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1.
BMJ Case Rep ; 14(2)2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33547121

RESUMO

Renal involvement in mantle cell lymphoma (MCL) is rare. We present the case of a man followed for MCL presented with acute kidney injury and positive antineutrophil cytoplasmic antibody (ANCA) type anti proteinase 3 (PR3). He was treated as for a rapidly progressing glomerulonephritis with cyclophosphamide and methylprednisolone followed by oral prednisone. Renal biopsy revealed diffuse endocapillary proliferation and segmental extracapillary proliferation in four glomeruli. Immunohistochemistry confirmed the renal invasion of lymphomatous cells. He started improving his renal function shortly after starting treatment. The coexistence of renal MCL infiltration, extracapillary proliferation and ANCA positive is exceptional.


Assuntos
Glomerulonefrite/etiologia , Linfoma de Célula do Manto/complicações , Anticorpos Anticitoplasma de Neutrófilos/sangue , Protocolos de Quimioterapia Combinada Antineoplásica , Biomarcadores Tumorais/sangue , Biópsia , Ciclofosfamida , Diagnóstico Diferencial , Doxorrubicina , Glomerulonefrite/tratamento farmacológico , Glomerulonefrite/patologia , Humanos , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/patologia , Masculino , Pessoa de Meia-Idade , Prednisona , Rituximab , Vincristina
3.
Anticancer Res ; 41(2): 927-936, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33517299

RESUMO

BACKGROUND/AIM: Limited published real-world data describe adverse events (AEs) among patients treated for mantle-cell lymphoma (MCL). The aim of this retrospective study was to describe treatment patterns, AEs, and associated healthcare costs. PATIENTS AND METHODS: Patients had two or more claims coded for MCL diagnosis, the first claim date (07/01/2012-05/31/2017) was the index date. Patients with pre-index MCL diagnosis or systemic treatment, or hematopoietic stem cell transplantation were excluded. Cohorts by regimen were followed for up to three lines of therapy. RESULTS: Patients (n=395; median age 72 years; 31% female) were observed over a total of 576 lines of therapy, the most common being bendamustine plus rituximab; rituximab monotherapy; R-CHOP; and ibrutinib. The most frequent AEs were hypertension (40.5%), anemia (37.7%), and infection (36.1%). However, hepatotoxicity ($19,645), stroke ($18,893), and renal failure ($9,037) were associated with the highest medical costs per patient per month. CONCLUSION: Among patients receiving common systemic treatments for MCL, AEs occurred frequently; some imposed substantial inpatient care costs.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/economia , Linfoma de Célula do Manto/tratamento farmacológico , Insuficiência Renal/economia , Acidente Vascular Cerebral/economia , Adenina/efeitos adversos , Adenina/análogos & derivados , Adenina/economia , Adenina/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/economia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cloridrato de Bendamustina/efeitos adversos , Cloridrato de Bendamustina/economia , Cloridrato de Bendamustina/uso terapêutico , Ciclofosfamida/efeitos adversos , Ciclofosfamida/economia , Ciclofosfamida/uso terapêutico , Doxorrubicina/efeitos adversos , Doxorrubicina/economia , Doxorrubicina/uso terapêutico , Feminino , Custos de Cuidados de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Piperidinas/efeitos adversos , Piperidinas/economia , Piperidinas/uso terapêutico , Prednisona/efeitos adversos , Prednisona/economia , Prednisona/uso terapêutico , Insuficiência Renal/induzido quimicamente , Estudos Retrospectivos , Rituximab/efeitos adversos , Rituximab/economia , Rituximab/uso terapêutico , Acidente Vascular Cerebral/induzido quimicamente , Vincristina/efeitos adversos , Vincristina/economia , Vincristina/uso terapêutico
5.
Crit Rev Oncol Hematol ; 158: 103212, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33383209

RESUMO

Mantle cell lymphoma (MCL) is a rare form of non-Hodgkin's lymphoma (NHL) with a median overall survival (OS) of approximately 3-5 years. Systematic literature reviews (SLRs) identified efficacy and safety data for first-line therapies, reported in randomised controlled trials (RCTs) and non-randomised interventional studies (NRISs). Nine and 20 independent studies were included in the RCT and NRISs SLRs, respectively. Differences in the regimens and patient outcomes varied according to patient age and suitability for autologous stem cell transplantation (ASCT). In elderly patients ineligible for transplant, OS ranged from 40 months to 69.6 months. In young transplant-eligible patients, OS ranged from 53 months to 152.4 months. Despite the paucity of directly comparable evidence on the efficacy and safety of MCL therapies, these SLRs highlight that MCL remains a difficult NHL subtype to treat, with short survival highlighting the unmet need for newer treatments that improve patient outcomes.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Linfoma de Célula do Manto , Linfoma não Hodgkin , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica , Humanos , Linfoma de Célula do Manto/tratamento farmacológico , Transplante Autólogo , Resultado do Tratamento
6.
Drugs Today (Barc) ; 56(8): 531-539, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33025948

RESUMO

Mantle cell lymphoma (MCL) has historically been an aggressive disease with poor long-term survival. In the last decade, Bruton tyrosine kinase (BTK) inhibition has emerged as a new treatment strategy for MCL, especially in the relapsed/refractory (r/r) setting. Zanubrutinib, a second-generation BTK inhibitor, was approved by the U.S. Food and Drug Administration (FDA) in late 2019 for r/r MCL on the basis of combined overall response rate of 84% in a total of 118 patients from two multicenter clinical trials, BGB-3111-AU-003 and BGB-3111-206. Duration of response was 14-18 months. Although 57% of patients developed grade 3 and 4 adverse side effects including anemia, pneumonia and neutropenia, only 8% discontinued treatment suggesting zanubrutinib monotherapy was fairly well tolerated. As compared to first-generation ibrutinib, zanubrutinib has higher BTK selectivity which may result in fewer off-target effects and improved potential for combination with other targeted therapies. In addition to a confirmatory phase III trial, there are multiple ongoing studies evaluating zanubrutinib as part of two- and three-drug regimens in MCL and other B-cell malignancies. These current results and areas of further interest indicate an exciting future for zanubrutinib in the treatment of MCL.


Assuntos
Linfoma de Célula do Manto/tratamento farmacológico , Piperidinas/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Humanos , Estudos Multicêntricos como Assunto , Inibidores de Proteínas Quinases/uso terapêutico , Estados Unidos
7.
Lancet Haematol ; 7(11): e798-e807, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32971036

RESUMO

BACKGROUND: Obinutuzumab monotherapy has shown promising efficacy in mantle cell lymphoma. We aimed to investigate the activity of obinutuzumab plus DHAP (dexamethasone, high-dose cytarabine, and cisplatin), measured by minimal residual disease quantitative (q)PCR status in the bone marrow after four cycles. METHODS: LyMa-101 was a prospective, open-label, single-arm, phase 2 trial. Participants were enrolled from 28 hospitals in France. Newly diagnosed patients with mantle cell lymphoma (aged 18 to <66 years) who were eligible for autologous stem-cell transplantation received four cycles of obinutuzumab plus DHAP (obinutuzumab 1000 mg/m2 intravenously on days 1, 8, and 15 at cycle 1 and day 1 at cycles 2, 3, and 4; dexamethasone 40 mg intravenously on days 1-4, cytarabine 2 g/m2 intravenously every 12 h on day 1, and according to local investigator, cisplatin 100 mg/m2 by continuous infusion over 24 h on day 1 or carboplatin area under the curve 5 or oxaliplatin 130 mg/m2) every 21 days before transplantation, and 3 years of obinutuzumab (1000 mg/m2 every 2 months) maintenance followed by minimal residual disease-based obinutuzumab on-demand maintenance. The primary outcome was minimal residual disease negativity in the bone marrow after four cycles of obinutuzumab plus DHAP at the end of induction, measured in the efficacy set (all minimal residual disease-informative [bone marrow or peripheral blood] patients who received at least one dose of obinutuzumab). Obinutuzumab plus DHAP was considered effective if bone marrow minimal residual disease negativity was 70% or more by intention to treat. The trial is closed to recruitment and registered with ClinicalTrials.gov, NCT02896582. FINDINGS: 86 patients were enrolled between Nov 29, 2016, and May 2, 2018. 81 patients completed induction, 73 underwent autologous stem-cell transplantation, and 69 started maintenance therapy. 55 (75%) of 73 patients in the efficacy set reached minimal residual disease negativity in bone marrow at end of induction. According to the protocol definition, 18 (25%) of 73 patients in the efficacy set were minimal residual disease-positive: 12 patients who were minimal residual disease-positive in the bone marrow, plus two patients who progressed during induction, and four patients who did not have minimal residual disease assessment. The most common grade 3-4 treatment-emergent adverse events were anaemia (grade 3, 26 [31%] of 85 patients; grade 4, three [4%] of 85 patients) and neutropenia (grade 3, 13 [15%] of 85 patients; grade 4, 32 [38%] of 85 patients). 58 serious adverse events occurred during the induction phase. There were no treatment-related deaths. INTERPRETATION: Obinutuzumab plus DHAP is a well tolerated regimen and has good activity for inducing minimal residual disease negativity in the bone marrow of transplant-eligible patients with mantle cell lymphoma. Obinutuzumab plus DHAP has potential activity as induction chemotherapy, with bone marrow minimal residual disease negativity potentially predicting long-term disease control. FUNDING: Roche SAS.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Citarabina/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Linfoma de Célula do Manto/tratamento farmacológico , Adolescente , Adulto , Anemia/etiologia , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Área Sob a Curva , Medula Óssea/patologia , Citarabina/efeitos adversos , Dexametasona/administração & dosagem , Humanos , Linfoma de Célula do Manto/patologia , Linfoma de Célula do Manto/terapia , Pessoa de Meia-Idade , Neoplasia Residual , Estudos Prospectivos , Curva ROC , Transplante Autólogo , Resultado do Tratamento , Adulto Jovem
9.
Medicine (Baltimore) ; 99(28): e20961, 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32664099

RESUMO

BACKGROUND: Chemotherapy with or without consolidation followed by autologous hematopoietic stem cell transplantation is the first-line treatment for mantle cell lymphoma. However, the effectiveness and safety of bortezomib-based chemotherapy for patients with mantle cell lymphoma is still uncertain. METHODS: In this systematic review, the electronic databases of Cochrane Central Register of Controlled Trials, EMBASE, and PUBMED will be searched from inception to May 1, 2020. Randomized controlled trials that assessed the effectiveness and safety of bortezomib in combination with chemotherapy for patients with mantle cell lymphoma will be included. The patient's important outcomes include overall survival, progression-free survival, overall response rate, quality of life, and serious adverse events (eg, grade III-IV peripheral neuropathy, neutropenia, and infection). All process of the study selection, data extraction, and methodology evaluation will be carried out by 2 authors independently. RevMan 5.3 software will be utilized for statistical analysis. RESULTS: This study will provide a detailed summary of latest evidence related to the effectiveness and safety of bortezomib in combination with chemotherapy in overall survival, progression-free survival, overall response rate, quality of life, and serious adverse events for patients with mantle cell lymphoma CONCLUSION:: The findings of this study may provide possible guidance for bortezomib in combination with chemotherapy for patients with mantle cell lymphoma. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD 42020154938.


Assuntos
Antineoplásicos/administração & dosagem , Bortezomib/administração & dosagem , Linfoma de Célula do Manto/tratamento farmacológico , Metanálise como Assunto , Projetos de Pesquisa , Revisões Sistemáticas como Assunto , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bortezomib/efeitos adversos , Humanos , Resultado do Tratamento
10.
Int J Hematol ; 112(4): 504-509, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32613313

RESUMO

Duvelisib is a novel dual inhibitor of phosphoinositide-3-kinase (PI3K)-δ and -γ. This single-arm, multicenter phase I study investigated its safety, pharmacokinetics, and preliminary efficacy in Japanese patients with relapsed or refractory lymphoma. Duvelisib was administered orally twice daily at 25 mg in 28-day cycles. Seven patients, comprising 4 with follicular lymphoma (FL), 2 with diffuse large B-cell lymphoma, and 1 with mantle cell lymphoma (MCL) were enrolled. No dose-limiting toxicity occurred in any patient. The most commonly experienced treatment-related adverse events of any grade were neutropenia and thrombocytopenia, occurring in 3 patients each (42.9%); followed by lymphopenia, diarrhea, enterocolitis, stomatitis, hepatic function abnormal, ALT increased, and AST increased, occurring in 2 patients each (28.6%). The most common grade ≥ 3 treatment-related adverse events were neutropenia, which occurred in 3 patients (42.9%), and thrombocytopenia, lymphopenia, and hepatic function abnormal, which occurred in 2 patients each (28.6%). One patient with FL achieved a complete response; the remaining 3 with FL and the 1 with MCL achieved a partial response. The overall response rate was 71.4% (5/7 patients). Duvelisib was well tolerated in Japanese patients with relapsed or refractory lymphoma. Safety and preliminary efficacy data support further development of duvelisib in Japanese patients.


Assuntos
Isoquinolinas/administração & dosagem , Linfoma Folicular/tratamento farmacológico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma de Célula do Manto/tratamento farmacológico , Inibidores de Fosfoinositídeo-3 Quinase/administração & dosagem , Purinas/administração & dosagem , Grupo com Ancestrais do Continente Asiático , Esquema de Medicação , Feminino , Humanos , Isoquinolinas/efeitos adversos , Masculino , Neutropenia/etiologia , Inibidores de Fosfoinositídeo-3 Quinase/efeitos adversos , Purinas/efeitos adversos , Trombocitopenia/etiologia , Resultado do Tratamento
12.
Cancer Cell ; 37(6): 761-763, 2020 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-32516587

RESUMO

In the New England Journal of Medicine, Wang et al. report favorable ZUMA-2 trial results of CAR T cells for patients with relapsed and refractory mantle cell lymphoma following prior failed Bruton's tyrosine kinase inhibitor therapy, with an overall response rate of 93% and an expected safety profile.


Assuntos
Linfoma de Célula do Manto , Adulto , Humanos , Imunoterapia Adotiva , Linfoma de Célula do Manto/tratamento farmacológico , Linfócitos T
15.
Drugs Aging ; 37(7): 469-481, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32367497

RESUMO

Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma that is largely a disease of older adults with a median age at diagnosis of 67 years. MCL is considered incurable with current therapies and has historically been associated with a poor prognosis. A subset of patients will present with features of more indolent disease and can be safely observed for a period of time after diagnosis, but the majority will require treatment at some point in the disease course. Younger patients who are eligible to undergo intensive induction chemotherapy followed by consolidation with an autologous stem cell transplant can experience prolonged survival times with a median overall survival of 13 years; however, there are limited data to support this treatment approach in older adults and these patients often have medical comorbidities that preclude such intensive therapy. Fortunately, an increased understanding of the disease biology has led to the development of novel therapies in recent years that are well-tolerated and have led to improved outcomes in this patient population. In this article, we will review the current treatment landscape for older adults with MCL, with a focus on the safety and efficacy of chemotherapy regimens and novel agents such as lenalidomide, bortezomib, and the Bruton's tyrosine kinase inhibitors that have been formally studied in this population.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Célula do Manto/tratamento farmacológico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bortezomib/efeitos adversos , Bortezomib/uso terapêutico , Ensaios Clínicos como Assunto , Transplante de Células-Tronco Hematopoéticas , Humanos , Lenalidomida/efeitos adversos , Lenalidomida/uso terapêutico , Rituximab/administração & dosagem , Rituximab/uso terapêutico
16.
N Engl J Med ; 382(14): 1331-1342, 2020 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-32242358

RESUMO

BACKGROUND: Patients with relapsed or refractory mantle-cell lymphoma who have disease progression during or after the receipt of Bruton's tyrosine kinase (BTK) inhibitor therapy have a poor prognosis. KTE-X19, an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, may have benefit in patients with relapsed or refractory mantle-cell lymphoma. METHODS: In a multicenter, phase 2 trial, we evaluated KTE-X19 in patients with relapsed or refractory mantle-cell lymphoma. Patients had disease that had relapsed or was refractory after the receipt of up to five previous therapies; all patients had to have received BTK inhibitor therapy previously. Patients underwent leukapheresis and optional bridging therapy, followed by conditioning chemotherapy and a single infusion of KTE-X19 at a dose of 2×106 CAR T cells per kilogram of body weight. The primary end point was the percentage of patients with an objective response (complete or partial response) as assessed by an independent radiologic review committee according to the Lugano classification. Per the protocol, the primary efficacy analysis was to be conducted after 60 patients had been treated and followed for 7 months. RESULTS: A total of 74 patients were enrolled. KTE-X19 was manufactured for 71 patients and administered to 68. The primary efficacy analysis showed that 93% (95% confidence interval [CI], 84 to 98) of the 60 patients in the primary efficacy analysis had an objective response; 67% (95% CI, 53 to 78) had a complete response. In an intention-to-treat analysis involving all 74 patients, 85% had an objective response; 59% had a complete response. At a median follow-up of 12.3 months (range, 7.0 to 32.3), 57% of the 60 patients in the primary efficacy analysis were in remission. At 12 months, the estimated progression-free survival and overall survival were 61% and 83%, respectively. Common adverse events of grade 3 or higher were cytopenias (in 94% of the patients) and infections (in 32%). Grade 3 or higher cytokine release syndrome and neurologic events occurred in 15% and 31% of patients, respectively; none were fatal. Two grade 5 infectious adverse events occurred. CONCLUSIONS: KTE-X19 induced durable remissions in a majority of patients with relapsed or refractory mantle-cell lymphoma. The therapy led to serious and life-threatening toxic effects that were consistent with those reported with other CAR T-cell therapies. (Funded by Kite, a Gilead company; ZUMA-2 ClinicalTrials.gov number, NCT02601313.).


Assuntos
Antígenos CD19/uso terapêutico , Imunoterapia Adotiva , Linfoma de Célula do Manto/terapia , Receptores de Antígenos Quiméricos/antagonistas & inibidores , Adulto , Idoso , Antineoplásicos/uso terapêutico , Terapia Combinada , Humanos , Imunoterapia Adotiva/efeitos adversos , Infusões Intravenosas , Leucaférese , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/mortalidade , Pessoa de Meia-Idade , Recidiva , Análise de Sobrevida , Linfócitos T/transplante , Vidarabina/análogos & derivados , Vidarabina/uso terapêutico
17.
Adv Exp Med Biol ; 1233: 153-174, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32274756

RESUMO

Since its introduction in the clinics in early 2000s, the proteasome inhibitor bortezomib (BTZ) significantly improved the prognosis of patients with multiple myeloma (MM) and mantle cell lymphoma (MCL), two of the most challenging B cell malignancies in western countries. However, relapses following BTZ therapy are frequent, while primary resistance to this agent remains a major limitation for further development of its therapeutic potential. In the present chapter, we recapitulate the molecular mechanisms associated with intrinsic and acquired resistance to BTZ learning from MM and MCL experience, including mutations of crucial genes and activation of prosurvival signalling pathways inherent to malignant B cells. We also outline the preclinical and clinical evaluations of some potential druggable targets associated to BTZ resistance, considering the most meaningful findings of the past 10 years. Although our understanding of BTZ resistance is far from being completed, recent discoveries are contributing to develop new approaches to treat relapsed MM and MCL patients.


Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Linfoma de Célula do Manto/tratamento farmacológico , Mieloma Múltiplo/tratamento farmacológico , Inibidores de Proteassoma/farmacologia , Inibidores de Proteassoma/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/patologia , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Recidiva Local de Neoplasia , Complexo de Endopeptidases do Proteassoma/metabolismo
18.
J Oncol Pharm Pract ; 26(5): 1190-1199, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32279595

RESUMO

Mantle cell lymphoma is a rare subtype of B-cell non-Hodgkin's lymphomas that is generally classified as an aggressive lymphoma requiring front-line chemo-immunotherapy with stem cell rescue. Despite effective treatment, many patients relapse or are refractory to front-line therapy. In addition, these patients may also develop drug resistance requiring novel modalities for subsequent lines. Bruton's tyrosine kinase inhibitors have demonstrated a well-tolerated safety and efficacy profile across several B-cell malignancies. Ibrutinib, acalabrutinib, and zanubrutinib are FDA-approved as treatment options for patients with Mantle cell lymphoma following one prior line of therapy. Various factors should be considered which include the adverse event profile of these agents and ability to adhere to therapy. In this article, we review the role of Bruton's tyrosine kinase inhibitors for the management of Mantle cell lymphoma and review the clinical pharmacology, pharmacokinetics, safety and efficacy, and future directions.


Assuntos
Antineoplásicos/uso terapêutico , Linfoma de Célula do Manto/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Benzamidas/administração & dosagem , Humanos , Imunoterapia , Piperidinas/administração & dosagem , Pirazinas/administração & dosagem , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem
19.
Am J Hematol ; 95(6): 623-629, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32239765

RESUMO

Venetoclax is effective in relapsed patients with mantle cell lymphoma (MCL). Mechanisms of resistance to venetoclax in MCL are poorly understood. We describe the clinical outcomes and genomic characteristics of 24 multiply relapsed patients (median of five prior lines of therapy) who received venetoclax-based therapies; 67% had progressed on BTK inhibitors (BTKi) and 54% had blastoid or pleomorphic histology. Median follow up after venetoclax treatment was 17 months. The overall response rate was 50% and complete response (CR) rate was 21%, 16 patients had progressed and 15 died. The median progression free, overall and post venetoclax survival were 8, 13.5 and 7.3 months respectively. Whole-exome sequencing (WES) was performed on samples collected from seven patients (including five pairs; before starting venetoclax and after progression on venetoclax). The SMARCA4 and BCL2 alterations were noted only after progression, while TP53, CDKN2A, KMT2D, CELSR3, CCND1, NOTCH2 and ATM were altered 2-4-fold more frequently after progression. In two patients with serial samples, we demonstrated clonal evolution of novel SMARCA4 and KMT2C/D mutations at progression. Mutation dynamics in venetoclax resistant MCL is demonstrated. Our data indicates that venetoclax resistance in MCL is predominantly associated with non-BCL2 gene mutations. Further studies are ongoing in MCL patients to evaluate the efficacy of venetoclax in combination with other agents and understand the biology of venetoclax resistance in MCL.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Resistencia a Medicamentos Antineoplásicos/genética , Linfoma de Célula do Manto , Mutação , Proteínas de Neoplasias/genética , Sulfonamidas/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/genética , Masculino , Pessoa de Meia-Idade , Recidiva
20.
Int J Clin Pharmacol Ther ; 58(6): 343-350, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32213285

RESUMO

OBJECTIVE: Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease of the central nervous system, caused by reactivation of John Cunningham polyomavirus, affecting mainly patients in an immunocompromised state. Recently, drug-associated PML is gaining attention as more cases of PML in connection with the use of various immunomodulatory drugs emerge. Over the last couple of years, sporadic reports have occurred about a possible association between PML and the use of a new immunomodulatory drug, ibrutinib (Imbruvica), primarily indicated for the treatment of various B-cell malignancies. CASE REPORT: Herein, we report a case of a 62-year-old female patient with bilateral mantle cell lymphoma of conjunctiva diagnosed at IVA clinical stage (according to the Ann Arbor staging of lymphomas) of the disease. As a first line of treatment, the patient was given 6 cycles of rituximab-based chemotherapy followed by a complete remission. Seven years later, the patient relapsed, at which point the treatment with ibrutinib was initiated. Three weeks after the initial dosage, the patient started to show signs of progressive neurological symptomatology and died 4 months thereafter due to bilateral bronchopneumonia. Due to unspecific MRI signs and negative PCR results, the diagnosis of PML was confirmed only postmortem. CONCLUSION: This case report demonstrates a possible severe adverse effect of the immunomodulatory drug ibrutinib and the importance of a multidisciplinary approach in its diagnosis. Since PML is a rare but highly fatal disease, it is of utmost importance to be aware of the possible connection with the use of this drug to prevent missed or delayed diagnosis, considering that timely therapeutic intervention is crucial for improved prognosis.


Assuntos
Leucoencefalopatia Multifocal Progressiva/tratamento farmacológico , Linfoma de Célula do Manto/tratamento farmacológico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Evolução Fatal , Feminino , Humanos , Leucoencefalopatia Multifocal Progressiva/complicações , Linfoma de Célula do Manto/complicações , Pessoa de Meia-Idade
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