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 and myelodysplastic syndrome.

Abstract

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 myelodysplastic syndrome or AML were treated with quizartinib plus AZA or LDAC. Seventy-three patients were treated (34 frontline, 39 first-salvage). Among previously untreated patients, composite response (CRc) was achieved in 13/15 (87%, 8 CR, 4 Cri, 1 CRp) treated with quizartinib/AZA and 14/19 (74%, 1 CR, 8 CRi, 5 CRp) in quizartinib/LDAC. The median OS was 19.2 months for quizartinib/AZA and 8.5 months for quizartinib/LDAC cohort; RFS was 10.5 and 6.4 months, respectively. Among previously treated patients, 16 (64%) achieved CRc in quizartinib/AZA and 4 (29%) in quizartinib/LDAC. The median OS for patients treated with quizartinib/AZA and quizartinib/LDAC was 12.8 vs. 4 months, respectively. QTc prolongation grade 3 occurred in only 1 patient in each cohort. Quizartinib-based combinations, particularly with AZA, appear effective in both frontline and first-salvage for patients with FLT3-ITD-mutated AML and are well tolerated.

• Authors: Mahesh Swaminathan, Hagop M Kantarjian, Mark Levis, Veronica Guerra, Gautam Borthakur, Yesid Alvarado, Courtney D DiNardo, Tapan Kadia, Guillermo Garcia-Manero, Maro Ohanian, Naval Daver, Marina Konopleva, Naveen Pemmaraju, Alessandra Ferrajoli, Michael Andreeff, Nitin Jain, Zeev Estrov, Elias J Jabbour, William G Wierda, Sherry Pierce, Maria Rhona Pinsoy, Lianchun Xiao, Farhad Ravandi, Jorge E Cortes
• Journal: Haematologica (Haematologica) Vol. 106 Issue 8 Pg. 2121-2130 (08 01 2021) ISSN: 1592-8721 [Electronic] Italy
• PMID: 33853292 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Benzothiazoles
• Phenylurea Compounds
• Cytarabine
• quizartinib
• fms-Like Tyrosine Kinase 3
• Azacitidine

Topics

• Azacitidine
• Benzothiazoles
• Cytarabine
• Humans
• Leukemia, Myeloid, Acute (diagnosis, drug therapy, genetics)
• Middle Aged
• Mutation
• Myelodysplastic Syndromes (diagnosis, drug therapy, genetics)
• Phenylurea Compounds
• fms-Like Tyrosine Kinase 3 (genetics)