Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 Mutation

R. M. Stone, Sumithra J Mandrekar, B. L. Sanford, K. Laumann, S. Geyer, C. D. Bloomfield, C. Thiede, T. W. Prior, K. Dohner, G. Marcucci, F. Lo-Coco, R. B. Klisovic, A. Wei, J. Sierra, M. A. Sanz, J. M. Brandwein, T. De Witte, D. Niederwieser, F. R. Appelbaum, B. C. MedeirosM. S. Tallman, J. Krauter, R. F. Schlenk, A. Ganser, H. Serve, G. Ehninger, S. Amadori, R. A. Larson, H. Dohner

Research output: Contribution to journalArticle

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Abstract

BACKGROUND Patients with acute myeloid leukemia (AML) and a FLT3 mutation have poor outcomes. We conducted a phase 3 trial to determine whether the addition of midostaurin - an oral multitargeted kinase inhibitor that is active in patients with a FLT3 mutation - to standard chemotherapy would prolong overall survival in this population. METHODS We screened 3277 patients, 18 to 59 years of age, who had newly diagnosed AML for FLT3 mutations. Patients were randomly assigned to receive standard chemotherapy (induction therapy with daunorubicin and cytarabine and consolidation therapy with high-dose cytarabine) plus either midostaurin or placebo; those who were in remission after consolidation therapy entered a maintenance phase in which they received either midostaurin or placebo. Randomization was stratified according to subtype of FLT3 mutation: point mutation in the tyrosine kinase domain (TKD) or internal tandem duplication (ITD) mutation with either a high ratio (>0.7) or a low ratio (0.05 to 0.7) of mutant to wild-Type alleles (ITD [high] and ITD [low], respectively). Allogeneic transplantation was allowed. The primary end point was overall survival. RESULTS A total of 717 patients underwent randomization; 360 were assigned to the midostaurin group, and 357 to the placebo group. The FLT3 subtype was ITD (high) in 214 patients, ITD (low) in 341 patients, and TKD in 162 patients. The treatment groups were well balanced with respect to age, race, FLT3 subtype, cytogenetic risk, and blood counts but not with respect to sex (51.7% in the midostaurin group vs. 59.4% in the placebo group were women, P = 0.04). Overall survival was significantly longer in the midostaurin group than in the placebo group (hazard ratio for death, 0.78; one-sided P = 0.009), as was event-free survival (hazard ratio for event or death, 0.78; one-sided P = 0.002). In both the primary analysis and an analysis in which data for patients who underwent transplantation were censored, the benefit of midostaurin was consistent across all FLT3 subtypes. The rate of severe adverse events was similar in the two groups. CONCLUSIONS The addition of the multitargeted kinase inhibitor midostaurin to standard chemotherapy significantly prolonged overall and event-free survival among patients with AML and a FLT3 mutation.

Original languageEnglish (US)
Pages (from-to)454-464
Number of pages11
JournalNew England Journal of Medicine
Volume377
Issue number5
DOIs
StatePublished - Aug 3 2017

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4'-N-benzoylstaurosporine
Acute Myeloid Leukemia
Drug Therapy
Mutation
Placebos
Cytarabine
Random Allocation
Protein-Tyrosine Kinases
Disease-Free Survival
Survival
Phosphotransferases
Induction Chemotherapy
Daunorubicin

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Stone, R. M., Mandrekar, S. J., Sanford, B. L., Laumann, K., Geyer, S., Bloomfield, C. D., ... Dohner, H. (2017). Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 Mutation. New England Journal of Medicine, 377(5), 454-464. https://doi.org/10.1056/NEJMoa1614359

Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 Mutation. / Stone, R. M.; Mandrekar, Sumithra J; Sanford, B. L.; Laumann, K.; Geyer, S.; Bloomfield, C. D.; Thiede, C.; Prior, T. W.; Dohner, K.; Marcucci, G.; Lo-Coco, F.; Klisovic, R. B.; Wei, A.; Sierra, J.; Sanz, M. A.; Brandwein, J. M.; De Witte, T.; Niederwieser, D.; Appelbaum, F. R.; Medeiros, B. C.; Tallman, M. S.; Krauter, J.; Schlenk, R. F.; Ganser, A.; Serve, H.; Ehninger, G.; Amadori, S.; Larson, R. A.; Dohner, H.

In: New England Journal of Medicine, Vol. 377, No. 5, 03.08.2017, p. 454-464.

Research output: Contribution to journalArticle

Stone, RM, Mandrekar, SJ, Sanford, BL, Laumann, K, Geyer, S, Bloomfield, CD, Thiede, C, Prior, TW, Dohner, K, Marcucci, G, Lo-Coco, F, Klisovic, RB, Wei, A, 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, Larson, RA & Dohner, H 2017, 'Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 Mutation', New England Journal of Medicine, vol. 377, no. 5, pp. 454-464. https://doi.org/10.1056/NEJMoa1614359
Stone, R. M. ; Mandrekar, Sumithra J ; Sanford, B. L. ; Laumann, K. ; Geyer, S. ; Bloomfield, C. D. ; Thiede, C. ; Prior, T. W. ; Dohner, K. ; Marcucci, G. ; Lo-Coco, F. ; Klisovic, R. B. ; Wei, A. ; Sierra, J. ; Sanz, M. A. ; Brandwein, J. M. ; De Witte, T. ; Niederwieser, D. ; Appelbaum, F. R. ; Medeiros, B. C. ; Tallman, M. S. ; Krauter, J. ; Schlenk, R. F. ; Ganser, A. ; Serve, H. ; Ehninger, G. ; Amadori, S. ; Larson, R. A. ; Dohner, H. / Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 Mutation. In: New England Journal of Medicine. 2017 ; Vol. 377, No. 5. pp. 454-464.
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abstract = "BACKGROUND Patients with acute myeloid leukemia (AML) and a FLT3 mutation have poor outcomes. We conducted a phase 3 trial to determine whether the addition of midostaurin - an oral multitargeted kinase inhibitor that is active in patients with a FLT3 mutation - to standard chemotherapy would prolong overall survival in this population. METHODS We screened 3277 patients, 18 to 59 years of age, who had newly diagnosed AML for FLT3 mutations. Patients were randomly assigned to receive standard chemotherapy (induction therapy with daunorubicin and cytarabine and consolidation therapy with high-dose cytarabine) plus either midostaurin or placebo; those who were in remission after consolidation therapy entered a maintenance phase in which they received either midostaurin or placebo. Randomization was stratified according to subtype of FLT3 mutation: point mutation in the tyrosine kinase domain (TKD) or internal tandem duplication (ITD) mutation with either a high ratio (>0.7) or a low ratio (0.05 to 0.7) of mutant to wild-Type alleles (ITD [high] and ITD [low], respectively). Allogeneic transplantation was allowed. The primary end point was overall survival. RESULTS A total of 717 patients underwent randomization; 360 were assigned to the midostaurin group, and 357 to the placebo group. The FLT3 subtype was ITD (high) in 214 patients, ITD (low) in 341 patients, and TKD in 162 patients. The treatment groups were well balanced with respect to age, race, FLT3 subtype, cytogenetic risk, and blood counts but not with respect to sex (51.7{\%} in the midostaurin group vs. 59.4{\%} in the placebo group were women, P = 0.04). Overall survival was significantly longer in the midostaurin group than in the placebo group (hazard ratio for death, 0.78; one-sided P = 0.009), as was event-free survival (hazard ratio for event or death, 0.78; one-sided P = 0.002). In both the primary analysis and an analysis in which data for patients who underwent transplantation were censored, the benefit of midostaurin was consistent across all FLT3 subtypes. The rate of severe adverse events was similar in the two groups. CONCLUSIONS The addition of the multitargeted kinase inhibitor midostaurin to standard chemotherapy significantly prolonged overall and event-free survival among patients with AML and a FLT3 mutation.",
author = "Stone, {R. M.} and Mandrekar, {Sumithra J} and Sanford, {B. L.} and K. Laumann and S. Geyer and Bloomfield, {C. D.} and C. Thiede and Prior, {T. W.} and K. Dohner and G. Marcucci and F. Lo-Coco and Klisovic, {R. B.} and A. Wei and J. Sierra and Sanz, {M. A.} and Brandwein, {J. M.} and {De Witte}, T. and D. Niederwieser and Appelbaum, {F. R.} and Medeiros, {B. C.} and Tallman, {M. S.} and J. Krauter and Schlenk, {R. F.} and A. Ganser and H. Serve and G. Ehninger and S. Amadori and Larson, {R. A.} and H. Dohner",
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TY - JOUR

T1 - Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 Mutation

AU - Stone, R. M.

AU - Mandrekar, Sumithra J

AU - Sanford, B. L.

AU - Laumann, K.

AU - Geyer, S.

AU - Bloomfield, C. D.

AU - Thiede, C.

AU - Prior, T. W.

AU - Dohner, K.

AU - Marcucci, G.

AU - Lo-Coco, F.

AU - Klisovic, R. B.

AU - Wei, A.

AU - Sierra, J.

AU - Sanz, M. A.

AU - Brandwein, J. M.

AU - De Witte, T.

AU - Niederwieser, D.

AU - Appelbaum, F. R.

AU - Medeiros, B. C.

AU - Tallman, M. S.

AU - Krauter, J.

AU - Schlenk, R. F.

AU - Ganser, A.

AU - Serve, H.

AU - Ehninger, G.

AU - Amadori, S.

AU - Larson, R. A.

AU - Dohner, H.

PY - 2017/8/3

Y1 - 2017/8/3

N2 - BACKGROUND Patients with acute myeloid leukemia (AML) and a FLT3 mutation have poor outcomes. We conducted a phase 3 trial to determine whether the addition of midostaurin - an oral multitargeted kinase inhibitor that is active in patients with a FLT3 mutation - to standard chemotherapy would prolong overall survival in this population. METHODS We screened 3277 patients, 18 to 59 years of age, who had newly diagnosed AML for FLT3 mutations. Patients were randomly assigned to receive standard chemotherapy (induction therapy with daunorubicin and cytarabine and consolidation therapy with high-dose cytarabine) plus either midostaurin or placebo; those who were in remission after consolidation therapy entered a maintenance phase in which they received either midostaurin or placebo. Randomization was stratified according to subtype of FLT3 mutation: point mutation in the tyrosine kinase domain (TKD) or internal tandem duplication (ITD) mutation with either a high ratio (>0.7) or a low ratio (0.05 to 0.7) of mutant to wild-Type alleles (ITD [high] and ITD [low], respectively). Allogeneic transplantation was allowed. The primary end point was overall survival. RESULTS A total of 717 patients underwent randomization; 360 were assigned to the midostaurin group, and 357 to the placebo group. The FLT3 subtype was ITD (high) in 214 patients, ITD (low) in 341 patients, and TKD in 162 patients. The treatment groups were well balanced with respect to age, race, FLT3 subtype, cytogenetic risk, and blood counts but not with respect to sex (51.7% in the midostaurin group vs. 59.4% in the placebo group were women, P = 0.04). Overall survival was significantly longer in the midostaurin group than in the placebo group (hazard ratio for death, 0.78; one-sided P = 0.009), as was event-free survival (hazard ratio for event or death, 0.78; one-sided P = 0.002). In both the primary analysis and an analysis in which data for patients who underwent transplantation were censored, the benefit of midostaurin was consistent across all FLT3 subtypes. The rate of severe adverse events was similar in the two groups. CONCLUSIONS The addition of the multitargeted kinase inhibitor midostaurin to standard chemotherapy significantly prolonged overall and event-free survival among patients with AML and a FLT3 mutation.

AB - BACKGROUND Patients with acute myeloid leukemia (AML) and a FLT3 mutation have poor outcomes. We conducted a phase 3 trial to determine whether the addition of midostaurin - an oral multitargeted kinase inhibitor that is active in patients with a FLT3 mutation - to standard chemotherapy would prolong overall survival in this population. METHODS We screened 3277 patients, 18 to 59 years of age, who had newly diagnosed AML for FLT3 mutations. Patients were randomly assigned to receive standard chemotherapy (induction therapy with daunorubicin and cytarabine and consolidation therapy with high-dose cytarabine) plus either midostaurin or placebo; those who were in remission after consolidation therapy entered a maintenance phase in which they received either midostaurin or placebo. Randomization was stratified according to subtype of FLT3 mutation: point mutation in the tyrosine kinase domain (TKD) or internal tandem duplication (ITD) mutation with either a high ratio (>0.7) or a low ratio (0.05 to 0.7) of mutant to wild-Type alleles (ITD [high] and ITD [low], respectively). Allogeneic transplantation was allowed. The primary end point was overall survival. RESULTS A total of 717 patients underwent randomization; 360 were assigned to the midostaurin group, and 357 to the placebo group. The FLT3 subtype was ITD (high) in 214 patients, ITD (low) in 341 patients, and TKD in 162 patients. The treatment groups were well balanced with respect to age, race, FLT3 subtype, cytogenetic risk, and blood counts but not with respect to sex (51.7% in the midostaurin group vs. 59.4% in the placebo group were women, P = 0.04). Overall survival was significantly longer in the midostaurin group than in the placebo group (hazard ratio for death, 0.78; one-sided P = 0.009), as was event-free survival (hazard ratio for event or death, 0.78; one-sided P = 0.002). In both the primary analysis and an analysis in which data for patients who underwent transplantation were censored, the benefit of midostaurin was consistent across all FLT3 subtypes. The rate of severe adverse events was similar in the two groups. CONCLUSIONS The addition of the multitargeted kinase inhibitor midostaurin to standard chemotherapy significantly prolonged overall and event-free survival among patients with AML and a FLT3 mutation.

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