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