Outcome of adolescents and young adults with acute lymphoblastic leukemia in a single center in Brazil

ABSTRACT Introduction: Acute lymphoblastic leukemia (ALL) presents a poor prognosis in adults. The adoption of pediatric protocols has been changing this scenario, especially for adolescents and young adults (AYA). Objective and method: We aimed to evaluate a consecutive series of patients treated at the State Institute of Hematology of Rio de Janeiro between 2012 and 2020, focusing on the AYA subgroup. Result: The B-ALL was the most frequent subtype (81.6%) and AYA, the predominant age group (57.7%). The median overall survival (OS) was 9.4 months. High early mortality was observed and sepsis was the main cause of death. Better OS results were noted in AYA, in comparison to over 39y (13.3 × 6.2 months, respectively), the Berlin-Frankfurt-Münster (BFM) being the protocol of choice in this group. Conclusion: The use of the pediatric protocol seems to improve the OS of AYA, however, high rates of deaths from infection were observed, demonstrating the need for advances in the Brazilian public system clinical support.

IKZF1 deletions associate with CRLF2 overexpression leading to a poor prognosis in B-cell precursor acute lymphoblastic leukaemia.

Cytokine Receptor-Like Factor 2 (CRLF2) overexpression occurs in 5-15% of B-cell precursor acute lymphoblastic leukaemia (B-ALL). In ∼50% of these cases, the mechanisms underlying this dysregulation are unknown. IKAROS Family Zinc Finger 1 (IKZF1) is a possible candidate to play a role in this dysregulation since it binds to the CRLF2 promoter region and suppresses its expression. We hypothesised that IKZF1 loss of function, caused by deletions or its short isoforms expression, could be associated with CRLF2 overexpression in B-ALL. A total of 131 paediatric and adult patients and 7 B-ALL cell lines were analysed to investigate the presence of IKZF1 deletions and its splicing isoforms expression levels, the presence of CRLF2 rearrangements or mutations, CRLF2 expression and JAK2 mutations. Overall survival analyses were performed according to the CRLF2 and IKZF1 subgroups. Our analyses showed that 25.2% of patients exhibited CRLF2 overexpression (CRLF2-high). CRLF2-high was associated with the presence of IKZF1 deletions (IKZF1del, p = 0.001), particularly with those resulting in dominant-negative isoforms (p = 0.006). Moreover, CRLF2 expression was higher in paediatric samples with high loads of the short isoform IK4 (p = 0.011). It was also associated with the occurrence of the IKZF1 plus subgroup (p = 0.004). Furthermore, patients with CRLF2-high/IKZF1del had a poorer prognosis in the RELLA05 protocol (p = 0.067, 36.1 months, 95%CI 0.0-85.9) and adult cohort (p = 0.094, 29.7 months, 95%CI 11.8-47.5). In this study, we show that IKZF1 status is associated with CRLF2-high and dismal outcomes in B-ALL patients regardless of age.

IKZF1 deletion and co-occurrence with other aberrations in a child with chronic myeloid leukemia progressing to acute lymphoblastic leukemia.

Chronic myeloid leukemia (CML) is a rare disease in children. Different from that in adults, childhood CML involves transformative events occurring over a short time period. CML transformation to lymphoid blast phase (BP) is associated with copy number abnormalities, characteristic of BCR-ABL1 positive acute lymphoblastic leukemia, but not of CML in the chronic phase. Here, we present an unusual case of CML progressing to BP in a 1.6-year-old child, harboring IKZF1, PAX5, CDKN2A, and ETV6 deletions at diagnosis. It remains to be addressed whether distinct mechanisms might account for CML pathogenesis in early childhood.

Intragenic amplification of PAX5: a novel subgroup in B-cell precursor acute lymphoblastic leukemia?

Intragenic PAX5 amplification defines a novel, relapse-prone subtype of B-cell precursor acute lymphoblastic leukemia with a poor outcome.

Identificação de alterações genéticas submicroscópicas em leucemias linfoblásticas pediátricas

Introdução:Estudos de associação genômica identificaram uma alta frequência de alterações de número de cópias gênicas (CNAs) em leucemia linfoblástica aguda de células precursoras B (LLA-CPB) afetando genes envolvidos em processos importantes na hematopoiese. Mutações em IKZF1, CRLF2e BTG1foram associadas com sobrevida desfavorável em um subgrupo de LLA-CPB. Nossos objetivos foram identificar as alterações nos genes IKZF1, PAX5, CDKN2A/2B, BTG1, EBF1, ETV6, RB1, CRLF2, CSF2RA e IL3RA e avaliar o impacto no prognóstico das LLAs-CPB no Brasil. Metodologia:Foram incluídos pacientes com LLA-CPB (idade ≤18 anos) no período de 2004-2011. Os critérios do National Cancer Institute(NCI) foram adotados para a definição dos grupos de riscos (risco padrão e alto risco). Os dados clínicos e demográficos dos pacientes foram coletados tanto ao diagnóstico como na busca de sobrevida. A caracterização da LLA-CPB foi realizada através de imunofenotipagem e testes citogenético-moleculares. As extrações de DNA foram realizadas em amostras com ≥50% de blastos, obtidas para diagnóstico antes de qualquer procedimento terapêutico. As CNAs foram identificadas através multiplexligation-dependent probe amplification (SALSA MLPA P335-A4). Foi utilizado o teste de Chi squarepara comparação das alterações com as características clínicas e moleculares. As análises de sobrevida (SG) foram realizadas pelo método de Kaplan-Meier e diferenças entre os grupos foram comparadas pelo teste de log-rank. Análises multivariadas foram realizadas através do modelo Cox regression. Resultados: Deleção/amplificação em pelo menos um gene foram identificadas em 84,3% do total (n=274) de casos analisados. Foi observada associação entre idades ≥1-10 anos e a presença de deleções em IKZF1, CDKN2A/B, ETV6,IL3RA e CSF2RA (p<0,05)...

ntroduction: Genome wide studies have identified a high frequency of copy number alterations (CNAs) in B cell precursor acute lymphoblastic leukemia (BCP-ALL) in genes involved in key process of hematopoiesis. Mutations in IKZF1, CRLF2 and BTG1 were associated with poor survival in subgroups of BCP-ALL. We aimed to identify alterations in IKZF1, PAX5, CDKN2A/2B,BTG1, EBF1, ETV6, RB1, CRLF2, CSF2RA andIL3RA, and to evaluate their prognostic impact in BCP-ALL in Brazil. Methodology: Patients with BCP-ALL (age ≤18years) were included from 2004-2011. The risk classification was based on the National Cancer Institute (NCI) criteria. Clinical and demographic data of patients were collected either at diagnosis or at follow-up search. CP-ALL characterization were performed through immunophenotyping and cytogenetic-molecular tests. DNA extraction was done using in samples with ≥50% blast, obtained previously to any treatment. CNAs were identified through multiplex ligation-dependent probe amplification (SALSA MLPA P335-A4). The χ2 test was used to comparethe alterations with the clinical-molecular characteristics. The overall survival (OS) was performed by the Kaplan-Meier method and the differences between the groups were compared by log-rank test. Multivariate analysis were realized through Cox regression model. Results: Deletions/amplifications in at least one gene were identified in 84.3% of total (n=274) analyzed cases. There was an association between age range ≥1-10 years, and the presence of IKZF1, CDKN2A/2B, ETV6, IL3RA and CSF2RA deletions (p<0.05). Among cases categorized as high risk, 61% showed more than 3 genes with deletions, whereas 53% of standard risk cases had no deletions. Based in cytogenetic subgroup, BCP-ALL ETV6-RUNX1 showed more deletions than others subgroups. ETV6 deletions were associated with the presence of ETV6-RUNX1 fusion (p<0.05). TCF3-PBX1 cases showed a high frequency of deletions in RB1, and absence of deletions in IKZF1 and genes...