title: The FLT3 inhibitor tandutinib (formerly MLN518) has sequence-independent synergistic effects with cytarabine and daunorubicin.
abstract: AML remains a difficult disease to treat. Despite response to induction chemotherapy, most patients ultimately relapse. Further, among elderly patients, aggressive therapy options are often limited due to other medical conditions and decreased tolerance of these patients to conventional chemotherapy. Internal tandem duplications (ITD) of the FLT3 juxtamembrane domain occur in 20-30% of AML patients and predict poor outcome. First clinical data with the FLT3 inhibitor tandutinib demonstrated antileukemic activity in approximately half of the patients--predominantly with FLT3 ITD positive AML. But the data also show that optimal use of tandutinib will require combination therapy with cytotoxic agents. Notably, single agent tandutinib has not been associated with myelosuppression, mucositis or cardiac toxicity--the dose limiting toxicities of AML chemotherapy. We determined the feasibility of combining tandutinib with the standard "3 + 7" induction regimen in AML and show that, in contrast to other structurally unrelated FLT3 inhibitors recently evaluated in clinical trials, the use of tandutinib displayed application sequence independent synergistic antileukemic effects in combination with cytarabine and daunorubicin. Strong synergistic antiproliferative and proapoptotic effects were thereby predominantly seen on FLT3 ITD positive blasts. Further we demonstrate, that addition of tandutinib may allow dose reduction of chemotherapy without loss of overall antileukemic activity--resulting in a potential decrease of side effects. This approach might be an interesting novel strategy especially in the treatment of elderly/comorbid patients. Our data provide a rationale for combining tandutinib with induction chemotherapy in intensified as well as in dose reduction protocols for FLT3 ITD positive AML.
authors.affiliation: Medizinische Universitätsklinik, Department of Hematology, Oncology, Rheumatology, Immunology and Pulmology, Eberhard-Karls-University, Tübingen, Germany. marcus.schittenhelm@med.uni-tuebingen.de
authors.forename: Marcus M
authors.initials: MM
authors.lastname: Schittenhelm
authors.forename: Kerstin M
authors.initials: KM
authors.lastname: Kampa
authors.forename: Kevin W H
authors.initials: KW
authors.lastname: Yee
authors.forename: Michael C
authors.initials: MC
authors.lastname: Heinrich
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003561:Cytarabine / Q000494:pharmacology*; D003630:Daunorubicin / Q000494:pharmacology*; D004357:Drug Synergism; D005434:Flow Cytometry; D018922:HL-60 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy; D010879:Piperazines / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors*
chemical_list: D000903:Antibiotics, Antineoplastic; D000964:Antimetabolites, Antineoplastic; D010879:Piperazines; D011799:Quinazolines; D003561:Cytarabine; C464670:tandutinib; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D003630:Daunorubicin