FLT3 kinase inhibitors in the management of acute myeloid leukemia.
FMS-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase (TK) expressed by immature hematopoietic cells and is important for the normal development of stem cells and the immune system. Mutations of the juxtamembranous and TK domain of the gene are described in 30%-35% of patients with acute myeloid leukemia (AML). These mutations alter the biologic properties of AML and are associated with prognosis. In recent years, there has been an enormous development of potential inhibitors of FLT3 mutations. These substances are now being studied in clinical protocols. The initial trials reveal that, unlike in patients with chronic myeloid leukemia, TK inhibitor (TKI) therapy in AML is more complex. To date, most FLT3 TKIs investigated in clinical studies show a favorable toxicity profile with considerable biologic activity. However, refractory disease and/or the rapid development of resistance toward these new drugs remain major challenges. Strategies to circumvent this unsatisfactory clinical potential of FLT3 TKIs are mainly based on the combination with cytotoxic chemotherapy. Herein, we summarize results from studies using FLT3 TKIs as single agents and report on the first clinical trials investigating FLT3 TKIs in combination with chemotherapy.
Illmer
Thomas
T
Medical Clinic and Policlinic I, Hospital of the Technical University, Technical University Dresden, Fetscherstrasse 74, Dresden, Germany.
Ehninger
Gerhard
G
D001557:Benzenesulfonates / Q000627:therapeutic use; D002227:Carbazoles / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D005663:Furans; D006801:Humans; D007211:Indoles / Q000627:therapeutic use; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D010879:Piperazines / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use; D011758:Pyrroles / Q000627:therapeutic use; D011799:Quinazolines / Q000627:therapeutic use; D000077157:Sorafenib; D019311:Staurosporine / Q000031:analogs & derivatives / Q000627:therapeutic use; D000077210:Sunitinib; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors*
D001557:Benzenesulfonates; D002227:Carbazoles; D005663:Furans; D007211:Indoles; D010671:Phenylurea Compounds; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011758:Pyrroles; D011799:Quinazolines; D009536:Niacinamide; D000077157:Sorafenib; C119379:lestaurtinib; C464670:tandutinib; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D019311:Staurosporine; C059539:midostaurin; D000077210:Sunitinib