Midostaurin in patients with acute myeloid leukemia and FLT3-TKD mutations: A subanalysis from the RATIFY trial

Maria Teresa Voso; Richard A. Larson; Dan Jones; Guido Marcucci; Thomas Prior; Jürgen Krauter; Michael Heuser; Serena Lavorgna; Josep Nomdedeu; Susan M. Geyer; Alison Walker; Andrew H. Wei; Jorge Sierra; Miguel A. Sanz; Joseph M. Brandwein; Theo M. de Witte; Joop H. Jansen; Dietger Niederwieser; Frederick R. Appelbaum; Bruno C. Medeiros; Martin S. Tallman; Richard F. Schlenk; Arnold Ganser; Sergio Amadori; Yuan Cheng; Yin Miao Chen; Celine Pallaud; Ling Du; Alfonso Piciocchi; Gerhard Ehninger; John Byrd; Christian Thiede; Konstanze Döhner; Richard M. Stone; Hartmut Döhner; Clara D. Bloomfield; Francesco Lo-Coco

doi:10.1182/BLOODADVANCES.2020002904

Midostaurin in patients with acute myeloid leukemia and FLT3-TKD mutations: A subanalysis from the RATIFY trial

Maria Teresa Voso^*, Richard A. Larson, Dan Jones, Guido Marcucci, Thomas Prior, Jürgen Krauter, Michael Heuser, Serena Lavorgna, Josep Nomdedeu, Susan M. Geyer, Alison Walker, Andrew H. Wei, Jorge Sierra, Miguel A. Sanz, Joseph M. Brandwein, Theo M. de Witte, Joop H. Jansen, Dietger Niederwieser, Frederick R. Appelbaum, Bruno C. MedeirosMartin S. Tallman, Richard F. Schlenk, Arnold Ganser, Sergio Amadori, Yuan Cheng, Yin Miao Chen, Celine Pallaud, Ling Du, Alfonso Piciocchi, Gerhard Ehninger, John Byrd, Christian Thiede, Konstanze Döhner, Richard M. Stone, Hartmut Döhner, Clara D. Bloomfield, Francesco Lo-Coco

^*Corresponding author for this work

Medicine, Hematology Oncology Division

Research output: Contribution to journal › Article › peer-review

46 Scopus citations

Abstract

The results from the RATIFY trial (ClinicalTrials.gov: NCT00651261; CALGB 10603) showed that midostaurin combined with standard chemotherapy significantly improved outcomes in patients with FMS-like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia (AML), compared with placebo. In this post hoc subgroup analysis from the trial, we evaluated the impact of midostaurin in 163 patients with FLT3-tyrosine kinase domain (TKD) mutations. At a median follow-up of 60.7 months (95% CI, 55.0-70.8), the 5-year event-free survival (EFS) rate was significantly higher in patients treated with midostaurin than in those treated with placebo (45.2% vs 30.1%; P 5.044). A trend toward improved disease-free survival was also observed with midostaurin (67.3% vs 53.4%; P 5.089), whereas overall survival (OS) was similar in the 2 groups. Patients with AML and NPM1^mut/FLT3-TKD^mut or core binding factor (CBF)-rearranged/FLT3-TKD^mut genotypes had significantly prolonged OS with or without censoring at hematopoietic cell transplantation (HCT), compared with NPM1^WT/CBF-negative AMLs. The multivariable model for OS and EFS adjusted for allogeneic HCT in first complete remission as a time-dependent covariable, revealed NPM1 mutations and CBF rearrangements as significant favorable factors. These data show that NPM1 mutations or CBF rearrangements identify favorable prognostic groups in patients with FLT3-TKD AMLs, independent of other factors, also in the context of midostaurin treatment.

Original language	English (US)
Pages (from-to)	4945-4954
Number of pages	10
Journal	Blood Advances
Volume	4
Issue number	19
DOIs	https://doi.org/10.1182/BLOODADVANCES.2020002904
State	Published - Oct 2020

Funding

The authors acknowledge the support of the National Institutes of Health, National Cancer Institute grants U24 CA196171 and U10 CA180821 (Alliance for Clinical Trials in Oncology), UG1 CA233338 (C.D.B.), and U10 CA180867 (Dana-Farber Cancer Institute); AIRC 5x1000 call “Metastatic disease: the key unmet need in oncology to MYNERVA” project, #21267 (MYeloid NEoplasms Research Venture AIRC) (M.T.V.); the Deutsche Forschungs-gemeinschaft (SFB 1074, project B3) (K.D.); and Catalan and Spanish government grants (2017 SGR 1395 and PERIS SLT002/ 16/00433 and ISCIII FIS PI17/01246) (J.S.). Study CALGB (Alliance) 10603 was funded in part by Novartis (CALGB is now part of the Alliance for Clinical Trials in Oncology).

ASJC Scopus subject areas

Hematology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1182/BLOODADVANCES.2020002904

Cite this

Voso, M. T., Larson, R. A., Jones, D., Marcucci, G., Prior, T., Krauter, J., Heuser, M., Lavorgna, S., Nomdedeu, J., Geyer, S. M., Walker, A., Wei, A. H., Sierra, J., Sanz, M. A., Brandwein, J. M., de Witte, T. M., Jansen, J. H., Niederwieser, D., Appelbaum, F. R., ... Lo-Coco, F. (2020). Midostaurin in patients with acute myeloid leukemia and FLT3-TKD mutations: A subanalysis from the RATIFY trial. Blood Advances, 4(19), 4945-4954. https://doi.org/10.1182/BLOODADVANCES.2020002904

@article{ad127ce836f946eb8bc73c029d4d2335,

title = "Midostaurin in patients with acute myeloid leukemia and FLT3-TKD mutations: A subanalysis from the RATIFY trial",

abstract = "The results from the RATIFY trial (ClinicalTrials.gov: NCT00651261; CALGB 10603) showed that midostaurin combined with standard chemotherapy significantly improved outcomes in patients with FMS-like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia (AML), compared with placebo. In this post hoc subgroup analysis from the trial, we evaluated the impact of midostaurin in 163 patients with FLT3-tyrosine kinase domain (TKD) mutations. At a median follow-up of 60.7 months (95% CI, 55.0-70.8), the 5-year event-free survival (EFS) rate was significantly higher in patients treated with midostaurin than in those treated with placebo (45.2% vs 30.1%; P 5.044). A trend toward improved disease-free survival was also observed with midostaurin (67.3% vs 53.4%; P 5.089), whereas overall survival (OS) was similar in the 2 groups. Patients with AML and NPM1mut/FLT3-TKDmut or core binding factor (CBF)-rearranged/FLT3-TKDmut genotypes had significantly prolonged OS with or without censoring at hematopoietic cell transplantation (HCT), compared with NPM1WT/CBF-negative AMLs. The multivariable model for OS and EFS adjusted for allogeneic HCT in first complete remission as a time-dependent covariable, revealed NPM1 mutations and CBF rearrangements as significant favorable factors. These data show that NPM1 mutations or CBF rearrangements identify favorable prognostic groups in patients with FLT3-TKD AMLs, independent of other factors, also in the context of midostaurin treatment.",

author = "Voso, {Maria Teresa} and Larson, {Richard A.} and Dan Jones and Guido Marcucci and Thomas Prior and J{\"u}rgen Krauter and Michael Heuser and Serena Lavorgna and Josep Nomdedeu and Geyer, {Susan M.} and Alison Walker and Wei, {Andrew H.} and Jorge Sierra and Sanz, {Miguel A.} and Brandwein, {Joseph M.} and {de Witte}, {Theo M.} and Jansen, {Joop H.} and Dietger Niederwieser and Appelbaum, {Frederick R.} and Medeiros, {Bruno C.} and Tallman, {Martin S.} and Schlenk, {Richard F.} and Arnold Ganser and Sergio Amadori and Yuan Cheng and Chen, {Yin Miao} and Celine Pallaud and Ling Du and Alfonso Piciocchi and Gerhard Ehninger and John Byrd and Christian Thiede and Konstanze D{\"o}hner and Stone, {Richard M.} and Hartmut D{\"o}hner and Bloomfield, {Clara D.} and Francesco Lo-Coco",

note = "Funding Information: The authors acknowledge the support of the National Institutes of Health, National Cancer Institute grants U24 CA196171 and U10 CA180821 (Alliance for Clinical Trials in Oncology), UG1 CA233338 (C.D.B.), and U10 CA180867 (Dana-Farber Cancer Institute); AIRC 5x1000 call “Metastatic disease: the key unmet need in oncology to MYNERVA” project, #21267 (MYeloid NEoplasms Research Venture AIRC) (M.T.V.); the Deutsche Forschungs-gemeinschaft (SFB 1074, project B3) (K.D.); and Catalan and Spanish government grants (2017 SGR 1395 and PERIS SLT002/ 16/00433 and ISCIII FIS PI17/01246) (J.S.). Study CALGB (Alliance) 10603 was funded in part by Novartis (CALGB is now part of the Alliance for Clinical Trials in Oncology). Publisher Copyright: {\textcopyright} 2020 by The American Society of Hematology",

year = "2020",

month = oct,

doi = "10.1182/BLOODADVANCES.2020002904",

language = "English (US)",

volume = "4",

pages = "4945--4954",

journal = "Blood Advances",

issn = "2473-9529",

publisher = "American Society of Hematology",

number = "19",

}

Voso, MT, Larson, RA, Jones, D, Marcucci, G, Prior, T, Krauter, J, Heuser, M, Lavorgna, S, Nomdedeu, J, Geyer, SM, Walker, A, Wei, AH, Sierra, J, Sanz, MA, Brandwein, JM, de Witte, TM, Jansen, JH, Niederwieser, D, Appelbaum, FR, Medeiros, BC, Tallman, MS, Schlenk, RF, Ganser, A, Amadori, S, Cheng, Y, Chen, YM, Pallaud, C, Du, L, Piciocchi, A, Ehninger, G, Byrd, J, Thiede, C, Döhner, K, Stone, RM, Döhner, H, Bloomfield, CD & Lo-Coco, F 2020, 'Midostaurin in patients with acute myeloid leukemia and FLT3-TKD mutations: A subanalysis from the RATIFY trial', Blood Advances, vol. 4, no. 19, pp. 4945-4954. https://doi.org/10.1182/BLOODADVANCES.2020002904

TY - JOUR

T1 - Midostaurin in patients with acute myeloid leukemia and FLT3-TKD mutations

T2 - A subanalysis from the RATIFY trial

AU - Voso, Maria Teresa

AU - Larson, Richard A.

AU - Jones, Dan

AU - Marcucci, Guido

AU - Prior, Thomas

AU - Krauter, Jürgen

AU - Heuser, Michael

AU - Lavorgna, Serena

AU - Nomdedeu, Josep

AU - Geyer, Susan M.

AU - Walker, Alison

AU - Wei, Andrew H.

AU - Sierra, Jorge

AU - Sanz, Miguel A.

AU - Brandwein, Joseph M.

AU - de Witte, Theo M.

AU - Jansen, Joop H.

AU - Niederwieser, Dietger

AU - Appelbaum, Frederick R.

AU - Medeiros, Bruno C.

AU - Tallman, Martin S.

AU - Schlenk, Richard F.

AU - Ganser, Arnold

AU - Amadori, Sergio

AU - Cheng, Yuan

AU - Chen, Yin Miao

AU - Pallaud, Celine

AU - Du, Ling

AU - Piciocchi, Alfonso

AU - Ehninger, Gerhard

AU - Byrd, John

AU - Thiede, Christian

AU - Döhner, Konstanze

AU - Stone, Richard M.

AU - Döhner, Hartmut

AU - Bloomfield, Clara D.

AU - Lo-Coco, Francesco

N1 - Funding Information: The authors acknowledge the support of the National Institutes of Health, National Cancer Institute grants U24 CA196171 and U10 CA180821 (Alliance for Clinical Trials in Oncology), UG1 CA233338 (C.D.B.), and U10 CA180867 (Dana-Farber Cancer Institute); AIRC 5x1000 call “Metastatic disease: the key unmet need in oncology to MYNERVA” project, #21267 (MYeloid NEoplasms Research Venture AIRC) (M.T.V.); the Deutsche Forschungs-gemeinschaft (SFB 1074, project B3) (K.D.); and Catalan and Spanish government grants (2017 SGR 1395 and PERIS SLT002/ 16/00433 and ISCIII FIS PI17/01246) (J.S.). Study CALGB (Alliance) 10603 was funded in part by Novartis (CALGB is now part of the Alliance for Clinical Trials in Oncology). Publisher Copyright: © 2020 by The American Society of Hematology

PY - 2020/10

Y1 - 2020/10

N2 - The results from the RATIFY trial (ClinicalTrials.gov: NCT00651261; CALGB 10603) showed that midostaurin combined with standard chemotherapy significantly improved outcomes in patients with FMS-like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia (AML), compared with placebo. In this post hoc subgroup analysis from the trial, we evaluated the impact of midostaurin in 163 patients with FLT3-tyrosine kinase domain (TKD) mutations. At a median follow-up of 60.7 months (95% CI, 55.0-70.8), the 5-year event-free survival (EFS) rate was significantly higher in patients treated with midostaurin than in those treated with placebo (45.2% vs 30.1%; P 5.044). A trend toward improved disease-free survival was also observed with midostaurin (67.3% vs 53.4%; P 5.089), whereas overall survival (OS) was similar in the 2 groups. Patients with AML and NPM1mut/FLT3-TKDmut or core binding factor (CBF)-rearranged/FLT3-TKDmut genotypes had significantly prolonged OS with or without censoring at hematopoietic cell transplantation (HCT), compared with NPM1WT/CBF-negative AMLs. The multivariable model for OS and EFS adjusted for allogeneic HCT in first complete remission as a time-dependent covariable, revealed NPM1 mutations and CBF rearrangements as significant favorable factors. These data show that NPM1 mutations or CBF rearrangements identify favorable prognostic groups in patients with FLT3-TKD AMLs, independent of other factors, also in the context of midostaurin treatment.

AB - The results from the RATIFY trial (ClinicalTrials.gov: NCT00651261; CALGB 10603) showed that midostaurin combined with standard chemotherapy significantly improved outcomes in patients with FMS-like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia (AML), compared with placebo. In this post hoc subgroup analysis from the trial, we evaluated the impact of midostaurin in 163 patients with FLT3-tyrosine kinase domain (TKD) mutations. At a median follow-up of 60.7 months (95% CI, 55.0-70.8), the 5-year event-free survival (EFS) rate was significantly higher in patients treated with midostaurin than in those treated with placebo (45.2% vs 30.1%; P 5.044). A trend toward improved disease-free survival was also observed with midostaurin (67.3% vs 53.4%; P 5.089), whereas overall survival (OS) was similar in the 2 groups. Patients with AML and NPM1mut/FLT3-TKDmut or core binding factor (CBF)-rearranged/FLT3-TKDmut genotypes had significantly prolonged OS with or without censoring at hematopoietic cell transplantation (HCT), compared with NPM1WT/CBF-negative AMLs. The multivariable model for OS and EFS adjusted for allogeneic HCT in first complete remission as a time-dependent covariable, revealed NPM1 mutations and CBF rearrangements as significant favorable factors. These data show that NPM1 mutations or CBF rearrangements identify favorable prognostic groups in patients with FLT3-TKD AMLs, independent of other factors, also in the context of midostaurin treatment.

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DO - 10.1182/BLOODADVANCES.2020002904

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AN - SCOPUS:85096194729

SN - 2473-9529

VL - 4

SP - 4945

EP - 4954

JO - Blood Advances

JF - Blood Advances

IS - 19

ER -

Midostaurin in patients with acute myeloid leukemia and FLT3-TKD mutations: A subanalysis from the RATIFY trial

Abstract

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UN SDGs

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