Non-Hodgkin lymphomas (NHL) are lymphoid tumors that arise by a complex process of malignant transformation of mature lymphocytes during various stages of differentiation. The WHO classification of NHL recognizes more than 90 nosological units with peculiar pathophysiology and prognosis. Since the end of the 20th century, our increasing knowledge of the molecular biology of lymphoma subtypes led to the identification of novel druggable targets and subsequent testing and clinical approval of novel anti-lymphoma agents, which translated into significant improvement of patients' outcome. Despite immense progress, our effort to control or even eradicate malignant lymphoma clones has been frequently hampered by the development of drug resistance with ensuing unmet medical need to cope with relapsed or treatment-refractory disease. A better understanding of the molecular mechanisms that underlie inherent or acquired drug resistance might lead to the design of more effective front-line treatment algorithms based on reliable predictive markers or personalized salvage therapy, tailored to overcome resistant clones, by targeting weak spots of lymphoma cells resistant to previous line(s) of therapy. This review focuses on the history and recent advances in our understanding of molecular mechanisms of resistance to genotoxic and targeted agents used in clinical practice for the therapy of NHL.

• Klíčová slova
• chemotherapy, drug resistance, non-Hodgkin lymphomas, targeted agents,
• MeSH
• chemorezistence * MeSH
• individualizovaná medicína MeSH
• lidé MeSH
• nádorové biomarkery metabolismus   MeSH
• nehodgkinský lymfom * klasifikace   metabolismus   patologie   terapie   MeSH
• protinádorové látky škodlivé účinky   terapeutické užití   MeSH
• záchranná terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• nádorové biomarkery MeSH
• protinádorové látky MeSH

Non-Hodgkin lymphomas (NHLs) are lymphoid malignancies of B- or T-cell origin. Despite great advances in treatment options and significant improvement of survival parameters, a large part of NHL patients either present with a chemotherapy-refractory disease or experience lymphoma relapse. Chemotherapy-based salvage therapy of relapsed/refractory NHL is, however, capable of re-inducing long-term remissions only in a minority of patients. Immunotherapy-based approaches, including bispecific antibodies, immune checkpoint inhibitors and genetically engineered T-cells carrying chimeric antigen receptors, single-agent or in combination with therapeutic monoclonal antibodies, immunomodulatory agents, chemotherapy or targeted agents demonstrated unprecedented clinical activity in heavily-pretreated patients with NHL, including chemotherapy-refractory cases with complex karyotype changes and other adverse prognostic factors. In this review, we recapitulate currently used immunotherapy modalities in NHL and discuss future perspectives of combinatorial immunotherapy strategies, including patient-tailored approaches.

• Klíčová slova
• CAR T-cells, bispecific antibodies, immune checkpoint inhibitors, immunomodulatory agents, non-Hodgkin lymphomas,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

BACKGROUND: Constitutional mismatch repair deficiency syndrome (CMMRD) is a rare childhood cancer predisposition syndrome associated with a broad spectrum of malignancies, including non-Hodgkin lymphomas (NHL). Most patients die due to cancer before the age of 20 years. Limited data exist on CMMRD-associated lymphomas and their outcome. METHODS: We conducted a retrospective study including all CMMRD-associated NHL patients registered before 2020 in the European and North American databases or reported by members of the European Intergroup for Childhood Non-Hodgkin Lymphoma (EICNHL). Events considered to define event-free survival included relapse/progression, second malignancy (SML), or death, whichever occurred first. FINDINGS: The analysis included 74 patients, with 20 having multiple metachronous NHL. The median age at diagnosis was 9.4 years. Previous malignancies were reported in 36% of the patients, café au lait spots in 96%, and consanguinity in 54%. The initial lymphoma subtypes were 53 T-cell lymphoblastic lymphomas (T-LBL), four B-lymphoblastic lymphomas, and 17 mature B-cell non-Hodgkin lymphoma (B-NHL). All patients were treated with curative intent, with current chemotherapy regimens adapted to their subtype. The median follow-up was 8.7 years. After the first lymphoma, the 5-year event-free and overall survival rates were, respectively, 23.5% [95% confidence interval (CI): 14.9-35.1] and 61.5% [95% CI: 49.6-72.1]. The 5-year cumulative risk of progression/relapse, SML or death as a first event was 20.8%, 52.9%, and 2.7%. INTERPRETATION: Standard treatments for sporadic NHL are effective in most CMMRD-associated NHL cases, but multiple malignancies, including lymphomas, impair prognosis. Future strategies should evaluate the potential of less genotoxic therapies, including immunotherapy, in preventing SMLs while maintaining effective control of NHL.

• Klíčová slova
• CMMRD, genetic predisposition, lymphoblastic lymphomas, lymphomas, second malignancy,
• MeSH
• dědičné nádorové syndromy genetika   mortalita   MeSH
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• kolorektální nádory MeSH
• lidé MeSH
• míra přežití MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nádory mozku MeSH
• následné studie MeSH
• nehodgkinský lymfom * mortalita   genetika   epidemiologie   MeSH
• předškolní dítě MeSH
• prognóza MeSH
• retrospektivní studie MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

OBJECTIVES: ⁹⁰Y-labeled anti-CD66b monoclonal antibody clone BW 250/183 was developed for treatment of tumors. The aim of the study was the analysis of CD66 expression in lymphoproliferative malignancies to expand the potential of anti-CD66-based therapy. PATIENTS AND METHODS: Bone marrow samples from 260 patients were examined for the expression of CD66 on tumor cells in 104 B-chronic lymphocytic leukemias (B-CLL), 28 mantle cell lymphomas (MCL), 22 follicular lymphomas (FCL), 15 marginal zone lymphomas (MZL), 12 lymphoplasmacytic lymphomas (LPL), 13 diffuse large B cell lymphomas (DLBCL), 4 T-non-Hodgkin lymphomas (T-NHL), 3 B-NHL not otherwise specified (B-NHL NOS), 3 B acute lymphoblastic leukemias (B-ALL), and in 56 multiple myelomas (MM) by flow cytometry. RESULTS: Positive (≥ 20%) expression of CD66abce clone Kat4c was detected in 76% of B-CLL and 76.8% of MM. The highest number of CD66abce-positive samples was in MCL and LPL (96.4% of 28 and 91.7% of 12 patients, respectively). Expression of CD66b clone BW 250/183 was examined in 114 of 260 samples. Positive expression was detected in 23.3% of B-CLL (6/35), 17.1% of MM (7/30), and 21.4% of MCL (3/14) samples. CONCLUSION: The expression of CD66b compared to CD66abce was lower in all measured samples. Use of radiolabeled anti-CD66b antibody for the treatment of lymphoproliferative diseases appears to have limited preclinical substantiation.

• MeSH
• CD antigeny biosyntéza   MeSH
• kostní dřeň metabolismus   patologie   MeSH
• lidé MeSH
• mnohočetný myelom metabolismus   patologie   radioterapie   MeSH
• molekuly buněčné adheze biosyntéza   MeSH
• monoklonální protilátky chemie   terapeutické užití   MeSH
• nehodgkinský lymfom metabolismus   patologie   radioterapie   MeSH
• radioimunoterapie metody   MeSH
• regulace genové exprese u nádorů * MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• CD antigeny MeSH
• CD66 antigens MeSH Prohlížeč
• molekuly buněčné adheze MeSH
• monoklonální protilátky MeSH

The European Intergroup for Childhood Non-Hodgkin Lymphoma (EICNHL) was established 25 years ago with the goal to facilitate clinical trials and research collaborations in the field both within Europe and worldwide. Since its inception, much progress has been made whereby major improvements in outcomes have been achieved. In this Review, we describe the different diagnostic entities of non-Hodgkin lymphoma in children and young adults describing key features of each entity and outlining clinical achievements made in the context of the EICNHL framework. Furthermore, we provide an overview of advances in biopathology with an emphasis on the role of biological studies and how they have shaped available treatments. Finally, for each entity, we describe future goals, upcoming clinical trials, and highlight areas of research that require our focus going forward.

• MeSH
• dítě MeSH
• lidé MeSH
• mladý dospělý MeSH
• nehodgkinský lymfom * MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladý dospělý MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Geografické názvy
• Evropa MeSH

Mature non-Hodgkin lymphomas (NHL) in the childhood, adolescent and young adult (CAYA) population are rare and exhibit unique clinical, immunophenotypic and genetic characteristics. Application of large-scale unbiased genomic and proteomic technologies such as gene expression profiling and next generation sequencing (NGS) have led to enhanced understanding of the genetic basis for many lymphomas in adults. However, studies to investigate the pathogenetic events in CAYA population are relatively sparse. Enhanced understanding of the pathobiologic mechanisms involved in non-Hodgkin lymphomas in this unique population will allow for improved recognition of these rare lymphomas. Elucidation of the pathobiologic differences between CAYA and adult lymphomas will also lead to the design of more rational and much needed, less toxic therapies for this population. In this review, we summarize recent insights gained from the proceedings of the recent 7th International CAYA NHL Symposium held in New York City, New York October 20-23, 2022.

• Klíčová slova
• Adolescent and young adult, Childhood, Genetic, Non-Hodgkin lymphoma, Pathobiology,
• MeSH
• genomika MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nehodgkinský lymfom * farmakoterapie   MeSH
• proteomika * MeSH
• stanovení celkové genové exprese MeSH
• Check Tag
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

B-cell non-Hodgkin lymphomas (B-NHL) represent the most common type of hematologic malignancies in the Western hemisphere. The therapy of all B-NHL is based on the combination of different genotoxic cytostatics and anti-CD20 monoclonal antibody (mAb) rituximab. Unfortunately, many patients relapse after the mentioned front-line treatment approaches. The therapy of patients with relapsed/refractory (R/R) B-NHL represents an unmet medical need. We designed, developed and tested novel actively targeted hybrid mAb-polymer-drug conjugate (APDC) containing anti-CD20, anti-CD38 or anti-CD19 mAbs. Biocompatible copolymers based on N-(2-hydroxypropyl)methacrylamide (HPMA) with cytostatic agent doxorubicin attached via stimuli-sensitive hydrazone bond were employed for the mAb grafting. Anti-lymphoma efficacy of the APDC nanotherapeutics was evaluated in vivo on a panel of three patient-derived lymphoma xenografts derived from two patients with R/R B-NHL and one patient with so far untreated B-NHL. In both PDX models derived from patients with R/R B-NHL, the targeting with anti-CD38 antibody daratumumab demonstrated highly improved anti-lymphoma efficacy compared to the targeting with anti-CD20 rituximab, two experimental anti-CD19 antibodies and non-targeted controls. The results represent a proof-of-concept of a new algorithm of personalized anti-tumor therapy based on highly innovative APDC biomaterials.

• Klíčová slova
• APDC, Active targeting, CD38, Daratumumab, Drug delivery, Non-Hodgkin lymphoma, Polymer nanomaterials, Rituximab,
• MeSH
• léčivé přípravky * MeSH
• lidé MeSH
• monoklonální protilátky terapeutické užití   MeSH
• nehodgkinský lymfom * farmakoterapie   MeSH
• polymery terapeutické užití   MeSH
• protinádorové látky * terapeutické užití   MeSH
• rituximab MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• daratumumab MeSH Prohlížeč
• léčivé přípravky * MeSH
• monoklonální protilátky MeSH
• polymery MeSH
• protinádorové látky * MeSH
• rituximab MeSH

The ability to inhibit mitochondrial apoptosis is a hallmark of B-cell non-Hodgkin lymphomas (B-NHL). Activation of mitochondrial apoptosis is tightly controlled by members of B-cell leukemia/lymphoma-2 (BCL-2) family proteins via protein-protein interactions. Altering the balance between anti-apoptotic and pro-apoptotic BCL-2 proteins leads to apoptosis evasion and extended survival of malignant cells. The pro-survival BCL-2 proteins: B-cell leukemia/lymphoma-2 (BCL-2/BCL2), myeloid cell leukemia-1 (MCL-1/MCL1) and B-cell lymphoma-extra large (BCL-XL/BCL2L1) are frequently (over)expressed in B-NHL, which plays a crucial role in lymphoma pathogenesis, disease progression, and drug resistance. The efforts to develop inhibitors of anti-apoptotic BCL-2 proteins have been underway for several decades and molecules targeting anti-apoptotic BCL-2 proteins are in various stages of clinical testing. Venetoclax is a highly specific BCL-2 inhibitor, which has been approved by the US Food and Drug Agency (FDA) for the treatment of patients with chronic lymphocytic leukemia (CLL) and is in advanced clinical testing in other types of B-NHL. In this review, we summarize the biology of BCL-2 proteins and the mechanisms of how these proteins are deregulated in distinct B-NHL subtypes. We describe the mechanism of action of BH3-mimetics and the status of their clinical development in B-NHL. Finally, we summarize the mechanisms of sensitivity/resistance to venetoclax.

• Klíčová slova
• B-cell leukemia/lymphoma-2 (BCL-2), apoptosis, non-Hodgkin lymphomas (NHL), venetoclax,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Children and adolescents with pre-existing conditions such as DNA repair defects or other primary immunodeficiencies have an increased risk of non-Hodgkin lymphoma. However, large-scale data on patients with non-Hodgkin lymphoma and their entire spectrum of pre-existing conditions are scarce. A retrospective multinational study was conducted by means of questionnaires sent out to the national study groups or centers, by the two largest consortia in childhood non-Hodgkin lymphoma, the European Intergroup for Childhood non-Hodgkin Lymphoma, and the international Berlin-Frankfurt-Münster Study Group. The study identified 213 patients with non-Hodgkin lymphoma and a pre-existing condition. Four subcategories were established: a) cancer predisposition syndromes (n=124, 58%); b) primary immunodeficiencies not further specified (n=27, 13%); c) genetic diseases with no increased cancer risk (n=40, 19%); and d) non-classifiable conditions (n=22, 10%). Seventy-nine of 124 (64%) cancer predispositions were reported in groups with more than 20 patients: ataxia telangiectasia (n=32), Nijmegen breakage syndrome (n=26), constitutional mismatch repair deficiency (n=21). For the 151 patients with a known cancer risk, 5-year event-free survival and overall survival rates were 40%±4% and 51%±4%, respectively. Five-year cumulative incidences of progression/relapse and treatment-related death as a first event were 22%±4% and 24%±4%, respectively. Ten-year incidence of second malignancy was 24%±5% and 7-year overall survival of the 21 patients with a second malignancy was 41%±11%. Patients with non-Hodgkin lymphoma and pre-existing conditions have an inferior survival rate with a large proportion of therapy-related deaths compared to patients with non-Hodgkin lymphoma and no pre-existing conditions. They may require special vigilance when receiving standard or modified/reduced-intensity chemotherapy or when undergoing allogeneic stem cell transplantation.

• MeSH
• dítě MeSH
• Kaplanův-Meierův odhad MeSH
• kojenec MeSH
• kombinovaná terapie MeSH
• komorbidita * MeSH
• lidé MeSH
• mladiství MeSH
• náchylnost k nemoci * MeSH
• nehodgkinský lymfom diagnóza   epidemiologie   mortalita   terapie   MeSH
• novorozenec MeSH
• ochrana veřejného zdraví * MeSH
• předškolní dítě MeSH
• progrese nemoci MeSH
• recidiva MeSH
• sekundární malignity epidemiologie   etiologie   MeSH
• výsledek terapie MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH

Epidemiologic studies show an increased risk of non-Hodgkin lymphoma (NHL) in patients with autoimmune disease (AD), due to a combination of shared environmental factors and/or genetic factors, or a causative cascade: chronic inflammation/antigen-stimulation in one disease leads to another. Here we assess shared genetic risk in genome-wide-association-studies (GWAS). Secondary analysis of GWAS of NHL subtypes (chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, and marginal zone lymphoma) and ADs (rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis). Shared genetic risk was assessed by (a) description of regional genetic of overlap, (b) polygenic risk score (PRS), (c)"diseasome", (d)meta-analysis. Descriptive analysis revealed few shared genetic factors between each AD and each NHL subtype. The PRS of ADs were not increased in NHL patients (nor vice versa). In the diseasome, NHLs shared more genetic etiology with ADs than solid cancers (p = .0041). A meta-analysis (combing AD with NHL) implicated genes of apoptosis and telomere length. This GWAS-based analysis four NHL subtypes and three ADs revealed few weakly-associated shared loci, explaining little total risk. This suggests common genetic variation, as assessed by GWAS in these sample sizes, may not be the primary explanation for the link between these ADs and NHLs.

• Klíčová slova
• autoimmune disease, genome-wide association study, meta-analysis, non-Hodgkin lymphoma,
• MeSH
• alely MeSH
• autoimunitní nemoci genetika   MeSH
• genetická predispozice k nemoci * MeSH
• HLA antigeny genetika   MeSH
• jednonukleotidový polymorfismus genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• multifaktoriální dědičnost genetika   MeSH
• nehodgkinský lymfom genetika   MeSH
• rizikové faktory MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, N.I.H., Intramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Názvy látek
• HLA antigeny MeSH