Influência das características clínicas e biológicas no prognóstico de lactentes com leucemia linfocítica aguda: proposta de um escore preditivo com inclusão de polimorfismo genético / Clinical and biologic characteristics on the prognosis of infants with acute lymphoblastic leukemia. proposal of a predictive score including genetic polymorphism

RESUMO

Leucemias agudas da infância formam um grupo heterogêneo de doenças hematológicas malignas. Revisando-se sua epidemiologia descritiva e analítica, pode-se enfatizar que além de fatores clínicos e laboratoriais, aspectos biológicos, como subtipos morfológicos, achados citogenéticos e marcadores moleculares, também interferem de maneira significativa na sobrevida dos pacientes. De forma geral, leucemias em lactentes têm características epidemiológicas, biológicas e clínicas distintas em relação aos pacientes mais velhos... Objetivos: Analisar as características clínicas e biológicas de pacientes lactentes (< 24 meses de vida), identificar fatores prognósticos clínicos e biológicos, construir escore prognóstico e estimar a probabilidade de sobrevida global (SG) para o grupo estudado. Casuística e métodos: Retrospectivamente, foram analisadas as informações clínicas e biológicas de 249 pacientes com leucemia linfóide aguda (LLA), menores de 24 meses de idade e inscritos na Divisão de Medicina Experimental, Centro de Pesquisa (MedEx, CPq) do Instituto Nacional de Câncer, Rio de Janeiro, entre janeiro de 1990 e dezembro de 2003. Resultados: O grupo apresentou as seguintes características discreta predominância do sexo feminino; 74% de raça branca; mediana de idade de 14,1 meses (57% eram lactentes ≤ 14 meses de idade); para pacientes ≤ 14 meses, 57% tinham entre 6 e 14 meses e 26% tinham ≤ 3 meses; 55% dos pacientes apresentavam contagem leucocitária menor que 50x109/l; 54% apresentavam CD10 negativo; 50% dos casos tinham imunofenótipo B comum e 42% eram pró-B ... Conclusões: Na casuística estudada, os resultados obtidos mostraram que a LLA em pacientes lactentes origina-se de células mais imaturas e preditivas de doença mais agressiva. A continuação do estudo das características biológicas de forma contínua e ativa se faz necessária em nosso país, assim como o estabelecimento de tratamentos padronizados e feitos cooperativamente.

ABSTRACT

Childhood acute leukemias are a heterogeneous group of malignant hematologic diseases. Reviewing the descriptive and analytical epidemiology of them, it can be observed that besides clinical and laboratory factors, biological aspects, such as morphological subtypes, cytogenetic features, and molecular markers, interfere significantly on the survival of patients. In a general view, leukemia in infants has different epidemiological, biological, and clinical characteristics compared to older patients. The majority of cases present with high tumor load at diagnosis (high white blood cell count on peripheral blood, hepatosplenomegaly, and CNS involvement), with leukemic cells being phenotypically early B-cell precursor (CD34+, CD19+), lacking the CD10 antigen, while often expressing myeloid precursor antigens (CD15/CD65s) and increased myeloperoxidase expression. It is known that the combination of factors presented at diagnosis allows the identification of different risk groups, defining each patient prognosis and consequently determining the best therapeutic approach. Objectives: To analyze clinical and biological characteristics in infants (< 24 month year old) in order to identify clinical and biological prognostic factors, to prepare a prognostic score, and to estimate overall survival (OS) to the cohort. Patients and methods: Two hundred and forty-nine acute lymphoblastic leukemia (ALL) patients were retrospectively analyzed according to their clinical and biological information. They were younger than 24 months and enrolled at the Divisão de Medicina Experimental, Centro de Pesquisa (MedEx, CPq) of Instituto Nacional de Câncer, Rio de Janeiro, from January 1990 to December 2003. Results: The following characteristics were found small predominance of females; 74% of Caucasian with median age of 14.1 months (57% younger than 14 months); among patients younger than 14 months, 57% were 6 to 14 months old and 26% were younger than 3 months old; 55% presented white blood count < 50x109/l, negative CD10; 50% common B immunophenotype and 42% early B immunophenotype according to the EGIL classification; MTHFRC677T or MTHFRT677T genotypes were more frequent than MTHFRC677C; MTHFRA1298A was more frequent than genotypes involving C allele and 81% of patients received treatment according to GBTLI protocols. Patients younger than 14 months old had statistically significant association with antigen CD10, EGIL early B-cell classification, and presence of MLL gene rearrangements. MLL rearrangements presented significantly association with negative CD10 and EGIL early B-cell classification; 93% of EGIL early B-cell classification patients presented negative CD10. The entire group presented 45% 5-year overall survival and the worst survival rates were observed in patients younger than 14 months, patients with white blood count > 100x109/l at diagnosis, negative CD10, those with EGIL early B-cell classification, and patients who were treated with a protocol different from GBTLI. When only patients younger than 14 months were analyzed, the OS was worse in those with white blood count > 100x109/l, negative CD10, patients with EGIL early B-cell classification, and those who presented with MTHFRT677T or MTHFRC677T genotype. For patients under 14 months, the prognostic score model identified the following characteristics as factors that can influence overall survival statistically significant high white blood cells, negative CD10, pro-B EGIL immunophenotype and MTHFRC677T or MTHFRT677T genotype. Conclusions: Results have shown that on this cohort ALL originates from very immature cells and can predict an aggressive disease. It is imperative to continue studying its biological characteristics in our country as well as to establish standardized and co-operative treatments.