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1.
Lancet Oncol ; 21(9): 1188-1200, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32888452

RESUMO

BACKGROUND: Venetoclax plus obinutuzumab has been established as a fixed-duration treatment regimen for patients with chronic lymphocytic leukaemia. We compared the long-term efficacy after treatment cessation of the combination of venetoclax plus obinutuzumab with chlorambucil plus obinutuzumab in patients with previously untreated chronic lymphocytic leukaemia. METHODS: CLL14 is a multicentre, randomised, open-label, phase 3 trial done at 196 sites in 21 countries. Eligible patients were aged 18 years or older, had untreated chronic lymphocytic leukaemia, and coexisting conditions with a cumulative illness rating scale greater than 6, a creatinine clearance of 30-69 mL/min, or both. Patients were randomly assigned (1:1) via a web and voicemail system with allocation concealment and based on a computer-generated randomisation schedule with a block size of six and stratified by Binet stage and geographical region. Patients received either venetoclax plus obinutuzumab (oral venetoclax initiated on day 22 of cycle 1 [28-day cycles], with a 5-week dose ramp-up [20 mg, 50 mg, 100 mg, and 200 mg, then 400 mg daily for 1 week], thereafter continuing at 400 mg daily until completion of cycle 12; combined with intravenous obinutuzumab for six cycles starting with 100 mg on day 1 and 900 mg on day 2 [or 1000 mg on day 1], 1000 mg on days 8 and day 15 of cycle 1, and subsequently 1000 mg on day 1 of cycles 2 through 6) or chlorambucil plus obinutuzumab (oral chlorambucil at 0·5 mg/kg bodyweight on days 1 and 15 of each cycle for 12 cycles combined with the same obinutuzumab regimen). The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. Patient enrolment is complete, and the study is registered with ClinicalTrails.gov, NCT02242942. FINDINGS: Between Aug 7, 2015, and Aug 4, 2016, 432 patients were enrolled and randomly assigned to receive either venetoclax plus obinutuzumab (n=216) or chlorambucil plus obinutuzumab (n=216). All patients had been off treatment for at least 24 months at data collection. At a median follow-up of 39·6 months (IQR 36·8-43·0), patients given venetoclax plus obinutuzumab had a significantly longer progression-free survival than did patients given chlorambucil plus obinutuzumab (HR 0·31, 95% CI 0·22-0·44; p<0·0001). Median progression-free survival was not reached (95% CI not estimable to not estimable) in the venetoclax plus obinutuzumab group vs 35·6 months (33·7-40·7) in the chlorambucil plus obinutuzumab group. The most common grade 3 or 4 adverse event in both groups was neutropenia (112 [53%] of 212 patients in the venetoclax plus obinutuzumab group versus 102 [48%] of 214 patients in the chlorambucil plus obinutuzumab group). Serious adverse events occurred in 115 (54%) of 212 patients in the venetoclax plus obinutuzumab group and 95 (44%) of 214 patients in the chlorambucil plus obinutuzumab group. Venetoclax or chlorambucil treatment-related deaths were reported in one (1%) of 212 patients in the venetoclax plus obinutuzumab group (n=1 sepsis) and two (1%) of 214 patients in the chlorambucil plus obinutuzumab group (n=1 septic shock, n=1 metastatic skin squamous carcinoma). INTERPRETATION: 2 years after treatment cessation, venetoclax plus obinutuzumab continues to significantly improve progression-survival compared with chlorambucil plus obinutuzumab, thereby providing a limited duration treatment option for patients with previously untreated chronic lymphocytic leukaemia. FUNDING: F Hoffmann-La Roche and AbbVie.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Clorambucila/administração & dosagem , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Sulfonamidas/administração & dosagem , Adolescente , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Clorambucila/efeitos adversos , Feminino , Seguimentos , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Sulfonamidas/efeitos adversos , Resultado do Tratamento
2.
Curr Oncol ; 27(4): e420-e432, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32905290

RESUMO

Because of the global coronavirus pandemic, the 2020 annual scientific meeting of the American Society of Clinical Oncology took place virtually, 29-30 May. At the meeting, results from key studies about the treatment of chronic lymphocytic leukemia (cll) were disseminated. Studies examined the efficacy and safety of ibrutinib, acalabrutinib, zanubrutinib, and venetoclax as monotherapy or in combination with novel agents for patients with treatment-naïve and relapsed or refractory cll. Our meeting report describes the foregoing studies and presents interviews with investigators and commentaries by Canadian hematologists about potential effects on Canadian practice.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Congressos como Assunto , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Oncologia/métodos , Inibidores de Proteínas Quinases/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Canadá , Ensaios Clínicos como Assunto , Humanos , Oncologia/organização & administração , Oncologia/tendências , Inibidores de Proteínas Quinases/efeitos adversos , Sociedades Médicas , Resultado do Tratamento
3.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(4): 1419-1423, 2020 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-32798437

RESUMO

Venetoclax is a selective inhibitor of the anti-apoptotic protein B-cell lymphoma 2(BCL-2)and has great potential in treating a variety of hematological tumors. In recent years, domestic and foreign scholars have tried to use venetoclax singal or in combination with some drugs to treat the patients with hematological tumors, including elderly acute myeloid leukemia(AML)patients un suitable for intensive chemotherapy, relapsed or refractory chronic lymphocytic leukemia(CLL), Non-Hodgkin's lymphoma(NHL)and multiple myeloma(MM)patients, these studies have achieved good results.At the same time,some scholars found that the secondary drug-resistance occurred in some patients who continuous treated with Venetoclax, and explored the Venetoclax-resistant mechanism. In this review, the research advance of Venetoclax in hematological tumors and the mechanisms of drug resistance are summarized and discussed briefly.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Hematológicas , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Idoso , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Humanos , Sulfonamidas
5.
Ann Hematol ; 99(10): 2343-2349, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32833105

RESUMO

Ibrutinib-based therapy represents a recent success in managing high-risk CLL patients with 17p/TP53 deletion. However, a subset of CLL patients are resistant to therapy. Deletion of lipoprotein lipase (LPL) has been postulated as a potential evasion mechanism to ibrutinib-based therapy. In this study, we assessed for LPL deletion by fluorescence in situ hybridization in 176 consecutive CLL patients with 17p/TP53 deletion. LPL deletion was detected in 35 (20%) of CLL patients. Patients with LPL deletion (del) showed a higher frequency of CD38 expression but have comparable frequencies of somatic hypermutation and ZAP-70 expression compared with patients with normal (nml) LPL. Gene mutation analysis showed that TP53 was mutated in 68% of LPL-del versus 91% of LPL-nml patients. The overall response to ibrutinib-based therapy was 57%, including 37% complete remission (CR) and 20% partial remission (PR) in patients with LPL-del versus 90% (56% CR and 34% PR) in patients with LPL-nml (p < 0.001). LPL-del patients also showed a poorer overall survival (OS) compared with patients with LPL-nml (median OS, 236 months versus undefined, p < 0.001). In summary, the data presented establish an association between LPL deletion, resistance to ibrutinib-based therapy, and poorer overall survival in TP53-deleted CLL patients. We suggest that LPL deletion might be utilized as a biomarker for risk stratification and to predict therapeutic response in this high-risk group of CLL patients.


Assuntos
Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Deleção de Genes , Leucemia Linfocítica Crônica de Células B/genética , Lipase Lipoproteica/deficiência , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Feminino , Genes p53 , Humanos , Hibridização in Situ Fluorescente , Estimativa de Kaplan-Meier , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/mortalidade , Lipase Lipoproteica/genética , Lipase Lipoproteica/fisiologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Modelos de Riscos Proporcionais , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem , Medição de Risco , Rituximab/administração & dosagem , Sulfonamidas/administração & dosagem , Resultado do Tratamento , Proteína Supressora de Tumor p53/deficiência , Proteína-Tirosina Quinase ZAP-70/biossíntese , Proteína-Tirosina Quinase ZAP-70/genética
8.
Anticancer Res ; 40(7): 4059-4066, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620653

RESUMO

BACKGROUND/AIM: To study the long-term clinical efficacy and tolerability of ibrutinib monotherapy in real-world relapsed and refractory chronic lymphocytic leukemia (RR-CLL) patients outside clinical trials. PATIENTS AND METHODS: Clinical data of 171 RR-CLL patients treated with ibrutinib were collected within the observational study of the Polish Adult Leukemia Study Group. RESULTS: Median patient age was 64 years. Patients were pretreated with 3 (1-10) median lines of therapy, while 42 (24.6%) had 17p deletion. The median observation time was 40 months (range=1-59 months), while median ibrutinib monotherapy reached 37.5 months (range=0.4-59.2 months). Response was noted in 132 (77.2%) patients. The estimated 5-year progression-free survival (PFS) and overall survival (OS) rates were 61.1% (95%CI=49.3-70.9%) and 56.8% (95%CI=45.6-66.6%), respectively. At the time of analysis 97 (56.7%) remained under ibrutinib monotherapy. CONCLUSION: Ibrutinib is clinically effective and tolerable as a monotherapy in real-world RR-CLL patients.


Assuntos
Antineoplásicos/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Polônia , Inibidores de Proteínas Quinases/efeitos adversos , Pirazóis/efeitos adversos , Pirimidinas/efeitos adversos , Recidiva , Análise de Sobrevida , Resultado do Tratamento
9.
Medicine (Baltimore) ; 99(28): e21167, 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32664154

RESUMO

INTRODUCTION: The global burden of chronic lymphocytic leukemia (CLL) has constantly increased over the years, with a current incidence of 3.5 cases per 100,000 people. Although the conventional drugs used to treat CLL patients have been effective treatment failure rate in some of the patients is alarming. Therefore, as a result, novel treatment strategies with improved outcomes such as the blockade of immune checkpoints have emerged. However, consensus on the risk-benefit effects of the using these drugs in patients with CLL is controversial and has not been comprehensively evaluated. This systemic review and meta-analysis provide a comprehensive synthesis of available data assessing adverse events associated with the use of immune checkpoint inhibitors in patients with CLL as well as their influence on the overall survival rate. METHODS: This protocol for a systematic review and meta-analysis has been prepared in accordance with Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols 2015 guidelines. A search strategy will be developed using medical subject headings words in PubMed search engine with MEDLINE database. The search terms will also be adapted for gray literature, Embase, and Cochrane Central Register of Controlled Trials electronic databases. Two reviewers (AN and SRN) will independently screen studies, with a third reviewer consulted in cases of disagreements using a defined inclusion and exclusion criteria. Data items will be extracted using a predefined data extraction sheet. Moreover, the risk of bias and quality of the included studies will be appraised using the Downs and Black checklist and the quality and strengths of evidence across selected studies will be assessed using the Grading of Recommendations Assessment Development and Evaluation approach. The Cochran's Q statistic and the I statistics will be used to analyze statistical heterogeneity across studies. If the included studies show substantial level of statistical heterogeneity (I > 50%), a random-effects meta-analysis will be performed using R statistical software. ETHICS AND DISSEMINATION: The review and meta-analysis will not require ethical approval and the findings will be published in peer-reviewed journals and presented at local and international conferences. This review may help provide clarity on the risk-benefit effects of using immune checkpoint inhibitors in patients with CLL. SYSTEMATIC REVIEW REGISTRATION: International prospective Register of Systematic Reviews (PROSERO) number: CRD42020156926.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Adulto , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/mortalidade , Masculino , Metanálise como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa , Análise de Sobrevida , Revisões Sistemáticas como Assunto , Resultado do Tratamento
10.
Leukemia ; 34(9): 2354-2363, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32647324

RESUMO

Chronic lymphocytic leukemia (CLL) is a disease of the elderly, characterized by immunodeficiency. Hence, patients with CLL might be considered more susceptible to severe complications from COVID-19. We undertook this retrospective international multicenter study to characterize the course of COVID-19 in patients with CLL and identify potential predictors of outcome. Of 190 patients with CLL and confirmed COVID-19 diagnosed between 28/03/2020 and 22/05/2020, 151 (79%) presented with severe COVID-19 (need of oxygen and/or intensive care admission). Severe COVID-19 was associated with more advanced age (≥65 years) (odds ratio 3.72 [95% CI 1.79-7.71]). Only 60 patients (39.7%) with severe COVID-19 were receiving or had recent (≤12 months) treatment for CLL at the time of COVID-19 versus 30/39 (76.9%) patients with mild disease. Hospitalization rate for severe COVID-19 was lower (p < 0.05) for patients on ibrutinib versus those on other regimens or off treatment. Of 151 patients with severe disease, 55 (36.4%) succumbed versus only 1/38 (2.6%) with mild disease; age and comorbidities did not impact on mortality. In CLL, (1) COVID-19 severity increases with age; (2) antileukemic treatment (particularly BTK inhibitors) appears to exert a protective effect; (3) age and comorbidities did not impact on mortality, alluding to a relevant role of CLL and immunodeficiency.


Assuntos
Betacoronavirus , Infecções por Coronavirus/patologia , Leucemia Linfocítica Crônica de Células B/complicações , Pneumonia Viral/patologia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Comorbidade , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/mortalidade , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/mortalidade , Prognóstico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Estudos Retrospectivos , Índice de Gravidade de Doença , Inquéritos e Questionários
11.
Leukemia ; 34(8): 2225-2229, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32601378
12.
J Infect Dis ; 222(7): 1103-1107, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32702095

RESUMO

The antiviral drug remdesivir has been shown clinically effective for treatment of COVID-19. We here demonstrate suppressive but not curative effect of remdesivir in an immunocompromised patient. A man in his fifties treated with chemoimmunotherapy for chronic lymphocytic leukemia experienced a 9-week course of COVID-19 with high fever and severe viral pneumonia. During two 10-day courses of remdesivir starting 24 and 45 days after fever onset, pneumonia and spiking fevers remitted, but relapsed after discontinuation. Kinetics of temperature, C-reactive protein, and lymphocyte counts mirrored the remitting/relapsing SARS-CoV-2 infection. Combination therapy or longer treatment duration may be needed in immunocompromised patients.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/complicações , Pneumonia Viral/tratamento farmacológico , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Monofosfato de Adenosina/uso terapêutico , Alanina/uso terapêutico , Infecções por Coronavirus/complicações , Infecções por Coronavirus/virologia , Febre/tratamento farmacológico , Febre/virologia , Humanos , Hospedeiro Imunocomprometido , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/virologia , Síndrome Respiratória Aguda Grave/virologia , Fatores de Tempo , Resultado do Tratamento
14.
Hautarzt ; 71(7): 553-556, 2020 Jul.
Artigo em Alemão | MEDLINE | ID: mdl-32394077

RESUMO

We report the case of an 85-year-old chronic lymphocytic leukemia patient with a local metastatic MCVPyV-negative Merkel cell carcinoma at initial diagnosis. Therapy comprised surgical excision and radiotherapy but without lymphadenectomy. Six months after the primary diagnosis, liver metastases were detected. They responded to the PD-L1 inhibitor avelumab for more than 15 months. Thus, we postulate a synergistic effect of combined therapy with chlorambucil and avelumab through a mutual improvement of immune function, from which both diseases benefit.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Carcinoma de Célula de Merkel/tratamento farmacológico , Clorambucila/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Idoso de 80 Anos ou mais , Carcinoma de Célula de Merkel/patologia , Carcinoma de Célula de Merkel/secundário , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Resultado do Tratamento
18.
Medicine (Baltimore) ; 99(15): e19806, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32282746

RESUMO

RATIONALE: Acute lymphoblastic leukemia (ALL) has acute and severe onset characterized by fever, moderate to severe anemia, bone and joint pain, and sternal tenderness. It is easy to be misdiagnosed as rheumatic disease when joint pain is the first symptom. PATIENT CONCERNS: A male Han, 18 years of age was admitted on July 15th, 2016 for multi-joint swelling and pain with intermittent fever for half a year which had aggravated in the last 10 days. DIAGNOSIS: Based on symptoms, imaging, family history, and blood tests, he was first diagnosed with ankylosing spondylitis, but he was refractory to treatment. Bone marrow biopsy then revealed acute B-lymphoblastic leukemia (possibility Pro-B-ALL). INTERVENTIONS: The patient was transferred to the hematology department on July 23rd, 2016 for chemotherapy. OUTCOMES: No joint pain occurred during follow-up, which ended on November 4th, 2018. LESSONS: ALL may present with symptoms suggestive of rheumatic diseases like ankylosing spondylitis. Physicians should be aware of this possibility, especially in young patients.


Assuntos
Artralgia/etiologia , Leucemia Linfocítica Crônica de Células B/patologia , Espondilite Anquilosante/diagnóstico , Adolescente , Antineoplásicos/uso terapêutico , Artralgia/diagnóstico , Biópsia , Medula Óssea/patologia , Diagnóstico Diferencial , Erros de Diagnóstico , Febre/diagnóstico , Febre/etiologia , Humanos , Artropatias/diagnóstico por imagem , Artropatias/patologia , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Masculino , Espondilite Anquilosante/sangue , Espondilite Anquilosante/terapia , Tomografia Computadorizada por Raios X/métodos , Resultado do Tratamento
20.
Toxicol Appl Pharmacol ; 398: 115016, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32325063

RESUMO

Chronic lymphocytic leukemia (CLL) cells change their metabolic program between normoxia and hypoxia, possibly affecting cytotoxic drug potency by altering mitochondria-related cell stress responses (MRCSR) including mitophagy, mitochondrial biogenesis, and mitochondrial proteostasis. We evaluated in CLL cells from nine patients, the single and multiple-combined drug potency of arsenic trioxide (ATO), valproic acid (VPA), vincristine (VCR) and MG132 as four pharmacological sensors influencing mitochondrial apoptosis, mitochondrial biogenesis, mitophagy, and mitochondrial proteostasis respectively, under normoxia and hypoxia to force hypoxia-induced metabolic reprogramming (HMR). Untreated cells from all patients remained viable under O2 levels below 0.5% for 72 h. We obtained 21 measures of drug potency and interaction at 50% effect level that we denoted drug potency signature (DPS). Using the comparative DPS between normoxia and hypoxia, two non-supervised classification algorithms discriminated CLL patients with active disease (ADT) and stable disease (NAD) and showed complete consistency with their clinical characteristics. In ADT group under hypoxia, the potency of MG132 was increased, the interaction of ATO + VPA and ATO + VPA + VCR shifted towards antagonism, and ATO + VPA + VCR + MG132 shifted towards synergism, indicating a prominent role of mitochondrial proteostasis. Classification of patients based on DPS, depended on the contrasting response of drugs under hypoxia and normoxia, owing to HMR. Using these drugs as pharmacological sensors, we linked the metabolic arrangement of CLL cells under hypoxia, to potency of drugs targeting MRCSR, and to the clinical features of individual patients, therefore providing new sources of data on disease progression, drug response and risk prognosis.


Assuntos
Antineoplásicos/farmacologia , Hipóxia/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Progressão da Doença , Feminino , Humanos , Hipóxia/metabolismo , Hipóxia/patologia , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Transdução de Sinais/efeitos dos fármacos
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