abt-199 and Lymphoma--B-Cell

Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia in the western world. In Italy, venetoclax was approved for use in patients with CLL as monotherapy in 2017 and in combinations in 2019. As a result of this delayed approval, there are relatively few real-world studies from Italian clinical practice and much of the data are in heavily pretreated patients. We have collected the available studies in Italian routine practice. Three studies confirm the effectiveness and tolerability of this agent in patients with relapsed/refractory CLL and high-risk disease characteristics, many of whom had received prior B-cell receptor signaling treatment. Addition of rituximab to venetoclax produced more complete responses in patients with relapsed/refractory CLL, while higher disease burden and progression while receiving a prior Bruton's tyrosine kinase inhibitor were both associated with poorer outcomes in patients treated with venetoclax. Venetoclax was well-tolerated with low discontinuation rates. No studies of venetoclax plus obinutuzumab for the first-line treatment of patients with CLL were available due to the short time since approval in Italy. Several cohorts addressed the impact of COVID-19 on patient management and outcomes, suggesting that treated patients and those in clinical observation had similar rates of COVID-19-related hospital admission, intensive care unit admission, and mortality. Overall, the responses and tolerance to venetoclax observed in the Italian real-world setting confirm the tolerability and effectiveness of venetoclax regimens in high-risk patients.

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; COVID-19; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Recurrence; Rituximab

The availability of novel targeted agents has revolutionized the management of chronic lymphocytic leukemia (CLL). Both B-cell lymphoma 2 (BCL2) and Bruton tyrosine kinase (BTK) inhibitors are highly effective agents for CLL treatment. Several clinical trials have demonstrated the efficacy and safety of these agents in the management of newly diagnosed and relapsed/refractory CLL. This has led to two broad approaches in the frontline management of CLL, namely venetoclax-based time-limited therapy versus BTK inhibitor-based continuous therapy. In this review, we discussed why we consider venetoclax-based therapy as a suitable frontline option for patients with CLL.

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Sulfonamides

BH3-mimetics are a novel drug class of small molecule inhibitors of BCL2 family proteins which restore apoptosis in malignant cells. The only currently approved BH3-mimetic, the selective BCL2 inhibitor venetoclax, is highly efficacious in chronic lymphocytic leukemia and has rapidly advanced to an approved standard of care in frontline and relapsed disease in combination with anti-CD20 monoclonal antibodies. In this context, tumour lysis syndrome and myelosuppression are the most commonly encountered toxicities and are readily manageable with established protocols. Venetoclax is active in other lymphoid malignancies including several B cell non-Hodgkin lymphomas, acute lymphoblastic leukemia and multiple myeloma, with the highest intrinsic sensitivity observed in mantle cell lymphoma and Waldenstrom macroglobulinemia. Venetoclax combination with standard regimens in follicular lymphoma, multiple myeloma and aggressive B cell neoplasms has shown some promise, but further studies are required to optimize dose and scheduling to mitigate increased myelosuppression and infection risk, and to find validated biomarkers of venetoclax sensitivity. Future research will focus on overcoming venetoclax resistance, targeting other BCL2 family members and the rational design of synergistic combinations.

Topics: Adult; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Humans; Lymphoma, B-Cell; Multiple Myeloma; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

Mantle cell lymphoma (MCL), an aggressive, but incurable B-cell lymphoma, is genetically characterized by the t(11;14) translocation, resulting in the overexpression of Cyclin D1. In addition, deregulation of the B-cell lymphoma-2 (BCL-2) family proteins BCL-2, B-cell lymphoma-extra large (BCL-X

Topics: Adult; Antineoplastic Agents; bcl-X Protein; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Drug Resistance, Neoplasm; Humans; Lymphoma, B-Cell; Lymphoma, Mantle-Cell; Myeloid Cell Leukemia Sequence 1 Protein; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Tumor Microenvironment

Abnormal cell apoptosis is closely related to the occurrence of hematologic tumors, B-cell lymphoma-2 (BCL-2), as a key anti-apoptotic protein in intrinsic programmed cell death, has become a hot spot in the treatment of hematologic tumors in recent years. Venetoclax is an oral small-molecule selective BCL-2 inhibitor approved by the Food and Drug Administration (FDA） for the treatment of chronic lymphocytic leukemia (CLL) patients or small lymphocytic lymphoma (SLL) patients and for the treatment of elderly acute myeloid leukemia (AML) patients that is not suitable for aggressive chemotherapy. In addition, it also showed a promising clinical application in treatment of non-Hodgkin's lymphoma (NHL) patients, which is a new expansion of the clinical indications for venetoclax. In this review, the role of BCL-2 protein family played in the regulation of NHL cell apoptosis, the development of BCL-2 inhibitors and the recent research progress of venetoclax in the treatment of NHL are reviewed.. 维奈克拉在非霍奇金淋巴瘤治疗中的研究进展.. 细胞凋亡异常与血液肿瘤的发生密切相关，BCL-2作为细胞固有程序性死亡的关键抗凋亡蛋白，近年来成为血液肿瘤治疗的热点。维奈克拉是美国食品和药物管理局批准的一种口服小分子选择性BCL-2抑制剂，用于治疗慢性淋巴细胞白血病患者或小淋巴细胞淋巴瘤患者以及不适合进行化疗的老年急性髓系白血病患者。此外，在非霍奇金淋巴瘤患者的治疗中也显示出良好的临床应用前景，这是维奈克拉临床应用的新拓展。本文就BCL-2蛋白家族在非霍奇淋巴瘤细胞凋亡调控中的作用、BCL-2抑制剂的开发以及维奈克拉治疗非霍奇金淋巴瘤的最新研究进展作一综述.

Topics: Aged; Antineoplastic Agents; Apoptosis Regulatory Proteins; Bridged Bicyclo Compounds, Heterocyclic; Hematologic Neoplasms; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

B-cell lymphoma-2 (BCL-2) family dysfunction and impairment of apoptosis are common in most B-cell lymphoid malignancies. Venetoclax (Venclexta™, formerly ABT-199, GDC-0199) is a highly selective BCL-2 inhibitor, which mimics its BCL-2 homology 3-domain to induce apoptosis. It was approved for treatment of previously treated chronic lymphocytic leukemia (CLL) patients with 17p deletion early in 2016. It has also been in clinical trials for other B-cell lymphoid malignancies. Unlike the other recently approved targeted agents idelalisib and ibrutinib, so far there has been no relapse reported in some patients. Also, unlike the other targeted agents, it is effective against tumor cells that reside in the blood marrow. Despite its promising outcome in CLL, preclinical data have already uncovered mechanistic insights underlying venetoclax resistance, such as upregulation of MCL-1 or BCL-xL expression and protective signaling from the microenvironment. In this review, we describe the role of the BCL-2 family in the pathogenesis of B-cell lymphoid malignancies, the development of venetoclax, and its current clinical outcome in CLL and other B-cell malignancies. We also discuss the resistance mechanisms that develop following venetoclax therapy, potential strategies to overcome them, and how this knowledge can be translated into clinical applications.

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Humans; Lymphoma, B-Cell; Sulfonamides

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Protein Kinase Inhibitors; Purines; Quinazolinones; Sulfonamides

Myeloid neoplasms with erythroid or megakaryocytic differentiation include pure erythroid leukemia, myelodysplastic syndrome with erythroid features, and acute megakaryoblastic leukemia (FAB M7) and are characterized by poor prognosis and limited treatment options. Here, we investigate the drug sensitivity landscape of these rare malignancies. We show that acute myeloid leukemia (AML) cells with erythroid or megakaryocytic differentiation depend on the antiapoptotic protein B-cell lymphoma (BCL)-XL, rather than BCL-2, using combined ex vivo drug sensitivity testing, genetic perturbation, and transcriptomic profiling. High-throughput screening of >500 compounds identified the BCL-XL-selective inhibitor A-1331852 and navitoclax as highly effective against erythroid/megakaryoblastic leukemia cell lines. In contrast, these AML subtypes were resistant to the BCL-2 inhibitor venetoclax, which is used clinically in the treatment of AML. Consistently, genome-scale CRISPR-Cas9 and RNAi screening data demonstrated the striking essentiality of BCL-XL-encoding BCL2L1 but not BCL2 or MCL1, for the survival of erythroid/megakaryoblastic leukemia cell lines. Single-cell and bulk transcriptomics of patient samples with erythroid and megakaryoblastic leukemias identified high BCL2L1 expression compared with other subtypes of AML and other hematological malignancies, where BCL2 and MCL1 were more prominent. BCL-XL inhibition effectively killed blasts in samples from patients with AML with erythroid or megakaryocytic differentiation ex vivo and reduced tumor burden in a mouse erythroleukemia xenograft model. Combining the BCL-XL inhibitor with the JAK inhibitor ruxolitinib showed synergistic and durable responses in cell lines. Our results suggest targeting BCL-XL as a potential therapy option in erythroid/megakaryoblastic leukemias and highlight an AML subgroup with potentially reduced sensitivity to venetoclax-based treatments.

Topics: Animals; Apoptosis; bcl-X Protein; Bridged Bicyclo Compounds, Heterocyclic; Cell Differentiation; Cell Line, Tumor; Humans; Leukemia, Megakaryoblastic, Acute; Leukemia, Myeloid, Acute; Lymphoma, B-Cell; Mice; Myeloid Cell Leukemia Sequence 1 Protein; Proto-Oncogene Proteins c-bcl-2

The infection risk in patients receiving ibrutinib, idelalisib or venetoclax for chronic lymphocytic leukaemia (CLL) or B-cell lymphoma treated outside of clinical trials is incompletely defined. We sought to identify the severe infection rate and associated risk factors in a 'real-world' cohort.. We conducted a retrospective cohort study of adult patients with CLL or lymphoma treated with ibrutinib, idelalisib or venetoclax.. Of 67 patients identified (ibrutinib n = 53, idelalisib n = 8 and venetoclax n = 6), 32 (48%) experienced severe infection. Severe infection occurred at a rate of 65 infections per 100 person-years, with a median of 17.8 months of therapy. Median time to first infection (IQR) was 5.4 months (1.4-15.9). Poor baseline Eastern Cooperative Oncology Group (ECOG) performance status and high Charlson Comorbidity Index (CCI) score associated with increased risk of severe infection [hazard ratios (95% CI) 1.57 (1.07-2.31, p = .018) and 1.3 (1.05-1.62, p = .016) respectively].. The severe infection rate for patients receiving ibrutinib, idelalisib or venetoclax for lymphoma and CLL exceeded those reported in clinical trials. Patients with poor ECOG or high CCI should be closely monitored for early signs of infection and prevention strategies actively pursued. Further prospective research is required to define optimal antimicrobial prophylaxis recommendations.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Retrospective Studies

Chimeric antigen receptor T-cell (CART) immunotherapy led to unprecedented responses in patients with refractory/relapsed B-cell non-Hodgkin lymphoma (NHL); nevertheless, two thirds of patients experience treatment failure. Resistance to apoptosis is a key feature of cancer cells, and it is associated with treatment failure. In 87 patients with NHL treated with anti-CD19 CART, we found that chromosomal alteration of B-cell lymphoma 2 (BCL-2), a critical antiapoptotic regulator, in lymphoma cells was associated with reduced survival. Therefore, we combined CART19 with the FDA-approved BCL-2 inhibitor venetoclax and demonstrated in vivo synergy in venetoclax-sensitive NHL. However, higher venetoclax doses needed for venetoclax-resistant lymphomas resulted in CART toxicity. To overcome this limitation, we developed venetoclax-resistant CART by overexpressing mutated BCL-2(F104L), which is not recognized by venetoclax. Notably, BCL-2(F104L)-CART19 synergized with venetoclax in multiple lymphoma xenograft models. Furthermore, we uncovered that BCL-2 overexpression in T cells intrinsically enhanced CART antitumor activity in preclinical models and in patients by prolonging CART persistence.. This study highlights the role of BCL-2 in resistance to CART immunotherapy for cancer and introduces a novel concept for combination therapies-the engineering of CART cells to make them resistant to proapoptotic small molecules, thereby enhancing the therapeutic index of these combination therapies. This article is highlighted in the In This Issue feature, p. 2221.

Topics: Bridged Bicyclo Compounds, Heterocyclic; Humans; Immunotherapy; Immunotherapy, Adoptive; Lymphoma; Lymphoma, B-Cell; Proto-Oncogene Proteins c-bcl-2; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen; Sulfonamides; T-Lymphocytes

Inhibitors of B cell receptor (BCR) signaling such as the Bruton's tyrosine kinase (BTK) inhibitors are effective therapeutics for chronic lymphocytic leukemia (CLL). The first-in-class covalent BTK inhibitor, ibrutinib, produces durable responses in most CLL patients; however, complete responses are only observed in a minority of patients. B cell lymphoma 2 (BCL2), an anti-apoptotic protein that contributes to CLL cell survival, has also been investigated as a therapeutic target. The BCL2 inhibitor venetoclax is effective in patients with CLL and can produce undetectable minimal residual disease, allowing discontinuation of therapy. In combination, ibrutinib and venetoclax have shown preclinical synergy and clinical efficacy. Nemtabrutinib is a next generation, reversible inhibitor of BTK that potently inhibits BCR signaling in treatment-naïve and ibrutinib-refractory CLL cells ex vivo. The clinical efficacy of combining BTK inhibitors with BCL2 inhibitors motivated us to evaluate the novel combination of nemtabrutinib and venetoclax. In vitro studies show that nemtabrutinib and venetoclax are not antagonistic to each other. In an adoptive transfer CLL mouse model, mice treated with nemtabrutinib and venetoclax had prolonged survival compared to mice treated with ibrutinib and venetoclax. Our preclinical studies further validate the combination of BTK inhibitors with venetoclax and justify further investigation of combining nemtabrutinib with venetoclax in CLL.

Topics: Agammaglobulinaemia Tyrosine Kinase; Animals; Antineoplastic Agents; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Mice; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-bcl-2; Pyrazoles; Pyrimidines

The BCL2 inhibitor venetoclax has shown efficacy in several hematologic malignancies, with the greatest response rates in indolent blood cancers such as chronic lymphocytic leukaemia. There is a lower response rate to venetoclax monotherapy in diffuse large B-cell lymphoma (DLBCL).. We tested inhibitors of cap-dependent mRNA translation for the ability to sensitise DLBCL and mantle cell lymphoma (MCL) cells to apoptosis by venetoclax. We compared the mTOR kinase inhibitor (TOR-KI) MLN0128 with SBI-756, a compound targeting eukaryotic translation initiation factor 4G1 (eIF4G1), a scaffolding protein in the eIF4F complex.. Treatment of DLBCL and MCL cells with SBI-756 synergised with venetoclax to induce apoptosis in vitro, and enhanced venetoclax efficacy in vivo. SBI-756 prevented eIF4E-eIF4G1 association and cap-dependent translation without affecting mTOR substrate phosphorylation. In TOR-KI-resistant DLBCL cells lacking eIF4E binding protein-1, SBI-756 still sensitised to venetoclax. SBI-756 selectively reduced translation of mRNAs encoding ribosomal proteins and translation factors, leading to a reduction in protein synthesis rates in sensitive cells. When normal lymphocytes were treated with SBI-756, only B cells had reduced viability, and this correlated with reduced protein synthesis.. Our data highlight a novel combination for treatment of aggressive lymphomas, and establishes its efficacy and selectivity using preclinical models.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Cell Proliferation; Drug Resistance, Neoplasm; Eukaryotic Initiation Factor-4E; Female; Humans; Lactams; Lymphoma, B-Cell; Mice; Mice, Inbred NOD; Mice, SCID; Molecular Targeted Therapy; Quinolones; Sulfonamides; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Topics: Adenine; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Epigenesis, Genetic; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Lymphoma, B-Cell; Molecular Targeted Therapy; Nerve Tissue Proteins; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-bcl-2; Receptors, Cell Surface; Sulfonamides; Waldenstrom Macroglobulinemia

Copanlisib is a pan-class I phosphoinositide 3-kinase (PI3K) inhibitor with preferred activity toward PI3Kα and PI3Kδ. Despite the clear overall clinical benefit, the number of patients achieving complete remissions with the single agent is relatively low, a problem shared by the vast majority of targeted agents. Here, we searched for novel copanlisib-based combinations. Copanlisib was tested as a single agent, in combination with an additional 17 drugs in 26 cell lines derived from mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), and T-cell lymphomas. In vivo experiments, transcriptome analyses, and immunoblotting experiments were also performed. Copanlisib as a single agent showed in vitro dose-dependent antitumor activity in the vast majority of the models. Combination screening identified several compounds that synergized with copanlisib. The strongest combination was with the B-cell lymphoma 2 (BCL2) inhibitor venetoclax. The benefit of the combination over single agents was also validated in an MZL xenograft model and in MCL primary cells, and was due to increased induction of apoptosis, an effect likely sustained by the reduction of the antiapoptotic proteins myeloid cell leukemia 1 (MCL1) and BCL-XL, observed in MCL and MZL cell lines, respectively. These data supported the rationale for the design of the Swiss Group for Clinical Cancer Research (SAKK) 66/18 phase 1 study currently exploring the combination of copanlisib and venetoclax in relapsed/refractory lymphomas.

Topics: Adult; Bridged Bicyclo Compounds, Heterocyclic; Humans; Lymphoma, B-Cell; Lymphoma, T-Cell; Phosphatidylinositol 3-Kinases; Pyrimidines; Quinazolines; Sulfonamides

Topics: Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Cyclophosphamide; Doxorubicin; Etoposide; Humans; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Prednisone; Sulfonamides; Vincristine

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Cell Proliferation; Drug Synergism; Humans; Hydrazines; Lymphoma, B-Cell; Lymphoma, Mantle-Cell; Niacinamide; Piperidines; Pyrazoles; Pyrimidines; Sulfonamides; Triazoles; Tumor Cells, Cultured

Large collections of genome-wide data can facilitate the characterization of disease states and subtypes, permitting pan-cancer analysis of molecular phenotypes and evaluation of disease context for new therapeutic approaches. We analyzed 9,544 transcriptomes from more than 30 hematologic malignancies, normal blood cell types, and cell lines, and showed that disease types could be stratified in a data-driven manner. We then identified cluster-specific pathway activity, new biomarkers, and

Topics: Antineoplastic Agents; Biomarkers, Tumor; Bridged Bicyclo Compounds, Heterocyclic; Hematologic Neoplasms; Humans; Immunotherapy; Internet; Leukemia, Myeloid, Acute; Lymphoma, B-Cell; Phenotype; Proto-Oncogene Proteins c-bcl-2; Small Molecule Libraries; Sulfonamides; Transcriptome

Our present study has shown a potential role for VEGF-A-mediated autocrine signalling to promote survival and proliferation of SU-DHL-6 cells, but the cells could not undergo apoptosis but rather decrease proliferation after bevacizumab treatment. Therefore, we would like to further study the antitumour efficacy of venetoclax (BCL2 inhibitor) in combination with bevacizumab in B-cell NHL.. The human cytokine antibody array, RT-qPCR, Western blot, ELISA, apoptosis assay and xenografted mouse model et al were used.. We described a unique phenomenon that SU-DHL-6 cells showed cell density-dependent survival and growth. Then, we suggested the expression of VEGF-A was positively correlated with the cell density using a human cytokine antibody array and indicated an important role of VEGF-A in the survival and proliferation of SU-DHL-6 cells. Additionally, xenografted SU-DHL-6 cells formed tumours in mice that grew in response to VEGF stimulation. GEO data set also suggested that high VEGF-A expression reflected poor prognosis. The combination therapy with bevacizumab and navitoclax could significantly induce of cell death in vitro and reduce the tumour size and weight with well tolerated in vivo.. Our findings propose a novel combined strategy in which bevacizumab synergises with the BCL2 inhibitor venetoclax that is effective against B-cell NHL.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biomarkers; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cytokines; Disease Models, Animal; Drug Synergism; Female; Humans; Lymphoma, B-Cell; Mice; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Sulfonamides; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2; Xenograft Model Antitumor Assays

Topics: Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Sulfonamides

Constitutive B-cell receptor signaling leads to overexpression of the antiapoptotic BCL-2 protein and is implicated in the pathogenesis of many types of B-cell non-Hodgkin lymphoma (B-NHL). The BCL-2 small-molecule inhibitor venetoclax shows promising clinical response rates in several lymphomas, but is not curative as monotherapy. Radiotherapy is a rational candidate for combining with BCL-2 inhibition, as DNA damage caused by radiotherapy increases the activity of pro-apoptotic BCL-2 pathway proteins, and lymphomas are exquisitely sensitive to radiation. We tested B-NHL responses to venetoclax combined with either external beam radiotherapy or radioimmunotherapy (RIT), which joins the selectivity of antibody targeting with the effectiveness of irradiation. We first tested cytotoxicity of cesium-137 irradiation plus venetoclax in 14 B-NHL cell lines representing five lymphoma subtypes. Combination treatment synergistically increased cell death in 10 of 14 lines. Lack of synergy was predicted by resistance to single-agent venetoclax and high BCL-XL expression. We then assessed the efficacy of external beam radiotherapy plus venetoclax in murine xenograft models of mantle cell (MCL), germinal-center diffuse large B-cell (GCB-DLBCL), and activated B-cell (ABC-DLBCL) lymphomas. In each model, external beam radiotherapy plus venetoclax synergistically increased mouse survival time, curing up to 10%. We finally combined venetoclax treatment of MCL and ABC-DLBCL xenografts with a pretargeted RIT (PRIT) system directed against the CD20 antigen. Optimal dosing of PRIT plus venetoclax cured 100% of mice with no detectable toxicity. Venetoclax combined with radiotherapy may be a promising treatment for a wide range of lymphomas

Topics: Animals; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cesium Radioisotopes; Chemoradiotherapy; Female; Humans; Lymphoma, B-Cell; Mice; Mice, Inbred NOD; Radiation Tolerance; Radioimmunotherapy; Sulfonamides; Xenograft Model Antitumor Assays

Double hit lymphoma or triple hit lymphoma (DHL/THL) is a rare form of aggressive B-Cell Lymphoma. Overexpression of MYC, BCL2 or/and BCL6 due to genomic rearrangements are the key molecular features of DHL/THL. Patients with DHL/THL show very aggressive disease course and poor survival due to the lack of effective treatment modalities. Here, we established new THL cell model and assessed its in vitro growth characteristics along with the DHL cell line in response to potent MYC inhibitors, 10058-F4 and JQ-1, and a BCL2 inhibitor, ABT-199, with or without chemotherapeutic agent vincristine or doxorubicin. We found that 10058-F4, JQ-1 or ABT-199 exposure as a single agent inhibited the growth of DHL/THL cells in a dose-dependent manner. Combined exposure of 10058-F4 or JQ-1 and ABT-199 as well as vincristine or doxorubicin markedly suppressed the growth of DHL/THL cells compared with the single treatment. As assessed by multiple approaches, apoptosis induced by ABT-199, 10058-F4 or JQ-1 was underlying cause of the observed growth suppression. These findings suggest that co-inhibition of MYC and BCL2 signaling is a promising therapeutic strategy for patients with DHL/THL lymphomas.

Topics: Bridged Bicyclo Compounds, Heterocyclic; Genes, myc; Humans; Lymphoma, B-Cell; Proto-Oncogene Proteins c-bcl-2; Sulfonamides