Abstract 3605


AC220 is a novel class III receptor tyrosine kinase (RTK) inhibitor that is potent and highly selective for mutant and wild type (WT) FLT3 and other class III RTK's including KIT, CSF1R, RET and PDGFR. In childhood acute myeloid leukemia (AML), ∼18% of children have FLT3 internal tandem duplication mutations (FLT3-ITD), and ∼10% high WT FLT3 expression. FLT3-ITD is associated with poor prognosis. In childhood acute lymphoblastic leukemia (ALL), the highest levels of FLT3 mRNA expression occur in cases of infants (80%) and childhood ALL with MLL rearrangements (MLL-r) (5%), both conferring poor prognosis.1,2

Study Design:

TACL 2009–004is a first-in-children study using AC220 in combination with cytarabine and etoposide. Children > 1 month and < 21 years of age with relapsed/refractory AML or MLL-rearranged ALL are eligible. A standard 3+3 dose escalation design is utilized. The three doses tested (25, 40 and 60 mg/m2/day) are significantly lower than those tested in adults. Dose escalation past 60 mg/m2 occurs only if adequate biologic activity as determined by a plasma inhibitory assay (PIA) is not achieved. Intravenous (IV) cytarabine (1 gm/m2/dose every 12 hours) and IV etoposide (150 mg/m2/dose daily) are given over 5 days. AC220 is administered once daily as an oral solution on days 7–28. Patients can receive up to 2 courses of therapy. PIA testing is performed at trough time points weekly during exposure to AC220 to determine biologic activity.


To date, 13 patients (pts) were enrolled and 12 are evaluable for toxicity and response. One pt died from infectious complications (not drug-related) after a single dose of AC220 and was replaced. Median age at study entry was 10.2 years (range 11 mo – 20 yrs), average number of prior regimens was 2.8 (range 1–5), and 5 pts had prior stem cell transplant. Nine pts had relapsed AML, 2 had relapsed MLL-r ALL, and 1 had secondary AML. Of patients with AML, 4 had FLT3-ITD mutations and one had a D835 mutation. Toxicities were consistent with intensive relapsed leukemia regimens. Across all dose levels, non-hematologic toxicities ≥ grade 3 attributed to AC220 included vomiting (n=1), elevated transaminases (n=1), anorexia (n=2), and infection (n=3). One pt experienced a dose-limiting toxicity (DLT) on dose level 2 (40 mg/m2/day) of recurrent grade 3 elevated lipase. Dose level 2 was expanded to 6 pts without additional DLTs. Of 3 pts treated at 60 mg/m2/day, there have been no DLTs. Near total (>99%) inhibition of FLT3 phosphorylation by PIA is seen in every patient across all dose levels. Of 12 pts evaluable for response to date, 1 patient achieved a complete response (CR), 3 achieved complete response with incomplete neutrophil and platelet recovery (CRi), 5 had stable disease (SD), and 3 had progressive disease (PD). Responses in the 4 FLT3-ITD pts include 1 CR, 2 CRi and 1 SD. The FLT3-ITD patient with SD had reduction in marrow blasts without peripheral blood count recovery. An additional 6 pts will be enrolled at 60 mg/m2/day to complete safety evaluation and confirm biologic activity.


AC220 plus intensive chemotherapy is well tolerated at doses up to 60 mg/m2/day with near complete inhibition of FLT3 phosphorylation in all pts tested to date. Response rates to date in pre-treated children with relapsed FLT3-ITD AML are encouraging.


Off Label Use: AC220 in relapsed/refractory pediatric acute leukemia. Gammon:Ambit Biosciences: Employment.


Author notes


Asterisk with author names denotes non-ASH members.