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 - 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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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 -