Prognostic implications of the ID1 expression in acute myeloid leukemia patients treated in a resource-constrained setting.

INTRODUCTION: The aberrant expression of the inhibitor of DNA binding (ID1) gene has been frequently associated with the leukemogenesis and prognostication acute myeloid leukemia (AML), although its clinical importance has never been investigated in patients treated outside well-controlled clinical trials. METHODS: Using quantitative real-time polymerase chain reaction, we investigated the role of the ID1 expression in the clinical outcomes of non-selected patients with acute myeloid leukemia treated in a real-life setting. RESULTS: Overall, 128 patients were enrolled. Patients with high ID1 expression had a lower 3-year overall survival (OS) rate of 9%, with the 95% confidence interval (95%CI) at 3 to 20%, compared to patients with a low ID1 expression (22%, 95%CI: 11 - 34%) (p = 0.037), although these findings did not retain significance after adjustment (hazard ratio (HR): 1.5, 95%CI: 0.98 - 2.28; p = 0.057). The ID1 expression had no impact on post-induction outcomes (disease-free survival, p = 0.648; cumulative incidence of relapse, p = 0.584). CONCLUSIONS: Although we are aware thar our data are confronted with many variables that cannot be fully controlled, including drug unavailability, risk-adapted treatment, comorbidities and the time from diagnosis to treatment initiation, we are firm believers that such an initiative can provide more realistic data on understudied populations, in particular those from low- and middle-income countries.

Screening for myeloid mutations in patients with myelodysplastic syndromes and AML with myelodysplasia-related changes

ABSTRACT Introduction: One of the most critical complications in myelodysplastic syndromes (MDS) is the progression to acute myeloid leukemia (AML). The dynamics of clonal evolution in MDS and how acquired mutations can be used as biomarkers to track disease progression remains under investigation. Objective and method: Herein, we investigated the frequency of common myeloid clonal mutations (FLT3, NPM1, JAK2, IDH1 and IDH2) in 88 patients with MDS and 35 AML patients with myelodysplasia-related changes, followed at a single reference center in northeastern Brazil. Results: Overall, 9/88 (10%) ofthe MDSpatients and 9/35 (26%) of the secondary AML patients had at least one mutation. While the JAK2 V617F mutation was the most frequent in the MDS patients, the FLT3, NPM1, IDH1 and IDH2 mutations were more frequently found in the secondary AML group. Furthermore, there was a higher frequency of FLT3, NPM1, IDH1 and IDH2 mutations in MDS patients classified as high-risk subtypes than in those of lower risk. Conclusion: Despite the limited sample size, our data suggest that mutations in FLT3, NPM1, IDH1 and IDH2 genes could be potential biomarkers to detect early disease progression in MDS.

Screening for myeloid mutations in patients with myelodysplastic syndromes and AML with myelodysplasia-related changes.

INTRODUCTION: One of the most critical complications in myelodysplastic syndromes (MDS) is the progression to acute myeloid leukemia (AML). The dynamics of clonal evolution in MDS and how acquired mutations can be used as biomarkers to track disease progression remains under investigation. OBJECTIVE AND METHOD: Herein, we investigated the frequency of common myeloid clonal mutations (FLT3, NPM1, JAK2, IDH1 and IDH2) in 88 patients with MDS and 35 AML patients with myelodysplasia-related changes, followed at a single reference center in northeastern Brazil. RESULTS: Overall, 9/88 (10%) of the MDS patients and 9/35 (26%) of the secondary AML patients had at least one mutation. While the JAK2 V617F mutation was the most frequent in the MDS patients, the FLT3, NPM1, IDH1 and IDH2 mutations were more frequently found in the secondary AML group. Furthermore, there was a higher frequency of FLT3, NPM1, IDH1 and IDH2 mutations in MDS patients classified as high-risk subtypes than in those of lower risk. CONCLUSION: Despite the limited sample size, our data suggest that mutations in FLT3, NPM1, IDH1 and IDH2 genes could be potential biomarkers to detect early disease progression in MDS.

Evaluation of the European LeukemiaNet recommendations for predicting outcomes of patients with acute myeloid leukemia treated in low- and middle-income countries (LMIC): A Brazilian experience.

BACKGROUND: Current results regarding treatment outcomes in acute myeloid leukemia (AML) point to significant differences between low- and middle-income countries (LMIC) and high-income countries (HIC). Excluding well-known socioeconomic issues, genetic markers important for prognosis have not been properly incorporated into the clinical practice so far and their usefulness outside of well-controlled clinical trials remain unknown. METHODS: Here, we assessed the clinical significance of the European LeukemiaNet (ELN) recommendations in 196 consecutive patients with AML in a real-life setting. All patients were younger than 60 years of age (49% male) and treated with conventional chemotherapy for induction and consolidation in three Brazilian Institutions that well represent Brazilian geographic and socioeconomic diversity. FINDINGS: Multivariable analysis showed that ELN recommendations had a slight association with complete remission achievement (odds ratio: 0.74, 95% confidence interval, CI: 0.53-1.01; P=0.06), but were independently associated with poor overall survival (OS) (hazard ratio, HR: 1.3, 95% CI: 1.1-1.54; P=0.002), disease-free survival (DFS) (HR: 1.42, 95% CI: 1.03-1.95; P=0.028) and event-free survival (EFS) (HR: 1.24, 95% CI: 1.06-1.47; P=0.007), considering initial leukocyte counts and age as confounders. ELN recommendations had no impact on cumulative incidence of relapse (P=0.09). INTERPRETATION: Our results suggest that within the context of LMIC, the prognostic markers recommended by ELN may be useful to predict patient's clinical outcomes; however, the OS, DFS and EFS were shorter than the reported in Europe and US for the respective risk groups.

Mannose-binding lectin 2 (MBL2) gene polymorphisms do not influence frequency of infections in chronic lymphocytic leukemia patients.

BACKGROUND: Infectious complications represent the main cause of morbidity and mortality in chronic lymphocytic leukemia. It has been reported that polymorphisms of the mannosebinding lectin 2 (MBL2) genes are correlated with MBL protein serum levels and, consequently, are associated with the development of infectious diseases. OBJECTIVE: The purpose of this study was to investigate the possible association between MBL2 gene polymorphisms and risk of infection in chronic lymphocytic leukemia patients. METHODS: Peripheral blood samples from 116 chronic lymphocytic leukemia patients were collected; after genomic DNA extraction, real time polymerase chain reaction was used to determine the polymorphisms of the promoter region and exon 1 of the MBL2 gene. RESULTS: A high frequency of Binet stage A (p-value = 0.005) and absence of splenomegaly (p-value = 0.002) were observed in patients with no infection; however, variant alleles/ genotypes and haplotypes of this gene had no impact on the risk of infection. CONCLUSION: To the authors' knowledge, this is the first study describing the association between MBL2 polymorphisms and infectious disease in chronic lymphocytic leukemia. Although it was not possible to demonstrate any influence of MBL2 polymorphisms as a genetic modulator of infection in chronic lymphocytic leukemia, the authors believe that the present data are clinically relevant and provide the basis for future studies.

Mannose-binding lectin 2 (MBL2) gene polymorphisms do not influence frequency of infections in chronic lymphocytic leukemia patients

Background: Infectious complications represent the main cause of morbidity and mortality in chronic lymphocytic leukemia. It has been reported that polymorphisms of the mannosebinding lectin 2 (MBL2) genes are correlated with MBL protein serum levels and, consequently, are associated with the development of infectious diseases. Objective: The purpose of this study was to investigate the possible association between MBL2 gene polymorphisms and risk of infection in chronic lymphocytic leukemia patients. Methods: Peripheral blood samples from 116 chronic lymphocytic leukemia patients were collected; after genomic DNA extraction, real time polymerase chain reaction was used to determine the polymorphisms of the promoter region and exon 1 of the MBL2 gene. Results: A high frequency of Binet stage A (p-value = 0.005) and absence of splenomegaly (p-value = 0.002) were observed in patients with no infection; however, variant alleles/ genotypes and haplotypes of this gene had no impact on the risk of infection. Conclusion: To the authors' knowledge, this is the first study describing the association between MBL2 polymorphisms and infectious disease in chronic lymphocytic leukemia. Although it was not possible to demonstrate any influence of MBL2 polymorphisms as a genetic modulator of infection in chronic lymphocytic leukemia, the authors believe that the present data are clinically relevant and provide the basis for future studies. .

JAK2 V617F mutation prevalence in myeloproliferative neoplasms in Pernambuco, Brazil.

BACKGROUND: The JAK2 V617F mutation is associated with three myeloproliferative neoplasms (MPNs): polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). It generates an unregulated clonal hematopoietic progenitor and leads to abnormal increased proliferation of one or more myeloid lineages. Subjects bearing this mutation may present more frequently with complications such as thrombosis and bleeding, and no specific treatment has yet been developed for BCR-ABL-negative JAK2 V617F-negative MPNs. AIMS: To determine the prevalence of JAK2 V617F in MPNs in Pernambuco, Brazil, and to compare it with previous studies. MATERIAL AND METHODS: 144 blood samples were collected at the Hospital of Hematology of the HEMOPE Foundation and were genotyped by polymerase chain reaction-restriction fragment length polymorphism with BsaXI enzymatic digestion. RESULTS AND DISCUSSION: 88% (46/52) of the patients with PV, 47% (39/81) with ET, and 77% (8/11) with PMF were positive for JAK2 V617F, while more than 35% of the individuals were JAK2 V617F-negative, confirming a high prevalence of this abnormality in MPNs, more frequently with a low mutated allele burden, similar to what has been reported in other Western countries, despite differences among methods used to detect this mutation. Screening for JAK2 V617F may allow specific management of these diseases with JAK2 inhibitors in the future and highlights the need for further studies on the pathogenesis of BCR-ABL-negative JAK2 V617F-negative MPNs.