Pediatric Acute Promyelocytic Leukemia in Brazil: Epidemiology, Molecular Features, and Importance of GST-Theta 1 in Chemotherapy Response and Outcome

Abstract

Background. Previous studies have suggested a variation in the incidence of acute promyelocytic leukemia (APL) among geographic regions with relatively higher percentages within the Latin American population. We aimed to describe the population burden of pediatric APL (p-APL) in Brazil assessing the incidence rates according to a hospital-based and population-based cancer (PBCR) registries. We also explored mutations in genes of the RAS pathway and the association of polymorphisms in genes of glutathione S-transferases (GSTs) with outcome. Our goal was to provide insights into the distribution of clinical-demographic data and the molecular epidemiology characteristics associated with APL outcome. Methods. One hundred and sixty-four p-APL cases (<19 years old) were identified from a dataset of a hospital-based registry based at a leukemia diagnostic central reference laboratory (2002-2018) and from 15 PBCR (2002-2009). Diagnostic criteria included morphological, immunophenotypic, and cytogenetic-molecular features. The PML-RARafusion gene was detected by FISH and/or RT-PCR. Additionally, mutations in FLT3 [D835 and internal tandem duplications (ITD)], KRAS, NRAS, and PTPN11 mutations were analyzed. We also evaluated the risk association of pharmacogenetically important GST deletion polymorphisms (GSTT1 and GSTM1) by multiplex-PCR, in a case-case analysis to test the effect of genetic susceptibility on overall survival (OS). Patients were treated with the inclusion of all-trans retinoic acid in chemotherapy with anthracyclines and cytarabine. Kaplan-Meier survival analysis was used to calculate the 5-year probabilities of OS (pOS), and estimated survival values were compared using the log-rank test. Cox proportional-hazard regression model estimated the hazard ratio (HR) and 95% confidence intervals (CI). All p-values were two-sided using significance level of 0.05. Results. From the hospital-based registry, APL patients represented 17.6% of the cohort (164 out of 933 acute myeloid leukemia cases), while in the PBCR, they represented 4.4% (35 out of 805 acute myeloid leukemia cases registered). The age-adjusted incidence rate was 0.32 per million persons during 2000-2009 based on PBCR. According to the hospital-based registry, we found similar distribution of patients among age ranges >2-10 and >10-21 years old (43.3% and 51.8%, respectively) and sex. RAS mutations were observed in 51.7% of APLs, including FLT3 (43.0%), NRAS (6.5%), and KRAS (2.2%). Variants in PTPN11 were silent amino acid substitutions (rs61736914; 4.9%). We observed a statistically significant association between FLT3 mutations and high white blood cell count at diagnosis (>10x109/L; 72.6%), low platelet count (<40×109/L; 83.0%), and the PML-RARa breakpoint cluster region 3 (90.5%). Death in the first ten days after diagnosis (early death) affected 17.5% (24/137) patients and these cases were excluded from the survival analysis. The mean of overall survival was 45.1 months (95% CI 40.1-50.1 months; pOS 66.9±5.8%). Univariate analysis did not show an association between variables and OS rates, except for APL patients carrying the GSTT1 polymorphism. GSTT1 null genotype conferred adverse prognosis compared to wild-type genotype (pOS 48.2±13.4% and 79.0±6.3%, p=0.024; hazard ratio 2.6, 95% CI 1.1-6.2, p=0.030; Figure 1). Conclusions. APL represented 17.6% of acute myeloid leukemia in our cohort of Latino patients, which is a higher proportion compared to Northern European countries and the United States (5-10%). GSTT1 polymorphism modulated outcome, suggesting that lower enzyme activity may impact response to therapy. Decreasing early death and inclusion of GSTT1 polymorphism in therapeutic protocols for chemotherapy dose modulation may allow patients to reach the same overall survival observed in the United States (>70%). Disclosures No relevant conflicts of interest to declare.

Acute Promyelocytic Leukemia in Children Cancer Hospital Egypt

“…A total of 62 pediatric patients with ages less than 18, had APL out of 823 patients of AML (7.5%) were evaluable for our study and treated at Children Cancer Hospital Egypt, from July 2012 till the end of December 2019. In FG Andrade • 2021, 163 (17.5%) patients who had APL were evaluated out of 931 AML cases [11]. The median age of pediatric APL cases is from 9 to 12 years [12,13] agreed with our result as the median age was 9.9 years old, Thirty-one (50%) patients were more than 10 years old.…”

Pediatric Acute Promyelocytic Leukemia: A Rare Case Report

“…Further family history and exposure to various agents via occupation or other risk factors should be studied to explain the epidemiological variation. [5] Verma et al…”

Update on acute promyelocytic leukemia in the pediatric population

“…163 cases of APL were characterized (17.5 %) of a total of 931 cases of AML that presented a median age at diagnosis of 10.1 years. 25 In both cases, they found a higher incidence in southern Brazil, compared to the other geographic regions of the country; which could be associated with exposure to environmental factors, since the main economic activities in that area are agriculture and the oil and gas industry. 25 Aksu et al 8 reported an incidence of 20.5% among a total of 83 patients under 18 years of age who were diagnosed with AML in a hospital in Turkey, between January 2006 and December 2016, with a median of age at diagnosis of 13.5 years.…”

“…25 In both cases, they found a higher incidence in southern Brazil, compared to the other geographic regions of the country; which could be associated with exposure to environmental factors, since the main economic activities in that area are agriculture and the oil and gas industry. 25 Aksu et al 8 reported an incidence of 20.5% among a total of 83 patients under 18 years of age who were diagnosed with AML in a hospital in Turkey, between January 2006 and December 2016, with a median of age at diagnosis of 13.5 years. Czogala et al 9 observed that in Poland 41 children under 18 years of age were diagnosed with APL out of a total of 627 patients in that age range who were diagnosed with AML in the period between January 2005 and December 2018, for an incidence of 6.5%.…”

“…Andrade et al 25 obtained incidence data in the Brazilian population between 0 and 19 years of age from two different sources. The first was extracted from the databases of 15 Population-Based Cancer Registries during the period 2000-2009 and resulted in a 4.3% incidence of APL among 805 children and adolescents who were diagnosed with AML.…”