Elsevier

Leukemia Research

Volume 38, Issue 7, July 2014, Pages 751-755
Leukemia Research

Prognostic value of TP53 gene mutations in myelodysplastic syndromes and acute myeloid leukemia treated with azacitidine

https://doi.org/10.1016/j.leukres.2014.03.012Get rights and content

Abstract

TP53 mutations are found in 5–10% of MDS and AML, where they are generally associated with complex karyotype and an overall poor prognosis. However, the impact of TP53 mutations in MDS treated with azacitidine (AZA) remains unclear. We analyzed TP53 mutations in 62 patients with high risk MDS or AML treated with AZA. A TP53 mutation was found in 23 patients (37.1%), associated with complex karyotype in 18 (78.3%) of them. TP53 mutations had no significant impact on response or complete response to AZA (p = 0.60 and p = 0.26, respectively). By univariate analysis, OS was negatively influenced by the presence of TP53 mutation (median OS 12.4 months versus 23.7 months, p < 10−4), abnormal cytogenetics (median OS 14.4 months vs 33 months, p = 0.02) complex cytogenetics (median OS 12.7 months versus 23.7 months, p = 0.0005), and a diagnosis of AML (median 14.5 months vs 21.2 months for MDS or CMML, p = 0.02). By multivariate analysis, only TP53 mutational status (HR 2.89 (95% confidence interval 1.38–6.04; p = 0.005) retained statistical significance for OS. Results were similar when the analysis was restricted to MDS and CMML patients, excluding AML (HR = 2.46 (95% confidence interval: 1.1–6.4); p = 0.04)).

Thus, TP53 mutations strongly correlated with poorer survival in higher risk MDS and AML treated with AZA.

Introduction

Azacitidine (AZA), a hypomethylating agent, can improve survival in higher risk myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) with 20–30% marrow blasts [1] and has become a reference first line treatment in those disorders. Prognostic factors of response and survival with AZA in high risk MDS and low blast AML are not completely known. No clear correlation between baseline gene methylation patterns (and/or their modification with treatment) and response and/or survival after hypomethylating agents has been identified [2]. However, conventional parameters, including higher marrow blast percentage and unfavorable karyotype [3], [4] or higher revised International Prognostic Scoring System (IPSS) [5] are associated to poorer response rates and/or survival. Acquired mutations of a few genes, including the TET2 gene [6] IDH1 and 2 and DNMT3A [7] gene have been also correlated with better or poorer response, but in relatively small series.

TP53 gene mutation is seen in 5–10% of MDS and AML [8], [9], [10], [11], [12], [13]. With the exception of low risk MDS with isolated del 5q, where they are observed in 20–25% of the cases [14] TP53 gene mutation are generally associated with complex karyotype, generally resulting in del (17p) (i.e. with loss of the remaining TP53 allele) [15], [16], [17]. Irrespective of treatment administered, TP53 mutations have been clearly associated with poor overall outcome in MDS and AML, independently [11], [12], [13] or not [18] of complex karyotype. TP53 mutations have more specifically been associated with resistance to chemotherapy, including anthracycline-Aracytine (AraC) combinations and low-dose cytarabine in AML and MDS [18]. In patients treated with AZA, a recent study found no difference in response between mutated and wild type TP53 patients, and survival based on TP53 status was not reported [13].

We assessed here the impact of TP53 mutations on response and survival after AZA treatment in MDS and AML, and found TP53 mutations to be the only prognostic factor for survival in multivariate analysis.

Section snippets

Patients and treatment

We analyzed 62 patients with MDS, AML and chronic myelomonocytic leukemia (CMML) treated with AZA, generally according to the approved schedule (75 mg/m2/day, 7 days every 4 weeks), and response to treatment was evaluated after 4–6 cycles of treatment (unless progression occurred before), according to IWG 2006 response criteria. Responders were to continue treatment until progression. All patients signed a consent form for analysis of TP53 mutation by FASAY and sequencing. This study was

Results

Between March 2007 and July 2011, 62 patients from one center (Hôpital Avicenne – Paris 13 University) were analyzed. Forty four patients had MDS, 18 had AML with 20–30% marrow blasts (refractory anemia with excess of blasts in transformation (RAEB-T) according to FAB classification, and 4 had CMML, AZA being also approved for treatment of the last 2 subsets in the EU. IPSS was high or intermediate 2 (int 2) in 54 patients, low or int 1 in 6 patients and could not be assessed in 2 patients. The

Discussion

In this work, we showed presence of TP53 mutation to constitute the only independent prognostic parameter of poorer survival in MDS, AML of the elderly with 20–30% blasts considered unfit for intensive chemotherapy and advanced CMML patients treated with AZA. Those patients fulfilled criteria for AZA treatment in the European Union, except for a few patients with lower risk MDS, with anemia resistant to EPO, or with del 5q and resistant to lenalidomide, known to have poor prognosis [22], [23],

Conflict of interest statement

The authors report no potential conflicts of interest.

Acknowledgements

Contributions. C.B., M.S., V.E. and M.J.M. recruited the patients and collected clinical data; C.B., A.R. and J.L.C. performed the laboratory work for this study; L.A. performed the statistical analysis; P.F., C.P., H.D.T. and J.L.C. co-ordinated the research; C.B., L.A., P.F. and J.L.C. wrote the paper.

References (29)

  • R. Itzykson et al.

    Prognostic significance of monosomal karyotype in higher risk myelodysplastic syndrome treated with azacitidine

    Leukemia

    (2011)
  • R. Itzykson et al.

    Impact of TET2 mutations on response rate to azacitidine in myelodysplastic syndromes and low blast count acute myeloid leukemias

    Leukemia

    (2011)
  • P. Jonveaux et al.

    Mutations in the p53 gene in myelodysplastic syndromes

    Oncogene

    (1991)
  • P. Fenaux et al.

    Mutations of the P53 gene in acute myeloid leukaemia

    Br J Haematol

    (1992)
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