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    • br AML therapies with curative intent

    2019-04-23


    AML therapies with curative intent
    Alternative treatment strategies
    Targeted therapies: the new kids on the block The recognition of specific mutations as genetic drivers or facilitators of AML has led to the development of new inhibitors and targeted treatment options. New promising drug candidates have been tested in clinical studies, for their ability to control disease as single agents or to improve cure rates and overall survival when combined with standard chemotherapy regimens (see Table 2). During the last decade, several studies have shown that the presence or absence of specific gene mutations and/or changes in gene s6 kinase can further classify AML cases and have an effect on the patients’ prognosis [2–5,33–35]. This is particularly relevant for patients with cytogenetically normal AML (CN-AML). In a very recent article by Papaemmanuil et al. the role of mutations and its correlation with pathophysiology was examined in a large cohort of 1540 AML patients [35]. They identified 5234 driver mutations across 76 genes or genomic regions, with 2 or more drivers identified in 86% of the patients. Patterns of co-mutation compartmentalized the cohort into 11 classes, each with distinct diagnostic features and clinical outcomes. In addition to currently defined AML subgroups, three heterogeneous genomic categories emerged: AML with mutations in genes encoding chromatin, RNAsplicing regulators, or both (in 18% of patients); AML with TP53 mutations, chromosomal aneuploidies, or both (in 13%); and, provisionally, AML with IDH2R172 mutations (in 1%). Patients with chromatin–spliceosome and TP53–aneuploidy AML had poor outcomes, with the various class-defining mutations contributing independently and additively to the outcome. They found gene–gene interactions which were especially pronounced for NPM1-mutated AML, in which patterns of co-mutation identified groups with a favorable or adverse prognosis [35]. In our review, we will focus on three relevant AML mutations.
    Strategies for prevention and treatment of relapse
    Conclusions
    Conflict of interest
    Introduction The ETV6-ABL1 (TEL-ABL) fusion is a rare aberration found in a range of haematologic malignancies. First described in 1995 [1], only 27 ETV6-ABL1-positive cases diagnosed with atypical chronic myeloid leukemia (aCML), chronic myeloproliferative neoplasm (cMPN), acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML) have been reported up to now [2–5]. The rarity of the ETV6-ABL1 rearrangement is thought to be due to the opposite transcriptional orientations of the ETV6 and the ABL1 genes relative to the telomere-centromere axis, which requires at least three DNA breaks to generate a functional ETV6-ABL1 fusion gene [5]. Thus in most ETV6-ABL1-positive cases, the fusion is generated as the result of complex, often cryptic, chromosomal rearrangements. The frequent cryptic nature of these rearrangements is likely to have resulted in underreporting of ETV6-ABL1-positive cases. Due to breakpoint heterogeneity, two types of ETV6-ABL1 fusion transcripts are found: the ‘type A’ transcript is a fusion of the first 4 ETV6 exons to the second exon of ABL1 and in the ‘type B’ transcript the first 5 exons of ETV6 are fused to the second exon of ABL1. ETV6-ABL1 activates similar cellular pathways like BCR-ABL1. In vitro studies have shown that both fusion proteins lead to the constitutive activation of the ABL1 tyrosine kinase [6]. Like BCR-ABL1, ETV6-ABL1 is sensitive to ABL1 tyrosine kinase inhibitors [7,8].
    Materials and methods
    Results A 26-year-old women with psoriasis was clinically evaluated with suspicion of psoriatic arthritis of the shoulder. Her psoriasis was not severe and well controlled with stress avoidance and mild topical ointments. Routine blood count showed an increased WBC of 40,000/µl. An RT-PCR assay for a BCR-ABL fusion from peripheral blood was negative. Although her shoulder pain resolved, the leukocytosis persisted. A bone marrow biopsy in December 2012 showed a packed marrow with trilineage hyperplasia and an eosinophilia of 20–30%. The neutrophils and eosinophils showed markedly hypersegmented nuclei. The findings were compatible with a myeloproliferative disease.