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Differentiation Induction in Acute Promyelocytic Leukemia
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
FLT3 is a tyrosine kinase receptor expressed in leukemic cells. FLT3 mutations that occur as internal tandem duplication (ITD) are the most common genetic abnormality in AML. In APL patients FLT3 mutations are found in approximately 20% to 40% of patients (72,73). The presence of FLT-3/ITD was associated with high peripheral leukemic cell count at presentation and may play a role in the progression of APL (72). Currently FLT3 inhibitors are under clinical investigation, and it remains to be seen if they will provide a therapeutic option in the treatment of APL.
Acute Myeloid Leukemia An Introduction
Published in Wojciech Gorczyca, Atlas of Differential Diagnosis in Neoplastic Hematopathology, 2014
fms FLT3 is a transmembrane receptor tyrosine kinase. The FLT3 mutations are present in 30%–40% of the AML patients and are associated with leukocytosis and a high percentage of blasts in BM [62,63]. FLT3 mutational status has a major impact on remission duration and overall survival in AML patients with normal cytogenetic. FLT3 mutations occur predominantly by ITDs and less commonly as point mutations in TKD, through an activation loop involving an aspartic acid residue at amino acid position 835 (Asp835 mutations). FLT3 mutations do not correlate with complete remission rate, but they predict relapse and are associated with shorter remission duration, shorter event-free survival, and shorter overall survival compared to AML patients without FLT3 mutations [62–66]. There is a statistically significant coincidence of invaginated nuclear morphology; lack of HLA-DR, CD34, and CD133 expression; and presence of the FLT3-ITD. Similar phenotype may be associated with NPM1 mutations. The expression of CD25 positively correlates with FLT3-ITD, DNMT3A− and NPM1− mutations [67]. The adverse prognostic impact of FLT3-ITD+ AML was restricted to CD25+ patients and CD25 expression improved AML prognostication independent of integrated, cytogenetic, and mutational data such that it reallocated 11% of patients with integrated intermediate-risk disease based on the cytogenetic/mutational profiling to the unfavorable-risk group with high risk of relapse [67]. FLT3-ITD is found in ~20%–35% of adult AMLs and 15% of pediatric AMLs. FLT3 with point mutations (Asp835 mutations; FLT3-TKD mutations) are less common, occurring in ~10% of AML. FLT3-ITDs are most common in AML with normal karyotype by metaphase cytogenetic and in AML with t(6;9), whereas FLT3-TKD point mutations are more common in AML with inv(16)/CBFB–MYH11. Both types of FLT3 mutations occur frequently in APL and are rare in AML with MLL rearrangements or AML with adverse chromosomal changes [68–70]. The prognostic significance of FLT3-TKD is not well established.
Leukaemias
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2014
Efforts assessing the genetic and molecular abnormalities in patients with AML have helped define risk category and personalized therapy. Patients can be classified into groups with different prognoses based on cytogenetic and molecular analyses (Figure 28.3).14 For example, leukaemia with an isolated mutation in NPM1 or bi-alleleic CEBPa is associated with a favourable prognosis; those with t(8;12), inv(16) or t(16;16) also appear to have a favourable prognosis, with the best response and remission rates (under age 60 years), except when associated with the kit mutation, when the relapse risk increases with, at least in some reports an adverse impact on survival thus potentially reclassifying them to an intermediate category. It is of interest that these translocations disrupt the core binding factor (CBF) complex, which plays an essential role in normal haematopoiesis. The CBF complex is composed of an alpha and a beta subunit, with the alpha subunit encoded by one of three homologous genes of the Runt-related transcription factor (RUNX) family, whereas CBF beta subunit by the CBFB (also known as PEBP2B) gene which is involved in inv(16)/t(16;16). The RUNX1 gene is involved in three different chromosomal translocations, which share a break-point at its site on chromosome 21q22: t(8;21), t(3;21) and t(12;21); the t(8;21) juxtaposes RUNX1 to RUNX1T1 (previously known as AML1-ETO).15 Patients with a normal karyotype but a mutation in FLT3 (FMS-like tyrosine kinase), a transmembrane tyrosine kinase with either a single amino-acid substitution in the kinase domain, or with an internal tandem duplication (ITD), tend to have an intermediate-risk AML although they may have associated features such as a high presenting white count which increases the risk. It is becoming increasingly clear that the prognostic implications of FLT3 mutations are influenced by the alleleic ration and whether it occurs in association with the more favourable NPM1c mutation. Leukaemia cells with translocations involving the mixed-lineage leukaemia (MLL) gene at 11q23, t(6;9) or complex (greater than 3) abnormalities, monosomies of any chromosome (typically chromosome 5 and/or 7), inv(3), t(3;3), t(6;9), and 17p abnormalities indicate a poor-risk AML.16
The favorable prognostic value of the loss of sex chromosomes in patients with t(8;21) acute myeloid leukemia: an exploratory study
Published in Hematology, 2022
Lixia Zhu, Rongrong Chen, Xueying Li, Mixue Xie, Xiudi Yang, Jianai Sun, Mingyu Zhu, Xiaolong Zheng, Li Li, Jingjing Zhu, De Zhou, Wanzhuo Xie, Xiujin Ye
To determine independent prognostic predictors for multivariable logistic regression, significant variables were identified by univariate analysis (P < .1). The cut-offs for continuous variables were based on a previous report [13]. In the analysis of DFS, five variables were identified by univariate analysis, and blasts ≥50% and FLT3-ITD mutation were confirmed as independent prognostic predictors for t(8;21) AML patients. In the analysis of OS, univariate analysis indicated that FLT3 mutations were all significantly associated with poor overall survival (P = .005). Conversely, t(8;21) with LOS AML patients tended to have better outcomes (P = .029). Ultimately, LOS and FLT3-ITD mutation were confirmed as independent prognosis predictors of t(8;21) AML by multivariable logistic regression analysis (LOS, HR 0.258, 95% confidence interval 0.077–0.871, P = .029; FLT3-ITD, HR 5.677, 95% confidence interval 1.681–19.168, P = .005). LOS was a favorable factor for overall survival, while FLT3-ITD mutation was significantly associated with poor progression-free survival. See Tables 3 and 4 for details.
Personalized patient care with aggressive hematological malignancies in non-responders to first-line treatment
Published in Expert Review of Precision Medicine and Drug Development, 2021
Katsuhiro Miura, Noriyoshi Iriyama, Yoshihiro Hatta, Masami Takei
The efficacy of several FLT3 inhibitors have been investigated in clinical trials. Midostaurin, a multitarget kinase inhibitor, is currently used in combination with standard chemotherapy for newly diagnosed FLT3-mutated AML [6]. Gilteritinib, a novel, specific FLT3 inhibitor, has successfully demonstrated its favorable anti-leukemic effects in FLT3-mutated AML in several major clinical studies [7,8]. Monotherapy with gilteritinib is currently available for relapsed or refractory (R/R) FLT3-mutated AML patients with both ITD and TKD types. The ADMIRAL study is a pivotal phase 3 trial that randomized 371 FLT3-mutated R/R AML either the gilteritinib group or the conventional salvage chemotherapy group at a 2:1 ratio. Gilteritinib demonstrated significantly longer overall survival (OS) and better CR rates than conventional salvage chemotherapies consisting of MEC, FLAG-IDA, low-dose cytarabine, or azacitidine. Gilteritinib showed toxicities such as febrile neutropenia, increased liver transferase, and prolonged QT interval [8]. Quizartinib, a selective type II FLT3 inhibitor, has also shown a survival benefit relative to conventional chemotherapy in patients with FLT3-ITD-positive R/R AML [9].
High expression of TARP correlates with inferior FLT3 mutations in non-adolescents and young adults with acute myeloid leukaemia
Published in Hematology, 2021
Yuye Shi, Zhengmei He, Liye Bei, Hong Tao, Banghe Ding, Shandong Tao, Chunling Wang, Liang Yu
FLT3 is a member of the receptor tyrosine kinase superfamily. FLT3 harbours five domains: an extracellular domain, one transmembrane domain, a cytoplasmic juxtamembrane domain (JMD) and two tyrosine kinase domains (TKD1 and TKD2) [6]. The internal tandem duplication (ITD) alteration of the JMD domain is a gain-of-function mutation in AML that is detected in 25% of de novo AML patients. The mutation induces auto-phosphorylation, which leads to excessive proliferation and survival of AML cells [7]. FLT3-ITD mutations have been reported to be associated with poor outcomes and high rates of relapse [7]. However, the clinical significance of genetic alterations in the TKD domain, including the D835 point mutation and I836 deletion, is not fully understood. A study reported that no difference in overall survival (OS) was observed between AML patients having an FLT3-TKD mutation and those with wild type (wt) FLT3 kinase, and that prognosis of FLT3-TKD positive cases was better than that of FLT3-ITD patients [8]. However, FLT3-TKD abnormalities were observed in no more than 10% of AML cases in Asia and were slightly higher in Europe and the United States [8].