Molecular characterization of V(D)J rearrangements in immature acute leukemias.

Early T-cell Precursor Acute Lymphoblastic Leukemia (ETP-ALL), T-Lymphoid/Myeloid Mixed Phenotype Acute Leukemia (T/M-MPAL), and Acute Myeloid Leukemia with minimal differentiation (AML-M0) are immature acute leukemias (AL) that present overlapping T-cell lymphoid and myeloid features at different degrees, with impact to disease classification. An interesting strategy to assess lymphoid lineage commitment and maturation is the analysis of V(D)J gene segment recombination, which can be applied to investigate leukemic cells in immature AL. Herein, we revisited 19 ETP-ALL, 8 T/M-MPAL, and 12 AML-M0 pediatric patients to characterize V(D)J rearrangement (V(D)J-r) profiles associated with other somatic alterations. V(D)J-r were identified in 74 %, 25 %, and 25 % of ETP-ALL, T/M-MPAL, and AML-M0, respectively. Forty-six percent of ETP-ALL harbored ≥ 3 V(D)J-r, while there was no more than one V(D)J-r per patient in AML-M0 and T/M-MPAL. TCRD was the most rearranged locus in ETPALL, but it was not rearranged in other AL. In ETP-ALL, N/KRAS mutations were associated with absence of V(D)J-r, while NF1 deletion was most frequent in patients with ≥ 3 V(D)J-r. Relapse and death occurred mainly in patients harboring one or no rearranged locus. Molecular characterization of V(D)J-r in our cohort indicates a distinct profile of ETP-ALL, compared to T/M-MPAL and AML-M0. Our findings also suggest that the clinical outcome of ETP-ALL patients may be affected by blast cell maturity, inferred from the number of rearranged TCR loci.

Acute promyelocytic leukemia in a long-standing HIV-positive patient: Case report and literature review.

The use of antiretroviral therapy has drastically improved the life quality and prognosis of people living with the human immunodeficiency virus (HIV). The risk of acute myeloid leukemia (AML) currently does not appear to be significantly increased compared to the general population. Acute promyelocytic leukemia (APL), infrequent in people with HIV, is a distinct subtype of AML with unique molecular pathogenesis, clinical manifestations, and treatment. Herein we describe a fatal case of APL hypogranular variant in an HIV-positive patient presenting with hyperleukocytosis. Also, we conducted a literature review of the ten cases reported so far.

Preventing treatment abandonment for children with solid tumors: A single-center experience in Brazil.

BACKGROUND: High rates of treatment abandonment have been considered one of the major limitations to achieving high cure rates of childhood cancer in developing countries. The aims of this study were to report the prevalence and factors associated with treatment abandonment for children diagnosed with solid tumors in one reference center in Brazil and to describe effective strategies to prevent it. PROCEDURES: A retrospective review was conducted using data from 1139 children (0-18 years) treated for solid tumors at the Brazilian National Cancer Institute, during the period between January 2012 and December 2017. Treatment abandonment was defined as recommended by the International Society of Pediatric Oncology. The impact of implementing a patient-tracking system was evaluated. Descriptive statistics were used to analyze patient characteristics. Chi-square test was used for statistical analysis, with the significance level <0.05. RESULTS: Of 1139 patients, 1.66% refused or abandoned treatment. Although from 2012 to 2013 there was an increase in the abandonment rate, it then decreased by 63.8% from 2013 to 2017 (2.5% to 0.9%). In the multivariate model, only retinoblastoma diagnosis was associated with abandonment (odds ratio = 5.0; 95% confidence interval, 1.2-20.4; P = 0.025). In our cohort, abandonment rates were not associated with increased death. CONCLUSION: Monitoring missed appointments, and early interventions to address issues associated with providing resources to help families during treatment were effective in achieving very low abandonment rates.

Mecanismos Moleculares subjacentes à Morte Precoce e à Resistência ao ATRA na Leucemia Promielocítica Aguda / [Molecular Mechanisms Underlying Early Death and Resistance to ATRA in Acute Promyelocytic Leukemia]

Apesar do sucesso da terapia com Ácido All-Trans Retinóico (ATRA) nos pacientes portadores de leucemia promielocítica aguda (LPA), ainda existem questões clínicas relevantes a serem solucionadas. A morte precoce é um evento que acomete até 30% dos pacientes recém-diagnosticados com LPA, assim como a recidiva da doença pode ser vista em cerca de » dos pacientes. Dessa forma, possíveis mecanismos moleculares subjacentes a esses eventos têm sido investigados. A presença da mutação FLT3-ITD ao diagnóstico parece estar relacionada à maior incidência de desfechos clínicos desfavoráveis, sobretudo morte precoce. Recentes trabalhos têm associado mutações no gene FLT3 à coagulopatia – principal causa de morte na indução nos pacientes com LPA. Todavia, a forte associação da mutação FLT3-ITD com valores mais altos de leucometria ao diagnóstico (≥ 10.000 x103/mm3) – classicamente um marcador de mau prognóstico – tem dificultado a análise precisa do papel preditivo da mutação FLT3-ITD nesta população. Adicionalmente, possíveis mecanismos de resistência celular ao processo de diferenciação induzido pelo ATRA poderiam estar relacionados à pior evolução clínica. Escassos estudos têm apontado que mutações pontuais no domínio de ligação do ATRA no gene RARα detectadas no momento de recaída estão relacionadas à resistência secundária ao ATRA. Entretanto, essas mutações não foram amplamente investigadas em casos de pacientes que evoluíram com morte precoce – como possível causa de resistência primária ao ATRA. Além disso, o valor preditivo da carga do transcrito PML-RARα detectada ao diagnóstico e em diferentes fases do tratamento ainda é incerto na evolução clínica desses pacientes, sobretudo na população pediátrica...

Despite the success of therapy with All-Trans Retinoic Acid (ATRA) in patientswith acute promyelocytic leukemia (APL), there are still relevant clinical issues to be resolved. Early death is an event that affects up to 30% of newly diagnosed patients with APL, as well as the recurrence of the disease can be seen in about a quarter of patients. Therefore, molecular mechanisms underlying these events have beeninvestigated. The presence of the FLT3-ITD mutation at diagnosis appears to berelated to a higher incidence of adverse clinical outcomes, especially early death. Recent studies have associated mutations in the FLT3 gene with coagulopathy - leading cause of death in the induction in patients with APL. However, the strong association of FLT3-ITD mutation with higher values of white blood cell count at diagnosis (≥ 10,000 x103 / mm3) - classically a worse prognostic marker - has made itdifficult to accurately analyze the predictive role of FLT3-ITD mutation in this population. In addition, possible mechanisms of resistance to the process of differentiation induced by ATRA could be related to worse clinical outcome. Few studies have shown that mutations in the ATRA-binding domain in the RARα gene detected in relapse time are related to secondary resistance to ATRA. However, these changes have not been widely investigated in cases of patients who developed early death - as a possible cause of primary resistance to ATRA. In addition, the predictive value of the load of PML-RARα transcript detected at diagnosis and atdifferent stages of treatment is uncertain in outcome of these patients, especially in children...