TY - JOUR
T1 - Clinical characteristics and outcomes in patients with acute myeloid leukemia with concurrent FLT3-ITD and IDH mutations
AU - Shoukier, Mahran
AU - Kadia, Tapan
AU - Konopleva, Marina
AU - Alotaibi, Ahmad S.
AU - Alfayez, Mansour
AU - Loghavi, Sanam
AU - Patel, Keyur P.
AU - Kanagal-Shamanna, Rashmi
AU - Cortes, Jorge
AU - Samra, Bachar
AU - Jabbour, Elias
AU - Garcia-Manero, Guillermo
AU - Takahashi, Koichi
AU - Pierce, Sherry
AU - Short, Nicholas J.
AU - Yilmaz, Musa
AU - Sasaki, Koji
AU - Masarova, Lucia
AU - Pemmaraju, Naveen
AU - Borthakur, Gautam
AU - Kantarjian, Hagop M.
AU - Ravandi, Farhad
AU - DiNardo, Courtney D.
AU - Daver, Naval
N1 - Funding Information:
Supported in part by The University of Texas MD Anderson Cancer Center Support Grant (CA016672), The University of Texas MD Anderson Cancer Center Leukemia SPORE (CA100632), the Charif Souki Cancer Research Fund, and generous philanthropic contributions to The University of Texas MD Anderson Cancer Center Moon Shots Program.
Funding Information:
Tapan Kadia has received grants from Bristol‐Myers Squibb, Celgene, Pfizer, Amgen, and AstraZeneca; grants and personal fees from Jazz Pharmaceuticals and Genentech; and personal fees from Novartis and Agios for work performed outside of the current study. Jorge Cortes has received grants to his institution and consulting fees from Daiichi‐Sankyo, Novartis, and Forma Therapeutics and grants from Astellas and Arog for work performed outside of the current study. Koichi Takahashi has acted as a paid advisor for SymBio Pharmaceuticals, Celgene, Novartis, and GlaxoSmithKline for work performed outside of the current study. Nicholas J. Short has received grants from Astellas Pharma Inc, grants and personal fees from Takeda Oncology, and personal fees from AstraZeneca and Amgen for work performed outside of the current study. Koji Sasaki has received research funding from Novartis, has acted as a paid member of the advisory board for Pfizer Japan and Daiichi‐Sankyo, and has received honorarium from Otsuka for work performed outside of the current study. Hagop M. Kantarjian has received grants and honoraria from AbbVie, Amgen, Daiichi‐Sankyo, Novartis, and Pfizer; has received grants from Ascentage, Bristol‐Myers Squibb, Immunogen, Jazz Pharmaceuticals, and Sanofi; has acted as a paid member of the advisory board for Actinium; and has received honoraria from Adaptive Biotechnologies, Aptitude Health, BioAscend, Delta Fly, Janssen Global, Oxford Biomedical, and Takeda for work performed as part of the current study. Courtney D. DiNardo has acted as a paid consultant for and/or held an advisory role with AbbVie, Agios, Celgene, Daiichi‐Sankyo, Jazz Pharmaceuticals, Syros, and Notable Labs and received institutional research funding from AbbVie, Agios, Calithera, Celgene, and Daiichi‐Sankyo for work performed outside of the current study. Naval Daver has received research funding from Daiichi‐Sankyo, Bristol‐Myers Squibb, Pfizer, Karyopharm, Sevier, Genentech, and ImmunoGen and has served in a consulting or advisory role for Daiichi‐Sankyo, Bristol‐Myers Squibb, Pfizer, Novartis, Celgene, AbbVie, and Agios. The other authors made no disclosures.
Publisher Copyright:
© 2020 American Cancer Society
PY - 2021/2/1
Y1 - 2021/2/1
N2 - Background: Isocitrate dehydrogenase (IDH1 and IDH2) mutations commonly co-occur with FMS-like tyrosine kinase 3 (FLT3) mutations in patients with acute myeloid leukemia (AML). Methods: The authors reviewed cases of patients with FLT3-internal tandem duplication (FLT3-ITD)–mutated AML with concurrent IDH mutations diagnosed between January 2011 and December 2018. Results: A total of 91 patients with FLT3-ITD and IDH1 or IDH2 “double-mutated” AML were identified; 36 patients had concurrent FLT3-ITD/IDH1 mutations (18 in the frontline and 18 in the recurrent and/or refractory [R/R] setting) and 55 patients had concurrent FLT3-ITD/IDH2 mutations (37 in the frontline and 18 in the R/R setting). FLT3 and/or IDH inhibitors (FLT3Is and/or IDHIs) were given as a single agent or in combination with cytotoxic chemotherapy (CCT) or low-intensity therapy (LIT). Rates of complete remission (CR) plus CR with incomplete count recovery (CRi) with the use of CCT and FLT3Is were 100% and 64%, respectively, in patients in the frontline and R/R settings. CCT with IDHIs was given in 2 frontline patients and both achieved a CR. LIT with FLT3Is in the frontline and R/R settings demonstrated CR and CRi rates of 67% and 28%, respectively. Single-agent FLT3Is and IDHIs demonstrated limited activity with a CR and/or CRi rate of 14% in patients with disease in the R/R setting. Conclusions: The combination of FLT3I-based therapy with CCT or LIT appeared to be effective in both the frontline and R/R settings among patients with FLT3-ITD/IDH co-mutated disease. Fewer patients with double-mutated disease received CCT or LIT with IDH1/2 inhibitor in the frontline setting; however, high response rates also were noted with this approach. Lay Summary: The prognostic influence of FMS-like tyrosine kinase 3–internal tandem duplication (FLT3-ITD) and isocitrate dehydrogenase (IDH) co-mutation status on outcomes in patients with acute myeloid leukemia receiving an FLT3 inhibitor, non–FLT3/IDH inhibitor–based regimens, or an IDH inhibitor is unclear. This is an important clinical question because multiple targeted therapies for FLT3 and IDH1/2 mutations have become available. The results of the current study demonstrated that a combination of a FLT3 inhibitor with cytotoxic chemotherapy or low-intensity therapy appears to be an effective approach in patients with FLT3-ITD/IDH co-mutated disease in both the frontline and recurrent and/or refractory settings. Fewer dual-mutated patients received cytotoxic chemotherapy or low-intensity therapy with an IDH1/2 inhibitor in the frontline setting; however, excellent responses also were observed with this approach.
AB - Background: Isocitrate dehydrogenase (IDH1 and IDH2) mutations commonly co-occur with FMS-like tyrosine kinase 3 (FLT3) mutations in patients with acute myeloid leukemia (AML). Methods: The authors reviewed cases of patients with FLT3-internal tandem duplication (FLT3-ITD)–mutated AML with concurrent IDH mutations diagnosed between January 2011 and December 2018. Results: A total of 91 patients with FLT3-ITD and IDH1 or IDH2 “double-mutated” AML were identified; 36 patients had concurrent FLT3-ITD/IDH1 mutations (18 in the frontline and 18 in the recurrent and/or refractory [R/R] setting) and 55 patients had concurrent FLT3-ITD/IDH2 mutations (37 in the frontline and 18 in the R/R setting). FLT3 and/or IDH inhibitors (FLT3Is and/or IDHIs) were given as a single agent or in combination with cytotoxic chemotherapy (CCT) or low-intensity therapy (LIT). Rates of complete remission (CR) plus CR with incomplete count recovery (CRi) with the use of CCT and FLT3Is were 100% and 64%, respectively, in patients in the frontline and R/R settings. CCT with IDHIs was given in 2 frontline patients and both achieved a CR. LIT with FLT3Is in the frontline and R/R settings demonstrated CR and CRi rates of 67% and 28%, respectively. Single-agent FLT3Is and IDHIs demonstrated limited activity with a CR and/or CRi rate of 14% in patients with disease in the R/R setting. Conclusions: The combination of FLT3I-based therapy with CCT or LIT appeared to be effective in both the frontline and R/R settings among patients with FLT3-ITD/IDH co-mutated disease. Fewer patients with double-mutated disease received CCT or LIT with IDH1/2 inhibitor in the frontline setting; however, high response rates also were noted with this approach. Lay Summary: The prognostic influence of FMS-like tyrosine kinase 3–internal tandem duplication (FLT3-ITD) and isocitrate dehydrogenase (IDH) co-mutation status on outcomes in patients with acute myeloid leukemia receiving an FLT3 inhibitor, non–FLT3/IDH inhibitor–based regimens, or an IDH inhibitor is unclear. This is an important clinical question because multiple targeted therapies for FLT3 and IDH1/2 mutations have become available. The results of the current study demonstrated that a combination of a FLT3 inhibitor with cytotoxic chemotherapy or low-intensity therapy appears to be an effective approach in patients with FLT3-ITD/IDH co-mutated disease in both the frontline and recurrent and/or refractory settings. Fewer dual-mutated patients received cytotoxic chemotherapy or low-intensity therapy with an IDH1/2 inhibitor in the frontline setting; however, excellent responses also were observed with this approach.
KW - FLT3 and/or IDH inhibitors
KW - FMS-like tyrosine kinase 3 (FLT3) with the internal tandem duplication (ITD) mutation
KW - acute myeloid leukemia
KW - isocitrate dehydrogenase (IDH) mutations
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UR - http://www.scopus.com/inward/citedby.url?scp=85094204092&partnerID=8YFLogxK
U2 - 10.1002/cncr.33293
DO - 10.1002/cncr.33293
M3 - Article
C2 - 33119202
AN - SCOPUS:85094204092
SN - 0008-543X
VL - 127
SP - 381
EP - 390
JO - Cancer
JF - Cancer
IS - 3
ER -
