Impacto da variação de fatores de estratificação de risco entre os protocolos de tratamento de leucemias linfoides agudas da infância

Introdução: O tratamento da Leucemia Linfoide Aguda (LLA) pediátrica é uma das terapias mais complexas dentre os programas terapêuticos contra o câncer. As crianças com LLA são tratadas de acordo com a estratificação em grupos de risco afim de que crianças com características clínicas e biológicas favoráveis recebam uma terapia menos tóxica, enquanto que uma terapia mais agressiva seja reservada aos pacientes com maior risco de recaída e com menor probabilidade de sobrevida a longo prazo. Objetivos: Analisar a concordância entre as estratificações dos grupos de riscos em pacientes classificados pelos diferentes protocolos utilizados para tratamento da LLA da infância em uma instituição de referência no sul do Brasil e avaliar a influência da Doença Residual Mínima (DRM) por citometria de fluxo na análise dessas classificações de risco. Metodologia: Estudo transversal, descritivo e retrospectivo a partir da revisão de prontuários dos pacientes com idade entre 1 e 18 anos portadores de LLA B atendidos no HCPA a partir de janeiro de 2013 até abril de 2017. Todos os pacientes foram estratificados conforme as classificações de risco dos protocolos mais utilizados em instituições brasileiras, que são a do grupo Berlim-Frankfurt-Münster (BFM) e a do Grupo Cooperativo Brasileiro para Tratamento da LLA (GBTLI). A concordância entre as classificações de risco de cada protocolo foi realizada através do coeficiente Kappa. Resultados: Foram analisados 75 pacientes. A concordância entre as estratificações de risco pelos protocolos GBTLI 2009 e BFM 95 (K= 0,22; p= 0,003), GBTLI 2009 e IC-BFM 2002 (K= 0,24; p= 0,002) foi baixa, moderada entre GBTLI 2009 e IC-BFM 2009 (K= 0,44; p 10% com piores resultados. A classificação pelo protocolo brasileiro demostrou um número maior de pacientes estratificados como alto risco quando comparado a do grupo BFM. As taxas de sobrevidas global e livre de eventos estimadas em 4 anos, independentes do protocolo de tratamento, foram 68,6% e 66,6% respectivamente. Conclusões: Este estudo nos fornece inúmeros pontos para reflexão sobre o tratamento da leucemia em nosso país. Observamos uma maior porcentagem de pacientes classificados como alto risco em nossa realidade e uma menor sobrevida em relação à literatura internacional. Compreender o papel das ferramentas para estratificação de risco disponíveis pode ajudar a melhorar este desfecho.Introduction: The treatment of childhood acute lymphoid leukemia (ALL) is one of the most complex therapies among cancer treatment programs. Children with ALL are treated according to stratification into risk groups so that children with favorable clinical and biological characteristics receive less toxic therapy, whereas more aggressive therapy is reserved for patients with higher risk of relapse and with lower probability of long-term survival. Objectives: First, to analyze the agreement between the risk stratification in patients classified by the different protocols already used to treat childhood ALL in a reference institution in southern Brazil and, second to evaluate the influence of minimal residual disease (MRD) by FC in the analysis of these risk. Methods: A cross-sectional, descriptive and retrospective study was carried out based on the review of medical records of patients aged 1 to 18 years with B-ALL attended at the HCPA from January 2013 to April 2017. All patients were stratified according to the risk classifications of the protocols most used in Brazilian institutions, which are those of the Berlin-Frankfurt-Münster group (BFM) and the Grupo Cooperativo Brasileiro para Tratamento da LLA (GBTLI). The agreement between the risk classifications of each protocol was performed using the Kappa coefficient. Results: A total of 75 patients were analyzed. There was a low agreement between the risk stratification by protocols GBTLI 2009 and BFM 95 (K = 0.22, p = 0.003), GBTLI 2009 and IC-BFM 2002 (K = 0.24, p = 0.002), moderate between GBTLI 2009 and IC-BFM 2009 (K = 0.44, p 10% with worse results. Classification by the Brazilian protocol showed a greater number of patients stratified as high risk when compared to the BFM group. The global and event-free survival rates estimated at 4 years, independent of the treatment protocol, were 68.6% and 66.6%, respectively. Conclusions: This study provides us with numerous points for reflection on the treatment of leukemia in our country. We observed a higher percentage of patients classified as high risk in our reality and a lower survival rate than the international literature. Understanding the role of risk classifications tools available may help us to improve treatment outcomes

Are there regional variations in the presentation of childhood leukemia?

Introduction: Treatment of childhood acute lymphoblastic leukemia (ALL) is based on risk stratification. This study aimed to assess the agreement between risk group classifications in the different childhood ALL treatment protocols used in a referral hospital in southern Brazil. Methods: We retrospectively reviewed the medical records of patients aged 1 to 18 years with B-cell ALL treated at a hospital from January 2013 to April 2017. Agreement between risk classifications was assessed by the kappa coefficient. Results: Seventy-five patients were analyzed. There was poor agreement between risk stratification by GBTLI 2009 and BFM 95 protocols (kappa=0.22; p = 0.003) and by GBTLI 2009 and IC-BFM 2002 protocols (kappa=0.24; p = 0.002). Risk group distribution was 13.3% for low risk, 32.0% for intermediate risk, and 54.7% for high risk based on stratification by the GBTLI 2009 protocol, and 28.0% for low risk, 42.7% for intermediate risk, and 29.3% for high risk based on stratification by the IC-BFM 2002 protocol. Overall survival was 68.6%. Conclusion: This study provides numerous points to ponder about the treatment of leukemia in Brazil. The percentage of patients classified as high risk in our sample was higher than that reported in the international literature. This difference, however, had no impact on overall survival, which was shorter than that reported in the international literature

Influence of minimal residual disease by multiparametric flow cytometry at day 15 of induction in risk stratification of children with B-cell acute lymphoblastic leukemia treated at a referral hospital in southern Brazil

Background: The minimal residual disease (MRD) is the most important prognostic factor for acute lymphoblastic leukemia (ALL) in children. This study aimed to investigate the influence of detecting the MRD by the multiparametric flow cytometry (MFC) at day 15 (D15) of the induction on the analysis of the risk group classifications of the different childhood ALL treatment protocols used in a referral hospital in southern Brazil. Method: We retrospectively reviewed the medical records of patients with B-cell ALL, aged 1 to 18 years, treated at a hospital from January 2013 to April 2017. Main results: Seventy-five patients were analyzed. Regarding the MRD by the MFC at D15, the analyses showed statistical significance when the MRD was grouped into three categories, 10%, with the following distribution: 30.7%, 52.0%, and 17.3%, respectively. There was a significant association between D15 MRD-MFC 10% and the likelihood of dying or relapsing. The cumulative hazard ratio for the relapse of patients with D15 MRD-MFC 10% was 19.2%, 59.8%, and 80.1%, respectively. Conclusion: Our analysis suggests D15 MRD-MFC < 0.1% as a cut-off point for patients with more favorable outcomes and that the MRD at D15 in risk classifications is particularly useful for the stratification of patients with a more favorable prognosis

Epidemiological evaluation and survival of children with acute myeloid leukemia

Objective: This study aims to describe the epidemiological characteristics and survival rates of children with acute myeloid leukemia treated in hospitals in southern Brazil and compare them with international data. Methods: A multicenter cohort study was conducted with retrospective data collection of all new patients with acute myeloid leukemia under 18 treated at five referral centers in pediatric hematology-oncology in southern Brazil between January 2005 and December 2015. Results: Of the 149 patients with acute myeloid leukemia, 63.0% (n = 94) were male. The median age at diagnosis was 10.5 years (range 0-18 years) and 40.3% (n = 60) had a white blood cell count below 50,000/mm2. The most common Franco-American-British (FAB) subtype was M3 (n = 43, 28.9%). Nine (6.0%) patients had central nervous system disease. In M3 patients, overall survival (OS) was 69.2% and 3-year event-free survival was 67.7%; in non-M3 patients, these rates were 45.3% and 36.7%, respectively. In non-M3 patients, OS was significantly different between transplanted (61.8%) and non-transplanted (38.2%) patients (p = 0.031). Conclusions: These results show a higher prevalence of the Franco-American-British M3 subtype than that reported in the international literature, as well as a decreased OS compared with that of developed countries. Further multicenter Brazilian studies with a larger sample size are encouraged to better understand the characteristics of acute myeloid leukemia, and to improve the treatment and prognosis in this population

Follow our path with asparaginase activity : one technique, but diferent uses in clinical practice

Acute lymphoblastic leukemia is the most common childhood malignancy. One of the drugs used in the treatment is Asparaginase, and monitoring of its activity levels enables better outcomes. Since 2018, our laboratory has been working to establish a regular analysis of activity. This implementation allowed to qualify care by detecting silent inactivation and also establishing desensitization as a safe way to overcome the lack of Erwinia. We were able to monitor children aged 0 to 18 years who were being treated with PEG-ASNase. The activity was assessed on days 7 (90 samples) and 14 (52 samples) after ASNase infusions. 142 samples were analyzed. 95.7% reached an adequate activity level (≥ 0.1 IU/mL). Patients treated with ASNase can develop allergic reactions. With the activity monitoring, is possible to circumvent situations like these and implement desensitization protocols for patients who had clinical hypersensitivity without inactivation. Desensitization induces temporary unresponsiveness to drug antigens, allowing the patients to proceed with the prescribed chemotherapy. We have received samples from four patients being treated with different desensitization protocols. Patients tolerated the protocols well. Only one had a grade 2 reaction during the infusion and activity < 0.1 IU/mL, which resulted in the switch to Erwinia. The dose adaptation is a possible and more recent use of ASNase monitoring and we were able to confirm the feasibility of PEG-ASNase desensitization protocols

Influence of different asparaginase formulations in the prognosis of children with acute lymphocytic leukaemia in Brazil : a multicentre, retrospective controlled study

Our group recently showed that the (ASNase) formulation available in Brazil from 2017 to 2018 when used at the same dose and frequency as the formulation provided previously did not reach the activity considered therapeutic. Based on these, our goal was to assess the impact of these facts on the prognosis of children with ALL at different oncology centers. A multicentre retrospective observational study followed by a prospective followup. Patients aged >1 and <18 years in first-line treatment followed up at 10 referral centres, between 2014 and 2018 who received the formulation Leuginase were identified (Group B). For each patient, the centre registered 2 patients who received ASNase in the presentation of Aginasa exclusively (Group A). Data collection was registered using (Redcap ). A total of 419 patients were included; 282 in Group A and 137 in B. Group A had a 3-year OS and EFS of 91 8% and 84 8% respectively, while Group B had a 3-year OS of 83 8% (P = 0 003) and EFS of 76 1% (P = 0 008). There was an impact on 3-year OS and EFS of children who received a formulation. This result highlights the importance of evaluating ASNase and monitoring its activity