Display Settings:

Format

Send to:

Choose Destination
See comment in PubMed Commons below
J Clin Oncol. 2009 Oct 1;27(28):4741-6. doi: 10.1200/JCO.2009.21.8172. Epub 2009 Aug 3.

Phase I/II trial of AEG35156 X-linked inhibitor of apoptosis protein antisense oligonucleotide combined with idarubicin and cytarabine in patients with relapsed or primary refractory acute myeloid leukemia.

Author information

  • 1Princess Margaret Hospital, Ontario Cancer Institute, Toronto, Ontario, Canada M5G 2M9. aaron.schimmer@utoronto.ca

Abstract

PURPOSE:

X-linked inhibitor of apoptosis protein (XIAP) is an inhibitor of caspases 3 and 9 which are overexpressed in acute myeloid leukemia (AML) and may contribute to chemoresistance. We report on a phase I/II trial of the XIAP antisense oligonucleotide AEG35156 in combination with reinduction chemotherapy.

PATIENTS AND METHODS:

Twenty-four patients with rapidly relapsed or refractory AML were treated with escalating doses of AEG35156 (12 to 250 mg/m(2)) as an intravenous solution over 2 hours and 32 patients were treated with the highest planned dose of 350 mg/m(2) in combination with idarubicin and high-dose cytarabine reinduction chemotherapy. Correlative studies were conducted to determine the effects of AEG35156 on levels of XIAP mRNA.

RESULTS:

Knockdown of XIAP mRNA during treatment increased with the dose of the antisense. All patients who received 350 mg/m(2) of AEG35156 had higher than 30% target knockdown with a median maximal knockdown of 90% (range, 48% to 100%). The overall response rate was higher among the patients receiving the highest dose of AEG35156. In this group, 15 (47%) of 32 patients achieved complete response (CR)/CR with incomplete platelet count recovery (CRp) compared with only one (4%) of 24 receiving 12 to 250 mg/m(2) AEG35156. Among the patients receiving 350 mg/m(2) of AEG35156 in combination with chemotherapy, 10 (91%) of 11 who were refractory to a single induction chemotherapy regimen achieved CR/CRp after reinduction with AEG35156 and chemotherapy. AEG35156 was well tolerated save for two cases of peripheral neuropathy in patients receiving multiple doses of AEG35156.

CONCLUSION:

At the highest dose tested, AEG35156 knocks down its target and appears very effective when combined with chemotherapy in patients with AML refractory to a single induction regimen.

PMID:
19652057
[PubMed - indexed for MEDLINE]
Free full text
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire
    Loading ...
    Write to the Help Desk