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1.
Hematol Oncol ; 38(1): 3-11, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31782972

RESUMO

The knowledge accumulated over the last decade on B-cell-derived non-Hodgkin lymphoma (B-NHL) pathogenesis has led to the identification of several molecular abnormalities, opening new perspectives in the design of novel therapies. Indeed, drugs targeting specific biochemical pathways critical for B-NHL cell survival, proliferation, and fitness within the malignant microenvironment are now available to the clinician: the B-cell receptor signaling inhibitors of BTK, PI3Kδ, ζ, γ, and SYK or the pro-apoptotic BH3-mimetics are clear examples of it. Moreover, it is emerging that malignant B-cell growth is sustained not only by mutations in oncogenes/tumor suppressors but also by the "addiction" to nononcogene (ie, nonstructurally altered) molecules. In this regard, a consistent body of data has established that the Ser/Thr kinases CK1, CK2, and GSK3 are involved in malignant lymphocyte biology and act as pro-survival and signaling-boosting molecules, both in precursor and mature B-cell tumors. Currently, an experimental and clinical groundwork is available, upon which to design CK1-, CK2-, and GSK3-directed antilymphoma/leukemia therapies. In this review, we have examined the main features of CK1, CK2, and GSK3 kinases, summarized the data in B-NHL supporting them as suitable therapeutic targets, and proposed a perspective on potential future research development.


Assuntos
Caseína Quinases/antagonistas & inibidores , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/enzimologia , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/uso terapêutico , Animais , Humanos , Prognóstico
2.
Cancer Sci ; 111(2): 749-759, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31849147

RESUMO

The revised WHO classification newly defined the entities "High-grade B-cell lymphoma with MYC and BCL2, and/or BCL6 rearrangements (HGBL-DH/TH)" and "HGBL, NOS." Standard immunochemotherapy for diffuse large B-cell lymphoma (DLBCL), R-CHOP, is insufficient for HGBL patients, and there are currently no optimized therapeutic regimens for HGBL. We previously reported that CCND3, which encodes cyclin D3, harbored high mutation rates in Burkitt lymphoma (BL), HGBL and a subset of DLBCL. Furthermore, the knockdown of cyclin D3 expression was toxic to germinal center (GC)-derived B-cell lymphomas. Thus, the fundamental function of cyclin D3 is important for the pathogenesis of GC-derived B-cell lymphoma. We herein used two structurally different CDK4/6 inhibitors, palbociclib and abemaciclib, and examined their suppressive effects on cell proliferation and their ability to induce apoptosis in various aggressive B-cell lymphoma cell lines. The results obtained demonstrated that abemaciclib more strongly suppressed cell proliferation and induced apoptosis in GC-derived B-cell lymphoma cell lines than the control, but only slightly inhibited those features in activated B-cell (ABC)-like DLBCL cell lines. Palbociclib exerted partial or incomplete effects compared with the control and the effect was intermediate between abemaciclib and the control. Moreover, the effects of abemaciclib appeared to depend on cyclin D3 expression levels based on the results of the expression analysis of primary aggressive B-cell lymphoma samples. Therefore, abemaciclib has potential as a therapeutic agent for aggressive GC-derived B-cell lymphomas.


Assuntos
Aminopiridinas/farmacologia , Benzimidazóis/farmacologia , Ciclina D3/genética , Linfoma de Células B/genética , Inibidores de Proteínas Quinases/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular , Ensaios de Seleção de Medicamentos Antitumorais , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Linfoma de Células B/tratamento farmacológico , Mutação , Piperazinas/farmacologia , Piridinas/farmacologia
3.
Vet J ; 254: 105398, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31836165

RESUMO

Canine lymphoma is one of the most common malignant tumours occurring in dogs and has a high incidence worldwide. Despite advances in cancer prevention, the treatment of neoplastic diseases still requires improvement. Some cancer cells may resist the effect of chemotherapeutic agents by up-regulating drug transporters leading to increased drug efflux, resulting in intrinsic or acquired drug resistance, which is a mechanism commonly seen in doxorubicin-resistant tumour cells. In this study, canine B-cell lymphoma cell line CLBL1-8.0, a doxorubicin-resistant B cell lymphoma cell line derived from CLBL-1 by increasing the doxorubicin concentration during culturing, exhibited high expression of P-glycoprotein (P-gp, ATP-binding cassette sub-family B member 1 [ABCB1]). These proteins are commonly involved in cancer cell resistance to doxorubicin. Imatinib, a tyrosine kinase inhibitor significantly potentiated the sensitivity of doxorubicin in P-gp-overexpressing doxorubicin-resistant cells. Moreover, a combination of these two drugs may increase the retention of doxorubicin by decreasing the efflux of doxorubicin without affecting P-gp protein overexpression. In conclusion, imatinib reversed doxorubicin resistance by decreasing drug efflux in P-gp-overexpressing doxorubicin-resistant canine lymphoma cells. These results suggest that combining doxorubicin, one of the most widely used chemotherapeutic drugs in the treatment of canine lymphoma, with imatinib might potentially overcome doxorubicin resistance in a clinical setting.


Assuntos
Antineoplásicos/farmacologia , Doenças do Cão/tratamento farmacológico , Doxorrubicina/farmacologia , Mesilato de Imatinib/farmacologia , Linfoma de Células B/veterinária , Inibidores de Proteínas Quinases/farmacologia , Animais , Linhagem Celular Tumoral , Cães , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Linfoma de Células B/tratamento farmacológico
4.
Rinsho Ketsueki ; 60(10): 1425-1430, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31695002

RESUMO

A 70-year-old man was admitted to our hospital due to fever, lymphadenopathy, and leukocytosis. White blood cell count was 22,700/µl with 92% blastoid cells. Bone marrow examination revealed abnormal lymphoid cell expansion. Abnormal cells expressed surface CD5 (dim), CD10, CD19, CD20, CD23 (dim) antigens, and kappa immunoglobulin light chains. Cytogenetic analysis of bone marrow cells at the time of diagnosis showed t (11:14) (q13;q32), t (14;18) (q32;q21), and t (8;14;18) (q24;q32;q21). Fluorescence in situ hybridization analyses of bone marrow identified translocations of IGH/MYC, IGH/BCL2, and IGH/CCND1. The patient was diagnosed with aggressive B-cell lymphoma with IGH/MYC, IGH/BCL2, and IGH/CCND1 translocation and was treated with various chemotherapies including R-CHOP, R-ESHAP, DA-EPOCH-R, R-hyper-CVAD, and radiotherapy. However, the lymphoma recurred after every chemotherapy session. Finally, he died after 6 months after first admission. Double-hit lymphoma/triple-hit lymphoma has previously been reported to present with an aggressive clinical course. In the present case, co-existence of IGH/CCND1, IGH/MYC, and IGH/BCL2 is very rare. Further clinical and biological investigations are necessary to establish an optimal treatment strategy.


Assuntos
Linfoma de Células B/genética , Translocação Genética , Idoso , Ciclina D1/genética , Evolução Fatal , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Hibridização in Situ Fluorescente , Linfoma de Células B/tratamento farmacológico , Masculino , Recidiva Local de Neoplasia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-myc/genética
5.
BMC Cancer ; 19(1): 936, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31601188

RESUMO

BACKGROUND: The phosphoinositol 3-kinase (PI3K) pathway is associated with poor prognosis of hematologic malignancies, providing a strong rationale for the use of PI3K inhibitors in the treatment of malignant lymphoma. However, development of resistance limits the use of PI3K inhibitors in lymphoma patients. METHODS: We established copanlisib (pan-PI3K inhibitor)-resistant B-cell lymphoma and duvelisib (PI3Kδ and -γ inhibitor)-resistant T-cell lymphoma cell lines. The cytokine array and the phospho-kinase array were used to identify up-regulated proteins in the resistant cells. Cytokine expression and phospho-kinase levels were examined by ELISA and Western blot analysis, respectively. Cell proliferation capabilities were measured by using CCK-8 kit and colony formation assay. The effects of inhibitors on apoptosis were detected using an Annexin V-FITC Apoptosis Detection Kit and a flow cytometry system. The underlying mechanisms were studied by transfecting recombinant plasmids or siRNA into lymphoma cell lines. Cells were transiently transfected using the Amaxa electroporation system. We evaluated the effects of PI3K inhibitor alone and in combination with JAK inhibitor (BSK805) on lymphoma proliferation and signaling pathway activation. RESULTS: Cytokine arrays revealed upregulation of interleukin (IL)-6 in both copanlisib- and duvelisib-resistant cell lines. Phosphorylated STAT5, AKT, p70S6K and MAPK were increased in copanlisib-resistant B-cell lymphoma cells, whereas phosphorylated STAT3 and NF-κB were increased in duvelisib-resistant T cell lymphoma cells. Conversely, depletion of IL-6 sensitized both resistant cell lines, and led to downregulation of phosphorylated STAT3 and STAT5 in copanlisib- and duvelisib-resistant cells, respectively. Moreover, combined treatment with a JAK inhibitor (BSK805) and a PI3K inhibitor circumvented the acquired resistance to PI3K inhibitors in lymphoma, and concurrent inhibition of the activated pathways produced combined effects. CONCLUSIONS: IL-6-induced STAT3 or STAT5 activation is a critical mechanism underlying PI3K inhibitor resistance in lymphoma, supporting the utility of IL-6 as an effective biomarker to predict therapeutic response to PI3K inhibitors.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Interleucina-6/metabolismo , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/metabolismo , Linfoma de Células T/tratamento farmacológico , Linfoma de Células T/metabolismo , Terapia de Alvo Molecular/métodos , Fosfatidilinositol 3-Quinases/metabolismo , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Interleucina-6/genética , Isoquinolinas/farmacologia , Inibidores de Janus Quinases/farmacologia , Linfoma de Células B/patologia , Linfoma de Células T/patologia , Purinas/farmacologia , Pirimidinas/farmacologia , Quinazolinas/farmacologia , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT5/metabolismo , Transfecção , Proteínas Supressoras de Tumor/metabolismo
6.
Blood ; 134(21): 1811-1820, 2019 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-31558467

RESUMO

Targeting both CD20 and phosphatidylinositol 3-kinase (PI3K), a protein that is critically involved in B-cell maturation, could be an efficacious strategy for treating B-cell malignancies. The safety of the next-generation compounds umbralisib, a PI3K-δ inhibitor, plus ublituximab, an anti-CD20 monoclonal antibody (combination referred to as U2), was evaluated in patients with chronic lymphocytic lymphoma (CLL) or non-Hodgkin lymphoma (NHL) in this phase 1/1b study. Phase 1 dose escalation was performed with a 3 + 3 design to establish the maximum tolerated dose. In this portion, ublituximab was given intravenously (NHL, 900 mg; CLL, 600 or 900 mg) for 12 cycles. Umbralisib was given orally once daily at 800 or 1200 mg (initial formulation) or 400 to 1200 mg (micronized formulation) in the phase 1 dose escalation portion, and at 800 to 1200 mg in the phase 1b portion until progression, toxicity, or study removal. The maximum tolerated dose was not reached in either the CLL or NHL cohort, and only 1 dose-limiting toxicity was observed. U2 had low instances of grade 3 or higher diarrhea (8%), pneumonia (8%), or hepatic toxicity (4%). Treatment discontinuation due to adverse events occurred in 13% of patients, and umbralisib dose reductions occurred in 15% of patients. The overall response rate for all patients was 46% with 17% complete responses. The median duration of response was 20 months (95% confidence interval, 11.3-not reached). U2 was well tolerated, and no new safety signals were observed over single-agent umbralisib. Preliminary efficacy with this combination is promising and warrants further investigation. This study was registered at www.clinicaltrials.gov as #NCT02006485.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Linfoma de Células B/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Relação Dose-Resposta a Droga , Feminino , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico
7.
Medicine (Baltimore) ; 98(31): e16688, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31374054

RESUMO

The objectives of this study were to analyze the clinical features of patients with bone involved lymphoma and identify the prognostic factors and to explore the optimized treatment strategy for bone involved lymphoma.A total of 1948 patients with lymphoma in our cancer center from September 2006 to October 2017 were retrospectively evaluated. Among these, 109 patients with skeletal involvement in lymphoma were enrolled. According to the pathologic subtypes, the patients were divided into 3 subgroups: classic Hodgkin lymphoma (cHL), B-cell non-Hodgkin lymphoma (B-NHL), and T-cell non-Hodgkin lymphoma (T-NHL). The clinical characteristics and overall survival (OS) of 3 groups of patients were reviewed, and the prognostic factors were analyzed.There were 9 (3 unifocal, 6 multifocal) patients with primary bone lymphoma. The 5-year OS of cHL, B-NHL, and T-NHL patients was 88.24%, 54.09%, and 61.58%, respectively. Advanced stage, elevated lactate dehydrogenase (LDH), age above 60, high International Prognostic Index score, and treatment without radiotherapy for the bone involved were significant poor prognostic factors for OS of all patients in univariate analysis. There was a trend toward better OS not only in limited-stage but also in advanced-stage patients with radiotherapy for the bone involved compared with the patients without radiotherapy. Elevated LDH level and age above 60 were the independent unfavorable prognostic factor in multivariate analysis.Elevated LDH level and age above 60 predict the poor prognosis of patients with bone involvement. The potential for long-term survival suggests that additional consolidative radiotherapy for the site of skeleton involvement may have a better chance of long-term success.


Assuntos
Neoplasias Ósseas/radioterapia , Doença de Hodgkin/radioterapia , Linfoma de Células B/radioterapia , Linfoma de Células T/radioterapia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/mortalidade , Estudos de Casos e Controles , Terapia Combinada , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Feminino , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/mortalidade , Humanos , Estimativa de Kaplan-Meier , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/mortalidade , Linfoma de Células T/tratamento farmacológico , Linfoma de Células T/mortalidade , Masculino , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Estudos Retrospectivos , Vincristina/uso terapêutico
8.
Pediatr Cardiol ; 40(8): 1756-1758, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31367951

RESUMO

The evaluation of oncologic patients at risk of chemotherapy-induced cardiotoxicity usually focuses on left ventricular function. However, recent studies have demonstrated that right ventricle impairment often coexists (and in some cases precedes) left-side affectation. We present the case of a 19-year-old heart transplant recipient who developed severe right ventricular dysfunction secondary to treatment of an abdominal lymphoma.


Assuntos
Antibióticos Antineoplásicos/efeitos adversos , Doxorrubicina/efeitos adversos , Linfoma de Células B/tratamento farmacológico , Disfunção Ventricular Direita/etiologia , Função Ventricular Direita/efeitos dos fármacos , Cardiotoxicidade/etiologia , Ecocardiografia , Feminino , Transplante de Coração/efeitos adversos , Humanos , Transplantados , Disfunção Ventricular Direita/fisiopatologia , Adulto Jovem
9.
Blood ; 134(11): 851-859, 2019 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-31340982

RESUMO

Zanubrutinib is a potent and highly selective inhibitor of Bruton tyrosine kinase (BTK). In this first-in-human, open-label, multicenter, phase 1 study, patients in part 1 (3 + 3 dose escalation) had relapsed/refractory B-cell malignancies and received zanubrutinib 40, 80, 160, or 320 mg once daily or 160 mg twice daily. Part 2 (expansion) consisted of disease-specific cohorts, including treatment-naive or relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The primary end points were safety and tolerability, and definition of the maximum tolerated dose (part 1). Additional end points included pharmacokinetics/pharmacodynamics and preliminary efficacy. Reported herein are results from 144 patients enrolled in the dose-finding and CLL/SLL cohorts. No dose-limiting toxicities occurred in dose escalation. Median BTK occupancy in peripheral blood mononuclear cells was >95% at all doses. Sustained complete (>95%) BTK occupancy in lymph node biopsy specimens was more frequent with 160 mg twice daily than 320 mg once daily (89% vs 50%; P = .0342). Consequently, 160 mg twice daily was selected for further investigation. With median follow-up of 13.7 months (range, 0.4-30.5 months), 89 CLL/SLL patients (94.7%) remain on study. Most toxicities were grade 1/2; neutropenia was the only grade 3/4 toxicity observed in >2 patients. One patient experienced a grade 3 subcutaneous hemorrhage. Among 78 efficacy-evaluable CLL/SLL patients, the overall response rate was 96.2% (95% confidence interval, 89.2-99.2). Estimated progression-free survival at 12 months was 100%. Zanubrutinib demonstrated encouraging activity in CLL/SLL patients, with a low incidence of major toxicities. This trial was registered at www.clinicaltrials.gov as #NCT02343120.


Assuntos
Leucemia de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Linfoma de Células B/tratamento farmacológico , Piperidinas/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Adulto , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Leucemia de Células B/metabolismo , Leucemia de Células B/patologia , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Piperidinas/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/farmacocinética , Pirimidinas/farmacocinética , Resultado do Tratamento , Adulto Jovem
10.
Ann Hematol ; 98(9): 2025-2033, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31312929

RESUMO

Outcomes for patients with non-Hodgkin's lymphoma (NHL) that proves refractory to treatment remain poor. Treatment of such patients is individualized and can include enrolment in a clinical trial of novel agents or use of one of a wide array of drug regimens. Initial treatment with anthracyclines such as doxorubicin limits options at later stages of treatment because of anthracycline-related cumulative cardiotoxicity. The aza-anthracenedione pixantrone was developed to reduce the likelihood of cardiotoxicity without compromising efficacy and is currently conditionally approved for use as monotherapy in patients with multiply-relapsed or refractory aggressive B cell NHL. The use of pixantrone in combination therapy, often to replace doxorubicin or mitoxantrone, has or is currently being investigated in numerous studies in patients with aggressive or indolent NHL and is the focus of this review. These include the R-CPOP regimen (rituximab, cyclophosphamide, pixantrone, vincristine, prednisone) for aggressive NHL in the first-line setting, including a study in elderly patients with limited cardiac function, and for patients with relapsed NHL with prior anthracycline exposure; the PSHAP regimen (pixantrone, cytarabine, prednisone, cisplatin), also in the latter setting; the PREBen/PEBen regimen (pixantrone, bendamustine and etoposide with or without rituximab) as salvage therapy; and pixantrone in combination with fludarabine, dexamethasone, and rituximab (FPD-R) for relapsed indolent NHL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Isoquinolinas/uso terapêutico , Linfoma de Células B/tratamento farmacológico , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Humanos , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia , Mitoxantrona/uso terapêutico , Prednisona/uso terapêutico , Rituximab/uso terapêutico , Terapia de Salvação/métodos , Vidarabina/análogos & derivados , Vidarabina/uso terapêutico , Vincristina/uso terapêutico
11.
Drugs ; 79(12): 1355-1361, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31313098

RESUMO

Camrelizumab (AiRuiKa™), a programmed cell death 1 (PD-1) inhibitor being developed by Jiangsu Hengrui Medicine Co. Ltd, recently received conditional approval in China for the treatment of relapsed or refractory classical Hodgkin lymphoma. The drug is also being investigated as a treatment for various other malignancies, including B cell lymphoma, oesophageal squamous cell carcinoma, gastric/gastroesophageal junction cancer, hepatocellular carcinoma, nasopharyngeal cancer and non-squamous, non-small cell lung cancer. This article summarizes the milestones in the development of camrelizumab leading to this first approval for classical Hodgkin lymphoma.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Doença de Hodgkin/tratamento farmacológico , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , China , Aprovação de Drogas , Neoplasias Esofágicas/tratamento farmacológico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Linfoma de Células B/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Gástricas/tratamento farmacológico
12.
Lancet Haematol ; 6(8): e429-e437, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31296423

RESUMO

BACKGROUND: Lenalidomide plus rituximab is approved to treat patients with relapsed or refractory follicular lymphoma. Obinutuzumab has been shown to enhance antibody-dependent cellular cytotoxicity, phagocytosis, and direct B-cell killing better than rituximab. Our aim was to determine the activity and safety of lenalidomide plus obinutuzumab in previously treated patients with relapsed or refractory follicular lymphoma. METHODS: In this multicentre, single-arm, phase 2 study, patients were enrolled from 24 Lymphoma Academic Research Organisation centres in France. Eligible patients (age ≥18 years) had histologically confirmed CD20-positive relapsed or refractory follicular lymphoma of WHO grade 1, 2, or 3a; an ECOG performance status of 0-2; and received at least one previous rituximab-containing therapy. Patients received oral lenalidomide (20 mg) plus intravenously infused obinutuzumab as induction therapy (1000 mg; six 28-day cycles), 1-year maintenance with lenalidomide (10 mg; 12 28-day cycles; days 2-22) plus obinutuzumab (1000 mg; alternate cycles), and 1-year maintenance with obinutuzumab (1000 mg; six 56-day cycles; day 1). The primary endpoint was the proportion of patients who achieved an overall response at induction end as per investigator assessment using the 1999 international working group criteria. The secondary endpoints were event-free survival, progression-free survival, overall survival, and safety. Analyses were per-protocol; the efficacy population included all patients who received at least one dose of both obinutuzumab and lenalidomide, and the safety population included all patients who received one dose of either investigational drug. The study is registered with ClinicalTrials.gov, number NCT01582776, and is ongoing but closed to accrual. FINDINGS: Between June 11, 2014, and Dec 18, 2015, 89 patients were recruited and 86 patients were evaluable for efficacy and 88 for safety. Median follow-up was 2·6 years (IQR 2·2-2·8). 68 (79%) of 86 evaluable patients (95% CI 69-87) achieved an overall response at induction end, meeting the prespecified primary endpoint. At 2 years, event-free survival was 62% (95% CI 51-72), progression-free survival 65% (95% CI 54-74), duration of response 70% (95% CI 57-79), and overall survival 87% (95% CI 78-93). Complete response was achieved by 33 (38%, 95% CI 28-50) of 86 patients at induction end, and the proportion of patients achieving a best overall response was 70 (81%, 95% CI 72-89) and 72 (84%, 74-91) of 86 patients during induction and treatment, respectively. The most common adverse events were asthenia (n=54, 61%), neutropenia (n=38, 43%), bronchitis (n=36, 41%), diarrhoea (n=35, 40%), and muscle spasms (n=34, 39%). Neutropenia was the most common toxicity of grade 3 or more; four (5%) patients had febrile neutropenia. 57 serious adverse events were reported in 30 (34%) of 88 patients. The most common serious adverse events were basal cell carcinoma (n=5, 6%), febrile neutropenia (n=4, 5%), and infusion-related reaction (n=3, 3%). One patient died due to treatment-related febrile neutropenia. INTERPRETATION: Our data shows that lenalidomide plus obinutuzumab is active in previously treated patients with relapsed or refractory follicular lymphoma, including those with early relapse, and has a manageable safety profile. Randomised trials of new immunomodulatory regimens, such as GALEN or using GALEN as a backbone, versus lenalidomide plus rituximab, are warranted. FUNDING: Lymphoma Academic Research Organisation, and Celgene and Roche.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Lenalidomida/uso terapêutico , Linfoma de Células B/tratamento farmacológico , Linfoma Folicular/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Antígenos CD20/metabolismo , Antineoplásicos Imunológicos/efeitos adversos , Intervalo Livre de Doença , Esquema de Medicação , Quimioterapia Combinada , Feminino , Humanos , Lenalidomida/efeitos adversos , Linfoma de Células B/mortalidade , Linfoma de Células B/patologia , Linfoma Folicular/mortalidade , Linfoma Folicular/patologia , Masculino , Pessoa de Meia-Idade , Neutropenia/etiologia , Recidiva , Taxa de Sobrevida , Resultado do Tratamento
13.
Eur J Haematol ; 103(3): 234-246, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31211886

RESUMO

OBJECTIVES: 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. METHODS: The human cytokine antibody array, RT-qPCR, Western blot, ELISA, apoptosis assay and xenografted mouse model et al were used. RESULTS: 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. CONCLUSIONS: Our findings propose a novel combined strategy in which bevacizumab synergises with the BCL2 inhibitor venetoclax that is effective against B-cell NHL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Células B/tratamento farmacológico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/administração & dosagem , Biomarcadores , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Sinergismo Farmacológico , Feminino , Humanos , Linfoma de Células B/metabolismo , Linfoma de Células B/mortalidade , Linfoma de Células B/patologia , Camundongos , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Transdução de Sinais , Sulfonamidas/administração & dosagem , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Int J Hematol ; 110(1): 77-85, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31127456

RESUMO

This multicenter phase II study (UMIN000008145) aims to investigate the efficacy and safety of six cycles of combination therapy (RBD) comprising rituximab, bendamustine, and dexamethasone (DEX) for relapsed or refractory (RR) indolent B-cell non-Hodgkin lymphoma (B-NHL) and mantle cell lymphoma (MCL). Although the initial study protocol comprised 20 mg/body DEX on days 1 and 2, and 10 mg/body on days 3-5 [high-dose (HD-) DEX group], the dose of DEX was later decreased to 8 mg/body on days 1 and 2 [low-dose (LD-) DEX group] due to frequent cytomegalovirus (CMV) antigenemia and recurrent retinitis. We enrolled 33 patients, and LD-DEX and HD-DEX were administered in 15 and 18 patients, respectively. The overall response and the 3-year progression-free survival rates were 88% and 75.5%, respectively. The leading adverse event was myelosuppression. Incidence of grade 3-4 leukocytopenia, neutropenia, and lymphocytopenia was 55%, 67%, and 91%, respectively. The most frequent nonhematological adverse events were CMV antigenemia and rash (33% and 30%, respectively). Incidence of CMV antigenemia over 10/100,000 white blood cells was significantly lower with LD-DEX than that with HD-DEX (P = 0.0127). In conclusion, RBD showed significant effectiveness for RR indolent B-NHL and MCL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Células B/tratamento farmacológico , Linfoma de Célula do Manto/tratamento farmacológico , Terapia de Salvação/métodos , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cloridrato de Bendamustina/administração & dosagem , Infecções por Citomegalovirus/etiologia , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Leucopenia/etiologia , Linfoma de Células B/complicações , Linfoma de Célula do Manto/complicações , Masculino , Pessoa de Meia-Idade , Neutropenia/etiologia , Rituximab/administração & dosagem , Terapia de Salvação/efeitos adversos , Adulto Jovem
17.
Pediatr Hematol Oncol ; 36(2): 113-121, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31002269

RESUMO

OBJECTIVES: To assess the impact of second-look biopsy of residual mass during or after chemotherapy in pediatric mature B-cell NHL. METHODS: Patients with mature B-cell non-Hodgkin lymphoma (NHL) who were suspicious of radiological residual mass at mid or end of treatment and subjected to second biopsy were treated at our center between January 2001 and December 2015. Their clinical characteristics, imaging findings, pathological changes, management, and prognosis were reviewed retrospectively. RESULTS: A total of 31 children were included (13 boys and 18 girls, median age at diagnosis 6.1 years). The median time from diagnosis to second biopsy was 3.15 months (range 2.3-18 months). Biopsy confirmed the presence of viable tumor in eight patients. The specificity and positive predictive value of conventional imaging in detecting residual detectable by biopsy were at 9 and 28.6%, while sensitivity and negative predictive value of this approach were both 100%. Three of the histologic positive patients experienced progressive disease or relapse while the others achieved complete remission (CR) and 21 patients achieved long-time CR at median follow-up of 3.2 years. The median progression-free survival (PFS) time of all 31 was 28 months and 5-year PFS rate was 90.0%. Five-year PFS rate of negative-biopsy and positive-biopsy group were 100 and 62.5%, respectively (p = 0.002). CONCLUSION: Conventional imaging has very high sensitivity but very low specificity for the accurate determination of residual disease in pediatric NHL. Second-look biopsy is necessary to differentiate viable tumor from necrosis or fibrosis and is solid evidence-based foundation of subsequent treatment.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biópsia , Linfoma de Células B/patologia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Estimativa de Kaplan-Meier , Linfoma de Células B/diagnóstico por imagem , Linfoma de Células B/tratamento farmacológico , Imagem por Ressonância Magnética , Masculino , Neoplasia Residual , Valor Preditivo dos Testes , Prognóstico , Intervalo Livre de Progressão , Indução de Remissão , Estudos Retrospectivos , Sensibilidade e Especificidade , Tomografia Computadorizada por Raios X
19.
Cancer Res ; 79(10): 2466-2479, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30940663

RESUMO

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 in silico drug target prioritization through interrogation of drug target databases. Using known vulnerabilities and available drug screens, we highlighted the importance of integrating molecular phenotype with drug target expression for in silico prediction of drug responsiveness. Our analysis implicated BCL2 expression level as an important indicator of venetoclax responsiveness and provided a rationale for its targeting in specific leukemia subtypes and multiple myeloma, linked several polycomb group proteins that could be targeted by small molecules (SFMBT1, CBX7, and EZH1) with chronic lymphocytic leukemia, and supported CDK6 as a disease-specific target in acute myeloid leukemia. Through integration with proteomics data, we characterized target protein expression for pre-B leukemia immunotherapy candidates, including DPEP1. These molecular data can be explored using our publicly available interactive resource, Hemap, for expediting therapeutic innovations in hematologic malignancies. SIGNIFICANCE: This study describes a data resource for researching derailed cellular pathways and candidate drug targets across hematologic malignancies.


Assuntos
Neoplasias Hematológicas/genética , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Neoplasias Hematológicas/tratamento farmacológico , Humanos , Imunoterapia/métodos , Internet , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Linfoma de Células B/tratamento farmacológico , Fenótipo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Bibliotecas de Moléculas Pequenas/uso terapêutico , Sulfonamidas/uso terapêutico , Transcriptoma/genética
20.
Dermatol Ther ; 32(4): e12948, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31025498

RESUMO

It is known that individuals with immune dysregulation have an increased risk of non-Hodgkin lymphoma. This association has been proven for pemphigus as well as for other autoimmune disease. We describe the development of cutaneous B-cell lymphoma in two patients affected by long-standing pemphigus vulgaris and pemphigus foliaceus (i.e., characterized by histological and immunopathological features different from those of paraneoplastic pemphigus). In both cases, a therapy with rituximab allowed to achieve the complete remission for the lymphoproliferative disease (never recurred at follow up) and a substantial long-term improvement of the clinical manifestations of pemphigus, although persistent to serological disease and occasional recurrences. We suggest that clinicians should consider that patients with long-standing pemphigus, both vulgaris and foliaceus, may develop primary cutaneous B-cell lymphomas, as shown in our report, and in these cases the treatment with rituximab is elective, providing a therapeutic option for both low-grade or follicular, CD20-positive, B-cell non-Hodgkin lymphomas and pemphigus. Nevertheless, as shown in our cases, a constant surveillance for pemphigus is necessary.


Assuntos
Linfoma de Células B/tratamento farmacológico , Pênfigo/tratamento farmacológico , Rituximab/administração & dosagem , Neoplasias Cutâneas/tratamento farmacológico , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/administração & dosagem , Feminino , Humanos , Fatores Imunológicos/administração & dosagem , Linfoma de Células B/patologia , Masculino , Pessoa de Meia-Idade , Pênfigo/imunologia , Neoplasias Cutâneas/patologia , Resultado do Tratamento
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