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

Kanagal-Shamanna R1, Jain P2, Takahashi K2, Short NJ2, Tang G1, Issa GC2, Ravandi F2, Garcia-Manero G2, Yin CC1, Luthra R1, Patel KP1, Khoury JD1, Montalban-Bravo G1, Sasaki K2, Kadia TM2, Borthakur G2, Konopleva M2, Jain N2, Garris R2, Pierce S2, Wierda W2, Estrov Z2, Cortes J2, O'Brien S3, Kantarjian HM2, Jabbour E2.

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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:

KEYWORDS:

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