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Acute Myeloid Leukemia
A phase I/II study of the combination of quizartinib with azacitidine or low-dose cytarabine for the treatment of patients with acute myeloid leukemia or myelodysplastic syndrome
Ferrata Storti Foundation
Haematologica 2021 Volume 106(8):2121-2130
Mahesh Swaminathan,1,2 Hagop M. Kantarjian,1 Mark Levis,3
Veronica Guerra,1 Gautam Borthakur,1 Yesid Alvarado,1 Courtney D. DiNardo,1 Tapan Kadia,1 Guillermo Garcia-Manero,1 Maro Ohanian,1 Naval Daver,1 Marina Konopleva,1 Naveen Pemmaraju,1 Alessandra Ferrajol,1
Michael Andreeff,1 Nitin Jain,1 Zeev Estrov,1 Elias J. Jabbour,1
William G. Wierda,1 Sherry Pierce,1 Maria Rhona Pinsoy,1 Lianchun Xiao,4 Farhad Ravandi1 and Jorge E. Cortes1,5
1Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX; 2Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY; 3Department of Hematological Malignancies, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD; 4Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX and 5Georgia Cancer Center at Augusta University, Augusta, GA, USA
ABSTRACT
The FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutation in acute myeloid leukemia (AML) is associated with poor prognosis. We hypothesized that quizartinib, a selective and potent FLT3 inhibitor, with azacitidine (AZA) or low-dose cytarabine (LDAC) might improve the outcomes in patients with FLT3-ITD-mutated AML. In this open-label phase I/II trial, patients of any age receiving first-salvage treatment for FLT3-ITD AML or age >60 years with untreated myelodys- plastic syndrome or AML were treated with quizartinib plus AZA or LDAC. Seventy-three patients were treated (34 frontline, 39 first salvage). With regard to previously untreated patients, the composite response (CRc) rate was 87% (n=13/15: 8 complete responses [CR], 4 CR with incomplete hematologic recovery [CRi], 1 CR without platelet recovery [CRp]) among the patients treated with quizartinib/AZA and 74% (n=14/19: 1 CR, 8 CRi, 5 CRp) among those treated with quizartinib/LDAC. The median overall survival was 19.2 months for the cohort treated with quizartinib/AZA cohort and 8.5 months for the patients treated with quizartinib/LDAC; the corresponding relapse-free survival figures were 10.5 and 6.4 months, respectively. With regard to previously treated patients, the CRc rate was 64% (n=16/25 in the quizartinib/AZA cohort and 29% (n=4/14)) in the quizartinib/LDAC cohort. The median overall survival for patients treated with quizartinib/AZA and quizartinib/LDAC was 12.8 versus 4 months, respectively. QTc prolongation grade 3 occurred in only one patient in each cohort. Quizartinib-based combinations, particularly with AZA, appear effective in both frontline and first salvage therapy for patients with FLT3-ITD-mutated AML and are well tolerated. ClinicalTrials.gov identifier: NCT01892371.
Introduction
One of the most common types of genetic alterations in acute myeloid leukemia (AML) are mutations in the FMS-like tyrosine kinase 3 (FLT3) gene, which occurs in approximately 30% of all newly diagnosed AML cases.1 Internal tandem duplica- tions (ITD) are the most frequent FLT3 mutations, occurring in about 20% to 30% of patients with AML.2,3 FLT3-ITD mutations confer an adverse prognosis in patients
Correspondence:
JORGE CORTES
jorge.cortes@augusta.edu
Received: June 15, 2020. Accepted: December 11, 2020. Pre-published: April 15, 2021.
https://doi.org/10.3324/haematol.2020.263392
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