FLT3,   General AML

Therapeutic Mutations in Acute Myeloid Leukemia- FLT3 ITD mutations

Chromosomal abnormalities (e.g. deletions, translocations) are identified in approximately 50% of all adult patients with primary Acute Myeloid Leukemia (AML) and have long been recognized as the genetic events that cause and promote this disease. Furthermore, FLT3 ITD mutations have been associated with increased risk of relapse, whereas the prognostic significance of FLT3 TKD mutations is debatable.

There have been a few small-molecule inhibitors of FLT3 developed, however their efficacy is questionable. However, of emerging importance are the Second-generation agents. These novel agents are considered to have better potency and fewer side-effects. Medinger et al. reviewed the key therapeutic developments with respect to FLT3 inhibitors. Their report was published in Cancer Genomics and Proteomics in 2016.

Here are the key findings with reference to FLT3 inhibitors:
Quizartinib

Quizartinib is considered to be one of the more potent FLT3 ITD inhibitors. In terms of efficacy, the use of quizartinib in phase II studies as a single agent in relapsed/refractory (RR) FLT3-mutated AML has demonstrated composite complete remission (CR) rates between 44% and 54%. In addition, median duration of responses reported were between 11.3 and 12.7 weeks.

A randomized open-label phase III study of quizartinib versus chemotherapy (NCT02039726) with a primary endpoint of overall survival is currently recruiting patients.

A randomized double-blind study of quizartinib or placebo in combination with induction and consolidation chemotherapy is in development (NCT02668653).

Gilteritinib (ASP-2215)

Gilteritinib is also considered a potent inhibitor of FLT3. In terms of efficacy, gilteritinib demonstrated composite CR of 46% and 9% against FLT3 TKD in patients with RR AML from a phase I/II study. In addition, the median duration of response was 15.9 weeks. Responses were similar irrespective of whether patients had received prior FLT3-directed therapy.

A phase I study of ASP-2215 in combination with induction and consolidation chemotherapy is ongoing (NCT02236013).

A randomized phase III study of ASP-2215 versus salvage chemotherapy is currently recruiting patients (NCT02421939).

Conclusion

Quizartinib has some promising results in terms of CR and there are some interesting phase III trials taking place. Unfortunately, patients taking this novel agent have developed mutations in the TKD of the FLT3 gene (D835 and F691) and experienced resistance to ongoing treatment. As a result, the authors consider that quizartinib may be best used as a monotherapy “bridge” to a potentially curative allogeneic bone marrow transplant. Gilteritinib may also have some potential as it has demonstrated activity against both FLT3 ITD and FLT3 TKD mutations, however the CR rate against FLT3 TKD is not very efficacious.

Abstract

Acute myeloid leukemia (AML) is a biologically complex and molecularly and clinically heterogeneous disease, and its incidence increases with age. Cytogenetics and mutation testing remain important prognostic tools for treatment after induction therapy. The post-induction treatment is dependent on risk stratification. Despite rapid advances in determination of gene mutations involved in the pathophysiology and biology of AML, and the rapid development of new drugs, treatment improvements changed slowly over the past 30 years, with the majority of patients eventually experiencing relapse and dying of their disease. Allogenic hematopoietic stem cell transplantation remains the best chance of cure for patients with intermediate- or high-risk disease. This review gives an overview about advances in prognostic markers and novel treatment options for AML, focusing on new prognostic and probably therapeutic mutations, and novel drug therapies such as tyrosine kinase inhibitors.

References
  1. Medinger M. et al. Novel Prognostic and Therapeutic Mutations in Acute Myeloid Leukemia. Cancer Genomics & Proteomics. 2016 September 10; 13(5): 317-29.
  2. Altman J. K. et al. Antileukemic activity and tolerability of ASP2215 80 mg and greater in FLT3 mutation-positive subjects with relapsed or refractory acute myeloid leukaemia: results from a phase 1/2, open-label, dose-escalation/dose-response study. Blood; 126: 321.
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