Midostaurin reduces relapse in FLT3-mutant acute myeloid leukemia: the Alliance CALGB 10603/RATIFY trial

Richard A. Larson; Sumithra J. Mandrekar; Lucas J. Huebner; Ben L. Sanford; Kristina Laumann; Susan Geyer; Clara D. Bloomfield; Christian Thiede; Thomas W. Prior; Konstanze Döhner; Guido Marcucci; Maria Teresa Voso; Rebecca B. Klisovic; Ilene Galinsky; Andrew H. Wei; Jorge Sierra; Miguel A. Sanz; Joseph M. Brandwein; Theo de Witte; Dietger Niederwieser; Frederick R. Appelbaum; Bruno C. Medeiros; Martin S. Tallman; Jürgen Krauter; Richard F. Schlenk; Arnold Ganser; Hubert Serve; Gerhard Ehninger; Sergio Amadori; Insa Gathmann; Hartmut Döhner; Richard M. Stone

doi:10.1038/s41375-021-01179-4

Midostaurin reduces relapse in FLT3-mutant acute myeloid leukemia: the Alliance CALGB 10603/RATIFY trial

Richard A. Larson^*, Sumithra J. Mandrekar, Lucas J. Huebner, Ben L. Sanford, Kristina Laumann, Susan Geyer, Clara D. Bloomfield, Christian Thiede, Thomas W. Prior, Konstanze Döhner, Guido Marcucci, Maria Teresa Voso, Rebecca B. Klisovic, Ilene Galinsky, Andrew H. Wei, Jorge Sierra, Miguel A. Sanz, Joseph M. Brandwein, Theo de Witte, Dietger NiederwieserFrederick R. Appelbaum, Bruno C. Medeiros, Martin S. Tallman, Jürgen Krauter, Richard F. Schlenk, Arnold Ganser, Hubert Serve, Gerhard Ehninger, Sergio Amadori, Insa Gathmann, Hartmut Döhner, Richard M. Stone

^*Corresponding author for this work

Medicine, Hematology Oncology Division

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

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Abstract

The prospective randomized, placebo-controlled CALGB 10603/RATIFY trial (Alliance) demonstrated a statistically significant overall survival benefit from the addition of midostaurin to standard frontline chemotherapy in a genotypically-defined subgroup of 717 patients with FLT3-mutant acute myeloid leukemia (AML). The risk of death was reduced by 22% on the midostaurin-containing arm. In this post hoc analysis, we analyzed the cumulative incidence of relapse (CIR) on this study and also evaluated the impact of 12 4-week cycles of maintenance therapy. CIR analyses treated relapses and AML deaths as events, deaths from other causes as competing risks, and survivors in remission were censored. CIR was improved on the midostaurin arm (HR = 0.71 (95% CI, 0.54–0.93); p = 0.01), both overall and within European LeukemiaNet 2017 risk classification subsets when post-transplant events were considered in the analysis as events. However, when transplantation was considered as a competing risk, there was overall no significant difference between the risks of relapse on the two randomized arms. Patients still in remission after consolidation with high-dose cytarabine entered the maintenance phase, continuing with either midostaurin or placebo. Analyses were inconclusive in quantifying the impact of the maintenance phase on the overall outcome. In summary, midostaurin reduces the CIR.

Original language	English (US)
Pages (from-to)	2539-2551
Number of pages	13
Journal	Leukemia
Volume	35
Issue number	9
DOIs	https://doi.org/10.1038/s41375-021-01179-4
State	Published - Sep 2021

Funding

Acknowledgements We thank the patients who participated and their families, the clinical and laboratory research staff members of multiple international cooperative groups, CTEP of the NCI, and Novartis Pharmaceuticals. We acknowledge Dr. Francesco Lo-Coco’s and Dr. Clara D. Bloomfield’s key roles in the design and completion of this study. CALGB is now part of the Alliance for Clinical Trials in Oncology. Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under award numbers U10CA180821, U10CA180882, U24CA198171 (to the Alliance for Clinical Trials in Oncology), U10CA032291, U10CA041287, U10CA077651, U10CA077658, U10CA180791, U10CA180820 (ECOG-ACRIN), UG1CA233290, U10CA180836, U10CA180850, U10CA180863 (CCTG), U10CA180867, U10CA180888 (SWOG), and UG1CA233338 [https://acknow ledgments.alliancefound.org]. This study was also supported in part by funds from Novartis. Clinicaltrials.gov Identifier number: NCT00651261. This study was conducted at 225 sites in 17 countries. Participating cooperative groups included: Alliance/CALGB, AMLSG, CETLAM, ECOG, EORTC/HOVON, GIMEMA, NCIC, OSHO, PETHEMA, LATAM, SAL, SWOG, ALLG, and individual sites. Alliance/CALGB was the lead group and held the clinical trial data. The study was sponsored in North America by the Cancer Therapy and Evaluation Program (CTEP) of the National Cancer Institute (NCI) and in non-North American sites by Novartis Pharmaceutical Company. Patients enrolled in the study were randomized with equal probability to the two treatments. These randomizations were double-blinded and were stratified by the FLT3 mutation subgroup: TKD, ITD with mutant allelic ratio <0.7 (low), and ITD with allelic ratio ≥0.7 (high).

ASJC Scopus subject areas

Hematology
Oncology
Cancer Research

UN SDGs

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

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10.1038/s41375-021-01179-4

Cite this

Larson, R. A., Mandrekar, S. J., Huebner, L. J., Sanford, B. L., Laumann, K., Geyer, S., Bloomfield, C. D., Thiede, C., Prior, T. W., Döhner, K., Marcucci, G., Voso, M. T., Klisovic, R. B., Galinsky, I., Wei, A. H., Sierra, J., Sanz, M. A., Brandwein, J. M., de Witte, T., ... Stone, R. M. (2021). Midostaurin reduces relapse in FLT3-mutant acute myeloid leukemia: the Alliance CALGB 10603/RATIFY trial. Leukemia, 35(9), 2539-2551. https://doi.org/10.1038/s41375-021-01179-4

@article{a1515856790547818b99b17d97b96b9d,

title = "Midostaurin reduces relapse in FLT3-mutant acute myeloid leukemia: the Alliance CALGB 10603/RATIFY trial",

abstract = "The prospective randomized, placebo-controlled CALGB 10603/RATIFY trial (Alliance) demonstrated a statistically significant overall survival benefit from the addition of midostaurin to standard frontline chemotherapy in a genotypically-defined subgroup of 717 patients with FLT3-mutant acute myeloid leukemia (AML). The risk of death was reduced by 22% on the midostaurin-containing arm. In this post hoc analysis, we analyzed the cumulative incidence of relapse (CIR) on this study and also evaluated the impact of 12 4-week cycles of maintenance therapy. CIR analyses treated relapses and AML deaths as events, deaths from other causes as competing risks, and survivors in remission were censored. CIR was improved on the midostaurin arm (HR = 0.71 (95% CI, 0.54–0.93); p = 0.01), both overall and within European LeukemiaNet 2017 risk classification subsets when post-transplant events were considered in the analysis as events. However, when transplantation was considered as a competing risk, there was overall no significant difference between the risks of relapse on the two randomized arms. Patients still in remission after consolidation with high-dose cytarabine entered the maintenance phase, continuing with either midostaurin or placebo. Analyses were inconclusive in quantifying the impact of the maintenance phase on the overall outcome. In summary, midostaurin reduces the CIR.",

author = "Larson, {Richard A.} and Mandrekar, {Sumithra J.} and Huebner, {Lucas J.} and Sanford, {Ben L.} and Kristina Laumann and Susan Geyer and Bloomfield, {Clara D.} and Christian Thiede and Prior, {Thomas W.} and Konstanze D{\"o}hner and Guido Marcucci and Voso, {Maria Teresa} and Klisovic, {Rebecca B.} and Ilene Galinsky and Wei, {Andrew H.} and Jorge Sierra and Sanz, {Miguel A.} and Brandwein, {Joseph M.} and {de Witte}, Theo and Dietger Niederwieser and Appelbaum, {Frederick R.} and Medeiros, {Bruno C.} and Tallman, {Martin S.} and J{\"u}rgen Krauter and Schlenk, {Richard F.} and Arnold Ganser and Hubert Serve and Gerhard Ehninger and Sergio Amadori and Insa Gathmann and Hartmut D{\"o}hner and Stone, {Richard M.}",

note = "Funding Information: Acknowledgements We thank the patients who participated and their families, the clinical and laboratory research staff members of multiple international cooperative groups, CTEP of the NCI, and Novartis Pharmaceuticals. We acknowledge Dr. Francesco Lo-Coco{\textquoteright}s and Dr. Clara D. Bloomfield{\textquoteright}s key roles in the design and completion of this study. CALGB is now part of the Alliance for Clinical Trials in Oncology. Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under award numbers U10CA180821, U10CA180882, U24CA198171 (to the Alliance for Clinical Trials in Oncology), U10CA032291, U10CA041287, U10CA077651, U10CA077658, U10CA180791, U10CA180820 (ECOG-ACRIN), UG1CA233290, U10CA180836, U10CA180850, U10CA180863 (CCTG), U10CA180867, U10CA180888 (SWOG), and UG1CA233338 [https://acknow ledgments.alliancefound.org]. This study was also supported in part by funds from Novartis. Clinicaltrials.gov Identifier number: NCT00651261. Funding Information: This study was conducted at 225 sites in 17 countries. Participating cooperative groups included: Alliance/CALGB, AMLSG, CETLAM, ECOG, EORTC/HOVON, GIMEMA, NCIC, OSHO, PETHEMA, LATAM, SAL, SWOG, ALLG, and individual sites. Alliance/CALGB was the lead group and held the clinical trial data. The study was sponsored in North America by the Cancer Therapy and Evaluation Program (CTEP) of the National Cancer Institute (NCI) and in non-North American sites by Novartis Pharmaceutical Company. Patients enrolled in the study were randomized with equal probability to the two treatments. These randomizations were double-blinded and were stratified by the FLT3 mutation subgroup: TKD, ITD with mutant allelic ratio <0.7 (low), and ITD with allelic ratio ≥0.7 (high). Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature Limited part of Springer Nature.",

year = "2021",

month = sep,

doi = "10.1038/s41375-021-01179-4",

language = "English (US)",

volume = "35",

pages = "2539--2551",

journal = "Leukemia",

issn = "0887-6924",

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Larson, RA, Mandrekar, SJ, Huebner, LJ, Sanford, BL, Laumann, K, Geyer, S, Bloomfield, CD, Thiede, C, Prior, TW, Döhner, K, Marcucci, G, Voso, MT, Klisovic, RB, Galinsky, I, Wei, AH, Sierra, J, Sanz, MA, Brandwein, JM, de Witte, T, Niederwieser, D, Appelbaum, FR, Medeiros, BC, Tallman, MS, Krauter, J, Schlenk, RF, Ganser, A, Serve, H, Ehninger, G, Amadori, S, Gathmann, I, Döhner, H & Stone, RM 2021, 'Midostaurin reduces relapse in FLT3-mutant acute myeloid leukemia: the Alliance CALGB 10603/RATIFY trial', Leukemia, vol. 35, no. 9, pp. 2539-2551. https://doi.org/10.1038/s41375-021-01179-4

TY - JOUR

T1 - Midostaurin reduces relapse in FLT3-mutant acute myeloid leukemia

T2 - the Alliance CALGB 10603/RATIFY trial

AU - Larson, Richard A.

AU - Mandrekar, Sumithra J.

AU - Huebner, Lucas J.

AU - Sanford, Ben L.

AU - Laumann, Kristina

AU - Geyer, Susan

AU - Bloomfield, Clara D.

AU - Thiede, Christian

AU - Prior, Thomas W.

AU - Döhner, Konstanze

AU - Marcucci, Guido

AU - Voso, Maria Teresa

AU - Klisovic, Rebecca B.

AU - Galinsky, Ilene

AU - Wei, Andrew H.

AU - Sierra, Jorge

AU - Sanz, Miguel A.

AU - Brandwein, Joseph M.

AU - de Witte, Theo

AU - Niederwieser, Dietger

AU - Appelbaum, Frederick R.

AU - Medeiros, Bruno C.

AU - Tallman, Martin S.

AU - Krauter, Jürgen

AU - Schlenk, Richard F.

AU - Ganser, Arnold

AU - Serve, Hubert

AU - Ehninger, Gerhard

AU - Amadori, Sergio

AU - Gathmann, Insa

AU - Döhner, Hartmut

AU - Stone, Richard M.

N1 - Funding Information: Acknowledgements We thank the patients who participated and their families, the clinical and laboratory research staff members of multiple international cooperative groups, CTEP of the NCI, and Novartis Pharmaceuticals. We acknowledge Dr. Francesco Lo-Coco’s and Dr. Clara D. Bloomfield’s key roles in the design and completion of this study. CALGB is now part of the Alliance for Clinical Trials in Oncology. Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under award numbers U10CA180821, U10CA180882, U24CA198171 (to the Alliance for Clinical Trials in Oncology), U10CA032291, U10CA041287, U10CA077651, U10CA077658, U10CA180791, U10CA180820 (ECOG-ACRIN), UG1CA233290, U10CA180836, U10CA180850, U10CA180863 (CCTG), U10CA180867, U10CA180888 (SWOG), and UG1CA233338 [https://acknow ledgments.alliancefound.org]. This study was also supported in part by funds from Novartis. Clinicaltrials.gov Identifier number: NCT00651261. Funding Information: This study was conducted at 225 sites in 17 countries. Participating cooperative groups included: Alliance/CALGB, AMLSG, CETLAM, ECOG, EORTC/HOVON, GIMEMA, NCIC, OSHO, PETHEMA, LATAM, SAL, SWOG, ALLG, and individual sites. Alliance/CALGB was the lead group and held the clinical trial data. The study was sponsored in North America by the Cancer Therapy and Evaluation Program (CTEP) of the National Cancer Institute (NCI) and in non-North American sites by Novartis Pharmaceutical Company. Patients enrolled in the study were randomized with equal probability to the two treatments. These randomizations were double-blinded and were stratified by the FLT3 mutation subgroup: TKD, ITD with mutant allelic ratio <0.7 (low), and ITD with allelic ratio ≥0.7 (high). Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Nature Limited part of Springer Nature.

PY - 2021/9

Y1 - 2021/9

N2 - The prospective randomized, placebo-controlled CALGB 10603/RATIFY trial (Alliance) demonstrated a statistically significant overall survival benefit from the addition of midostaurin to standard frontline chemotherapy in a genotypically-defined subgroup of 717 patients with FLT3-mutant acute myeloid leukemia (AML). The risk of death was reduced by 22% on the midostaurin-containing arm. In this post hoc analysis, we analyzed the cumulative incidence of relapse (CIR) on this study and also evaluated the impact of 12 4-week cycles of maintenance therapy. CIR analyses treated relapses and AML deaths as events, deaths from other causes as competing risks, and survivors in remission were censored. CIR was improved on the midostaurin arm (HR = 0.71 (95% CI, 0.54–0.93); p = 0.01), both overall and within European LeukemiaNet 2017 risk classification subsets when post-transplant events were considered in the analysis as events. However, when transplantation was considered as a competing risk, there was overall no significant difference between the risks of relapse on the two randomized arms. Patients still in remission after consolidation with high-dose cytarabine entered the maintenance phase, continuing with either midostaurin or placebo. Analyses were inconclusive in quantifying the impact of the maintenance phase on the overall outcome. In summary, midostaurin reduces the CIR.

AB - The prospective randomized, placebo-controlled CALGB 10603/RATIFY trial (Alliance) demonstrated a statistically significant overall survival benefit from the addition of midostaurin to standard frontline chemotherapy in a genotypically-defined subgroup of 717 patients with FLT3-mutant acute myeloid leukemia (AML). The risk of death was reduced by 22% on the midostaurin-containing arm. In this post hoc analysis, we analyzed the cumulative incidence of relapse (CIR) on this study and also evaluated the impact of 12 4-week cycles of maintenance therapy. CIR analyses treated relapses and AML deaths as events, deaths from other causes as competing risks, and survivors in remission were censored. CIR was improved on the midostaurin arm (HR = 0.71 (95% CI, 0.54–0.93); p = 0.01), both overall and within European LeukemiaNet 2017 risk classification subsets when post-transplant events were considered in the analysis as events. However, when transplantation was considered as a competing risk, there was overall no significant difference between the risks of relapse on the two randomized arms. Patients still in remission after consolidation with high-dose cytarabine entered the maintenance phase, continuing with either midostaurin or placebo. Analyses were inconclusive in quantifying the impact of the maintenance phase on the overall outcome. In summary, midostaurin reduces the CIR.

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ER -

Midostaurin reduces relapse in FLT3-mutant acute myeloid leukemia: the Alliance CALGB 10603/RATIFY trial

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