Prognostic significance of baseline FLT3-ITD mutant allele level in acute myeloid leukemia treated with intensive chemotherapy with/without sorafenib.

Abstract

Internal tandem duplication (ITD) of the fms-related tyrosine kinase-3 gene (FLT3) confer a poor prognosis in adult AML. Studies have reported that a higher mutant allelic burden is associated with a worse prognosis. Adult patients with FLT3-ITD mutated AML treated at our institution were identified. Patients were assigned into 2 groups; patients who received idarubicin and cytarabine (IA, group one) containing induction, and who received sorafenib in addition to IA containing regimens at induction (group two). The optimal FLT3-ITD mutant allele cut-off was defined as the cut-off to divide the whole cohort with the highest statistical significance. A total of 183 patients including 104 (57%) in group one and 79 (43%) in group two were identified. The complete remission (CR)/CR with incomplete hematologic recovery (CRi) for group one and group two were 85% and 99%, respectively (P = .004). The median relapse free survival (RFS) for group one and two were 12 and 45 months, respectively (P = .02). The median overall survival (mOS) was 17 months in group one, and has not been reached in group two (P = .008). The optimal FLT3-ITD mutant allele cut-off for OS was 6.9% in group one, there was no optimal cut-off in group two. On multivariate analysis, poor performance status (PS) (P = .003), sorafenib (P = .01), and presenting white blood cells (WBC) (P < .001) were independent predictors of OS. Higher FLT3-ITD allele burden is associated with a worse outcome in patients treated with IA-based chemotherapy. Addition of sorafenib to chemotherapy not only nullifies the negative prognostic impact of higher allele burden, but also improves outcome of FLT3-ITD mutated AML patients regardless of the allele burden.

• Authors: Fevzi Yalniz, Iman Abou Dalle, Hagop Kantarjian, Gautam Borthakur, Tapan Kadia, Keyur Patel, Sanam Loghavi, Guillermo Garcia-Manero, Koji Sasaki, Naval Daver, Courtney DiNardo, Naveen Pemmaraju, Nicholas J Short, Musa Yilmaz, Prithviraj Bose, Kiran Naqvi, Sherry Pierce, Graciela M Nogueras González, Marina Konopleva, Michael Andreeff, Jorge Cortes, Farhad Ravandi
• Journal: American journal of hematology (Am J Hematol) Vol. 94 Issue 9 Pg. 984-991 (09 2019) ISSN: 1096-8652 [Electronic] United States
• PMID: 31237017 (Publication Type: Clinical Trial, Journal Article)
• Copyright: © 2019 Wiley Periodicals, Inc.

Chemical References

• Cytarabine
• Sorafenib
• FLT3 protein, human
• fms-Like Tyrosine Kinase 3
• Idarubicin

Topics

• Adolescent
• Adult
• Aged
• Alleles
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage)
• Cytarabine (administration & dosage)
• Disease-Free Survival
• Female
• Follow-Up Studies
• Humans
• Idarubicin (administration & dosage)
• Leukemia, Myeloid, Acute (drug therapy, enzymology, genetics, mortality)
• Male
• Middle Aged
• Mutation
• Retrospective Studies
• Sorafenib (administration & dosage)
• Survival Rate
• Tandem Repeat Sequences
• fms-Like Tyrosine Kinase 3 (genetics, metabolism)