Accepted Article Preview: Published ahead of advance online publication Molecular prognostic factors in acute myeloid leukemia (AML) receiving first-line therapy with azacitidine J Desoutter, J Gay, C Berthon, L Ades, B Gruson, S Geffroy, I Plantier, M Alice, N Helevaut, J Fernandes, M Bemba, L Stalnikiewicz, C Frimat, J Labreuche, O Nibourel, C Roumier, M Figeac, P Fenaux, B Quesnel, A Renneville, A Duhamel, C Preudhomme
Cite this article as: J Desoutter, J Gay, C Berthon, L Ades, B Gruson, S Geffroy, I Plantier, M Alice, N Helevaut, J Fernandes, M Bemba, L Stalnikiewicz, C Frimat, J Labreuche, O Nibourel, C Roumier, M Figeac, P Fenaux, B Quesnel, A Renneville, A Duhamel, C Preudhomme, Molecular prognostic factors in acute myeloid leukemia (AML) receiving first-line therapy with azacitidine, Leukemia accepted article preview 19 November 2015; doi: 10.1038/leu.2015.314. This is a PDF file of an unedited peer-reviewed manuscript that has been accepted for publication. NPG are providing this early version of the manuscript as a service to our customers. The manuscript will undergo copyediting, typesetting and a proof review before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers apply.
Accepted article preview online 19 November 2015
©
2015 Macmillan Publishers Limited. All rights reserved.
LETTER TO THE EDITOR
Molecular prognostic factors in acute myeloid leukemia (AML) receiving first-line therapy with azacitidine.
Elderly patients with acute myeloid leukemia (AML), secondary AML and high-risk cytogenetics AML patients are generally not candidates or respond poorly to potentially curative treatment with intensive chemotherapy (ICT) followed or not by allogeneic stem cell transplantation (allo-SCT) (1). Azacitidine (AZA) has demonstrated a survival improvement in high-risk myelodysplastic syndromes (MDS) and AML with 20 to 30% bone marrow (BM) blasts, and is also promising in AML with >30% BM blasts (2–4). While gene mutations are now routinely included among prognostic factors of AML treated with ICT (5), their prognostic impact on AML treated with AZA is unknown. We report prognostic factors, including the mutational status of 18 genes assessed by next-generation sequencing (NGS), in 96 newly diagnosed AML patients who received first line treatment with AZA. Following approval of AZA by FDA and EMA for MDS, the French health agency (ANSM) opened a compassionate patient named program (ATU program) of AZA for AML patients ineligible for ICT. We analyzed retrospectively 96 previously untreated AML patients from 8 centers treated with AZA in this program between 2007 and 2012. Patients could be included if ineligible for ICT due to advanced age, major comorbidities or high-risk cytogenetics. Patients gave informed consent in accordance with the Declaration of Helsinki. AZA was administered according to the approved schedule (75 mg/m2/day, 7 days /4 weeks SC) for at least 6 cycles. Cytogenetic risk was evaluated according to MRC Classification. The mutational status of 16 genes was analyzed by NGS: ASXL1, CEBPA, DNMT3A, EZH2, FLT3, IDH1, IDH2, 1 ©
2015 Macmillan Publishers Limited. All rights reserved.
NPM1, NRAS, KRAS, RUNX1, SF3B1, SRSF2, U2AF1, TET2, TP53 (PGM, Life technologies, Supplemental Data). Because of the limits of our NGS assay, all mutations were also screened by Sanger sequencing. In addition, MLL-PTD and EVI1 expression were assessed as previously described (6). Initial response was evaluated on blood and marrow after 4-6 cycles of AZA. Complete remission (CR), partial remission (PR), CR with incomplete recovery (CRi) and failure were defined according to IWG-2003 response criteria for AML (7). OS was measured from onset of AZA, and time was censored at the date of last follow-up in patients who were still alive (n=8). Median age of the 96 patients included was 74 years (range, 44-88) and M/F 56/40. In addition to age, this population was characterized by high risk features including secondary AML in 55% of the patients (post-MDS or post-MPN-AML in 39, therapy-related AML in 14), ECOG-PS ≥2 in 20%, unfavorable cytogenetics in 64% (including 37 monosomal karyotypes), while only one patient had favorable cytogenetics. Median WBC count was 3.9 G/L, and >10G/L in 28 patients, median circulating blast % was 15% (range, 0-95) and BM blasts were >30% in 55 patients (TableS1). The median total number of mutations per patient was 2 (range, 0-5) (FigureS1). The most frequently mutated gene was TP53 (n= 38, 40%, associated in 2 patients with intermediate risk karyotype and in 36 with unfavorable karyotype, including 29 monosomal and 7 other complex karyotypes) (FigureS1), followed by TET2 (n=21, 22%) and by SRSF2 (n=18, 19%, a high incidence for AML) (8) , and mutations in DNMT3A (14%), ASXL1 (13.5%), IDH2 (11%) and RUNX1 (11%) genes. EVI1 overexpression was found in 11/72 evaluable cases (FigureS2). No patient had isolated NPM1 or double mutant CEBPa mutation. The median number of AZA cycles administered was 7 (range, 1-33). Overall response rate (ORR) was 32% (16% CR, 9% PR and 7% CRi), 19 patients had stable disease and 46 patients had disease progression. Median response duration was 9.4 months (range, 1.5-58.6)
2 ©
2015 Macmillan Publishers Limited. All rights reserved.
and median overall survival (OS) was 10.9 months, with a 1 and 2-year survival rate of 37% and 8%, respectively. ORR and median OS were close to those found in the Italian AZA compassionate program (9), where the population’s baseline features were however somewhat more favorable. We assessed the prognostic impact of clinical and conventional biological parameters, and molecular markers on results of AZA treatment using univariate Cox’s regression hazard models (TableS1). In univariate analysis, we considered 8 molecular markers independently (TP53, TET2, SRSF2, DNMT3A, ASXL1, IDH2, RUNX1, EVI1) for their impact on OS (Table1). Factors associated with OS in univariate analysis with P30%, had an impact on OS. Age and WBC count did not influence OS in our cohort, in line with several previous experiences (3,9,10), although Thepot et al found an adverse prognostic impact of WBC count >15 G/l (3). Adverse cytogenetics (except monosomal karyotype) had no significant prognostic influence in our cohort, in agreement with Pleyer et al (10), but contrary to 2 other studies (3,11). However, most of our patients had adverse cytogenetic whereas this proportion was below 40%) in the 3 other studies (3,11).
3 ©
2015 Macmillan Publishers Limited. All rights reserved.
For molecular abnormalities, in univariate analysis, only TP53 mutations were significantly associated with adverse impact on OS (P=0.019) (Figure1A, Table1). TP53 mutations have been associated with poor outcome in AML treated with ICT, with or without allo-SCT, including in our experience (12) and in high-risk MDS and AML with 20-30% BM blast treated with AZA (13). We confirmed this result in a larger cohort of AML regardless of the BM blast %. Interestingly, however, the median OS of 8.9 months seen in the present series may be superior to the median OS of about 4 months observed in elderly AML patients with mutated TP53 treated with ICT (12). TET2 mutations also tended to be associated with poorer OS (P=0.20) in our cohort, whereas in our experience and that of another group in higher risk MDS and AML with 2030% blasts, they were associated with better response to AZA (that did not however translate into a survival advantage) (14,15). We also found a trend for an adverse impact of SRSF2 mutation on OS in univariate analysis (P=0.16), a gene whose prognostic impact had so far been established in MDS and AML, but independently of treatment (8). ASXL1, DNMT3A and RUNX1 mutations have been shown to confer a negative impact on OS in AML treated by ICT (5) , which we did not observe with AZA, but numbers were probably too small for definite conclusions. No patient had isolated NPM1 or double mutant CEBPa mutation, precluding assessment of the prognostic value of those mutations for AZA treatment. Importantly, while the adverse prognostic impact of EVI1 overexpression has been well established in AML treated with ICT (6), we found a trend for better OS in AML with EVI1 overexpression treated with AZA (P=0.08) (Table1). In multivariate analysis, higher ECOGPS (P=0.016), lower Hb level (P30% blasts. Blood. 2015 May 18;
5.
Patel JP, Gönen M, Figueroa ME, Fernandez H, Sun Z, Racevskis J, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012 Mar 22;366(12):1079–89.
6.
Gröschel S, Lugthart S, Schlenk RF, Valk PJM, Eiwen K, Goudswaard C, et al. High EVI1 expression predicts outcome in younger adult patients with acute myeloid leukemia and is associated with distinct cytogenetic abnormalities. J Clin Oncol Off J Am Soc Clin Oncol. 2010 Apr 20;28(12):2101–7.
5 ©
2015 Macmillan Publishers Limited. All rights reserved.
7.
Cheson BD, Bennett JM, Kopecky KJ, Büchner T, Willman CL, Estey EH, et al. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol Off J Am Soc Clin Oncol. 2003 Dec 15;21(24):4642–9.
8.
Taskesen E, Havermans M, van Lom K, Sanders MA, van Norden Y, Bindels E, et al. Two splice-factor mutant leukemia subgroups uncovered at the boundaries of MDS and AML using combined gene expression and DNA-methylation profiling. Blood. 2014 May 22;123(21):3327–35.
9.
Maurillo L, Venditti A, Spagnoli A, Gaidano G, Ferrero D, Oliva E, et al. Azacitidine for the treatment of patients with acute myeloid leukemia: report of 82 patients enrolled in an Italian Compassionate Program. Cancer. 2012 Feb 15;118(4):1014–22.
10. Pleyer L, Burgstaller S, Girschikofsky M, Linkesch W, Stauder R, Pfeilstocker M, et al. Azacitidine in 302 patients with WHO-defined acute myeloid leukemia: results from the Austrian Azacitidine Registry of the AGMT-Study Group. Ann Hematol. 2014 Jun 21;93(11):1825–38. 11. Van der Helm LH, Veeger NJGM, Kooy M van M, Beeker A, de Weerdt O, de Groot M, et al. Azacitidine results in comparable outcome in newly diagnosed AML patients with more or less than 30% bone marrow blasts. Leuk Res. 2013 Aug;37(8):877–82. 12. Wattel E, Preudhomme C, Hecquet B, Vanrumbeke M, Quesnel B, Dervite I, et al. p53 mutations are associated with resistance to chemotherapy and short survival in hematologic malignancies. Blood. 1994 Nov 1;84(9):3148–57. 13. Bally C, Adès L, Renneville A, Sebert M, Eclache V, Preudhomme C, et al. Prognostic value of TP53 gene mutations in myelodysplastic syndromes and acute myeloid leukemia treated with azacitidine. Leuk Res. 2014 Jul;38(7):751–5. 14. Itzykson R, Kosmider O, Cluzeau T, Mansat-De Mas V, Dreyfus F, Beyne-Rauzy O, et al. Impact of TET2 mutations on response rate to azacitidine in myelodysplastic syndromes and low blast count acute myeloid leukemias. Leukemia. 2011 Jul;25(7):1147–52. 15. Bejar R, Lord A, Stevenson K, Bar-Natan M, Pérez-Ladaga A, Zaneveld J, et al. TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients. Blood. 2014 Oct 23;124(17):2705–12.
6 ©
2015 Macmillan Publishers Limited. All rights reserved.
AUTHORS Judith Desoutter, PharmD1*, Julie Gay, MD2*, Céline Berthon, MD, PhD3, Lionel Ades, MD4, Bérengère Gruson, MD5, Sandrine Geffroy1, Isabelle Plantier, MD6, Marceau Alice, PharmD1, Nathalie Helevaut1, Jose Fernandes, MD7, Maxime Bemba, MD8, Laure Stalnikiewicz, MD9, Cécile Frimat1, Julien Labreuche10, Olivier Nibourel PharmD, PhD1, Christophe Roumier, PharmD1, Martin Figeac11, Pierre Fenaux, MD, PhD12, Bruno Quesnel, MD, PhD3, Aline Renneville, PharmD, PhD1, Alain Duhamel10, MD, and Claude Preudhomme, PharmD, PhD1 1 Laboratoire d’hématologie, Centre de Biologie Pathologie, CHRU Lille, France 2 Service d’hématologie clinique, Hôpital Saint Antoine, Université Paris 6, APHP, Paris, France 3 Service d’hématologie clinique, CHRU Lille, France 4 Service d’hématologie clinique, Hôpital d’Avicenne, Université Paris 13, Bobigny, France 5 Service d’hématologie clinique, CHU Amiens-Picardie, France 6 Service d’hématologie clinique, Hôpital de Roubaix, France 7 Service d’hématologie clinique, Hôpital de Valenciennes, France 8 Service d’hématologie clinique, Hôpital de Dunkerque, France 9 Service d’hématologie clinique, Hôpital de Lens, France 10 Unités de Biostatistiques, CHRU Lille, France 11 Plateforme de génomique structurale et fonctionnelle, IFR-114, Université Lille 2, France 12 Service d’hématologie clinique, Hôpital Saint-Louis, Université Paris 7, APHP, Paris, France J.D. and J.G. contributed equally to this study This work was the subject of an oral communication in 56th ASH Annual Meeting and Exposition held in San Francisco from 6-9 December 2014 Corresponding author : Claude Preudhomme - E-mail : [email protected]
ACKNOWLEDGEMENT INCA PRT-K 2010 : Institut National du Cancer – Programme de Recherche Translationnelle en Cancérologie.
CONFLICT OF INTEREST DISCLOSURE The authors declare no competing financial interests.
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2015 Macmillan Publishers Limited. All rights reserved.
FIGURE LEGENDS Figure1. Kaplan-Meier overall survival curves according to the mutational status of TP53 and EVI1 expression. A)Median survival of patients with mutation in TP53 gene was 8.9 compared to 12.3 months in wild-type TP53 patients. B)Patients with EVI1 overexpression without TP53 mutation had a median OS of 24.7 months, versus 7.2 months for patients carrying TP53 mutation and 10.4 months in the remaining patients.
Table1. Prognostic value of Molecular Parameters for survival by univariate analysis
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2015 Macmillan Publishers Limited. All rights reserved.
Table1. Prognostic value of Molecular Parameters for survival by univariate analysis n (%)
HR (95%CI) *
P-Value*
Number of somatic mutations ≤1 2 3 ≥4
44 (45.8)‡ 25 (26.0) 16 (16.7) 11 (11.5)§
1.00 (Ref.) 0.90 (0.54-1.51) 1.10 (0.60-1.99) 1.21 (0.60-2.46)
0.61† 0.69 0.76 0.59
TP53 Wild-type Mutated
58 (60.4) 38 (39.6)
1.00 (Ref.) 1.68 (1.09-2.58)
0.019
TET2 Wild-type Mutated
74 (77.9) 21 (22.1)
1.00 (Ref.) 1.38 (0.83-2.30)
0.20
SRSF2 Wild-type Mutated
78 (81.3) 18 (18.8)
1.00 (Ref.) 1.45 (0.86-2.45)
0.16
DNMT3A Wild-type Mutated
82 (85.4) 14 (14.6)
1.00 (Ref.) 0.62 (0.86-1.58)
0.62
ASXL1 Wild-type Mutated
81 (86.5) 13 (13.5)
1.00 (Ref.) 0.76 (0.40-1.44)
0.40
IDH2 Wild-type Mutated
85 (88.5) 11 (11.5)
1.00 (Ref.) 0.84 (0.42-1.67)
0.61
RUNX1 Wild-type Mutated
85 (88.5) 11 (11.5)
1.00 (Ref.) 0.74 (0.38-1.44)
0.38
EVI1 expression Normal Overexpression
61 (84.7) 11 (15.3)
1.00 (Ref.) 0.53 (0.26-1.08)
0.08
Abbreviations: AML=Acute myeloid leukemia, CI=confidence interval, HR=Hazard ratio. * HRs calculated from Univariate Cox’s regression hazard models.† p for trend test ‡ including 6 patients without somatic mutations § including 2 patients with 5 somatic mutations
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2015 Macmillan Publishers Limited. All rights reserved.
Figure1. Kaplan-Meier overall survival curves according to the mutational status of TP53 and EVI1 expression. A) Median survival of patients with mutation in TP53 gene was 8.9 compared to 12.3 months in wild-type TP53 patients. B) Patients with EVI1 overexpression without TP53 mutation had a median OS of 24.7 months, versus 7.2 months for patients carrying TP53 mutation and 10.4 months in the remaining patients.
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2015 Macmillan Publishers Limited. All rights reserved.
Cite this article as: J Desoutter, J Gay, C Berthon, L Ades, B Gruson, S Geffroy, I Plantier, M Alice, N Helevaut, J Fernandes, M Bemba, L Stalnikiewicz, C Frimat, J Labreuche, O Nibourel, C Roumier, M Figeac, P Fenaux, B Quesnel, A Renneville, A Duhamel, C Preudhomme, Molecular prognostic factors in acute myeloid leukemia (AML) receiving first-line therapy with azacitidine, Leukemia accepted article preview 19 November 2015; doi: 10.1038/leu.2015.314. This is a PDF file of an unedited peer-reviewed manuscript that has been accepted for publication. NPG are providing this early version of the manuscript as a service to our customers. The manuscript will undergo copyediting, typesetting and a proof review before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers apply.
Accepted article preview online 19 November 2015
©
2015 Macmillan Publishers Limited. All rights reserved.
LETTER TO THE EDITOR
Molecular prognostic factors in acute myeloid leukemia (AML) receiving first-line therapy with azacitidine.
Elderly patients with acute myeloid leukemia (AML), secondary AML and high-risk cytogenetics AML patients are generally not candidates or respond poorly to potentially curative treatment with intensive chemotherapy (ICT) followed or not by allogeneic stem cell transplantation (allo-SCT) (1). Azacitidine (AZA) has demonstrated a survival improvement in high-risk myelodysplastic syndromes (MDS) and AML with 20 to 30% bone marrow (BM) blasts, and is also promising in AML with >30% BM blasts (2–4). While gene mutations are now routinely included among prognostic factors of AML treated with ICT (5), their prognostic impact on AML treated with AZA is unknown. We report prognostic factors, including the mutational status of 18 genes assessed by next-generation sequencing (NGS), in 96 newly diagnosed AML patients who received first line treatment with AZA. Following approval of AZA by FDA and EMA for MDS, the French health agency (ANSM) opened a compassionate patient named program (ATU program) of AZA for AML patients ineligible for ICT. We analyzed retrospectively 96 previously untreated AML patients from 8 centers treated with AZA in this program between 2007 and 2012. Patients could be included if ineligible for ICT due to advanced age, major comorbidities or high-risk cytogenetics. Patients gave informed consent in accordance with the Declaration of Helsinki. AZA was administered according to the approved schedule (75 mg/m2/day, 7 days /4 weeks SC) for at least 6 cycles. Cytogenetic risk was evaluated according to MRC Classification. The mutational status of 16 genes was analyzed by NGS: ASXL1, CEBPA, DNMT3A, EZH2, FLT3, IDH1, IDH2, 1 ©
2015 Macmillan Publishers Limited. All rights reserved.
NPM1, NRAS, KRAS, RUNX1, SF3B1, SRSF2, U2AF1, TET2, TP53 (PGM, Life technologies, Supplemental Data). Because of the limits of our NGS assay, all mutations were also screened by Sanger sequencing. In addition, MLL-PTD and EVI1 expression were assessed as previously described (6). Initial response was evaluated on blood and marrow after 4-6 cycles of AZA. Complete remission (CR), partial remission (PR), CR with incomplete recovery (CRi) and failure were defined according to IWG-2003 response criteria for AML (7). OS was measured from onset of AZA, and time was censored at the date of last follow-up in patients who were still alive (n=8). Median age of the 96 patients included was 74 years (range, 44-88) and M/F 56/40. In addition to age, this population was characterized by high risk features including secondary AML in 55% of the patients (post-MDS or post-MPN-AML in 39, therapy-related AML in 14), ECOG-PS ≥2 in 20%, unfavorable cytogenetics in 64% (including 37 monosomal karyotypes), while only one patient had favorable cytogenetics. Median WBC count was 3.9 G/L, and >10G/L in 28 patients, median circulating blast % was 15% (range, 0-95) and BM blasts were >30% in 55 patients (TableS1). The median total number of mutations per patient was 2 (range, 0-5) (FigureS1). The most frequently mutated gene was TP53 (n= 38, 40%, associated in 2 patients with intermediate risk karyotype and in 36 with unfavorable karyotype, including 29 monosomal and 7 other complex karyotypes) (FigureS1), followed by TET2 (n=21, 22%) and by SRSF2 (n=18, 19%, a high incidence for AML) (8) , and mutations in DNMT3A (14%), ASXL1 (13.5%), IDH2 (11%) and RUNX1 (11%) genes. EVI1 overexpression was found in 11/72 evaluable cases (FigureS2). No patient had isolated NPM1 or double mutant CEBPa mutation. The median number of AZA cycles administered was 7 (range, 1-33). Overall response rate (ORR) was 32% (16% CR, 9% PR and 7% CRi), 19 patients had stable disease and 46 patients had disease progression. Median response duration was 9.4 months (range, 1.5-58.6)
2 ©
2015 Macmillan Publishers Limited. All rights reserved.
and median overall survival (OS) was 10.9 months, with a 1 and 2-year survival rate of 37% and 8%, respectively. ORR and median OS were close to those found in the Italian AZA compassionate program (9), where the population’s baseline features were however somewhat more favorable. We assessed the prognostic impact of clinical and conventional biological parameters, and molecular markers on results of AZA treatment using univariate Cox’s regression hazard models (TableS1). In univariate analysis, we considered 8 molecular markers independently (TP53, TET2, SRSF2, DNMT3A, ASXL1, IDH2, RUNX1, EVI1) for their impact on OS (Table1). Factors associated with OS in univariate analysis with P30%, had an impact on OS. Age and WBC count did not influence OS in our cohort, in line with several previous experiences (3,9,10), although Thepot et al found an adverse prognostic impact of WBC count >15 G/l (3). Adverse cytogenetics (except monosomal karyotype) had no significant prognostic influence in our cohort, in agreement with Pleyer et al (10), but contrary to 2 other studies (3,11). However, most of our patients had adverse cytogenetic whereas this proportion was below 40%) in the 3 other studies (3,11).
3 ©
2015 Macmillan Publishers Limited. All rights reserved.
For molecular abnormalities, in univariate analysis, only TP53 mutations were significantly associated with adverse impact on OS (P=0.019) (Figure1A, Table1). TP53 mutations have been associated with poor outcome in AML treated with ICT, with or without allo-SCT, including in our experience (12) and in high-risk MDS and AML with 20-30% BM blast treated with AZA (13). We confirmed this result in a larger cohort of AML regardless of the BM blast %. Interestingly, however, the median OS of 8.9 months seen in the present series may be superior to the median OS of about 4 months observed in elderly AML patients with mutated TP53 treated with ICT (12). TET2 mutations also tended to be associated with poorer OS (P=0.20) in our cohort, whereas in our experience and that of another group in higher risk MDS and AML with 2030% blasts, they were associated with better response to AZA (that did not however translate into a survival advantage) (14,15). We also found a trend for an adverse impact of SRSF2 mutation on OS in univariate analysis (P=0.16), a gene whose prognostic impact had so far been established in MDS and AML, but independently of treatment (8). ASXL1, DNMT3A and RUNX1 mutations have been shown to confer a negative impact on OS in AML treated by ICT (5) , which we did not observe with AZA, but numbers were probably too small for definite conclusions. No patient had isolated NPM1 or double mutant CEBPa mutation, precluding assessment of the prognostic value of those mutations for AZA treatment. Importantly, while the adverse prognostic impact of EVI1 overexpression has been well established in AML treated with ICT (6), we found a trend for better OS in AML with EVI1 overexpression treated with AZA (P=0.08) (Table1). In multivariate analysis, higher ECOGPS (P=0.016), lower Hb level (P30% blasts. Blood. 2015 May 18;
5.
Patel JP, Gönen M, Figueroa ME, Fernandez H, Sun Z, Racevskis J, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012 Mar 22;366(12):1079–89.
6.
Gröschel S, Lugthart S, Schlenk RF, Valk PJM, Eiwen K, Goudswaard C, et al. High EVI1 expression predicts outcome in younger adult patients with acute myeloid leukemia and is associated with distinct cytogenetic abnormalities. J Clin Oncol Off J Am Soc Clin Oncol. 2010 Apr 20;28(12):2101–7.
5 ©
2015 Macmillan Publishers Limited. All rights reserved.
7.
Cheson BD, Bennett JM, Kopecky KJ, Büchner T, Willman CL, Estey EH, et al. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol Off J Am Soc Clin Oncol. 2003 Dec 15;21(24):4642–9.
8.
Taskesen E, Havermans M, van Lom K, Sanders MA, van Norden Y, Bindels E, et al. Two splice-factor mutant leukemia subgroups uncovered at the boundaries of MDS and AML using combined gene expression and DNA-methylation profiling. Blood. 2014 May 22;123(21):3327–35.
9.
Maurillo L, Venditti A, Spagnoli A, Gaidano G, Ferrero D, Oliva E, et al. Azacitidine for the treatment of patients with acute myeloid leukemia: report of 82 patients enrolled in an Italian Compassionate Program. Cancer. 2012 Feb 15;118(4):1014–22.
10. Pleyer L, Burgstaller S, Girschikofsky M, Linkesch W, Stauder R, Pfeilstocker M, et al. Azacitidine in 302 patients with WHO-defined acute myeloid leukemia: results from the Austrian Azacitidine Registry of the AGMT-Study Group. Ann Hematol. 2014 Jun 21;93(11):1825–38. 11. Van der Helm LH, Veeger NJGM, Kooy M van M, Beeker A, de Weerdt O, de Groot M, et al. Azacitidine results in comparable outcome in newly diagnosed AML patients with more or less than 30% bone marrow blasts. Leuk Res. 2013 Aug;37(8):877–82. 12. Wattel E, Preudhomme C, Hecquet B, Vanrumbeke M, Quesnel B, Dervite I, et al. p53 mutations are associated with resistance to chemotherapy and short survival in hematologic malignancies. Blood. 1994 Nov 1;84(9):3148–57. 13. Bally C, Adès L, Renneville A, Sebert M, Eclache V, Preudhomme C, et al. Prognostic value of TP53 gene mutations in myelodysplastic syndromes and acute myeloid leukemia treated with azacitidine. Leuk Res. 2014 Jul;38(7):751–5. 14. Itzykson R, Kosmider O, Cluzeau T, Mansat-De Mas V, Dreyfus F, Beyne-Rauzy O, et al. Impact of TET2 mutations on response rate to azacitidine in myelodysplastic syndromes and low blast count acute myeloid leukemias. Leukemia. 2011 Jul;25(7):1147–52. 15. Bejar R, Lord A, Stevenson K, Bar-Natan M, Pérez-Ladaga A, Zaneveld J, et al. TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients. Blood. 2014 Oct 23;124(17):2705–12.
6 ©
2015 Macmillan Publishers Limited. All rights reserved.
AUTHORS Judith Desoutter, PharmD1*, Julie Gay, MD2*, Céline Berthon, MD, PhD3, Lionel Ades, MD4, Bérengère Gruson, MD5, Sandrine Geffroy1, Isabelle Plantier, MD6, Marceau Alice, PharmD1, Nathalie Helevaut1, Jose Fernandes, MD7, Maxime Bemba, MD8, Laure Stalnikiewicz, MD9, Cécile Frimat1, Julien Labreuche10, Olivier Nibourel PharmD, PhD1, Christophe Roumier, PharmD1, Martin Figeac11, Pierre Fenaux, MD, PhD12, Bruno Quesnel, MD, PhD3, Aline Renneville, PharmD, PhD1, Alain Duhamel10, MD, and Claude Preudhomme, PharmD, PhD1 1 Laboratoire d’hématologie, Centre de Biologie Pathologie, CHRU Lille, France 2 Service d’hématologie clinique, Hôpital Saint Antoine, Université Paris 6, APHP, Paris, France 3 Service d’hématologie clinique, CHRU Lille, France 4 Service d’hématologie clinique, Hôpital d’Avicenne, Université Paris 13, Bobigny, France 5 Service d’hématologie clinique, CHU Amiens-Picardie, France 6 Service d’hématologie clinique, Hôpital de Roubaix, France 7 Service d’hématologie clinique, Hôpital de Valenciennes, France 8 Service d’hématologie clinique, Hôpital de Dunkerque, France 9 Service d’hématologie clinique, Hôpital de Lens, France 10 Unités de Biostatistiques, CHRU Lille, France 11 Plateforme de génomique structurale et fonctionnelle, IFR-114, Université Lille 2, France 12 Service d’hématologie clinique, Hôpital Saint-Louis, Université Paris 7, APHP, Paris, France J.D. and J.G. contributed equally to this study This work was the subject of an oral communication in 56th ASH Annual Meeting and Exposition held in San Francisco from 6-9 December 2014 Corresponding author : Claude Preudhomme - E-mail : [email protected]
ACKNOWLEDGEMENT INCA PRT-K 2010 : Institut National du Cancer – Programme de Recherche Translationnelle en Cancérologie.
CONFLICT OF INTEREST DISCLOSURE The authors declare no competing financial interests.
7 ©
2015 Macmillan Publishers Limited. All rights reserved.
FIGURE LEGENDS Figure1. Kaplan-Meier overall survival curves according to the mutational status of TP53 and EVI1 expression. A)Median survival of patients with mutation in TP53 gene was 8.9 compared to 12.3 months in wild-type TP53 patients. B)Patients with EVI1 overexpression without TP53 mutation had a median OS of 24.7 months, versus 7.2 months for patients carrying TP53 mutation and 10.4 months in the remaining patients.
Table1. Prognostic value of Molecular Parameters for survival by univariate analysis
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2015 Macmillan Publishers Limited. All rights reserved.
Table1. Prognostic value of Molecular Parameters for survival by univariate analysis n (%)
HR (95%CI) *
P-Value*
Number of somatic mutations ≤1 2 3 ≥4
44 (45.8)‡ 25 (26.0) 16 (16.7) 11 (11.5)§
1.00 (Ref.) 0.90 (0.54-1.51) 1.10 (0.60-1.99) 1.21 (0.60-2.46)
0.61† 0.69 0.76 0.59
TP53 Wild-type Mutated
58 (60.4) 38 (39.6)
1.00 (Ref.) 1.68 (1.09-2.58)
0.019
TET2 Wild-type Mutated
74 (77.9) 21 (22.1)
1.00 (Ref.) 1.38 (0.83-2.30)
0.20
SRSF2 Wild-type Mutated
78 (81.3) 18 (18.8)
1.00 (Ref.) 1.45 (0.86-2.45)
0.16
DNMT3A Wild-type Mutated
82 (85.4) 14 (14.6)
1.00 (Ref.) 0.62 (0.86-1.58)
0.62
ASXL1 Wild-type Mutated
81 (86.5) 13 (13.5)
1.00 (Ref.) 0.76 (0.40-1.44)
0.40
IDH2 Wild-type Mutated
85 (88.5) 11 (11.5)
1.00 (Ref.) 0.84 (0.42-1.67)
0.61
RUNX1 Wild-type Mutated
85 (88.5) 11 (11.5)
1.00 (Ref.) 0.74 (0.38-1.44)
0.38
EVI1 expression Normal Overexpression
61 (84.7) 11 (15.3)
1.00 (Ref.) 0.53 (0.26-1.08)
0.08
Abbreviations: AML=Acute myeloid leukemia, CI=confidence interval, HR=Hazard ratio. * HRs calculated from Univariate Cox’s regression hazard models.† p for trend test ‡ including 6 patients without somatic mutations § including 2 patients with 5 somatic mutations
©
2015 Macmillan Publishers Limited. All rights reserved.
Figure1. Kaplan-Meier overall survival curves according to the mutational status of TP53 and EVI1 expression. A) Median survival of patients with mutation in TP53 gene was 8.9 compared to 12.3 months in wild-type TP53 patients. B) Patients with EVI1 overexpression without TP53 mutation had a median OS of 24.7 months, versus 7.2 months for patients carrying TP53 mutation and 10.4 months in the remaining patients.
©
2015 Macmillan Publishers Limited. All rights reserved.
