Mutations of TP53 gene in adult acute lymphoblastic leukemia at diagnosis do not affect the achievement of hematologic response but correlate with early relapse and very poor survival

Salmoiraghi, Silvia; Montalvo, Marie Lorena Guinea; Ubiali, Greta; Tosi, Manuela; Peruta, Barbara; Zanghì, Pamela; Oldani, Elena; Boschini, Cristina; Kohlmann, Alexander; Bungaro, Silvia; Intermesoli, Tamara; Terruzzi, Elisabetta; Angelucci, Emanuele; Cavattoni, Irene; Ciceri, Fabio; Bassan, Renato; Spinelli, Orietta

doi:10.3324/haematol.2015.137059

Cited by 25 publications

(28 citation statements)

References 8 publications

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“…Our data also confirmed previously published findings 6-8 that TP53 mutations predominantly occur in older B-ALL patients with low frequency of Philadelphia chromosome. However, in contrast with three previous studies that have analyzed the impact of TP53 mutations in newly diagnosed adult ALL, 6-8 our study did not observe any significant difference in survival and CR duration between TP53 mut and TP53 wt B-ALL patients.…”

Section: Discussionsupporting

confidence: 93%

“…Importantly, neither study analyzed the impact of TP53 mutations in uniformly treated patients, which may have confounded the results. Recently, Salmoiraghi et al 8 evaluated 171 Ph-negative ALL patients treated on the NILG-ALL 09/2000 clinical trial. TP53 mutation was independently associated with worse OS and higher cumulative incidence of relapse.…”

Section: Discussionmentioning

confidence: 99%

“…3-5 Limited studies available on TP53 mut in newly diagnosed adult ALL report variable mutation frequencies, ranging between 6% and 19%, 6-9 with significant enrichment within B-cell ALL with absent Philadelphia chromosome (Ph). 6,10 These studies suggested that TP53 mut ALL has inferior overall survival (OS) 6 , poor response to induction 7 and higher propensity of relapse 8 compared to wild-type TP53 ( TP53 wt ) ALL. However, most of these studies have analyzed patient cohorts that are heterogeneous with respect to age, treatment, and MYC rearrangement.…”

Section: Introductionmentioning

confidence: 99%

“…1,2 TP53 gene mutations (TP53 mut ) have been reported to be associated with refractoriness to chemotherapy and higher rates of disease recurrence in pediatric patients with acute lymphoblastic leukemia (ALL), similar to other malignancies. [3][4][5] The limited studies available regarding TP53 mut in newly diagnosed adult ALL patients have reported variable mutation frequencies, ranging between 6% and 19%, [6][7][8][9] with significant enrichment within B-cell immunophenotype ALL (B-ALL) with absent Philadelphia chromosome (Ph). 6,10 These studies suggest that patients with TP53 mut ALL have an inferior overall survival (OS), 6 a poor response to induction, 7 and a higher propensity of disease recurrence 8 compared with patients with wild-type TP53 (TP53 wt ) ALL.…”

Section: Introductionmentioning

confidence: 99%

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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

Jain

Takahashi

et al. 2017

Cancer

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BACKGROUND TP53 mutations are uncommon in adult acute lymphoblastic leukemia (ALL) and predict poor outcome. METHODS We performed TP53 mutation analysis in 164 newly diagnosed adult ALL patients 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%). Most were single nucleotide variants of missense type and involved the DNA-binding domain. TP53 mutated (TP53mut) ALL was significantly associated with older age, lower median WBC and platelet counts, lower frequency of Philadelphia chromosome and higher frequency of low-hypodiploid karyotype compared to ALL with wild-type TP53 (TP53wt). To evaluate the prognostic effect of TP53 mutations, we selected 146 B-ALL patients (24 TP53mut, 122 TP53wt) uniformly treated with frontline hyper-CVAD-based regimens; more than 90% 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 complete remission duration between TP53mut and TP53wt ALL patients. CONCLUSIONS Hyper-CVAD-based regimens negate the poor prognostic impact of TP53 mutations in adult B-ALL.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Jain

Takahashi

et al. 2017

Cancer

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“…32 Whether patients with LFS have lower remission rates with therapy remains to be determined; however, somatic mutations in TP53 in leukemia are associated with poor outcomes in childhood and adult leukemias. [33][34][35] Making a diagnosis of LFS or other cancer predisposition syndromes is critical, not only as it relates to genetic counseling and donor selection but also in considering tumor surveillance studies after successful treatment of a primary tumor. Importantly, as much as 40% of children with low hypodiploid ALL harbor germ line mutation in TP53, 36,37 suggesting that low hypodiploid ALL is a manifestation of LFS.…”

Section: Nonsyndromic Cancer/leukemia Predispositionmentioning

confidence: 99%

Germ line mutations associated with leukemias

Porter

2016

Hematology

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Several genetic syndromes have long been associated with a predisposition to the development of leukemia, including bone marrow failure syndromes, Down syndrome, and Li Fraumeni syndrome. Recent work has better defined the leukemia risk and outcomes in these syndromes. Also, in the last several years, a number of other germ line mutations have been discovered to define new leukemia predisposition syndromes, including ANKRD26, GATA2, PAX5, ETV6, and DDX41 In addition, data suggest that a substantial proportion of patients with therapy related leukemias harbor germ line mutations in DNA damage response genes such as BRCA1/2 and TP53 Recognition of clinical associations, acquisition of a thorough family history, and high index-of-suspicion are critical in the diagnosis of these leukemia predisposition syndromes. Accurate identification of patients with germ line mutations associated with leukemia can have important clinical implications as it relates to management of the leukemia, as well as genetic counseling of family members.

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RAS and TP53 can predict survival in adults with T‐cell lymphoblastic leukemia treated with hyper‐CVAD

et al. 2019

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Adult T‐cell acute lymphoblastic leukemia (T‐ALL) is a heterogeneous group of acute leukemias that account for about one third of all cases of Philadelphia chromosome (Ph)‐negative ALL. Recently, a molecular classifier using the mutational status of NOTCH1, FBXW7, RAS, and PTEN (NFRP) has been shown to distinguish low‐ vs high‐risk groups in adult T‐ALL patients treated using the Berlin‐Frankfurt‐Münster ALL protocol. However, it is unknown if this molecular classifier can stratify adult T‐ALL patients treated with hyper‐CVAD ± nelarabine. We identified a relatively small cohort of 27 adults with T‐ALL who were uniformly treated with hyper‐CVAD ± nelarabine with available mutational analysis at time of diagnosis. The most commonly mutated genes in this group were NOTCH1 (52%), NRAS (22%), DNMT3A (19%), KRAS (15%), and TP53 (7%). The NFRP molecular classifier failed to stratify overall survival (OS; P = .84) and relapse‐free survival (RFS; P = .18) in this cohort. We developed a new stratification model combining K/NRAS and TP53 mutations as high‐risk factors and showed that mutations in these genes predicted poorer OS (P = .03) and RFS (P = .04). While the current study is limited by cohort size, these data suggest that the NFRP molecular classifier might not be applicable to adult T‐ALL patients treated with hyper‐CVAD ± nelarabine. RAS/TP53 mutation status, however, was useful in risk stratification in adults with T‐ALL.

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Mutations of TP53 gene in adult acute lymphoblastic leukemia at diagnosis do not affect the achievement of hematologic response but correlate with early relapse and very poor survival

Cited by 25 publications

References 8 publications

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

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

Germ line mutations associated with leukemias

RAS and TP53 can predict survival in adults with T‐cell lymphoblastic leukemia treated with hyper‐CVAD

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