Clonal evolution of acute myeloid leukemia with FLT3-ITD mutation under treatment with midostaurin

被引：121

作者：

Schmalbrock, Laura K. ^{[1
,2
,3
,4
,5
]}

Dolnik, Anna ^{[3
,4
,6
]}

Cocciardi, Sibylle ^{[1
]}

Straeng, Eric ^{[3
,4
,6
]}

Theis, Frauke ^{[1
]}

Jahn, Nikolaus ^{[1
]}

Panina, Ekaterina ^{[1
]}

Blaette, Tamara J. ^{[3
,4
,6
]}

Herzig, Julia ^{[1
]}

Skambraks, Sabrina ^{[1
]}

Ruecker, Frank G. ^{[1
]}

Gaidzik, Verena, I ^{[1
]}

Paschka, Peter ^{[1
]}

Fiedler, Walter ^{[7
]}

Salih, Helmut R. ^{[8
]}

Wulf, Gerald ^{[9
]}

Schroeder, Thomas ^{[10
]}

Luebbert, Michael ^{[11
]}

Schlenk, Richard F. ^{[12
,13
,14
]}

Thol, Felicitas ^{[15
]}

Heuser, Michael ^{[15
]}

Larson, Richard A. ^{[16
]}

Ganser, Arnold ^{[15
]}

Stunnenberg, Hendrik G. ^{[17
]}

Minucci, Saverio ^{[18
]}

Stone, Richard M. ^{[19
]}

Bloomfield, Clara D. ^{[20
]}

Doehner, Hartmut ^{[1
]}

Doehner, Konstanze ^{[1
]}

Bullinger, Lars ^{[3
,4
,5
,6
]}

机构：

[1] Univ Hosp Ulm, Dept Internal Med 3, Albert Einstein Allee 23, D-89081 Ulm, Germany

[2] Charite Univ Med Berlin, Dept Hematol Oncol & Canc Immunol, Campus Benjamin Franklin, Berlin, Germany

[3] Free Univ Berlin, Berlin, Germany

[4] Humboldt Univ, Berlin, Germany

[5] Charite Univ Med Berlin, Berlin Inst Hlth, Berlin, Germany

[6] Charite Univ Med Berlin, Dept Hematol Oncol & Tumorimmunol, Campus Virchow Klinikum, Berlin, Germany

[7] Hubertus Wald Univ Canc Ctr, Univ Med Ctr Hamburg Eppendorf, Dept Oncol Hematol & Bone Marrow Transplantat, Sect Pneumol, Hamburg, Germany

[8] Eberhard Karls Univ Tubingen, Dept Hematol & Oncol, Tubingen, Germany

[9] Georg August Univ Gottingen, Dept Hematol & Oncol, Gottingen, Germany

[10] Heinrich Heine Univ Dusseldorf, Dept Hematol Oncol & Clin Immunol, Dusseldorf, Germany

[11] Univ Freiburg, Dept Hematol Oncol & Stem Cell Transplantat, Fac Med, Med Ctr, Freiburg, Germany

[12] German Canc Res Ctr, Natl Ctr Tumor Dis, NCT Trial Ctr, Heidelberg, Germany

[13] Heidelberg Univ Hosp, Heidelberg, Germany

[14] Heidelberg Univ Hosp, Dept Internal Med 5, Heidelberg, Germany

[15] Hannover Med Sch, Dept Hematol Hemostasis Oncol & Stem Cell Transpl, Hannover, Germany

[16] Univ Chicago, Dept Med, Sect Hematol Oncol, 5841 S Maryland Ave, Chicago, IL 60637 USA

[17] Radboud Univ Nijmegen, Fac Sci, Radboud Inst Mol Life Sci, Dept Mol Biol, Nijmegen, Netherlands

[18] European Inst Oncol, Dept Expt Oncol, Milan, Italy

[19] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[20] Ohio State Univ, Dept Internal Med, Div Hematol, Comprehens Canc Ctr, Columbus, OH 43210 USA

来源：

BLOOD | 2021年 / 137卷 / 22期

关键词：

INTERNAL TANDEM DUPLICATION; MINIMAL RESIDUAL DISEASE; KINASE INHIBITOR; NORMAL CYTOGENETICS; WILD-TYPE; RESISTANCE; AML; CHEMOTHERAPY; DIAGNOSIS; PKC412;

D O I：

10.1182/blood.2020007626

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

In the international randomized phase 3 RATIFY (Randomized AML Trial In FLT3 in patients less than 60 Years old) trial, the multikinase inhibitor midostaurin significantly improved overall and event-free survival in patients 18 to 59 years of age with FLT3-mutated acute myeloid leukemia (AML). However, only 59% of patients in the midostaurin arm achieved protocol-specified complete remission (CR), and almost half of patients achieving CR relapsed. To explore underlyingmechanisms of resistance, we studied patterns of clonal evolution in patients with FLT3-internal tandem duplications (ITD)-positive AML who were entered in the RATIFY or German-Austrian AcuteMyeloid Leukemia Study Group 16-10 trial and received treatment with midostaurin. To this end, paired samples from 54 patients obtained at time of diagnosis and at time of either relapsed or refractory disease were analyzed using conventional Genescan-based testing for FLT3-ITD and whole exome sequencing. At the time of disease resistance or progression, almost half of the patients (46%) became FLT3-ITD negative but acquired mutations in signaling pathways (eg, MAPK), thereby providing a new proliferative advantage. In cases with FLT3-ITD persistence, the selection of resistant ITD clones was found in 11% as potential drivers of disease. In 32% of cases, no FLT3-ITD mutational change was observed, suggesting either resistance mechanisms bypassing FLT3 inhibition or loss of midostaurin inhibitory activity because of inadequate drug levels. In summary, our study provides novel insights into the clonal evolution and resistance mechanisms of FLT3-ITD-mutated AML under treatment with midostaurin in combination with intensive chemotherapy.

引用

页码：3093 / 3104

页数：12

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