Clinical outcomes and co-occurring mutations in patients with RUNX1-mutated acute myeloid leukemia

Maliha Khan, Jorge Cortes, Tapan Kadia, Kiran Naqvi, Mark Brandt, Sherry Pierce, Keyur P. Patel, Gautam Borthakur, Farhad Ravandi, Marina Konopleva, Steven Kornblau, Hagop Kantarjian, Kapil Bhalla, Courtney D. DiNardo

Research output: Contribution to journalArticle

Abstract

(1) Runt-related transcription factor 1 (RUNX1) mutations in acute myeloid leukemia (AML) are often associated with worse prognosis. We assessed co-occurring mutations, response to therapy, and clinical outcomes in patients with and without mutant RUNX1 (mRUNX1); (2)We analyzed 328 AML patients, including 177 patients younger than 65 years who received intensive chemotherapy and 151 patients >65 years who received hypomethylating agents. RUNX1 and co-existing mutations were identified using next-generation sequencing; (3) RUNX1 mutations were identified in 5.1% of younger patients and 15.9% of older patients, and were significantly associated with increasing age (p = 0.01) as well as intermediate-risk cytogenetics including normal karyotype (p = 0.02) in the elderly cohort, and with lower lactate dehydrogenase (LDH; p = 0.02) and higher platelet count (p = 0.012) overall. Identified co-occurring mutations were primarily ASXL1 mutations in older patients and RAS mutations in younger patients; FLT3-ITD and IDH1/2 co-mutations were also frequent. Younger mRUNX1 AML patients treated with intensive chemotherapy experienced inferior treatment outcomes. In older patients with AML treated with hypomethylating agent (HMA) therapy, response and survival was independent of RUNX1 status. Older mRUNX1 patients with prior myelodysplastic syndrome or myeloproliferative neoplasms (MDS/MPN) had particularly dismal outcome. Future studies should focus on the prognostic implications of RUNX1 mutations relative to other co-occurring mutations, and the potential role of hypomethylating agents for this molecularly-defined group.

Original languageEnglish (US)
Article number1618
JournalInternational journal of molecular sciences
Volume18
Issue number8
DOIs
StatePublished - Aug 2017
Externally publishedYes

Fingerprint

leukemias
mutations
Acute Myeloid Leukemia
Chemotherapy
Mutation
Core Binding Factor Alpha 2 Subunit
Transcription factors
Platelets
L-Lactate Dehydrogenase
chemotherapy
therapy
Drug Therapy
neoplasms
lactates
dehydrogenases
sequencing
prognosis
Myelodysplastic Syndromes
platelets
Platelet Count

Keywords

  • Acute myeloid leukemia
  • Chemotherapy
  • Hypomethylating agents
  • Mutations
  • Prognosis
  • RUNX1

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

Cite this

Clinical outcomes and co-occurring mutations in patients with RUNX1-mutated acute myeloid leukemia. / Khan, Maliha; Cortes, Jorge; Kadia, Tapan; Naqvi, Kiran; Brandt, Mark; Pierce, Sherry; Patel, Keyur P.; Borthakur, Gautam; Ravandi, Farhad; Konopleva, Marina; Kornblau, Steven; Kantarjian, Hagop; Bhalla, Kapil; DiNardo, Courtney D.

In: International journal of molecular sciences, Vol. 18, No. 8, 1618, 08.2017.

Research output: Contribution to journalArticle

Khan, M, Cortes, J, Kadia, T, Naqvi, K, Brandt, M, Pierce, S, Patel, KP, Borthakur, G, Ravandi, F, Konopleva, M, Kornblau, S, Kantarjian, H, Bhalla, K & DiNardo, CD 2017, 'Clinical outcomes and co-occurring mutations in patients with RUNX1-mutated acute myeloid leukemia', International journal of molecular sciences, vol. 18, no. 8, 1618. https://doi.org/10.3390/ijms18081618
Khan, Maliha ; Cortes, Jorge ; Kadia, Tapan ; Naqvi, Kiran ; Brandt, Mark ; Pierce, Sherry ; Patel, Keyur P. ; Borthakur, Gautam ; Ravandi, Farhad ; Konopleva, Marina ; Kornblau, Steven ; Kantarjian, Hagop ; Bhalla, Kapil ; DiNardo, Courtney D. / Clinical outcomes and co-occurring mutations in patients with RUNX1-mutated acute myeloid leukemia. In: International journal of molecular sciences. 2017 ; Vol. 18, No. 8.
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abstract = "(1) Runt-related transcription factor 1 (RUNX1) mutations in acute myeloid leukemia (AML) are often associated with worse prognosis. We assessed co-occurring mutations, response to therapy, and clinical outcomes in patients with and without mutant RUNX1 (mRUNX1); (2)We analyzed 328 AML patients, including 177 patients younger than 65 years who received intensive chemotherapy and 151 patients >65 years who received hypomethylating agents. RUNX1 and co-existing mutations were identified using next-generation sequencing; (3) RUNX1 mutations were identified in 5.1{\%} of younger patients and 15.9{\%} of older patients, and were significantly associated with increasing age (p = 0.01) as well as intermediate-risk cytogenetics including normal karyotype (p = 0.02) in the elderly cohort, and with lower lactate dehydrogenase (LDH; p = 0.02) and higher platelet count (p = 0.012) overall. Identified co-occurring mutations were primarily ASXL1 mutations in older patients and RAS mutations in younger patients; FLT3-ITD and IDH1/2 co-mutations were also frequent. Younger mRUNX1 AML patients treated with intensive chemotherapy experienced inferior treatment outcomes. In older patients with AML treated with hypomethylating agent (HMA) therapy, response and survival was independent of RUNX1 status. Older mRUNX1 patients with prior myelodysplastic syndrome or myeloproliferative neoplasms (MDS/MPN) had particularly dismal outcome. Future studies should focus on the prognostic implications of RUNX1 mutations relative to other co-occurring mutations, and the potential role of hypomethylating agents for this molecularly-defined group.",
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AU - Brandt, Mark

AU - Pierce, Sherry

AU - Patel, Keyur P.

AU - Borthakur, Gautam

AU - Ravandi, Farhad

AU - Konopleva, Marina

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AU - Kantarjian, Hagop

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AB - (1) Runt-related transcription factor 1 (RUNX1) mutations in acute myeloid leukemia (AML) are often associated with worse prognosis. We assessed co-occurring mutations, response to therapy, and clinical outcomes in patients with and without mutant RUNX1 (mRUNX1); (2)We analyzed 328 AML patients, including 177 patients younger than 65 years who received intensive chemotherapy and 151 patients >65 years who received hypomethylating agents. RUNX1 and co-existing mutations were identified using next-generation sequencing; (3) RUNX1 mutations were identified in 5.1% of younger patients and 15.9% of older patients, and were significantly associated with increasing age (p = 0.01) as well as intermediate-risk cytogenetics including normal karyotype (p = 0.02) in the elderly cohort, and with lower lactate dehydrogenase (LDH; p = 0.02) and higher platelet count (p = 0.012) overall. Identified co-occurring mutations were primarily ASXL1 mutations in older patients and RAS mutations in younger patients; FLT3-ITD and IDH1/2 co-mutations were also frequent. Younger mRUNX1 AML patients treated with intensive chemotherapy experienced inferior treatment outcomes. In older patients with AML treated with hypomethylating agent (HMA) therapy, response and survival was independent of RUNX1 status. Older mRUNX1 patients with prior myelodysplastic syndrome or myeloproliferative neoplasms (MDS/MPN) had particularly dismal outcome. Future studies should focus on the prognostic implications of RUNX1 mutations relative to other co-occurring mutations, and the potential role of hypomethylating agents for this molecularly-defined group.

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