Clonal evolution of AML on novel FMS-like tyrosine kinase-3 (FLT3) inhibitor therapy with evolving actionable targets

Abstract

For acute myeloid leukemia (AML), identification of activating mutations in the FMS-like tyrosine kinase-3 (FLT3) has led to the development of several FLT3-inhibitors. Here we present clinical and next generation sequencing data at the time of progression of a patient on a novel FLT3-inhibitor clinical trial (ASP2215) to show that employing therapeutic interventions with these novel targeted therapies can lead to consequences secondary to selective pressure and clonal evolution of cancer. We describe novel findings alongside data on treatment directed towards actionable aberrations acquired during the process. (

Clinical trial: NCT02014558; registered at: 〈https://ichgcp.net/clinical-trials-registry/NCT02014558〉).

Keywords: ASP2215; Acute Leukemia; Clonal evolution; FMS-like tyrosine kinase-3 (FLT3) inhibitors; Philadelphia chromosome (BCR-ABL); Ponatinib.

Figures

Fig. 1

Clinical course and various treatments received for our patient with FLT3+/trisomy 8 acute myeloid leukemia (AML). (a) The bone marrow blasts (%) are shown at different time points alongside the treatments received. (b) Schematic representation of selection pressure leading to development of a new clone of FLT3+/Trisomy 8 leukemia with the Philadelphia t(9;22) translocation. (c) The FLT3-ITD gene mutated to un-mutated peak height ratio is shown at different time points. Abbreviations: 7+3 - Induction chemotherapy with an anthracycline and cytarabine (see text for details/doses); SFN – Sorafenib; AZA – 5-Azacitadine; ASP2215 – Novel FLT3 inhibitor (NCT02014558); FluBu – Conditioning chemotherapy with fludarabine and busulfan; FluMel – Conditioning chemotherapy with Fludarabine and melphalan; MRD-SCT – Matched related stem cell transplant; MUD – SCT – Matched unrelated stem cell transplant; S-HAM – sequential high dose Ara-C chemotherapy with mitoxantrone.