Internal tandem duplication of the FLT3 gene confers poor overall survival in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline-based chemotherapy: an International Consortium on Acute Promyelocytic Leukemia study

Lucena-Araújo, Antonio R.; Kim, Haesook T.; Jácomo, Rafael H.; Melo, Raul Antônio Morais; Bittencourt, Rosane; Pasqüini, Ricardo; Pagnano, Kátia Bórgia Barbosa; Fagundes, Evandro M.; Chauffaille, Maria de Lourdes Lopes Ferrari; Chiattone, Carlos S.; Lima, Agnaldo Soares; Ruíz‐Argüelles, Guillermo J.; Undurraga, María Soledad; Martinez, Lem; Kwaan, Hau C.; Gallagher, Robert E.; Niemeyer, Charlotte M.; Schrier, Stanley L.; Tallman, Martin S.; Grimwade, David; Ganser, Arnold; Berliner, Nancy; Ribeiro, Raul C.; Lo‐Coco, Francesco; Löwenberg, Bob; Sanz, Miguel Á.; Rego, Eduardo Magalhães

doi:10.1007/s00277-014-2142-9

Cited by 57 publications

(45 citation statements)

References 51 publications

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“…A study of an International Consortium on APL included 171 patients, 35 of whom were positive for FLT3-ITD mutation. After 38 months of median follow-up, FLT3-ITD mutant APLs had lower overall survival compared to FLT3-wild-type cases with no differences however in disease-free survival, complete remission rate, and cumulative incidence of relapse [51]. Another study attempted to define the variables within the FLT3-ITD group that could affect prognosis: (a) the FLT3-ITD/FLT3-wild-type ratio was an important prognostic parameter in that only patients with a high ratio and not those with a low ratio have a reduced probability of relapse-free survival; (b) the size of the ITD region within the FLT3 mutant molecule is another important prognostic determinant, with only APL patients with a long FLT3-ITD molecule exhibiting a reduced probability of relapse-free survival [52].…”

Section: Molecular Prognostic Markersmentioning

confidence: 89%

Prognostic factors in acute promyelocytic leukemia: strategies to define high-risk patients

Testa

Lo‐Coco

2016

Ann Hematol

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All trans retinoic acid (ATRA) has revolutionized the therapy of acute promyelocytic leukemia (APL). Treatment of this leukemia with ATRA in combination with chemotherapy has resulted in complete remission rates >90 % and long-term remission rates above 80 %. Furthermore, the combination of ATRA and arsenic trioxide (ATO) was shown to be safe and effective in frontline treatment and, for patients with low and intermediate risk disease, possibly superior to the standard ATRA and anthracycline-based regimen. However, in spite of this tremendous progress, APL still remains associated with a high incidence of early death due to the frequent occurrence of an abrupt bleeding diathesis. This hemorrhagic syndrome more frequently develops in high-risk APL patients, currently defined as those exhibiting >10 × 10(9)/L WBC at presentation. In addition to high WBC count, other molecular and immunophenotypic features have been associated with high-risk APL. Among them, the expression in APL blasts of the stem/progenitor cell antigen CD34, the neural adhesion molecule (CD56), and the T cell antigen CD2 help to identify a subset of patients at higher risk of relapse and often the expression of these markers is associated with high WBC count. At the molecular level, the short PML/RARA isoform and FLT3-internal tandem duplication (ITD) mutations have been associated with increased relapse risk. These observations indicate that extended immunophenotypic and molecular characterization of APL at diagnosis including evaluation of CD2, CD56, and CD34 antigens and of FLT3 mutations may help to better design risk-adapted treatment in this disease.

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Section: Molecular Prognostic Markersmentioning

confidence: 89%

Prognostic factors in acute promyelocytic leukemia: strategies to define high-risk patients

Testa

Lo‐Coco

2016

Ann Hematol

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“…The most well-known risk factors are WBC and platelet counts at diagnosis, 11 although internal tandem duplications of the FLT3 gene, 12 aberrant expression of the CD56 antigen, 13 deregulated expression of the MLL5 gene, 14 and a polymorphic variant involving the promoter of the gene encoding the CD95 cell death receptor 15 are potential predictors of poor prognosis in APL. Here, we provide the first evidence that higher DNp73/TAp73 ratio is associated with a lower remission rate, shorter survival, and higher risk of relapse in a relatively large series of patients with APL homogeneously treated with all-trans retinoic acid (ATRA) and anthracyclinebased chemotherapy.…”

Section: Resultsmentioning

confidence: 99%

High ΔNp73/TAp73 ratio is associated with poor prognosis in acute promyelocytic leukemia

Lucena-Araújo

Kim

Thomé

et al. 2015

Blood

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Key Points• High DNp73/TAp73 expression ratio is associated with lower overall survival and higher cumulative incidence of relapse in APL.• DNp73/TAp73 expression ratio is an independent prognostic marker in APL.The TP73 gene transcript is alternatively spliced and translated into the transcriptionally active (TAp73) or inactive (DNp73) isoforms, with opposite effects on the expression of p53 target genes and on apoptosis induction. The imbalance between DNp73 and TAp73 may contribute to tumorigenesis and resistance to chemotherapy in human cancers, including hematologic malignancies. In acute promyelocytic leukemia (APL), both isoforms are expressed, but their relevance in determining response to therapy and contribution to leukemogenesis remains unknown. Here, we provide the first evidence that a higher DNp73/ TAp73 RNA expression ratio is associated with lower survival, lower disease-free survival, and higher risk of relapse in patients with APL homogeneously treated with all-trans retinoic acid and anthracycline-based chemotherapy, according to the International Consortium on Acute Promyelocytic Leukemia (IC-APL) study. Cox proportional hazards modeling showed that a high DNp73/TAp73 ratio was independently associated with shorter overall survival (hazard ratio, 4.47; 95% confidence interval, 1.64-12.2; P 5 .0035). Our data support the hypothesis that the DNp73/TAp73 ratio is an important determinant of clinical response in APL and may offer a therapeutic target for enhancing chemosensitivity in blast cells. (Blood. 2015;126(20):2302-2306

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“…[7][8][9] Excluding the well-known differences between low-and middleincome vs high-income countries, outcomes in APL are variable among studies, 1,5,7,10 and, in our experience, patients with newly diagnosed APL may present a specific genomic profile important for predicting prognosis. [11][12][13][14] In line with these findings, overexpression of the brain and acute leukemia, cytoplasmic (BAALC) gene, either alone or in association with the aberrant expression of other genes, is frequently associated with poor prognosis in different subsets of acute myeloid leukemia (AML), [15][16][17][18] although its functional role in leukemogenesis has not been investigated to the same extent. In contrast, very few studies have investigated the clinical impact of BAALC expression in APL.…”

Section: Introductionmentioning

confidence: 69%

“…The estimated 5-year DFS rate was 87% (95% CI, 80-92), and the cumulative incidence of relapse (CIR) rate was 14% (95% CI, [8][9][10][11][12][13][14][15][16][17][18][19][20]. Patients with high BAALC expression had a lower 5-year DFS rate (78%; 95% CI, 66-86) than those with low BAALC expression (95%; 95% CI, 86-98) (P 5 .009) ( Figure 2B).…”

Section: Resultsmentioning

confidence: 99%

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Clinical impact of BAALC expression in high-risk acute promyelocytic leukemia

et al. 2017

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Key Points• BAALC expression is significantly lower in APL compared with other subsets of AML and healthy volunteers.• BAALC overexpression can independently predict shorter DFS in patients with high-risk disease. /L) (HR, 5.3; 95% CI, 1.14-24.5; P 5 .033). We conclude that BAALC expression could be useful for refining risk stratification in APL, although this needs to be confirmed in independent cohorts.

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Internal tandem duplication of the FLT3 gene confers poor overall survival in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline-based chemotherapy: an International Consortium on Acute Promyelocytic Leukemia study

Cited by 57 publications

References 51 publications

Prognostic factors in acute promyelocytic leukemia: strategies to define high-risk patients

Prognostic factors in acute promyelocytic leukemia: strategies to define high-risk patients

High ΔNp73/TAp73 ratio is associated with poor prognosis in acute promyelocytic leukemia

Clinical impact of BAALC expression in high-risk acute promyelocytic leukemia

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