scholarly journals Combating drug resistance in acute myeloid leukaemia by drug rotations: the effects of quizartinib and pexidartinib

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jingmei Yang ◽  
H. Jonathan G. Lindström ◽  
Ran Friedman
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Kinase Inhibitors ◽  
Computational Modelling ◽  
Driver Mutations ◽  
Common Mutation ◽  
Resistance Mutations ◽  
Flt3 Inhibitors ◽  
Emergence Of Resistance ◽  
Acute Myeloid

Abstract Background Acute myeloid leukaemia (AML) is an aggressive blood cancer. In approximately 30% of the cases, driver mutations in the FLT3 gene are identified. FLT3 inhibitors are used in treatment of such patients together with cytotoxic drugs or (in refractory AML) as single agents. Unfortunately, resistance to FLT3 inhibitors limits their efficacy. Resistance is often due to secondary mutations in the gene encoding the molecular target. The gatekeeper mutation F691L confers resistance to specific FLT3 inhibitors such as quizartinib, but pexidartinib is much less resistance to this mutation. Pexidartinib alone is however sensitive to many other resistance mutations. In chronic myeloid leukaemia (CML), it has been suggested that rotation between drugs with a different landscape of resistance mutations might postpone the emergence of resistance. Methods We studied the effect of quizartinib and pexidartinib in AML cell lines that express FLT3 (MOLM-14 and MV4-11). Using a rotation protocol, we further examined whether the emergence of resistance could be postponed. Computational modelling was used to analyse the onset of resistance and suggest which mutations are most likely to occur in a quantitative fashion. Results The cells were sensitive to both inhibitors but quickly developed resistance that could be inherited, suggesting a genetic origin. Rotation protocols were not useful to postpone the emergence of resistance, which implies that such protocols, or changing from pexidartinib to quizartinib (or vice-versa) should not be used in patients. The computational modelling led to similar conclusions and suggested that F691L is the most common mutation to occur with quizartinib, and also when both drugs are used in rotation. Conclusions AML patients are not likely to benefit from a quizartinib/pexidartinib rotation protocol. A combination of tyrosine kinase inhibitors (with different molecular targets) might be more useful in the future. Development of specific FLT3 inhibitors that are less sensitive to resistance mutations might also lead to a better outcome.

scholarly journals Quantitative phosphoproteomics uncovers synergy between DNA-PK and FLT3 inhibitors in acute myeloid leukaemia

Leukemia ◽  
2020 ◽  
Author(s):  
Heather C. Murray ◽  
Anoop K. Enjeti ◽  
Richard G. S. Kahl ◽  
Hayley M. Flanagan ◽  
Jonathan Sillar ◽  
...  
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Flt3 Inhibitors ◽  
Quantitative Phosphoproteomics ◽  
Acute Myeloid

scholarly journals Next-generation sequencing-based molecular genetic profiling in adults with acute myeloid leukaemia

2020 ◽  
Vol 65 (4) ◽  
pp. 444-459
Author(s):  
A. I. Kashlakova ◽  
E. N. Parovichnikova ◽  
B. V. Biderman ◽  
Y. V. Sidorova ◽  
Y. A. Chabaeva ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Molecular Genetic ◽  
Driver Mutations ◽  
Next Generation ◽  
Old Patients ◽  
Generation Sequencing ◽  
Acute Myeloid

Introduction. Acute myeloid leukaemia (AML) is associated with multiple driver mutations, which prognostic value remains understudied.Aim. Assessment of the frequency of mutations in various genes and their impact on acute myeloid leukaemia outcome in adults.Materials and methods. The study included 90 adult patients with newly diagnosed AML; 76 were aged under 60, 14 were 60 and more years old. Patients under 60 had chemotherapy (CT) “7+3” as induction, the elder cohort had variant low-dose CT with hypomethylating agents. The molecular genetic status of patients was determined using next-generation sequencing; the in-house gene panel included ASXL1, BCOR, DNMT3, FLT3, IDH1, IDH2, PIGA, RUNX1, SETBP1, SF3B1, SRSF2, TET2, TP53 and U2AF2.Results. Nucleotide substitutions were identified in genes DNMT3, TET2, TP53, SETBP1, BCOR, RUNX1, IDH2, IDH1, FLT3, U2AF2, SF3B1 in 57.8 % of the patients (n = 52), with 17.8 % (n = 16) having compound mutations in two or three genes. Treatment efficacy and long-term outcomes were assessed against age, ELN-2017 risk groups and mutations in genes TP53, RUNX1, IDH1, IDH2 and DNMT3. In the long term, a reliable variation was revealed in the overall survival (OS) rate with respect to mutations in genes TP53 and RUNX1. Patients with mutant TP53 had 30 % OS, those with the intact gene — 53.4 % (p = 0.0037). Similar results were obtained with RUNX1: mutations marked 20 % OS, intact patients had 54% OS (p = 0.0466).Conclusion. Mutations in genes FLT3-ITD, NPM1 and CEBPA are proxy to AML. However, a more accurate prognosis and optimal choice of therapy require detailed molecular profiling due to genetic heterogeneity of AML patients.

scholarly journals FLT3 Inhibition in Acute Myeloid Leukaemia – Current Knowledge and Future Prospects

2020 ◽  
Vol 20 (7) ◽  
pp. 513-531 ◽  
Author(s):  
Francesca L. Hogan ◽  
Victoria Williams ◽  
Steven Knapper
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukaemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Current Knowledge ◽  
Clinical Development ◽  
Clinical Prognosis ◽  
Acquired Drug Resistance ◽  
Acute Myeloid

Activating mutations of FMS-like tyrosine kinase 3 (FLT3) are present in 30% of acute myeloid leukaemia (AML) patients at diagnosis and confer an adverse clinical prognosis. Mutated FLT3 has emerged as a viable therapeutic target and a number of FLT3-directed tyrosine kinase inhibitors have progressed through clinical development over the last 10-15 years. The last two years have seen United States Food and Drug Administration (US FDA) approvals of the multi-kinase inhibitor midostaurin for newly-diagnosed FLT3-mutated patients, when used in combination with intensive chemotherapy, and of the more FLT3-selective agent gilteritinib, used as monotherapy, for patients with relapsed or treatment-refractory FLT3-mutated AML. The ‘second generation’ agents, quizartinib and crenolanib, are also at advanced stages of clinical development. Significant challenges remain in negotiating a variety of potential acquired drug resistance mechanisms and in optimizing sequencing of FLT3 inhibitory drugs with existing and novel treatment approaches in different clinical settings, including frontline therapy, relapsed/refractory disease, and maintenance treatment. In this review, the biology of FLT3, the clinical challenge posed by FLT3-mutated AML, the developmental history of the key FLT3-inhibitory compounds, mechanisms of disease resistance, and the future outlook for this group of agents, including current and planned clinical trials, is discussed.

scholarly journals Targeting the FLT3 Mutation in Acute Myeloid Leukaemia

2017 ◽  
Vol 13 (02) ◽  
pp. 139 ◽  
Author(s):  
Sabine Kayser ◽  
Richard F Schlenk ◽  
◽  
◽  
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukaemia ◽  
Kinase Inhibitors ◽  
Point Mutations ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Prognostic Impact ◽  
Newly Diagnosed ◽  
Acute Myeloid

Acute myeloid leukaemia (AML) exhibiting an internal tandem duplication of the FLT3 gene (FLT3-ITD) is an aggressive haematologic malignancy with a poor prognosis due to a high relapse rate and very limited options after relapse with conventional salvage regimens, whereas the prognostic impact of point mutations in the tyrosine kinase domain of the FLT3 gene (FLT3-TKD) are less clear. A number of tyrosine kinase inhibitors (TKIs) have been developed that inhibit the constitutively activated kinase activity caused by the FLT3 mutation, thus interrupting signalling pathways. Early clinical trials of these agents as monotherapy failed to elicit enduring complete responses, leading to clinical testing of FLT3 TKI in combination with conventional chemotherapy. Midostaurin has demonstrated improved survival in combination with standard intensive chemotherapy as compared to standard chemotherapy alone in younger adult patients with newly diagnosed FLT3-mutated AML and is the first and currently the only approved FLT3 TKI. Newer, more selective compounds, such as gilteritinib and crenolanib, have also demonstrated significant potency and specificity. Several combination trials are ongoing or planned in both relapsed and newly diagnosed AML patients with activating FLT3 mutations.

CCT245718, a dual FLT3/Aurora A inhibitor overcomes D835Y-mediated resistance to FLT3 inhibitors in acute myeloid leukaemia cells

2021 ◽  
Vol 125 (7) ◽  
pp. 966-974
Author(s):  
Muhammad Usama Tariq ◽  
Muhammad Furqan ◽  
Hira Parveen ◽  
Rahim Ullah ◽  
Muhammad Muddassar ◽  
...  
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Aurora A ◽  
Flt3 Inhibitors ◽  
Acute Myeloid

Clinical Management of Relapsed/Refractory Acute Myeloid Leukaemia

2010 ◽  
Vol 00 (04) ◽  
pp. 43
Author(s):  
Sameer A Parikh ◽  
Stefan Faderl ◽  
◽  
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Dose Schedule ◽  
Conventional Chemotherapy ◽  
Curative Therapy ◽  
Flt3 Inhibitors ◽  
First Relapse ◽  
Definition Of ◽  
Molecular Aberrations ◽  
Acute Myeloid

Conventional chemotherapy for patients with relapsed/refractory acute myeloid leukaemia (AML) remains unsatisfactory, with median survival ranging from 18 weeks following first relapse to six weeks in those with a second or higher relapse. The only potentially curative therapy is stem cell transplantation. Duration of first complete remission (CR) is the best predictor of response to salvage therapy. Novel therapies directed against a number of molecular aberrations associated with AML are being developed, including anti-CD33 monoclonal antibodies, FMS-like tyrosine kinase (FLT3) inhibitors, nucleoside analogues, hypomethylating agents and histone deacetylatase inhibitors, among others. Clinical trials combining novel agents with conventional chemotherapy are of particular interest, and definition of dose, schedule and combination partners remains an area of intense research.

The acute myeloid leukaemia market

2019 ◽  
Vol 19 (4) ◽  
pp. 233-234
Author(s):  
Jorrit Schaefer ◽  
Sorcha Cassidy ◽  
Rachel M. Webster
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Acute Myeloid
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