SENEX-mediated CDK4/6 inhibition promotes senescence and confers apoptosis resistance in B-cell non-Hodgkin lymphoma

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.

2022 Chinese expert consensus and guidelines on clinical management of toxicity in anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma

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.

Heterochronous multiple primary prostate cancer and lymphoma:A case report

BACKGROUND Multiple primary malignant tumors(MPMTs)are rare type of cancer,especially when solid tumors are the first and lymphoma is the second primary malignancy.We report a patient with heterochronous MPMTs consisting of prostate cancer and rectal diffuse large B-cell lymphoma(DLBCL).CASE SUMMARY We report a 77-year-old male patient diagnosed with prostate cancer who was treated with radiation therapy and one year of endocrine therapy with bicalutamide(50 mg per day)and an extended-release implant of goserelin(1/28 d).Seven years later,rectal DLBCL with lung metastases was found.CONCLUSION Although rare,the possibility of prostate cancer combined with a double primary cancer of DLBCL can provide a deeper understanding.

‘Les liaisons dangereuses’: Hepatitis C, Rituximab and B-cell non-Hodgkin’s lymphomas

Rituximab has provided a revolutionary contribution to the treatment of B-cell non-Hodgkin’s lymphomas (NHL). A high prevalence of hepatitis C virus (HCV) infection has been described in B-cell NHL patients. Cases of liver dysfunction in HCV-positive patients have been reported with Rituximab-containing regimens. In this paper we review the recent data regarding the effects of Rituximab in NHL patients with HCV infection. We also added a section devoted to improving communication between oncohaematologists and hepatologists. Furthermore, we propose a common methodological ground to study hepatic toxicity emerging during chemotherapy.

Unusual Presentation of Non-Hodgkin’s B-Cell Lymphoma with Unilateral Right Limb Lymphedema

Background: In clinical practice and setting of general practice it is common to see patients with leg edema. To correctly identify the etiology of the edema and then properly manage the cause is not always easy. The unilateral lymphedema of the lower limb has rarely been reported as an initial presentation for lymphoma, especially in females, usually without classic signs or symptoms, but often with inguinal lymphadenopathy or abdominal masses. Case Report: In this article, we report a rare case of unilateral lower limb edema in a healthy obese woman who complained about the appearance of the disease for several months and for whom deep vein thrombosis and other diseases had been excluded. The histological examination of the biopsy of an enlarged lymph node in the right groin, which was compressing the iliac and femoral vein, revealed the presence of B cell non-Hodgkin lymphoma with high-grade malignancy. Conclusions: A common challenge for primary care physicians is to determine the cause and find an effective treatment for leg edema of unclear etiology. Non-Hodgkin’s B-cell Lymphoma should be considered in the differential diagnosis in patients with unilateral leg edema when the swelling is chronic and deep venous thrombosis is promptly excluded.

Primary gastric non-Hodgkin lymphomas:Recent advances regarding disease pathogenesis and treatment

Primary gastric lymphomas(PGLs)are distinct lymphoproliferative neoplasms described as heterogeneous entities clinically and molecularly.Their main histological types are diffuse large B-cell lymphoma(DLBCL)or mucosaassociated lymphoma tissue.PGL has been one of the main fields of clinical research of our group in recent years.Although gastric DLBCLs are frequent,sufficient data to guide optimal care are scarce.Until today,a multidisciplinary approach has been applied,including chemotherapy,surgery,radiotherapy or a combination of these treatments.In this minireview article,we provide an overview of the clinical manifestations,diagnosis and staging of these diseases,along with their molecular pathogenesis and the most important related clinical published series.We then discuss the scientific gaps,perils and pitfalls that exist regarding the aforementioned studies,in parallel with the unmet need for future research and comment on the proper methodology for such retrospective studies.Aiming to fill this gap,we retrospectively evaluated the trends in clinical presentation,management and outcome among 165 patients with DLBCL PGL who were seen in our institutions in 1980-2014.The study cohort was divided into two subgroups,comparing the main 2 therapeutic options[cyclophosphamide doxorubicin vincristine prednisone(CHOP)vs rituximab-CHOP(R-CHOP)].A better outcome with immunochemotherapy(R-CHOP)was observed.In the next 2 mo,we will present the update of our study with the same basic conclusion.

Gastrointestinal B-cell lymphomas:From understanding B-cell physiology to classification and molecular pathology

The gut is the most common extranodal site where lymphomas arise. Although all histological lymphoma types may develop in the gut, small and large B-cell lymphomas predominate. The sometimes unexpected finding of a lymphoid lesion in an endoscopic biopsy of the gut may challenge both the clinician (who is not always familiar with lymphoma pathogenesis) and the pathologist (who will often be hampered in his/her diagnostic skill by the limited amount of available tissue). Moreover, the past 2 decades have spawned an avalanche of new data that encompasses both the function of the reactive B-cell as well as the pathogenic pathways that lead to its neoplastic counterpart, the B-cell lymphoma. Therefore, this review aims to offer clinicians an overview of B-cell lymphomas in the gut, and their pertinent molecular features that have led to new insights regarding lymphomagenesis. It addresses the question as how to incorporate all presently available information on normal and neoplastic B-cell differentiation, and how this knowledge can be applied in daily clinical practice (e.g., diagnostic tools, prognostic biomarkers or therapeutic targets) to optimalise the managment of this heterogeneous group of neoplasms.

Case Report: Fever of Unknown Origin <br/>—An Unusual Presentation for Diffuse Large B-Cell Lymphoma

A 61-year-old male initially presented with fever of unknown origin. He had extensive work-up over two years including an infectious diseases panel, autoimmune studies, and Rheumatology and Hematology evaluations. The patient was initially diagnosed with Adult Still’s disease and underwent an out-patient right nodal fine-needle aspiration that was indeterminate. After continued failure of treatment for Adult Still’s disease, the patient had surgical resection of a right axillary lymph node that yielded the diagnosis of diffuse large B-cell lymphoma. Further work-up revealed Epstein-Barr virus positivity, the possible trigger behind his mutation for diffuse large B-cell lymphoma and its uncommon presentation. The patient met criteria for central nervous system prophylaxis and received multiple administrations throughout his therapy. He ultimately expired following recurrence of his disease at its initial site but without central nervous system involvement. We report an uncommon presentation of a patient with diffuse large B-cell lymphoma. This lymphoma can have numerous, vague presentations requiring a broad differential diagnosis and may lead to multiple evaluations prior to an ultimate diagnosis. We will also discuss the need for central nervous system prophylaxis, how this patient is qualified for prophylaxis, and how central nervous system prophylaxis benefits, harms, or does not affect patients with diffuse large B-cell lymphoma.

Rare Primary Diffuse Large B-Cell Lymphoma of a Male Breast

Background: Breast lymphomas are typical extranodal types of lymphoma, also known as Extranodal-lymphoma (ENL), which occur extremely infrequently, aggregating into a very small proportion of malignant breast tumors. The rarity of breast lymphomas is attributed to the scant lymphoid tissue content of the chest wall. Aims of Study: This case report is aimed at providing an up-to-date review of the literature on breast lymphomas for clinicians to, therefore, consider the possibility of this disease entity while treating a breast mass. Case Presentation: A case was reported of a 52-year man with chief mammary non-Hodgkin breast ENL when fine-needle aspiration cytology (FNAC) was not leading to a firm conclusion or result. Following an incisional biopsy, he was found to have a primary breast lymphoma. Later, the patient was diagnosed with the diffuse large B-cell type of lymphoma also known as non-Hodgkin’s Lymphoma (NHL). He had a complete reduction and disappearances of all the signs and symptoms of the disease after a course of neoadjuvant chemotherapy: Cyclophosphamide, Doxorubicin, Vincristine and Prednisolone (CHOP). CONCLUSION: Based on the above case presentation, it is vital for health care professionals and oncologists to recognize the disease by assessing the breast mass accurately with more entities so that proper diagnosis via core biopsy (incisional biopsy) can eliminate the PBL before further treatment is required.

Non Hodgkin’s Lymphoma with Right Atrial Intra Cardiac Metastases

Background: Diffuse Large B-Cell Lymphoma (DLBCL) is the most variant of Non-Hodgkin’s Lymphoma (NHL) and also the most common variant with secondary intracardiac masses. Case summary: 7 years old child presented to emergency with acute decompensated cardiac failure, ascites and tender hepatomegaly. 2D echo evaluation was suggestive of large intracardiac mass in the right atrium almost completely obstructing Tricuspid valve orifice, gross pericardial effusion and dilated Inferior Vena Cava (IVC). Emergency tumor excision surgery was performed which revealed 4 × 4 cm pinkish firm mass arising from anterior Tricuspid annulus which was completely excised. Child was extubated on postoperative day (POD) 0 and was on minimal inotropic support. Ascites reduced significantly on POD1 allowing abdominal palpation which revealed a mass in the epigastric region. This prompted evaluation by pediatrician and oncology workup suggestive of increased 18-Flouro Deoxy Glucose (18-FDG) uptake in the mediastinum, abdomen, bilateral proximal thighs, all mediastinal lymph nodal stations, bilateral lung hilar stations 10R, 10L involving all encasing the heart and great vessels with pleural deposits, Celiac trunk, superior Mesenteric Artery (SMA), Portal vein, IVC and abdominal aorta. Histo pathology Examination (HPE) and Immuno Histo Chemistry (IHC) of intracardiac mass revealed DLBCL which is metastatic in nature. Chemotherapy was started as per (French American British Lymphomes Malins B) FAB LMB-96 protocol with the child currently in the Induction phase having poor prognosis and less survival interval. Conclusion: Surgery can be considered a treatment option for metastatic intracardiac masses during emergency scenarios like cardiogenic shock to relieve obstruction along the pathway of blood flow in the heart even though we may not be able to completely excise the tumor surgically.

Non-anthracycline chemotherapy associated with a poor outcome in elderly Egyptian patients with diffuse large B-cell non-Hodgkin lymphoma

Aim:Rituximab plus cyclophosphamide,doxorubicin,vincristine,and prednisone(CHOP)is the standard treatment for patients with diffuse large B-cell non-Hodgkin lymphoma(DLBCNHL).Nevertheless,anthracyclines are contraindicated for some patients,e.g.cardiac dysfunction,severe hepatic dysfunction,jaundice.Thus,this study assessed the effectiveness of non-anthracycline chemotherapy regimen cyclophosphamide,vincristine,and prednisone(CVP)in elderly DLBCNHL patients vs.the standard CHOP.Methods:This retrospective study included 418 DLBCNHL patients diagnosed between 2003 and 2006 and followed until March 2014.During this period of time,rituximab was not available for all patients,particularly for patients older than 60 years.Results:CHOP and CVP were administered to 351(84%)and 67(16%)patients,respectively.Older age and comorbidities,particularly cardiovascular and diabetes mellitus,were independent determinants for not receiving CHOP.Patients received more courses of CHOP treatment than that of CVP(6 vs.3 courses;P<0.001)and developed more toxicities(48.4%vs.23.9%;P<0.001),particularly fatigue,alopecia,and gastrointestinal tract toxicities.Complete response rate was higher in CHOP than in CVP(69.9%vs.29.9%;P<0.001).Moreover,early death was significantly higher in CVP group of patients than in CHOP(43.3%vs.8.6%;P<0.001).After a median follow-up of 71 months,the median overall survival(OS)and event-free survival(EFS)were signifi cantly better in CHOP than in CVP(49.5 vs.3.7 months and 32.2 vs.3.5 months;P<0.001 for both,respectively).Older age,poor age-adjusted International Prognostic Index scores,not receiving CHOP or consolidative radiotherapy were independent predictors of poor OS and EFS.Conclusion:Use of the CVP regime to treat DLBCNHL patients who were unfit to the standard CHOP treatment was associated with lower remission rates and poorer EFS and OS in this group of patients.

Primary diffuse large B-cell non-Hodgkin lymphoma of the cranial vault

Primary non-Hodgkin lymphoma of the cranial vault with extra and intracranial extension in a nonimmunocompromised patient is extremely uncommon.Until date,only limited number of such cases has been reported in the literature and none was the lesion located as a diffuse swelling in the forehead.Imaging of the present case showed in a homogenous contrast enhancement mass involving the scalp of bifrontal supraorbital compartment and intracranial extra axial extension through the frontal bone with extension to the right orbit and right ethmoidal sinus.The intracranial mass was excised along with involved dura.Histopathology of the mass showed diffuse large B-cell non-Hodgkin lymphoma.

灰区淋巴瘤的研究进展

淋巴系统恶性肿瘤的分类取决于临床特点、形态学、免疫表型和分子遗传学特征。其中一些特征介于2种不同类型淋巴瘤的侵袭性 b 细胞淋巴瘤分类困难。1998年的霍奇金病及相关疾病专题讨论会上，欧美血液病理学专家首次提出了灰区淋巴瘤（gray zone lymphoma，GZL）的概念［1］。2004年 WHO 首次提出GZL 的概念［2］，并定义 GZL 为肿瘤在形态学、生物学和临床特点等方面介于经典型霍奇金淋巴瘤（classical Hodgkin lymphoma，CHL）与间变性大细胞非霍奇金淋巴瘤（non-Hodgkin lymphoma，NHL）之间的未明确分类病变。在2008年造血和淋巴组织肿瘤 WHO 分类中列入2种 GZL，分别为：b 细胞淋巴瘤，不能明确分类，其特点介于弥漫大 b 细胞淋巴瘤和经典型霍奇金淋巴瘤之间（b-cell lymphoma，unclassifiable，with features intermediate between diffuse large b-cell lymphoma and classical Hodgkin lymphoma，bCLu-DLbCL/ CHL）；b 细胞淋巴瘤，不能明确分类，其特点介于弥漫大 b 细胞淋巴瘤和伯基特淋巴瘤之间（b-cell lymphoma，unclas-sifiable，with features intermediate between diffuse large b-cell lymphoma and burkitt lymphoma，bCLu-DLbCL/bL）［3］。对 GZL 定义的明确可为临床研究提供指导意义。

Bendamustine treatment of Chinese patients with relapsed indolent non-Hodgkin lymphoma: a multicenter, open-label, single-arm, phase 3 study

Background:Bendamustine was approved in China on May 26th,2019 by the National Medical Product Administration for the treatment of indolent B-cell non-Hodgkin lymphoma(NHL).The current study was the registration trial and the first reported evaluation of the efficacy,safety,and pharmacokinetics of bendamustine in Chinese adult patients with indolent B-cell NHL following relapse after chemotherapy and rituximab treatment.Methods:This was a prospective,multicenter,open-label,single-arm,phase 3 study(NCT01596621;C18083/3076)with a 2-year follow-up period.Eligible patients received bendamustine hydrochloride 120 mg/m2 infused intravenously on days 1 and 2 of each 21-day treatment cycle for at least six planned cycles(and up to eight cycles).The primary endpoint was the overall response rate(ORR);and secondary endpoints were duration of response(DoR),progression-free survival(PFS),safety,and pharmacokinetics.Patients were classified according to their best overall response after initiation of therapy.Proportions of patients in each response category(complete response[CR],partial response[PR],stable disease,or progressive disease)were summarized along with a twosided binomial exact 95%confidence intervals(CIs)for the ORR.Results:A total of 102 patients were enrolled from 20 centers between August 6th,2012,and June 18th,2015.At the time of the primary analysis,the ORR was 73%(95%CI:63%–81%)per Independent Review Committee(IRC)including 19%CR and 54%PR.With the follow-up period,the median DoR was 16.2 months by IRC and 13.4 months by investigator assessment;the median PFS was 18.6 months and 15.3 months,respectively.The most common non-hematologic adverse events(AEs)were gastrointestinal toxicity,pyrexia,and rash.Grade 3/4 neutropenia was reported in 76%of patients.Serious AEs were reported in 29 patients and five patients died during the study.Pharmacokinetic analysis indicated that the characteristics of bendamustine and its metabolites M3 and M4 were generally consistent with those reported for other ethnicities.Conclusion:Bendamustine is an active and effective therapy in Chinese patients with relapsed,indolent B-cell NHL,with a comparable risk/benefit relationship to that reported in North American patients.

CAR T-Cell therapies in lymphoma: current landscape, ongoing investigations, and future directions

Chimeric antigen receptor(CAR)T-cell therapy has significantly improved outcomes for patients with relapsed/refractory large B-cell lymphoma,mantle cell lymphoma,and follicular lymphoma,with multiple FDA-approved CAR T products now commercially available.Ongoing studies seek to move CAR T-cells to earlier lines of therapy and to characterize the efficacy and safety of CAR T-cell approaches in additional lymphoma histologies including relapsed/refractory follicular lymphoma and chronic lymphocytic leukemia.Other areas of active research address CAR T in combination with other lymphoma-directed therapies,and mechanisms of CAR T resistance.This review focuses on the FDA-approved anti-CD19 CAR T products for B-cell lymphomas,management of CAR T-cell-associated toxicities,approaches to bridging therapy,and ongoing clinical trials and future research directions across a broad range of lymphoma histologies.