TP53 mutation does not confer a poor outcome in adult patients with acute lymphoblastic leukemia who are treated with frontline hyper-CVAD-based regimens

Rashmi Kanagal-Shamanna, Preetesh Jain, Koichi Takahashi, Nicholas J. Short, Guilin Tang, Ghayas C. Issa, Farhad Ravandi, Guillermo Garcia-Manero, Cameron C. Yin, Rajyalakshmi Luthra, Keyur P. Patel, Joseph D. Khoury, Guillermo Montalban-Bravo, Koji Sasaki, Tapan M. Kadia, Gautam Borthakur, Marina Konopleva, Nitin Jain, Rebecca Garris, Sherry PierceWilliam Wierda, Zeev Estrov, Jorge Cortes, Susan O'Brien, Hagop M. Kantarjian, Elias Jabbour

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

BACKGROUND: Tumor protein 53 (TP53) mutations are uncommon in adult patients with acute lymphoblastic leukemia (ALL) and predict a poor outcome. METHODS: TP53 mutation analysis was performed in 164 newly diagnosed adult patients with ALL using a combination of targeted amplicon-based next-generation sequencing and Sanger sequencing. RESULTS: TP53 mutations were detected in 25 patients (15%), with a median allelic frequency of 42.2% (range, 5.6%-93.8%). The majority of mutations were single-nucleotide variants of missense type and involved the DNA-binding domain. TP53-mutated (TP53mut) ALL was found to be significantly associated with older age, lower median white blood cell and platelet counts, lower frequency of Philadelphia chromosome and a higher frequency of low hypodiploid karyotype compared with ALL with wild-type TP53 (TP53wt). To evaluate the prognostic effect of TP53 mutations, the authors selected 146 patients with B-cell immunophenotype ALL (24 with TP53mut and 122 with TP53wt) who were uniformly treated with frontline hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD)-based regimens; >90% of these individuals also received a monoclonal antibody. Over a median follow-up duration of 15 months, there was no significant difference in the median overall survival, event-free survival, and duration of complete remission noted between patients with TP53mut ALL and those with TP53wt ALL. CONCLUSIONS: Hyper-CVAD-based regimens appear to negate the poor prognostic impact of TP53 mutations in patients with adult B-cell immunophenotype ALL. Cancer 2017;123:3717-24.

Original languageEnglish (US)
Pages (from-to)3717-3724
Number of pages8
JournalCancer
Volume123
Issue number19
DOIs
StatePublished - Oct 1 2017
Externally publishedYes

Keywords

  • acute lymphoblastic leukemia (ALL)
  • hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD)
  • next-generation sequencing
  • tumor protein 53 (TP53)

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Kanagal-Shamanna, R., Jain, P., Takahashi, K., Short, N. J., Tang, G., Issa, G. C., Ravandi, F., Garcia-Manero, G., Yin, C. C., Luthra, R., Patel, K. P., Khoury, J. D., Montalban-Bravo, G., Sasaki, K., Kadia, T. M., Borthakur, G., Konopleva, M., Jain, N., Garris, R., ... Jabbour, E. (2017). TP53 mutation does not confer a poor outcome in adult patients with acute lymphoblastic leukemia who are treated with frontline hyper-CVAD-based regimens. Cancer, 123(19), 3717-3724. https://doi.org/10.1002/cncr.30810