Inibidores BTK e BCL-2 no Tratamento de Primeira Linha da Leucemia Linfocítica Crônica em Pacientes de Alto Risco: Revisão Sistemática e Meta-Análise em Rede / BTK and BCL-2 Inhibitors in the First-Line Treatment of Chronic Lymphocytic Leukemia in High-Risk Patients: Systematic Review and Network Meta-Analysis / Inhibidores de BTK Y BCL-2 en el Tratamiento de Primera Línea de la Leucemia Linfocítica Crónica en Pacientes de Alto Riesgo: Revisión Sistemática y un Metaanálisis en Red

Introdução: Pacientes com leucemia linfocítica crônica (LLC) com alto risco têm menores taxas de resposta, curso clínico mais agressivo e resistência à quimioterapia padrão, representando um desafio para o tratamento. Os inibidores da tirosina quinase de Bruton (BTK ­ ibrutinibe e acalabrutinibe) e o inibidor BCL-2 (venetoclax) podem ser utilizados nesses casos. Objetivo: Identificar e avaliar a eficácia e a segurança do uso de ibrutinibe, acalabrutinibe e venetoclax no tratamento de primeira linha em pacientes com LLC de alto risco. Método: Revisão sistemática de ensaios clínicos randomizados que avaliaram pacientes adultos com LLC, portadores de deleção 17p ou mutação TP53 e sem tratamento prévio. Foram pesquisadas as bases PubMed, EMBASE, LILACS e Cochrane Library, e realizadas avaliação do risco de viés pela ferramenta RoB 2 da Cochrane e avaliação da qualidade da evidência pelo GRADE. Resultados: Na meta-análise em rede para sobrevida livre de progressão (SLP), venetoclax + obinutuzumabe (RR: 0,62; IC 95% 0,41-0,95; p = 0,027) e acalabrutinibe + obinutuzumabe (RR: 0,74; IC 95% 0,55-0,99; p = 0,043) apresentaram menor risco de progressão ou óbito, com significância considerada limítrofe. Ibrutinibe + obinutuzumabe (RR: 0,93; IC 95% 0,86-1,00; p = 0,054) não apresentou diferença significativa na SLP para pacientes com LLC de alto risco. Conclusão: O tratamento de primeira linha com inibidores de BTK (ibrutinibe e acalabrutinibe) e o inibidor BCL-2 (venetoclax), associados a agentes monoclonais anti-CD20 ­ especialmente o obinutuzumabe ­, tem sido proposto como padrão para a maioria dos pacientes com LLC. Entretanto, pelos resultados desta revisão com meta-análise em rede, não foi possível confirmar essa recomendação.

Introduction: Patients with high-risk chronic lymphocytic leukemia (CLL) have lower response rates, a more aggressive clinical course, and resistance to standard chemotherapy, representing a treatment challenge. Bruton's tyrosine kinase inhibitors (BTK ­ ibrutinib and acalabrutinib) and the BCL-2 inhibitor (venetoclax) can be used in these cases. Objective: To identify and evaluate studies on the efficacy and safety of the use of ibrutinib, acalabrutinib and venetoclax in first-line treatment in patients with high-risk CLL. Method:Systematic review of randomized clinical trials that evaluated adult patients with CLL, carriers of 17p deletion or TP53 mutation and without prior treatment. The PubMed, EMBASE, LILACS and Cochrane Library databases were searched, and the risk of bias was assessed using the Cochrane RoB 2 tool and the quality of evidence was assessed with GRADE. Results: In the network meta-analysis for progression-free survival (PFS) venetoclax + obinutuzumab (RR: 0.62; 95%CI 0.41-0.95; p value 0.027) and acalabrutinib + obinutuzumab (RR: 0. 74; 95% CI 0.55-0.99; p value 0.043) presented a lower risk of progression or death, with significance considered borderline. Ibrutinib + obinutuzumab (RR: 0.93; 95% CI 0.86-1.00; p value 0.054) did not show a significant difference in PFS for patients with high-risk CLL. Conclusion: First-line treatment with BTK inhibitors (ibrutinib and acalabrutinib) and the BCL-2 inhibitor (venetoclax) associated with anti-CD20 monoclonal agents ­ especially obinutuzumab ­ have been proposed as the standard for most patients with CLL. However, based on the results of this review with network meta-analysis, it was not possible to confirm this recommendation.

Introducción: Los pacientes con leucemia linfocítica crónica (LLC) de alto riesgo tienen tasas de respuesta más bajas, un curso clínico más agresivo y resistencia a la quimioterapia estándar, lo que representa un desafío para el tratamiento. En estos casos se pueden utilizar los inhibidores de la tirosina quinasa de Bruton (BTK - ibrutinib y acalabrutinib) y el inhibidor de BCL-2 (venetoclax). Objetivo:Identificar y evaluar estudios sobre la eficacia y seguridad del uso de ibrutinib, acalabrutinib y venetoclax en el tratamiento de primera línea en pacientes con LLC de alto riesgo. Método: Revisión sistemática de ensayos clínicos aleatorios que evaluaron pacientes adultos con LLC, portadores de deleción 17p o mutación TP53 y sin tratamiento previo. Se realizaron búsquedas en las bases de datos PubMed, EMBASE, LILACS y Cochrane Library y se evaluó el riesgo de sesgo mediante la herramienta Cochrane RoB 2 y la calidad de la evidencia se evaluó mediante GRADE. Resultados: En el metaanálisis en red para la supervivencia libre de progresión (SSP) venetoclax + obinutuzumab (RR: 0,62; IC 95% 0,41-0,95; valor de p 0,027) y acalabrutinib + obinutuzumab (RR: 0,74; IC 95%). 0,55-0,99; valor de p 0,043) presentaron un menor riesgo de progresión o muerte, con una significación considerada límite. Ibrutinib + obinutuzumab (RR: 0,93; IC del 95 %: 0,86-1,00; valor de p 0,054) no mostró una diferencia significativa en la SSP para pacientes con LLC de alto riesgo. Conclusión: El tratamiento de primera línea con inhibidores de BTK (ibrutinib y acalabrutinib) y el inhibidor de BCL-2 (venetoclax), asociados con agentes monoclonales anti-CD20, especialmente obinutuzumab, se ha propuesto como estándar para la mayoría de los pacientes con LLC. Sin embargo, según los resultados de esta revisión con metaanálisis en red, no fue posible confirmar esta recomendación

Factors influencing severe cytopenia in chronic phase chronic myeloid leukemia patients receiving initial second generation tyrosine kinase inhibitors and its impact on treatment responses and outcomes / 中华血液学杂志

Objective: To explore the influencing covariates of severe neutrophils and/or thrombocytopenia and their effect on treatment response and outcome in patients with chronic-phase chronic myeloid leukemia (CP-CML) receiving initial second-generation tyrosine kinase inhibitors (2G-TKI) . Methods: Data from consecutive patients aged ≥18 years with newly diagnosed CP-CML who received initial 2G-TKI at Peking University People's Hospital from September 2008 to November 2021 were interrogated. Binary logistic regression models and Fine-Gray and Cox regression models were applied. Results: Data from 267 patients who received initial 2G-TKI, including nilotinib (n=239, 89.5% ) and dasatinib (n=28, 10.5% ) , were interrogated. The median age was 36 (range, 18-73) years, and 156 (58.4% ) patients were male. At a median treatment period of 1.0 (0.1-3.0) month, 43 (16.1% ) patients developed grade ≥3 neutrophils and/or thrombocytopenia and recovered within 1.0 (0.1-24.6) month. Male (OR=2.9, 95% CI 1.2-6.8; P=0.018) , age of ≥36 years (OR=3.2, 95% CI 1.4-7.2, P=0.005) , a spleen below a costal margin of ≥7 cm (OR=2.8, 95% CI 1.2-6.6, P=0.020) , and a hemoglobin (HGB) level of <100 g/L (OR=2.9, 95% CI 1.3-6.8, P=0.012) at diagnosis were significantly associated with grade ≥ 3 neutrophils and/or thrombocytopenia. Based on their regression coefficients, male, age of ≥36 years, a spleen below a costal margin of ≥7 cm, and an HGB level of <100 g/L were given 1 point to form a predictive system. All patients were divided into three risk subgroups, and the incidence of severe cytopenia significantly differed among the three groups (P < 0.001) . Grade ≥3 neutrophils and/or thrombocytopenia for >2 weeks was significantly associated with lower cumulative incidences of complete cytogenetic response (CCyR, HR=0.5, 95% CI 0.3-0.7, P<0.001) and major molecular response (MMR, HR=0.4, 95% CI 0.3-0.8, P=0.004) and was not significantly associated with failure, progression, and survival. Conclusion: Male, advanced age, a large spleen, and a low HGB level were significantly associated with severe cytopenia. The four covariates were used to establish a prediction model, in which the incidence of severe cytopenia among different risk groups was significantly different. Severe cytopenia for >2 weeks was a negative factor for responses but not for outcomes.

The efficacy and safety of Bruton tyrosine kinase inhibitors as monotherapy in the treatment of newly diagnosed patients with Waldenström macroglobulinemia / 中华血液学杂志

Objective: To investigate the efficacy and safety of Bruton tyrosine kinase inhibitors (BTKi) ibrutinib or zanubrutinib monotherapy in newly diagnosed patients with Waldenström macroglobulinemia (WM) . Methods: The efficacy and adverse effects of 58 patients with newly diagnosed WM receiving BTKi monotherapy in Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine were analyzed retrospectively from January 2018 to August 2022. Results: The response of 55 patients may be examined. Forty patients received ibrutinib monotherapy for a median of 15 months, with an overall response rate (ORR) of 85%, a main remission rate (MRR) of 70%, and a very good partial remission (VGPR) rate of 10%. Fifteen patients received zanubrutinib monotherapy for a median of 13 months, with an ORR of 93%, an MRR of 73%, and a VGPR rate of 0%. For various reasons, 10 patients were converted from ibrutinib to zanubrutinib. Ibrutinib treatment lasted an average of 7.5 months before conversion. The median duration of zanubrutinib therapy after conversion was 3.5 months. The ORRs before and after conversion were 90% and 100%, MRRs were 80% and 80%, and VGPR rates were 10% and 50%, respectively. After a median of 16 months, the 24-month progression-free survival (PFS) rate of patients who received both BTKi was 86%. PFS did not differ statistically across individuals with low, medium, and high-risk ISS scores (P=0.998). All of the patients survived. The most common side effects of BTKi were neutropenia and thrombocytopenia, which occurred in 12% and 10% of all patients, respectively. Ibrutinib accounts for 5% of atrial fibrillation, and zanubrutinib has a 7% risk of bleeding. Conclusions: In treating WM, ibrutinib or zanubrutinib provides good efficacy and tolerable adverse effects.

Efficacy of Tyrosine Kinase Inhibitor Combined with Decitabine, Homoharringtonine, Interferon in the Maintenance Therapy of Blast Phase Chronic Myeloid Leukemia / 中国实验血液学杂志

OBJECTIVE@#To explore the efficacy of tyrosine kinase inhibitor (TKI) combined with decitabine, homoharringtonine, and interferon regimen as maintenance therapy for blast phase chronic myeloid leukemia (CML-BP).@*METHODS@#The clinical data of CML-BP patients who received the first major hematological response after induction therapy at The Affiliated Cancer Hospital of Zhengzhou University from June 2015 to December 2021 were analyzed retrospectively. The event-free survival, duration of remission, and overall survival of patients in TKI combined with decitabine, homoharringtonine, interferon group(n=18) and TKI combined with conventional chemotherapy group(n=10) were compared by log-rank test.@*RESULTS@#A total of 28 patients were included, with a median age of 46 (24-58) years old. Kaplan-Meier survival analysis showed that patients in TKI combined with decitabine, homoharringtonine, interferon group had longer event-free survival (7.4 vs 4.3 months, P=0.043, HR＝0.44, 95% CI: 0.17-1.14), duration of overall remission (16.1 vs 6.6 months, P=0.005, HR＝0.32, 95% CI: 0.11-0.89), overall survival (34.3 vs 13.5 months, P=0.006, HR＝0.29, 95% CI: 0.10-0.82) compared with patients in TKI combined with conventional chemotherapy group.@*CONCLUSION@#The TKI combined with decitabine, homoharringtonine and interferon regimen can significantly prolong the survival of CML-BP patients who obtained the major hematological response compared with TKI combined with conventional chemotherapy regimen.

Bioequivalence/bioavailability Study of a New Formulation of Imatinib Mesylate 100 mg Coated Tablets versus Glivec® in Brazilian Healthy Male Volunteers in Fed State / Estudo de Bioequivalência/Biodisponibilidade de uma Nova Formulação de Mesilato de Imatinibe versus Glivec® em Voluntários Saudáveis Brasileiros em Condições Alimentares / Estudio de Bioequivalencia/Biodisponibilidad de una Nueva Formulación de Mesilato de Imatinib versus Glivec® en Voluntarios Saludables Brasileños Bajo Condiciones Alimentarias

Introduction: Imatinib mesylate is currently the first-line oral treatment for all stages of chronic myeloid leukemia (CML) and is also used in some cases of gastrointestinal stromal tumor (GIST) and acute lymphoblastic leukemia (ALL). Objective: Investigate the bioavailability of two products containing imatinib mesylate, 100 mg coated tablet, to determine if they are bioequivalent. Method: The study was conducted using an open-label, randomized, balanced design and the formulations were administered orally in a single dose to 48 healthy adult males, in fed state, followed by sequential blood withdraws for the next 72 hours. Forty-eight male healthy volunteers were selected to participate in the study. Test formulation from Eurofarma Laboratórios S.A. Brazil was compared to from Novartis Biociências S.A. The comparative bioavailability of the formulations was assessed based on statistical comparisons of relevant pharmacokinetic parameters obtained from drug concentration data from collected blood samples measured using an analytical method based on high-performance liquid chromatography coupled to mass spectrometry. Results: The ratio of the geometric means between the test and the reference, with a 90% confidence interval, of pharmacokinetic parameters for Cmax was 102.26% (94.17-111.04%) and for AUC0-t was 101.24% (95.19-107.68%). Conclusion: Imatinib mesylate 100 mg (test product) from Eurofarma Laboratórios S.A. was considered bioequivalent to the reference Glivec® 100 mg manufactured by Novartis Biociências S.A, and the test product can be interchangeable with the reference, based on their pharmacokinetic performance

Introdução: O mesilato de imatinibe é atualmente o tratamento oral de primeira linha para todos os estágios de leucemia mieloide crônica (LMC) e é usado também em alguns casos de tumores gastrointestinais (GIST) e na leucemia linfoide aguda (LLA). Objetivo: Investigar a biodisponibilidade de dois produtos contendo mesilato de imatinibe de 100 mg em comprimidos revestidos para determinar se são bioequivalentes. Método: Estudo conduzido usando um desenho aberto, randomizado e balanceado. As formulações foram administradas de forma oral em única dose a 48 participantes saudáveis do sexo masculino após alimentação, seguido de coletas de sangue por 72 horas. Quarenta e oito participantes saudáveis foram selecionados para participar do estudo. A formulação teste da Eurofarma Laboratórios S.A. foi comparada com a formulação referência da Novartis Biociências S.A. A biodisponibilidade relativa das formulações foi avaliada em comparações estatísticas dos parâmetros farmacocinéticos relevantes obtidos de concentrações de droga das amostras coletadas mediante a utilização de um método analítico baseado em cromatografia líquida de alta performance acoplada à espectrometria de massas. Resultados: A razão das médias geométricas entre teste e referência com intervalo de confiança 90% dos parâmetros farmacocinéticos para Cmáx foi de 102,26% (94,17-111,04%) e para ASC0-t foi de 101,24% (95,19-107,68). Conclusão: Mesilato de imatinib 100 mg (produto teste) da Eurofarma Laboratórios S.A. foi considerado bioequivalente ao Glivec® 100 mg produzido por Novartis Biociências S.A., e o produto teste pode ser intercambiável como referência com base em seu desempenho farmacocinético

Introducción: El mesilato de imatinibe es actualmente el tratamiento oral de primera línea para todos los estadios de leucemia mieloide crónica (LMC) y es usado también en algunos casos de tumores gastrointestinales (GIST) y leucemia linfoide aguda (LLA). Objetivo: Investigar la biodisponibilidad de dos productos de mesilato de imatinibe de 100 mg en comprimidos revestidos para determinar si son bioequivalentes. Método: Estudio ejecutado usando un diseño abierto, aleatorizado y balanceado. Las formulaciones fueron administradas de forma oral en dosis única a 48 participantes saludables de sexo masculino en condiciones de alimentación, seguidas de muestras de sangre por 72 horas. Cuarenta y ocho participantes saludables fueron seleccionados para participar del estudio. La formulación de prueba de Eurofarma Laboratórios S.A. fue comparada con la formulación referencia de Novartis Biociências S.A. La biodisponibilidad relativa de las formulaciones fue evaluada mediante comparaciones estadísticas de los parámetros farmacocinéticos relevantes obtenidos de concentraciones del fármaco de muestras recolectadas con la utilización de un método analítico basado en cromatografía de alto rendimiento acoplada a espectrometría de masas. Resultados: La relación de las medias geométricas entre la prueba y la referencia con un intervalo de confianza del 90% de los parámetros farmacocinéticos para Cmax fue 102,26% (94,17-111,04%) y para AUC0-t fue 101,24% (95,19-107,68). Conclusión: El mesilato de imatinib 100 mg (producto de prueba) de Eurofarma Laboratórios S.A. fue considerado bioequivalente al Glivec® 100 mg producido por Novartis Biociências S.A. y el producto de prueba puede ser intercambiable con el de referencia en función de su desempeño farmacocinético

Osimertinibe comparado a Erlotinibe Gefitinibe ou quimioterapia para tratamento de carcinoma pulmonar de células não pequenas com mutação do gene do receptor do fator de crescimento epidérmico (EFGR): revisão rápida / Osimertinib compared to erlotinib, gefitinib or chemotherapy for the treatment of non-small cell pumonary carcinoma with epidermal growth factor receptor (EFGR) gene mutation: rapid review

Mesilato de osimertinibe, gefitinibe, erlotinibe, quimioterapia padrão. Indicação: Câncer de pulmão de células não pequenas com mutação do receptor do fator de crescimento epidérmico (EGFR). Pergunta: Mesilato de osimertinibe é mais eficaz e seguro que gefitinibe, erlotinibe ou quimioterapia para os desfechos de sobrevida global, sobrevida livre de progressão e de segurança no tratamento de carcinoma pulmonar de células não pequenas com mutação do EGFR? Métodos: Levantamento bibliográfico foi realizado na base de dados PUBMED e EPISTEMONIKOS, seguindo estratégias de buscas predefinidas. Foi feita avaliação da qualidade metodológica das revisões sistemáticas com a ferramenta AMSTAR-2 (Assessing the Methodological Quality of Systematic Reviews Version 2). Resultados: Foram selecionadas duas revisões sistemáticas que atenderam aos critérios de elegibilidade. Conclusão: Mesilato de osimertinibe é mais eficaz do que gefitinibe ou erlotinibe na melhora da sobrevida global e da sobrevida livre de progressão em pacientes virgens de tratamento. Em pacientes previamente tratados, o mesilato de osimertinibe não é superior à quimioterapia padrão à base de platina no prolongamento da sobrevida global, mas é mais eficaz no aumento da sobrevida livre de progressão. Para câncer avançado, mesilato de osimertinibe não é mais eficaz do que a quimioterapia com ou sem pemetrexede para prolongar a sobrevida global, mas é mais eficaz em melhorar a sobrevida livre de progressão. Gefitinibe combinado com quimioterapia à base de pemetrexede foi superior à quimioterapia com ou sem pemetrexede na melhora da sobrevida global e da sobrevida livre de progressão

Osimertinib mesylate, gefitinib, erlotinib, standard chemotherapy. Indication: Non-small cell lung cancer with epidermal growth factor receptor (EGFR) mutation. Question: Is osimertinib mesylate more effective and safer than gefitinib, erlotinib or chemotherapy for overall survival, progression-free survival and safety outcomes in the treatment of non-small cell lung cancer with EGFR mutation? Methods: A bibliographic search was done in the PUBMED and EPISTEMONIKOS database, following predefined search strategies. The methodological quality of systematic reviews was evaluated using the Assessing the Methodological Quality of Systematic Reviews Version 2 tool. Results: Two systematic reviews were selected because they met the eligibility criteria. Conclusion: Osimertinib mesylate is more effective than gefitinib or erlotinib in improving overall survival and progression-free survival in treatment-naive patients. In previously treated patients, osimertinib mesylate is not superior to standard platinum-based chemotherapy in prolonging overall survival, but it is more effective in increasing progression-free survival. For advanced cancer, osimertinib mesylate is not more effective than chemotherapy with or without pemetrexed in prolonging overall survival, but it is more effective in improving progression-free survival. Gefitinib combined with pemetrexed-based chemotherapy was superior to chemotherapy with or without pemetrexed in improving overall survival and progression-free survival