Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapse.

Abstract

In a randomized trial of therapy for FMS-like tyrosine kinase-3 (FLT3) mutant acute myeloid leukemia in first relapse, 224 patients received chemotherapy alone or followed by 80 mg of the FLT3 inhibitor lestaurtinib twice daily. Endpoints included complete remission or complete remission with incomplete platelet recovery (CR/CRp), overall survival, safety, and tolerability. Correlative studies included pharmacokinetics and analysis of in vivo FLT3 inhibition. There were 29 patients with CR/CRp in the lestaurtinib arm and 23 in the control arm (26% vs 21%; P = .35), and no difference in overall survival between the 2 arms. There was evidence of toxicity in the lestaurtinib-treated patients, particularly those with plasma levels in excess of 20 μM. In the lestaurtinib arm, FLT3 inhibition was highly correlated with remission rate, but target inhibition on day 15 was achieved in only 58% of patients receiving lestaurtinib. Given that such a small proportion of patients on this trial achieved sustained FLT3 inhibition in vivo, any conclusions regarding the efficacy of combining FLT3 inhibition with chemotherapy are limited. Overall, lestaurtinib treatment after chemotherapy did not increase response rates or prolong survival of patients with FLT3 mutant acute myeloid leukemia in first relapse. This study is registered at www.clinicaltrials.gov as #NCT00079482.

• Authors: Mark Levis, Farhad Ravandi, Eunice S Wang, Maria R Baer, Alexander Perl, Steven Coutre, Harry Erba, Robert K Stuart, Michele Baccarani, Larry D Cripe, Martin S Tallman, Giovanna Meloni, Lucy A Godley, Amelia A Langston, Sergio Amadori, Ian D Lewis, Arnon Nagler, Richard Stone, Karen Yee, Anjali Advani, Dan Douer, W Wiktor-Jedrzejczak, Gunnar Juliusson, Mark R Litzow, Stephen Petersdorf, Miguel Sanz, Hagop M Kantarjian, Takashi Sato, Lothar Tremmel, Debra M Bensen-Kennedy, Donald Small, B Douglas Smith
• Journal: Blood (Blood) Vol. 117 Issue 12 Pg. 3294-301 (Mar 24 2011) ISSN: 1528-0020 [Electronic] United States
• PMID: 21270442 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Carbazoles
• Furans
• Mutant Proteins
• Protein Kinase Inhibitors
• lestaurtinib
• FLT3 protein, human
• fms-Like Tyrosine Kinase 3

Topics

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Carbazoles (administration & dosage, adverse effects, therapeutic use)
• Chemotherapy, Adjuvant
• Female
• Furans
• Humans
• Leukemia, Myeloid, Acute (drug therapy, genetics, mortality)
• Male
• Middle Aged
• Mutant Proteins (genetics)
• Protein Kinase Inhibitors (administration & dosage, adverse effects, therapeutic use)
• Recurrence
• Remission Induction
• Salvage Therapy
• Survival Analysis
• Young Adult
• fms-Like Tyrosine Kinase 3 (genetics)