degradation, reinvigorating anti-tumor immunity, and inhibiting cell survival signaling pathways. Due to their specificity, HDAC6 inhibitors represent a very promising and feasible new development pipeline for high-efficacy drugs with limited side effects. This article reviews recent progress in the mechanisms of action of HDAC6 inhibitors for the treatment of B cell-associated hematological malignancies, such as multiple myeloma and B cell non-Hodgkin lymphoma, which are often resistant to targeted therapies.

Objective: Polymorphisms in the interleukin (IL)-2 and IL-10 genes are known to be associated with susceptibility to different immunedysregulated disorders and cancers such as non-Hodgkin lymphoma (NHL). To explore the possible association between IL-2-330T/G and IL- 10-1082A/G single-nucleotide polymorphisms and the susceptibility to B-cell NHL (B-NHL) in Egyptians, we conducted a case-control study. Materials and Methods: Genotyping of the studied genetic variations was done for 100 B-NHL patients as well as 100 age- and sex-matched healthy controls. Results: The IL-2 variant allele occurred at a significantly higher rate in patients than controls and was associated with susceptibility to B-NHL [odds ratio (OR): 1.91, 95% confidence interval (CI): 1.28-2.85]. It was also associated with advanced performance status score. IL-2 polymorphism conferred an almost threefold increased risk of diffuse large B-cell lymphoma (OR: 2.64, 95% CI: 1.35-5.15) and a fourfold increased risk of indolent subtypes (OR: 4.34, 95% CI: 1.20-15.7). The distribution of IL-10-1082A/G genotypes in our patients was close to that of the controls. Co-inheritance of the variant genotypes of IL-2 and the common genotype of IL-10 conferred an almost sixfold increased risk (OR: 5.75, 95% CI: 1.39-23.72), while co-inheritance of the variant genotypes of IL-2 and IL-10 conferred fivefold increased risk of B-NHL (OR: 5.43, 95% CI: 1.44-20.45). The variant genotypes of IL-2-330T/G and IL-10-1082A/G had no effect on the disease-free survival of B-NHL patients. Conclusion: The present study highlights the possible involvement of the IL-2-330T/G genetic polymorphism in the susceptibility to B-NHL in Egypt, especially indolent subtypes. Moreover, IL-10-1082A/G is not a molecular susceptibility marker for B-NHL in Egyptians.

The phase 2 portion of this open-label phase 2/3 study assessed the efficacy and safety of blinatumomab as second salvage for aggressive relapsed or refractory (r/r) aggressive B-cell non-Hodgkin lymphoma (B-NHL) following platinum-based first salvage chemotherapy. Forty-one patients with aggressive disease (32% relapsed; 68% refractory) enrolled and received stepwise blinatumomab (9–28–112 μg/day) in a 70-day cycle 1 and an optional 28-day cycle 2; 19 (46%) completed cycle 1 and 3 (7%) completed cycle 2. The overall response rate after 12 weeks was 37%, including 9 (22%) complete metabolic responses. Eight (20%) patients (all responders) subsequently received stem cell transplants. Grade ≥3 adverse events were reported in 29 (71%) patients. Grade 3 cytokine release syndrome occurred in one patient. Grade 3 neurologic events occurred in 10 (24%) patients; all resolved. Blinatumomab monotherapy appears effective as second salvage therapy in patients with r/r aggressive B-NHL. Trial registration: NCT02910063. [ABSTRACT FROM AUTHOR]

B lymphocytes play a critical role in humoral immunity. Abnormal B cell development and function cause a variety of hematological malignancies such as myeloma, B cell lymphoma, and leukemia. Histone deacetylase 6 (HDAC6) inhibitors alone or in combination with other drugs have shown efficacy in several hematological malignancies, including those resistant to targeted therapies. Mechanistically, HDAC6 inhibitors promote malignant tumor cell apoptosis by inhibiting protein degradation, reinvigorating anti-tumor immunity, and inhibiting cell survival signaling pathways. Due to their specificity, HDAC6 inhibitors represent a very promising and feasible new development pipeline for high-efficacy drugs with limited side effects. This article reviews recent progress in the mechanisms of action of HDAC6 inhibitors for the treatment of B cell-associated hematological malignancies, such as multiple myeloma and B cell non-Hodgkin lymphoma, which are often resistant to targeted therapies. [ABSTRACT FROM AUTHOR]

Purpose: The phase Ib/II open-label study (NCT01992653) evaluated the antibody-drug conjugate polatuzumab vedotin (pola) plus rituximab/obinutuzumab, cyclophosphamide, doxorubicin, and prednisone (R/G-CHP) as first-line therapy for B-cell non-Hodgkin lymphoma (B-NHL). We report the pharmacokinetics (PK) and drug-drug interaction (DDI) for pola.Methods: Six or eight cycles of pola 1.0-1.8 mg/kg were administered intravenously every 3 weeks (q3w) with R/G-CHP. Exposures of pola [including antibody-conjugated monomethyl auristatin E (acMMAE) and unconjugated MMAE] and R/G-CHP were assessed by non-compartmental analysis and/or descriptive statistics with cross-cycle comparisons to cycle 1 and/or after multiple cycles. Pola was evaluated as a potential victim and perpetrator of a PK drug-drug interaction with R/G-CHP. Population PK (popPK) analysis assessed the impact of prior treatment status (naïve vs. relapsed/refractory) on pola PK.Results: Pola PK was similar between treatment arms and independent of line of therapy. Pola PK was dose proportional from 1.0 to 1.8 mg/kg with R/G-CHP. Geometric mean volume of distribution and clearance of acMMAE ranged from 57.3 to 95.6 mL/kg and 12.7 to 18.2 mL/kg/day, respectively. acMMAE exhibited multi-exponential decay (elimination half-life ~ 1 week). Unconjugated MMAE exhibited formation rate-limited kinetics. Exposures of pola with R/G-CHP were similar to those in the absence of CHP; exposures of R/G-CHP in the presence of pola were comparable to those in the absence of pola.Conclusions: Pola PK was well characterized with no clinically meaningful DDIs with R/G-CHP. Findings are consistent with previous studies of pola + R/G, and support pola + R/G-CHP use in previously untreated diffuse large B-cell lymphoma. [ABSTRACT FROM AUTHOR]

Growing evidence now suggests that circulating tumour DNA (ctDNA) has great potential as a non-invasive biomarker for disease monitoring, since ctDNA carries tumour-specific modifications. In particular, monitoring ctDNA has important implications for identifying patients with haematological malignancies at clinical risk of disease progression. We hereby describe three patients with B-cell non-Hodgkin lymphoma and investigate the clinical value of sequential ctDNA profiling for the early detection of tumour relapse. Somatic mutations in diagnostic tumour biopsy samples of these three patients were identified by applying high-throughput next-generation sequencing. Droplet digital PCR probes and primers were designed and tested for each hotspot mutation. Serial ctDNA analysis was subsequently conducted among these three patients. We found that the longitudinal monitoring of plasma ctDNA could predict for at least one month in advance compared with flow cytometry, cytology and conventional imaging modalities. Therefore, our results support liquid biopsy based on ctDNA as a non-invasive complementary modality to other detection methods for detecting early relapse and contribute to more precise management for non-Hodgkin lymphoma patients.

DP-1 is a G1 cell cycle-related protein that forms heterodimers with E2F, a family of transcriptional factors regulating the expression of genes important for G1 to S progression. Although the exact role of DP-1 is not well understood, it has been shown to stabilize DNA binding of E2F proteins. By immunohistochemistry, the authors examined the expression of DP-1 in lymphoid tissues, including 8 cases of reactive follicular hyperplasia and 69 cases of B-cell non-Hodgkin lymphoma. The expression of the cell cycle-related proteins E2F-1 and Ki-67 was also assessed. Scoring was based on the proportion of labeled nuclei (1-10%, 11-25%, 26-50%, and > 50%). In reactive follicular hyperplasia, staining for DP-1, E2F-1, and Ki-67 was largely confined to the germinal centers. All 25 cases of follicular lymphoma, regardless of grade, had a high proportion (> 50%) of DP-1-positive cells but a lower proportion of cells marking for E2F-1 and Ki-67 (P < 0.001). The diffuse large B-cell lymphomas (n = 24) had high DP-1 and Ki-67 scores but low E2F-1 scores (P < 0.001). Small lymphocytic (n = 10), marginal zone (n = 3), and mantle cell lymphomas (n = 5) contained relatively low proportions of cells labeled for all three markers. Precursor B-cell lymphoblastic lymphoma (n = 2) displayed high proportions of cells positive for DP-1, Ki-67, and E2F-1 (> 50% in both cases). Except in follicular center cell lesions, DP-1 expression generally correlated with that of Ki-67. However, the expression of DP-1 was discordant with that of E2F-1 in benign and malignant follicular center cells, suggesting that DP-1 may have functions other than facilitating E2F-1-dependent gene regulation and cell cycle progression in these neoplasms.

Jozef Malysz,1 Juanita J Evans,2 Malcolm Acon-Laws,3 Michael G Bayerl,1 Michael H Creer1 1Department of Pathology, Penn State Milton S Hershey Medical Center, Hershey, PA, 2Department of Pathology, St. John Heath – Providence, Southfield, MI, USA; 3Laboratorio de Patologia Hospital Cima, San Jose, Costa Rica Abstract: Evaluation of mindbomb E3 ubiquitin protein ligase 1 (MIB1) (Ki67) proliferation index (PI) in B-cell non-Hodgkin lymphomas is increasingly a common addition to classification of lymphoma and staging procedures. Clinicians relay on PI as a surrogate marker of biologic activity; however, no established guidelines have been published whether PI at the primary site of the tumor gives the same answer as evaluation of tumor in staging marrow. In our study, dual immunohistochemical staining for MIB1 and CD20 was performed on tissue from primary site and bone marrow involved by B-cell non-Hodgkin lymphoma to compare PI for each individual patient. For all patients, MIB1 expression was higher at primary tumor site as compared to staging marrow. Additional analysis was performed to investigate the degree of difference depending on lymphoma morphology. Patients with large cell lymphoma at the primary site and large cell morphology in the marrow (LCL-L), those with large cell morphology at the primary site and small cell morphology in the marrow (LCL-S), and those with small cell morphology at the primary site and small cells in the marrow (SCL-S) were compared. As expected, LCL cases had a higher mean PI at the primary site when compared to SCL cases (28.5% vs 2.8%, P=0.0001). In addition, the most significant difference between medullary and extramedullary PI was observed in cases with discordant morphology (LCL-S) (21% vs 1.1%, P=0.009). Our results indicate that PI of lymphoma within the bone marrow should not be used as a surrogate prognostic indicator of lymphoma biology in its primary site. Keywords: proliferation index, biologic behavior, prognosis

Objective B-lymphocyte stimulator (BLyS) is a member of tumor necrosis factor family. BLyS is essential for the survival of normal and malignant B lymphocyte. Hepatitis C virus (HCV) infection likely represents the early event leading to BLyS upregulation. The aim of this study was to determine the relation between serum BLyS levels and the severity of HCV-related B-cell non-Hodgkin lymphoma (B-NHL). Patients and methods Seventy-eight B-NHL patients both HCV-positive and HCV-negative and 20 patients with HCV infection without lymphoproliferative disorders, in addition to 20 age-matched and sex-matched controls, were included in the study. PCR for HCV, evaluation of levels of soluble BLyS protein in blood, bone marrow aspirate and biopsy with flow cytometry, and lymph node biopsy with immunophenotyping for CD5, CD23, CD10, CD20, and cyclinD1 were performed. Results The serum BLyS levels were significantly higher in B-NHL patients and HCV patients without lymphoproliferative disorders compared with the control group. The serum BLyS levels were statistically significantly higher in aggressive lymphoma patients with HCV-positive infection compared with aggressive lymphoma patients with HCV-negative infection, but there was no statistically significant difference between BLyS levels in indolent B-NHL patients with or without HCV infections. Moreover, there was no statistically significant difference between BLyS levels in aggressive and indolent lymphoma patients with HCV-positive infection. Conclusion BLyS levels are increased in HCV-induced B-NHL but it cannot be considered as a marker for severity of the disease (indolent or aggressive). More studies are needed.

Summary: Patients with relapsed, refractory or advanced stage B non‐Hodgkin lymphoma (NHL) continue to have a dismal prognosis. This review summarises current and novel cellular and immunotherapy for these high‐risk populations, including haematopoietic stem cell transplant, bispecific antibodies, viral‐derived cytotoxic T cells, chimeric antigen receptor (CAR) T cells, and natural killer (NK) cell therapy, as discussed at the 6th International Symposium on Childhood, Adolescent and Young Adult Non‐Hodgkin Lymphoma on September 26th–29th 2018 in Rotterdam, the Netherlands, and explores the future of NK/CAR NK therapies. [ABSTRACT FROM AUTHOR]

Patients suffering from B‐cell non‐Hodgkin lymphomas (B‐NHL) have an increased likelihood of being exposed to proton pump inhibitors (PPIs), related to several factors which have been reported in the literature. PPIs are among the drugs most likely to be prescribed inappropriately. Consequently, B‐NHL patients could be particularly at risk of inappropriate PPI prescription, with potential adverse drug reactions. We aimed to evaluate the incidence of PPIs use and to identify factors associated with PPIs initiation during the active treatment phase of B‐NHL. We conducted a new‐user cohort study using regional data from the French national health insurance database in the Midi‐Pyrénées region (southwestern France). Incident B‐NHL patients were selected according to an algorithm of selection, validated with data from a cancer registry. Our study revealed that 48.9% (95% confidence interval [CI]: 45.2–52.6) of patients initiated PPIs during chemotherapy after B‐NHL diagnosis. According to information available in the SNDS, recommended indications for PPI prescriptions were identified in 21.1% of cases. Median duration of treatment was 65.3 days (CI: 35–112). Determinants of PPIs initiation were peptic ulcer disease, gastroprotection (appropriate or not) for medications considered at risk (NSAIDs, glucocorticoids and anticoagulants), age, nonfollicular lymphoma, polypharmacy, gastroenterologists' consultations and being hospitalized in a university hospital. Around 50% of patients initiated PPI treatment during the chemotherapy phase with only one‐fifth identified as appropriate prescriptions and with long durations of treatment in most cases. Given this background, appropriate PPI prescription should be promoted in B‐NHL to avoid potential inappropriate chronic use and related adverse events. [ABSTRACT FROM AUTHOR]