Co-occurrence of FLT3-TKD and NPM1 mutations defines a highly favorable prognostic AML group

Prajwal Boddu, Hagop Kantarjian, Gautam Borthakur, Tapan Kadia, Naval Daver, Sherry Pierce, Michael Andreeff, Farhad Ravandi, Jorge Cortes, Steven M. Kornblau

Research output: Contribution to journalArticle

Abstract

Although FLT3 internal tandem duplication (ITD) mutations in acute myeloid leukemia (AML) confer an adverse prognosis, co-occurrence with a nucleophosphomin (NPM1) mutation partially improves response and survival outcomes. In contrast, simultaneous NPM1 and FLT3 tyrosine kinase domain (TKD) mutations were reported to improve response over that of an isolated NPM1 mutation in one as yet unverified report. To validate this, we explored the impact of the co-occurrence of FLT3-TKD and NPM1 mutations on clinical outcomes. Study populations included 21 patients (8%) with FLT3-TKD1NPM11 mutated, 18 patients (7%) with FLT3-TKD-only-mutated, 117 patients (44%) with NPM1-only-mutated, and 107 patients (41%) with FLT3-ITD1NPM1-mutated AML. Compared with NPM11-only-mutated AML, FLT3-TKD/NPM1 double mutation status was associated with a significantly superior relapse-free survival (median, not reached vs 18.3 months; P 5 .03) and a trend toward improved overall survival (OS). The presence of FLT3-TKD/NPM1 double mutation status was an independent positive predictor in multivariable analysis. Allogeneic stem cell transplant did not improve outcomes in the FLT3-TKD/NPM1 cohort. Consistent with historical data, the co-mutation status defined a highly favorable prognostic group characterized by high response rates and prolonged disease-free and OS. These study findings substantiate previous data describing this intriguing paradoxical cooperative effect. Our results emphasize the need for elucidating the mechanistic links between FLT3-TKD and NPM1 in future molecular and murine model studies.

Original languageEnglish (US)
Pages (from-to)1546-1550
Number of pages5
JournalBlood Advances
Volume1
Issue number19
DOIs
StatePublished - Aug 22 2017
Externally publishedYes

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Acute Myeloid Leukemia
Protein-Tyrosine Kinases
Mutation
Survival
Molecular Models
Disease-Free Survival
Stem Cells
Transplants
Recurrence
Population

ASJC Scopus subject areas

  • Hematology

Cite this

Boddu, P., Kantarjian, H., Borthakur, G., Kadia, T., Daver, N., Pierce, S., ... Kornblau, S. M. (2017). Co-occurrence of FLT3-TKD and NPM1 mutations defines a highly favorable prognostic AML group. Blood Advances, 1(19), 1546-1550. https://doi.org/10.1182/bloodadvances.2017009019

Co-occurrence of FLT3-TKD and NPM1 mutations defines a highly favorable prognostic AML group. / Boddu, Prajwal; Kantarjian, Hagop; Borthakur, Gautam; Kadia, Tapan; Daver, Naval; Pierce, Sherry; Andreeff, Michael; Ravandi, Farhad; Cortes, Jorge; Kornblau, Steven M.

In: Blood Advances, Vol. 1, No. 19, 22.08.2017, p. 1546-1550.

Research output: Contribution to journalArticle

Boddu, P, Kantarjian, H, Borthakur, G, Kadia, T, Daver, N, Pierce, S, Andreeff, M, Ravandi, F, Cortes, J & Kornblau, SM 2017, 'Co-occurrence of FLT3-TKD and NPM1 mutations defines a highly favorable prognostic AML group', Blood Advances, vol. 1, no. 19, pp. 1546-1550. https://doi.org/10.1182/bloodadvances.2017009019
Boddu P, Kantarjian H, Borthakur G, Kadia T, Daver N, Pierce S et al. Co-occurrence of FLT3-TKD and NPM1 mutations defines a highly favorable prognostic AML group. Blood Advances. 2017 Aug 22;1(19):1546-1550. https://doi.org/10.1182/bloodadvances.2017009019
Boddu, Prajwal ; Kantarjian, Hagop ; Borthakur, Gautam ; Kadia, Tapan ; Daver, Naval ; Pierce, Sherry ; Andreeff, Michael ; Ravandi, Farhad ; Cortes, Jorge ; Kornblau, Steven M. / Co-occurrence of FLT3-TKD and NPM1 mutations defines a highly favorable prognostic AML group. In: Blood Advances. 2017 ; Vol. 1, No. 19. pp. 1546-1550.
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title = "Co-occurrence of FLT3-TKD and NPM1 mutations defines a highly favorable prognostic AML group",
abstract = "Although FLT3 internal tandem duplication (ITD) mutations in acute myeloid leukemia (AML) confer an adverse prognosis, co-occurrence with a nucleophosphomin (NPM1) mutation partially improves response and survival outcomes. In contrast, simultaneous NPM1 and FLT3 tyrosine kinase domain (TKD) mutations were reported to improve response over that of an isolated NPM1 mutation in one as yet unverified report. To validate this, we explored the impact of the co-occurrence of FLT3-TKD and NPM1 mutations on clinical outcomes. Study populations included 21 patients (8{\%}) with FLT3-TKD1NPM11 mutated, 18 patients (7{\%}) with FLT3-TKD-only-mutated, 117 patients (44{\%}) with NPM1-only-mutated, and 107 patients (41{\%}) with FLT3-ITD1NPM1-mutated AML. Compared with NPM11-only-mutated AML, FLT3-TKD/NPM1 double mutation status was associated with a significantly superior relapse-free survival (median, not reached vs 18.3 months; P 5 .03) and a trend toward improved overall survival (OS). The presence of FLT3-TKD/NPM1 double mutation status was an independent positive predictor in multivariable analysis. Allogeneic stem cell transplant did not improve outcomes in the FLT3-TKD/NPM1 cohort. Consistent with historical data, the co-mutation status defined a highly favorable prognostic group characterized by high response rates and prolonged disease-free and OS. These study findings substantiate previous data describing this intriguing paradoxical cooperative effect. Our results emphasize the need for elucidating the mechanistic links between FLT3-TKD and NPM1 in future molecular and murine model studies.",
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AU - Boddu, Prajwal

AU - Kantarjian, Hagop

AU - Borthakur, Gautam

AU - Kadia, Tapan

AU - Daver, Naval

AU - Pierce, Sherry

AU - Andreeff, Michael

AU - Ravandi, Farhad

AU - Cortes, Jorge

AU - Kornblau, Steven M.

PY - 2017/8/22

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N2 - Although FLT3 internal tandem duplication (ITD) mutations in acute myeloid leukemia (AML) confer an adverse prognosis, co-occurrence with a nucleophosphomin (NPM1) mutation partially improves response and survival outcomes. In contrast, simultaneous NPM1 and FLT3 tyrosine kinase domain (TKD) mutations were reported to improve response over that of an isolated NPM1 mutation in one as yet unverified report. To validate this, we explored the impact of the co-occurrence of FLT3-TKD and NPM1 mutations on clinical outcomes. Study populations included 21 patients (8%) with FLT3-TKD1NPM11 mutated, 18 patients (7%) with FLT3-TKD-only-mutated, 117 patients (44%) with NPM1-only-mutated, and 107 patients (41%) with FLT3-ITD1NPM1-mutated AML. Compared with NPM11-only-mutated AML, FLT3-TKD/NPM1 double mutation status was associated with a significantly superior relapse-free survival (median, not reached vs 18.3 months; P 5 .03) and a trend toward improved overall survival (OS). The presence of FLT3-TKD/NPM1 double mutation status was an independent positive predictor in multivariable analysis. Allogeneic stem cell transplant did not improve outcomes in the FLT3-TKD/NPM1 cohort. Consistent with historical data, the co-mutation status defined a highly favorable prognostic group characterized by high response rates and prolonged disease-free and OS. These study findings substantiate previous data describing this intriguing paradoxical cooperative effect. Our results emphasize the need for elucidating the mechanistic links between FLT3-TKD and NPM1 in future molecular and murine model studies.

AB - Although FLT3 internal tandem duplication (ITD) mutations in acute myeloid leukemia (AML) confer an adverse prognosis, co-occurrence with a nucleophosphomin (NPM1) mutation partially improves response and survival outcomes. In contrast, simultaneous NPM1 and FLT3 tyrosine kinase domain (TKD) mutations were reported to improve response over that of an isolated NPM1 mutation in one as yet unverified report. To validate this, we explored the impact of the co-occurrence of FLT3-TKD and NPM1 mutations on clinical outcomes. Study populations included 21 patients (8%) with FLT3-TKD1NPM11 mutated, 18 patients (7%) with FLT3-TKD-only-mutated, 117 patients (44%) with NPM1-only-mutated, and 107 patients (41%) with FLT3-ITD1NPM1-mutated AML. Compared with NPM11-only-mutated AML, FLT3-TKD/NPM1 double mutation status was associated with a significantly superior relapse-free survival (median, not reached vs 18.3 months; P 5 .03) and a trend toward improved overall survival (OS). The presence of FLT3-TKD/NPM1 double mutation status was an independent positive predictor in multivariable analysis. Allogeneic stem cell transplant did not improve outcomes in the FLT3-TKD/NPM1 cohort. Consistent with historical data, the co-mutation status defined a highly favorable prognostic group characterized by high response rates and prolonged disease-free and OS. These study findings substantiate previous data describing this intriguing paradoxical cooperative effect. Our results emphasize the need for elucidating the mechanistic links between FLT3-TKD and NPM1 in future molecular and murine model studies.

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