Análise dos desfechos clínicos da abordagem conservadora nas indicações de tratamento na leucemia linfocítica crônica
Data
2024-10-03
Autores
Marques, Fernanda de Morais 
Orientadores
Silva, Celso Arrais Rodrigues da
Tipo
Tese de doutorado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
Introdução: A leucemia linfocítica crônica (LLC) apresenta diversas indicações de tratamento, com alguns pacientes recebendo tratamento imediato enquanto outros permanecem em observação. Em 2008, o Workshop Internacional sobre Leucemia Linfocítica Crônica (IWCLL) estabeleceu critérios para indicações de tratamento, amplamente adotados na prática clínica e em estudos clínicos. O Grupo Brasileiro de LLC (GBLLC) vem avaliando uma abordagem mais conservadora na indicação e início do tratamento realizado em múltiplos centros, que evita níveis de corte predefinidos para citopenias e evita considerar linfocitose progressiva, envolvimento extranodal ou sintomas relacionados à doença como critérios isolados. No entanto, a segurança e os potenciais resultados diferentes desta abordagem conservadora em comparação com os critérios mais restritos do IWCLL ainda não haviam sido avaliados. Objetivo: Comparar os desfechos clínicos de pacientes com LLC cadastrados no Registro Brasileiro de LLC (RBLLC) sem indicação de tratamento segundo os critérios do GBLLC, que foram tratados ou não com base na decisão do centro. Pacientes e Métodos: Realizamos uma análise retrospectiva de pacientes com LLC inscritos no RBLLC, acompanhados entre janeiro de 2009 e julho de 2023, atendendo aos critérios mínimos de disponibilidade de dados para análise e seguindo as diretrizes de inclusão do IWCLL. Definimos dois grupos de interesse: 1) grupo de critérios liberais - critérios mais amplos e inclusivos definidos pelo IWCLL; 2) grupo de critérios restritivos - critérios mais restritos e seletivos definidos pelo GBLLC, indicando uma abordagem mais cautelosa para o início do tratamento. Resultados/Discussão: Foram incluídos 2.511 pacientes de 41 centros. Entre eles, 1.404 pacientes (56%) preencheram os critérios da IWCLL para indicação de tratamento, enquanto apenas 788 pacientes (31%) preencheram os critérios de indicação mais conservadores do GBLLC. As indicações comuns para o início do tratamento no grupo de critérios liberais foram citopenias em 771 pacientes (55%), linfonodomegalia sintomática em 330 pacientes (24%) e sintomas constitucionais relacionados à doença em 112 pacientes (8%). E as indicações mais comuns para o início do tratamento no grupo de critérios restritivos foram citopenias em 413 pacientes (52%), linfonodomegalia sintomática em 316 pacientes (40%) e complicações autoimunes em 22 pacientes (3%). Após um acompanhamento médio de 58 meses, a sobrevida global (SG) em 5 anos foi de 82%. O grupo cuja indicação de tratamento eram as citopenias demonstrou SG inferior em comparação com as demais indicações. Do total de 1404 pacientes com indicação de tratamento, 1149 receberam terapia específica. Entre os pacientes tratados, havia ainda 80 pacientes que receberam tratamento apesar de não terem indicação de acordo com os critérios do IWCLL. Esse grupo de pacientes apresentou SG inferior quando comparado aos pacientes que foram tratados do grupo de critérios liberais e do grupo de critérios restritivos (82% vs. 85% vs. 68%, respectivamente). Adicionalmente, uma parte significativa desses pacientes foi submetida a esquemas inadequados, como COP ou CHOP, reforçando a percepção de possíveis lacunas da educação médica no manejo da doença. A mediana do tempo para o primeiro tratamento (TPT1) foi de 3,4 meses (variação: 1 – 231). Ao se analisar o tempo que os pacientes aguardaram desde a indicação de tratamento até o início do mesmo, os pacientes que aguardaram mais de 18 meses apresentaram uma SG superior quando comparado aos que aguardaram menos de 18 meses (82% vs. 69%, respectivamente, com p=0,004). Entre os pacientes do grupo de critérios liberais, a SG foi significativamente pior nos pacientes tratados (83%) em comparação com os pacientes não tratados (97%, P <0,0001). E após análise multivariada, o fato de receber tratamento foi fator de risco independente para pior sobrevida global nesse grupo de critérios liberais. Conclusão: Esses dados de mundo real sugerem que uma abordagem conservadora na indicação do tratamento de primeira linha para LLC é segura e associada à melhora da sobrevida, possivelmente pela mitigação de toxicidades e complicações relacionadas ao tratamento, como infecções, toxicidades e seleção clonal. Além disso, esta estratégia pode conservar recursos, melhorando o acesso aos medicamentos para um maior número de pacientes com clara necessidade de tratamento, especialmente em países com limitação de recursos.
Introduction: Chronic lymphocytic leukemia (CLL) presents various treatment indications, with some patients receiving immediate treatment while others remain under observation. In 2008, the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) established criteria for treatment indications, widely adopted in clinical practice and clinical trials. The Brazilian Group of CLL (BGCLL) has been evaluating a more conservative approach in the indication and initiation of treatment carried out in multiple centers. This approach eschews predefined cut-off levels for cytopenias and refrains from considering progressive lymphocytosis, extranodal involvement, or disease-related symptoms as isolated criteria. However, the safety and potential divergent outcomes of this conservative strategy in comparison to the more stringent IWCLL criteria had not yet been tested. Objective: To compare the outcomes of patients with CLL registered in the Brazilian Registry of CLL (BRCLL) without indication of treatment according to the BGCLL criteria, who were treated or not based on the center's decision. Patients and Methods: We performed a retrospective analysis of patients with CLL registered in the BRCLL who were followed between January 2009 and July 2023, meeting the minimum data availability criteria for analysis and following the IWCLL inclusion guidelines. We established two interest groups: 1) liberal criteria group - broader and more inclusive criteria defined by the IWCLL; 2) restrictive criteria group - more restricted and selective criteria defined by the BGCLL, indicating a more cautious approach to initiating treatment. Results/Discussion: A total of 2,511 patients from 41 centers were included. Among them, 1,404 patients (56%) met the treatment indication criteria set by IWCLL, while only 788 patients (31%) met the more conservative criteria established by BGCLL. Predominant indications for treatment initiation in the liberal criteria group included cytopenias in 771 patients (55%), symptomatic lymphadenopathy in 330 patients (24%), and disease-related constitutional symptoms in 112 patients (8%). In the restrictive criteria group, common indications for treatment initiation comprised cytopenias in 413 patients (52%), symptomatic lymphadenopathy in 316 patients (40%), and autoimmune complications in 22 patients (3%). After a median follow-up of 58 months, the 5-year overall survival (OS) was 82%. The group of patients whose treatment indication were cytopenias demonstrated inferior OS compared to those with other indications. Of the total of 1,404 patients who had an indication according to the IWCLL, 1,149 received therapy. Among the treated patients, there were also 80 patients who underwent treatment despite lacking indications as per IWCLL criteria. This subset of patients displayed a lower OS when compared with those of liberal criteria group and restrictive criteria group (82% vs. 85% vs. 68%, respectively). Additionally, a significant portion of these patients treated without indication received inappropriate regimens, such as COP or CHOP, highlighting perceived medical education gaps in the comprehension of disease management. Median time to first treatment (TTT1) was 3.4 months (range: 1 – 231). Upon evaluating the duration between the treatment indication and its initiation, patients who waited over 18 months exhibited a superior OS in contrast to those with a waiting period of fewer than 18 months (82% vs. 69%, respectively; p=0.004). Among patients of the liberal criteria group, OS was significantly worse in treated patients (83%) as compared with untreated patients (97%, P < 0.0001). After multivariate analysis, receiving treatment was an independent risk factor for OS in liberal criteria group. Conclusion: These real-world data suggest that a conservative approach to first-line treatment for CLL is not only safe but also linked to enhanced survival, potentially by reducing treatment-related toxicities and complications, such as infections, toxicities and clonal selection. Additionally, this strategy holds the potential to save resources improving access to medications for a larger pool of patients with a clear need for treatment, particularly in resource-limited countries.
Introduction: Chronic lymphocytic leukemia (CLL) presents various treatment indications, with some patients receiving immediate treatment while others remain under observation. In 2008, the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) established criteria for treatment indications, widely adopted in clinical practice and clinical trials. The Brazilian Group of CLL (BGCLL) has been evaluating a more conservative approach in the indication and initiation of treatment carried out in multiple centers. This approach eschews predefined cut-off levels for cytopenias and refrains from considering progressive lymphocytosis, extranodal involvement, or disease-related symptoms as isolated criteria. However, the safety and potential divergent outcomes of this conservative strategy in comparison to the more stringent IWCLL criteria had not yet been tested. Objective: To compare the outcomes of patients with CLL registered in the Brazilian Registry of CLL (BRCLL) without indication of treatment according to the BGCLL criteria, who were treated or not based on the center's decision. Patients and Methods: We performed a retrospective analysis of patients with CLL registered in the BRCLL who were followed between January 2009 and July 2023, meeting the minimum data availability criteria for analysis and following the IWCLL inclusion guidelines. We established two interest groups: 1) liberal criteria group - broader and more inclusive criteria defined by the IWCLL; 2) restrictive criteria group - more restricted and selective criteria defined by the BGCLL, indicating a more cautious approach to initiating treatment. Results/Discussion: A total of 2,511 patients from 41 centers were included. Among them, 1,404 patients (56%) met the treatment indication criteria set by IWCLL, while only 788 patients (31%) met the more conservative criteria established by BGCLL. Predominant indications for treatment initiation in the liberal criteria group included cytopenias in 771 patients (55%), symptomatic lymphadenopathy in 330 patients (24%), and disease-related constitutional symptoms in 112 patients (8%). In the restrictive criteria group, common indications for treatment initiation comprised cytopenias in 413 patients (52%), symptomatic lymphadenopathy in 316 patients (40%), and autoimmune complications in 22 patients (3%). After a median follow-up of 58 months, the 5-year overall survival (OS) was 82%. The group of patients whose treatment indication were cytopenias demonstrated inferior OS compared to those with other indications. Of the total of 1,404 patients who had an indication according to the IWCLL, 1,149 received therapy. Among the treated patients, there were also 80 patients who underwent treatment despite lacking indications as per IWCLL criteria. This subset of patients displayed a lower OS when compared with those of liberal criteria group and restrictive criteria group (82% vs. 85% vs. 68%, respectively). Additionally, a significant portion of these patients treated without indication received inappropriate regimens, such as COP or CHOP, highlighting perceived medical education gaps in the comprehension of disease management. Median time to first treatment (TTT1) was 3.4 months (range: 1 – 231). Upon evaluating the duration between the treatment indication and its initiation, patients who waited over 18 months exhibited a superior OS in contrast to those with a waiting period of fewer than 18 months (82% vs. 69%, respectively; p=0.004). Among patients of the liberal criteria group, OS was significantly worse in treated patients (83%) as compared with untreated patients (97%, P < 0.0001). After multivariate analysis, receiving treatment was an independent risk factor for OS in liberal criteria group. Conclusion: These real-world data suggest that a conservative approach to first-line treatment for CLL is not only safe but also linked to enhanced survival, potentially by reducing treatment-related toxicities and complications, such as infections, toxicities and clonal selection. Additionally, this strategy holds the potential to save resources improving access to medications for a larger pool of patients with a clear need for treatment, particularly in resource-limited countries.
Descrição
Citação
MARQUES, Fernanda de Morais. Análise dos desfechos clínicos da abordagem conservadora nas indicações de tratamento na leucemia linfocítica crônica. 2024. 128 f. Tese (Doutorado em Hematologia) - Escola Paulista de Medicina, Universidade Federal de São Pauli (UNIFESP). São Paulo, 2024