The FLT3 inhibitor tandutinib (formerly MLN518) has sequence-independent synergistic effects with cytarabine and daunorubicin

Abstract

The FLT3 inhibitor tandutinib (formerly MLN518) has sequence-independent synergistic effects with cytarabine and daunorubicin , Cell Cycle, 8:16, 2621-2630 To link to this article: https://doi.org/10.4161/cc.8.16.9355 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.

Molecular genetics in acute myeloid leukemia

“…Both compounds show oral bioavailability and are now in phase III clinical trials. These agents are also being tested in combination with conventional chemotherapy [49,50]. However, AML patients being treated with FLT3-inhibiting TKIs frequently develop resistance [51][52][53].…”

Recent Advances in Small Molecule Inhibitors of VEGFR and EGFR Signaling Pathways

“…Strong synergistic antiproliferative and proapoptotic effects were observed in Flt-3-ITD positive blasts when MLN518 was used in combination with cytarabine and daunorubicin. The addition of MLN518 lowered doses of cytarabine and daunorubicin without attenuating overall antileukemic activity and at the same time decreasing side effects [114]. A phase I clinical results with MLN518 in patients with acute myelogenous leukemia (AML) showed antileukemic activity with decreases in both peripheral and bone marrow blasts.…”

Targeting the FMS-like tyrosine kinase 3 in acute myeloid leukemia

“…A phase 2 study in relapsed/refractory patients with FLT3-ITD AML is currently recruiting patients, with interim data supporting doses of quizartinib 135 and 90 mg in men and women, respectively, due to QTc prolongation at a starting dose of 200 mg. 74 Tandutinib (MLN518) Tandutinib is more selective for FLT3 than midostaurin or lestaurtinib, although it does have some activity against plateletderived growth factor receptor-b and c-KIT. 75 Although tandutinib demonstrated some antileukemic activity as a single agent and in combination with chemotherapy in phase 1 studies, 76,77 doselimiting muscle weakness (reversible) and high rates of nausea and vomiting were observed. This may be related to the slow clearance and resultant high plasma levels of the drug.…”