Abstract:Therapeutic options for acute myeloid leukemia (AML) have remained unchanged for nearly the past 5 decades, with cytarabine and anthracyclines and use of hypomethylating agents for less intensive therapy. Implementation of large-scale genomic studies in the past decade has unraveled the genetic landscape and molecular etiology of AML. The approval of several novel drugs for targeted therapy, including midostaurin, enasidenib, ivosidenib, gemtuzumab–ozogamicin, and CPX351 by the US Food and Drug Administration … Show more
“…This knowledge has important immediate implications for clinical decision-making related to therapy (eg, donor selection and conditioning regimen for transplantation), detection of an underlying genetic predisposition, identification of novel AML subclasses, and prognosis 44 , 45 . Perhaps most importantly, knowledge of a patient’s genomic status may be relevant in selecting an optimal induction regimen, such as all-trans retinoic acid plus arsenic trioxide for acute promyelocytic leukemia 46 , adding GO in core binding factor AML 47 , CPX-351 in patients with myelodysplasia-related changes of therapy-related AML 48 , adding midostaurin for FLT3 -mutated AML 47 , or considering IDH inhibitor-based approaches for IDH -mutant AML. Fig.…”
Section: Could Biologically Directed Therapies Deprioritize Traditionmentioning
Conventional therapy for acute myeloid leukemia is composed of remission induction with cytarabine- and anthracycline-containing regimens, followed by consolidation therapy, including allogeneic stem cell transplantation, to prolong remission. In recent years, there has been a significant shift toward the use of novel and effective, target-directed therapies, including inhibitors of mutant FMS-like tyrosine kinase 3 (FLT3) and isocitrate dehydrogenase (IDH), the B-cell lymphoma 2 inhibitor venetoclax, and the hedgehog pathway inhibitor glasdegib. In older patients the combination of a hypomethylating agent or low-dose cytarabine, venetoclax achieved composite response rates that approximate those seen with standard induction regimens in similar populations, but with potentially less toxicity and early mortality. Preclinical data suggest synergy between venetoclax and FLT3- and IDH-targeted therapies, and doublets of venetoclax with inhibitors targeting these mutations have shown promising clinical activity in early stage trials. Triplet regimens involving the hypomethylating agent and venetoclax with FLT3 or IDH1/2 inhibitor, the TP53-modulating agent APR-246 and magrolimab, myeloid cell leukemia-1 inhibitors, or immune therapies such as CD123 antibody-drug conjugates and programmed cell death protein 1 inhibitors are currently being evaluated. It is hoped that such triplets, when applied in appropriate patient subsets, will further enhance remission rates, and more importantly remission durations and survival.
“…This knowledge has important immediate implications for clinical decision-making related to therapy (eg, donor selection and conditioning regimen for transplantation), detection of an underlying genetic predisposition, identification of novel AML subclasses, and prognosis 44 , 45 . Perhaps most importantly, knowledge of a patient’s genomic status may be relevant in selecting an optimal induction regimen, such as all-trans retinoic acid plus arsenic trioxide for acute promyelocytic leukemia 46 , adding GO in core binding factor AML 47 , CPX-351 in patients with myelodysplasia-related changes of therapy-related AML 48 , adding midostaurin for FLT3 -mutated AML 47 , or considering IDH inhibitor-based approaches for IDH -mutant AML. Fig.…”
Section: Could Biologically Directed Therapies Deprioritize Traditionmentioning
Conventional therapy for acute myeloid leukemia is composed of remission induction with cytarabine- and anthracycline-containing regimens, followed by consolidation therapy, including allogeneic stem cell transplantation, to prolong remission. In recent years, there has been a significant shift toward the use of novel and effective, target-directed therapies, including inhibitors of mutant FMS-like tyrosine kinase 3 (FLT3) and isocitrate dehydrogenase (IDH), the B-cell lymphoma 2 inhibitor venetoclax, and the hedgehog pathway inhibitor glasdegib. In older patients the combination of a hypomethylating agent or low-dose cytarabine, venetoclax achieved composite response rates that approximate those seen with standard induction regimens in similar populations, but with potentially less toxicity and early mortality. Preclinical data suggest synergy between venetoclax and FLT3- and IDH-targeted therapies, and doublets of venetoclax with inhibitors targeting these mutations have shown promising clinical activity in early stage trials. Triplet regimens involving the hypomethylating agent and venetoclax with FLT3 or IDH1/2 inhibitor, the TP53-modulating agent APR-246 and magrolimab, myeloid cell leukemia-1 inhibitors, or immune therapies such as CD123 antibody-drug conjugates and programmed cell death protein 1 inhibitors are currently being evaluated. It is hoped that such triplets, when applied in appropriate patient subsets, will further enhance remission rates, and more importantly remission durations and survival.
“…Using a standard approach, this would require over 73,000 individual wells; however, using our screening strategy, we can reduce this to 3878 individual wells. For the most part, each of the cell lines demonstrated variability in response to these compound combinations, highlighting the heterogeneity of paediatric AML and the need for a personalised medicine approach [ 46 , 47 ]. We focused on compound combinations that demonstrated similar responses in both cell lines with the aim of identifying a robust combination.…”
Paediatric acute myeloid leukaemia (AML) is a heterogeneous disease characterised by the malignant transformation of myeloid precursor cells with impaired differentiation. Standard therapy for paediatric AML has remained largely unchanged for over four decades and, combined with inadequate understanding of the biology of paediatric AML, has limited the progress of targeted therapies in this cohort. In recent years, the search for novel targets for the treatment of paediatric AML has accelerated in parallel with advanced genomic technologies which explore the mutational and transcriptional landscape of this disease. Exploiting the large combinatorial space of existing drugs provides an untapped resource for the identification of potential combination therapies for the treatment of paediatric AML. We have previously designed a multiplex screening strategy known as Multiplex Screening for Interacting Compounds in AML (MuSICAL); using an algorithm designed in-house, we screened all pairings of 384 FDA-approved compounds in less than 4000 wells by pooling drugs into 10 compounds per well. This approach maximised the probability of identifying new compound combinations with therapeutic potential while minimising cost, replication and redundancy. This screening strategy identified the triple combination of glimepiride, a sulfonylurea; pancuronium dibromide, a neuromuscular blocking agent; and vinblastine sulfate, a vinca alkaloid, as a potential therapy for paediatric AML. We envision that this approach can be used for a variety of disease-relevant screens allowing the efficient repurposing of drugs that can be rapidly moved into the clinic.
“…5 The use of the newly approved treatment approaches to personalize therapy and improve outcomes in AML patients has progressed since 2017. 6 Advances in genome-wide molecular profiling and immunophenotyping (IPT) have identified mutations in genes associated with apoptosis (p53, nucleoplasmin, etc.) and regulation of cell proliferation (RAS, Fms-like tyrosine kinase 3, c-KIT, etc.)…”
Introduction
Acute myeloid leukemia (AML) is the most common type of leukemia among adults and is characterized by various genetic abnormalities.
HOXB4
and
PRDM16
are promising markers of AML. Our objective is to assess the potential roles of
HOXB4
and
PRDM16
as prognostic and predictive markers in newly diagnosed AML patients and determine the correlation between their expressions and other prognostic markers as
FLT3-ITD, NPM1 exon 12
mutations, response to treatment, and patient’s survival.
Methods
This study included 83 de novo AML adult patients. All patients were subjected to clinical, morphological, cytochemical, and molecular analysis to detect
HOXB4
and
PRDM16
gene expressions and
FLT3-ITD, NPM1 exon 12
mutations.
Results
The results showed that a low expression of
HOXB4
was found in 31.3% of AML patients, whereas a high expression of
PRDM16
was evident in 33.8% of AML patients.
FLT3-ITD
mutations were detected in 6 patients (7.2%), while
NPM1 exon 12
mutations were detected in 7 patients (19.4%) out of 36 patients with intermediate genetic risk. Out of the 50 patients who achieved complete remission (CR), relapse occurred in 16% of the cases. Low expression of
HOXB4
and high expression of
PRDM1
6 were associated with CR of 32% and 28%, respectively, and a short overall survival (OS) and disease-free survival (DFS).
Conclusion
Further larger study should be conducted to verify that high
PRDM16
and low
HOXB4
gene expressions could be used as a poor prognostic predictor for AML. The correlation between
PRDM16
and
HOXB4
gene expressions and
FLT3-ITD
and
NPM1 exon 12
mutations might have a role on CR, relapse, OS, and, however, this should be clarified in analysis with a larger number of samples.
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