G Model
ARTICLE IN PRESS
LR-5155; No. of Pages 2
Leukemia Research xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Leukemia Research journal homepage: www.elsevier.com/locate/leukres
Editorial
TP53 mutations and Azacitidine treatment: To be or not to be related?
During the last years, the number of patients affected by myelodysplastic syndromes (MDS) who received treatments able to modify the natural history of the disease rapidly increased [1]. Several prognostic scoring systems have been developed and updated to better describe the natural course of the disease and to better stratify and allocate patients to different treatment approaches [1]; however there are few data supporting the identification and validation of prognostic scores predicting response to different treatment approaches that are available today. This would be of utmost importance in order to minimize the number of patients with a low probability to respond to a specific treatment [2]. Azacitidine (AZA) is a hypomethylating agent approved for MDS patients with IPSS intermediate-2 or high-risk disease who are not eligible for AML-like chemotherapy and/or allogeneic stem cell transplant [3]. Recently, this agent was recommended by a panel of expert from the European Leukemia Net, for fit patients with IPSS intermediate-2 or high risk MDS and poor-risk cytogenetics who lack a stem cell donor and for fit MDS patients without poorrisk cytogenetics who lack a stem cell donor as an alternative to remission induction chemotherapy (recommendation level B)[4]. TP53 mutations are found in 5–10% of MDS, where they are generally associated with complex karyotype and an overall poor prognosis [5]. However, the impact of TP53 mutations in MDS treated with AZA remains unclear. In this issue [6], Bally et al. analyzed TP53 mutations in a relatively large series of patients with high risk MDS or AML treated with AZA. A TP53 mutation was found in a relatively high proportion of patients (37.1%) and was associated with complex karyotype in most of them (78.3%). The high incidence of TP53 mutations in this series may be accounted for by the IPSS characteristics of the MDS patients who are eligible for AZA treatment, as recently described in an independent series of MDS patients [7]. The occurrence of TP53 mutation had no significant impact on response to AZA, however this lesion was the only variable that retained statistical significance for overall survival by multivariate analysis. Some considerations can be drawn from this paper:
of these patients new treatments have been proposed [10] or are under investigation [11]. In recent years several genetic mutations have been described in hematologic disorders including MDS [5]. Although a wide screening for such molecular defects on a routine basis cannot currently be recommended, the data here presented support the inclusion of TP53 mutation testing in the diagnostic work-up of MDS patients who are candidate for non palliative treatments including AZA and lenalidomide. The availability of massive genotyping technology will soon make it possible for clinicians to detect this and other genetic aberrations in bone marrow and peripheral blood at a reasonable cost, making it easier to predict response to new treatments in MDS patients [4]. Furthermore the possibility to detect minor clones with TP53 mutation by deep sequencing, which would not be detected by traditional sanger sequencing, may improve our diagnostic accuracy and explain the loss of response that was observed in this genetically unstable subset of MDS [12]. 2. The data from this study opened some questions about the mechanism of action and resistance to AZA. Consistent experimental observations suggested that non-cytotoxic DNA methyltransferase depletion by AZA can trigger cell cycle exit independently of p53, thus circumventing resistance to apoptosis-based DNA damaging therapy [13]. However, as shown in this paper, the therapeutic benefit obtained by AZA in those patients with TP53 mutation was short lasting suggesting that the precise mechanisms involved in the response to AZA are not completely understood. In particular it was observed that hypomethylating therapies are not efficacious if DNA methyltransferase is not depleted by sufficient overlap between intracellular drug half-lives and S-phase entries of malignant cells suggesting that alternative schedule of treatment could be evaluated [12]. However other authors have demonstrated that apoptosis could also be a key determinant of AZA mechanism of action [14] and that AZA fails to eradicate leukemic stem/progenitor cell populations suggesting that a combined treatment using new drugs that target this cellular population in vivo are possibly required [15].
1. This study underscores the prognostic relevance of TP53 mutations in intermediate-2 and high risk MDS patients treated with AZA. TP53 mutations have also been demonstrate to predict response in several other groups of patients undergoing targeted therapies including 5q- syndrome patients treated with lenalidomide [8] and chronic lymphocytic leukemia (CLL) patients treated with Rituximab and chlorambucil [9]. For some
In conclusion, the analysis of TP53 mutations could be proposed as an important tool in the diagnostic work-up of MDS patients undergoing AZA treatment. We still need to better clarify the mechanisms of action and resistance to AZA for a more efficacious application of this treatment.
http://dx.doi.org/10.1016/j.leukres.2014.04.005 0145-2126/© 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Rigolin GM, Cuneo A. TP53 mutations and Azacitidine treatment: To be or not to be related? Leuk Res (2014), http://dx.doi.org/10.1016/j.leukres.2014.04.005
G Model LR-5155; No. of Pages 2
ARTICLE IN PRESS Editorial / Leukemia Research xxx (2014) xxx–xxx
2
Funding Work supported by FAR 2012 and 2013 and AIL Ferrara Section. Conflict of interest The authors declare that they have no conflict of interest. Acknowledgments
[10]
[11]
[12]
[13]
Contributors: GMR and AC wrote and approved the paper. [14]
References [1] Germing U, Kündgen A. Prognostic scoring systems in MDS. Leuk Res 2012;36:1463–9. [2] Rigolin GM, Porta MD, Ciccone M, et al. In patients with myelodysplastic syndromes response to rHuEPO and G-CSF treatment is related to an increase of cytogenetically normal CD34 cells. Br J Haematol 2004;126:501–7. [3] Fenaux P, Bowen D, Gattermann N, et al. Practical use of azacitidine in higher-riskmyelodysplastic syndromes: an expert panel opinion. Leuk Res 2010;34:1410–6. [4] Malcovati L, Hellstrom-Lindberg E, Bowen D, et al. Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet. Blood 2013;122:2943–64. [5] Haferlach T, Nagata Y, Grossmann V, et al. Landscape of genetic lesions in 944 patients with myelodysplastic syndromes. Leukemia 2014;28:241–7. [6] Bally C, Adès L, Renneville A, et al. Prognostic value of TP53 gene mutations in myelodysplastic syndromes and acutemyeloid leukemia treated with azacitidine. Leuk Res 2014;(March), http://dx.doi.org/10.1016/j.leukres.2014.03.012 [Epub ahead of print. This issue]. [7] Kulasekararaj AG, Smith AE, Mian SA, et al. TP53 mutations in myelodysplastic syndrome are strongly correlated with aberrations of chromosome 5, and correlate with adverse prognosis. Br J Haematol 2013;160:660–72. [8] Jädersten M, Saft L, Smith A, Kulasekararaj A, et al. TP53 mutations in lowrisk myelodysplastic syndromes with del(5q) predict disease progression. J Clin Oncol 2011;29:1971–9. [9] Foà R, Del Giudice I, Cuneo A, Del Poeta G. Chlorambucil plus rituximab with or without maintenance rituximab as first-line treatment for
[15]
elderly chronic lymphocytic leukemia patients. Am J Hematol 2014;(January), http://dx.doi.org/10.1002/ajh.23668 [Epub ahead of print]. Cuneo A, Cavazzini F, Ciccone M, et al. Modern treatment in chronic lymphocytic leukemia: impact on survival and efficacy in high-risk subgroups. Cancer Med 2014;(March), http://dx.doi.org/10.1002/cam4.226 [Epub ahead of print]. Caceres G, McGraw K, Yip BH, et al. TP53 suppression promotes erythropoiesis in del(5q) MDS, suggesting a targeted therapeutic strategy in lenalidomideresistant patients. Proc Natl Acad Sci U S A 2013;110:16127–32. Rossi D, Khiabanian H, Spina V, et al. Clinical impact of small TP53 mutated subclones in chronic lymphocytic leukemia. Blood 2014;(February) [Epub ahead of print] PubMed PMID: 24501221. Saunthararajah Y. Key clinical observations after 5-azacytidine and decitabine treatment of myelodysplastic syndromes suggest practical solutions for better outcomes. Hematology Am Soc Hematol Educ Program 2013:511–21. Schnekenburger M, Grandjenette C, Ghelfi J, et al. Sustained exposure to the DNA demethylating agent, 2 -deoxy-5-azacytidine, leads to apoptotic cell death in chronic myeloid leukemia by promoting differentiation, senescence, and autophagy. Biochem Pharmacol 2011;81:364–78. Craddock C, Quek L, Goardon N, et al. Azacitidine fails to eradicate leukemic stem/progenitor cell populations in patients with acute myeloid leukemia and myelodysplasia. Leukemia 2013;27:1028–36.
Gian Matteo Rigolin ∗ Antonio Cuneo Hematology Section, Azienda Ospedaliero Universitaria Arcispedale S. Anna, University of Ferrara, Italy ∗ Corresponding author at: Hematology Section, Azienda Ospedaliero Universitaria Arcispedale S. Anna, University of Ferrara, Via Aldo Moro, 8, 44124 Cona, Ferrara, Italy. Tel.: +39 0532 239674; fax: +39 0532 236049. E-mail address: [email protected] (G.M. Rigolin)
4 April 2014 Available online xxx
Please cite this article in press as: Rigolin GM, Cuneo A. TP53 mutations and Azacitidine treatment: To be or not to be related? Leuk Res (2014), http://dx.doi.org/10.1016/j.leukres.2014.04.005
ARTICLE IN PRESS
LR-5155; No. of Pages 2
Leukemia Research xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Leukemia Research journal homepage: www.elsevier.com/locate/leukres
Editorial
TP53 mutations and Azacitidine treatment: To be or not to be related?
During the last years, the number of patients affected by myelodysplastic syndromes (MDS) who received treatments able to modify the natural history of the disease rapidly increased [1]. Several prognostic scoring systems have been developed and updated to better describe the natural course of the disease and to better stratify and allocate patients to different treatment approaches [1]; however there are few data supporting the identification and validation of prognostic scores predicting response to different treatment approaches that are available today. This would be of utmost importance in order to minimize the number of patients with a low probability to respond to a specific treatment [2]. Azacitidine (AZA) is a hypomethylating agent approved for MDS patients with IPSS intermediate-2 or high-risk disease who are not eligible for AML-like chemotherapy and/or allogeneic stem cell transplant [3]. Recently, this agent was recommended by a panel of expert from the European Leukemia Net, for fit patients with IPSS intermediate-2 or high risk MDS and poor-risk cytogenetics who lack a stem cell donor and for fit MDS patients without poorrisk cytogenetics who lack a stem cell donor as an alternative to remission induction chemotherapy (recommendation level B)[4]. TP53 mutations are found in 5–10% of MDS, where they are generally associated with complex karyotype and an overall poor prognosis [5]. However, the impact of TP53 mutations in MDS treated with AZA remains unclear. In this issue [6], Bally et al. analyzed TP53 mutations in a relatively large series of patients with high risk MDS or AML treated with AZA. A TP53 mutation was found in a relatively high proportion of patients (37.1%) and was associated with complex karyotype in most of them (78.3%). The high incidence of TP53 mutations in this series may be accounted for by the IPSS characteristics of the MDS patients who are eligible for AZA treatment, as recently described in an independent series of MDS patients [7]. The occurrence of TP53 mutation had no significant impact on response to AZA, however this lesion was the only variable that retained statistical significance for overall survival by multivariate analysis. Some considerations can be drawn from this paper:
of these patients new treatments have been proposed [10] or are under investigation [11]. In recent years several genetic mutations have been described in hematologic disorders including MDS [5]. Although a wide screening for such molecular defects on a routine basis cannot currently be recommended, the data here presented support the inclusion of TP53 mutation testing in the diagnostic work-up of MDS patients who are candidate for non palliative treatments including AZA and lenalidomide. The availability of massive genotyping technology will soon make it possible for clinicians to detect this and other genetic aberrations in bone marrow and peripheral blood at a reasonable cost, making it easier to predict response to new treatments in MDS patients [4]. Furthermore the possibility to detect minor clones with TP53 mutation by deep sequencing, which would not be detected by traditional sanger sequencing, may improve our diagnostic accuracy and explain the loss of response that was observed in this genetically unstable subset of MDS [12]. 2. The data from this study opened some questions about the mechanism of action and resistance to AZA. Consistent experimental observations suggested that non-cytotoxic DNA methyltransferase depletion by AZA can trigger cell cycle exit independently of p53, thus circumventing resistance to apoptosis-based DNA damaging therapy [13]. However, as shown in this paper, the therapeutic benefit obtained by AZA in those patients with TP53 mutation was short lasting suggesting that the precise mechanisms involved in the response to AZA are not completely understood. In particular it was observed that hypomethylating therapies are not efficacious if DNA methyltransferase is not depleted by sufficient overlap between intracellular drug half-lives and S-phase entries of malignant cells suggesting that alternative schedule of treatment could be evaluated [12]. However other authors have demonstrated that apoptosis could also be a key determinant of AZA mechanism of action [14] and that AZA fails to eradicate leukemic stem/progenitor cell populations suggesting that a combined treatment using new drugs that target this cellular population in vivo are possibly required [15].
1. This study underscores the prognostic relevance of TP53 mutations in intermediate-2 and high risk MDS patients treated with AZA. TP53 mutations have also been demonstrate to predict response in several other groups of patients undergoing targeted therapies including 5q- syndrome patients treated with lenalidomide [8] and chronic lymphocytic leukemia (CLL) patients treated with Rituximab and chlorambucil [9]. For some
In conclusion, the analysis of TP53 mutations could be proposed as an important tool in the diagnostic work-up of MDS patients undergoing AZA treatment. We still need to better clarify the mechanisms of action and resistance to AZA for a more efficacious application of this treatment.
http://dx.doi.org/10.1016/j.leukres.2014.04.005 0145-2126/© 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Rigolin GM, Cuneo A. TP53 mutations and Azacitidine treatment: To be or not to be related? Leuk Res (2014), http://dx.doi.org/10.1016/j.leukres.2014.04.005
G Model LR-5155; No. of Pages 2
ARTICLE IN PRESS Editorial / Leukemia Research xxx (2014) xxx–xxx
2
Funding Work supported by FAR 2012 and 2013 and AIL Ferrara Section. Conflict of interest The authors declare that they have no conflict of interest. Acknowledgments
[10]
[11]
[12]
[13]
Contributors: GMR and AC wrote and approved the paper. [14]
References [1] Germing U, Kündgen A. Prognostic scoring systems in MDS. Leuk Res 2012;36:1463–9. [2] Rigolin GM, Porta MD, Ciccone M, et al. In patients with myelodysplastic syndromes response to rHuEPO and G-CSF treatment is related to an increase of cytogenetically normal CD34 cells. Br J Haematol 2004;126:501–7. [3] Fenaux P, Bowen D, Gattermann N, et al. Practical use of azacitidine in higher-riskmyelodysplastic syndromes: an expert panel opinion. Leuk Res 2010;34:1410–6. [4] Malcovati L, Hellstrom-Lindberg E, Bowen D, et al. Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet. Blood 2013;122:2943–64. [5] Haferlach T, Nagata Y, Grossmann V, et al. Landscape of genetic lesions in 944 patients with myelodysplastic syndromes. Leukemia 2014;28:241–7. [6] Bally C, Adès L, Renneville A, et al. Prognostic value of TP53 gene mutations in myelodysplastic syndromes and acutemyeloid leukemia treated with azacitidine. Leuk Res 2014;(March), http://dx.doi.org/10.1016/j.leukres.2014.03.012 [Epub ahead of print. This issue]. [7] Kulasekararaj AG, Smith AE, Mian SA, et al. TP53 mutations in myelodysplastic syndrome are strongly correlated with aberrations of chromosome 5, and correlate with adverse prognosis. Br J Haematol 2013;160:660–72. [8] Jädersten M, Saft L, Smith A, Kulasekararaj A, et al. TP53 mutations in lowrisk myelodysplastic syndromes with del(5q) predict disease progression. J Clin Oncol 2011;29:1971–9. [9] Foà R, Del Giudice I, Cuneo A, Del Poeta G. Chlorambucil plus rituximab with or without maintenance rituximab as first-line treatment for
[15]
elderly chronic lymphocytic leukemia patients. Am J Hematol 2014;(January), http://dx.doi.org/10.1002/ajh.23668 [Epub ahead of print]. Cuneo A, Cavazzini F, Ciccone M, et al. Modern treatment in chronic lymphocytic leukemia: impact on survival and efficacy in high-risk subgroups. Cancer Med 2014;(March), http://dx.doi.org/10.1002/cam4.226 [Epub ahead of print]. Caceres G, McGraw K, Yip BH, et al. TP53 suppression promotes erythropoiesis in del(5q) MDS, suggesting a targeted therapeutic strategy in lenalidomideresistant patients. Proc Natl Acad Sci U S A 2013;110:16127–32. Rossi D, Khiabanian H, Spina V, et al. Clinical impact of small TP53 mutated subclones in chronic lymphocytic leukemia. Blood 2014;(February) [Epub ahead of print] PubMed PMID: 24501221. Saunthararajah Y. Key clinical observations after 5-azacytidine and decitabine treatment of myelodysplastic syndromes suggest practical solutions for better outcomes. Hematology Am Soc Hematol Educ Program 2013:511–21. Schnekenburger M, Grandjenette C, Ghelfi J, et al. Sustained exposure to the DNA demethylating agent, 2 -deoxy-5-azacytidine, leads to apoptotic cell death in chronic myeloid leukemia by promoting differentiation, senescence, and autophagy. Biochem Pharmacol 2011;81:364–78. Craddock C, Quek L, Goardon N, et al. Azacitidine fails to eradicate leukemic stem/progenitor cell populations in patients with acute myeloid leukemia and myelodysplasia. Leukemia 2013;27:1028–36.
Gian Matteo Rigolin ∗ Antonio Cuneo Hematology Section, Azienda Ospedaliero Universitaria Arcispedale S. Anna, University of Ferrara, Italy ∗ Corresponding author at: Hematology Section, Azienda Ospedaliero Universitaria Arcispedale S. Anna, University of Ferrara, Via Aldo Moro, 8, 44124 Cona, Ferrara, Italy. Tel.: +39 0532 239674; fax: +39 0532 236049. E-mail address: [email protected] (G.M. Rigolin)
4 April 2014 Available online xxx
Please cite this article in press as: Rigolin GM, Cuneo A. TP53 mutations and Azacitidine treatment: To be or not to be related? Leuk Res (2014), http://dx.doi.org/10.1016/j.leukres.2014.04.005
