TP53 mutations are associated with very complex karyotype and suggest poor prognosis in newly diagnosed myelodysplastic syndrome patients with monosomal karyotype

2020 ◽  
Vol 16 (3) ◽  
pp. 172-179 ◽  
Author(s):  
Yanling Ren ◽  
Jinghan Wang ◽  
Hua Zhang ◽  
Chen Mei ◽  
Li Ye ◽  
...  
Keyword(s):  
Myelodysplastic Syndrome ◽  
Poor Prognosis ◽  
Complex Karyotype ◽  
Newly Diagnosed ◽  
Tp53 Mutations ◽  
Monosomal Karyotype

The Influence of Monosomal Karyotype On Survival in Patients with Acute Myeloid Leukemia After Allogeneic Hematopoietic Stem Cell Transplantation: A Retrospective Survey On Behalf of the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 158-158 ◽  
Author(s):  
Angelique V.M. Brands-Nijenhuis ◽  
Myriam Labopin ◽  
Harry C. Schouten ◽  
Liisa Volin ◽  
Gérard Socié ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
Complex Karyotype ◽  
Hematopoietic Stem ◽  
Monosomal Karyotype ◽  
Acute Myeloid

Abstract Abstract 158 Introduction: Monosomal karyotype (MK) has been shown to be associated with a very poor prognosis in AML patients (Breems, 2008). Whether allogeneic hematopoietic stem cell transplantation (alloHSCT) performed in an early phase can overcome the adverse prognosis in this cytogenetic patient category is currently unknown. To address this issue we performed a retrospective analysis on data from the registry of the EBMT among patients with primary AML who underwent alloHSCT in CR1. Patients and methods: A total of 4119 patients with primary AML and known cytogenetic abnormalities at diagnosis that underwent alloHSCT in CR1 were included in the analysis. Survival curves were calculated with Kaplan-Meier method. Log rank test and Cox regression analysis were used to determine statistical significance. Results: Median follow-up was 24 months (range 2–374). Overall, 171 patients (4.2%) fulfilled criteria for MK and 297 patients (7.2%) for complex karyotype (CK), with 115 patients fulfilling both conditions (MK and CK). Both the presence of a MK (2-yr OS: 35.5% versus 63.2%, p<0.0001) and CK (2-yr OS: 48.8% versus 61.9%, p<0.0001) were associated with a poorer outcome when compared with the remaining cytogenetics subtypes. Given the significant overlap between both categories, we further analyzed their prognostic impact after defining four subgroups of patients: MK but not CK (56 patients; MK+CK-), no MK but CK (180 patients; MK-CK+), MK and CK (115 patients; MK+CK+), and patients without either MK or CK (MK-CK-). Outcome of the MK-CK- subgroup did not differ according to cytogenetics. Patients harboring a MK, regardless concomitant presence of a CK, presented with a poorer OS after alloHSCT (2-yr OS: 31.7–43.0% versus 61.1%, p<0.0001). On the contrary patients with a CK but not MK showed a similar outcome than MK-CK- (2-yr OS: 61.1% versus 63.3%, p=0.170). Moreover, multivariate analysis confirmed the independent negative impact of MK (HR:1.90, range 1.5–2.4; p<0.0001) together with age, interval diagnosis-transplant, AML subtype, WBC at diagnosis, T-cell depletion, number of induction cycles and use of TBI during conditioning, whereas the presence of a CK did not retain its negative prognostic value. Conclusion: These results indicate that MK is a better indicator for poor outcome than CK after alloHSCT in patients with primary AML in CR1. Nonetheless, the potential curative role of alloHSCT for a subset of patients with MK should be further investigated. Reference: DA Breems, WLJ van Putten, GE de Greef, SL van Zelderen-Bhola, KBJ Gerssen-Schoorl, CHM Mellink, A Nieuwint et al. Monosomal karyotype in acute myeloid leukemia: a better indicator of poor prognosis than a complex karyotype. J Clin Oncol 2008;26(29):4791–7. Disclosures: No relevant conflicts of interest to declare.

scholarly journals PAS positivity of erythroid precursor cells is associated with a poor prognosis in newly diagnosed myelodysplastic syndrome patients

2018 ◽  
Vol 108 (1) ◽  
pp. 30-38
Author(s):  
Kenta Masuda ◽  
Shuichi Shiga ◽  
Hiroshi Kawabata ◽  
Akifumi Takaori-Kondo ◽  
Satoshi Ichiyama ◽  
...  
Keyword(s):  
Myelodysplastic Syndrome ◽  
Poor Prognosis ◽  
Precursor Cells ◽  
Newly Diagnosed ◽  
Erythroid Precursor

scholarly journals Clinical Features of Pediatric Acute Myeloid Leukemia with TP53 and CDKN2A/2B copy Number Alterations

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2727-2727
Author(s):  
Yusuke Hara ◽  
Tomohiko Taki ◽  
Genki Yamato ◽  
Kenichi Yoshida ◽  
Yusuke Shiozawa ◽  
...  
Keyword(s):  
Copy Number ◽  
Poor Prognosis ◽  
Snp Array ◽  
Complex Karyotype ◽  
Copy Number Alterations ◽  
Survival Analyses ◽  
Tp53 Mutations ◽  
Significant Difference ◽  
Equity Ownership ◽  
Pediatric Aml

[Background] Customized gene panel sequencing is commonly used in cancer research to detect point mutations and small insertions or deletions. This technique can also be used to detect copy number alterations (CNAs) in tumor samples based on the comparison of sequence depth of targeted regions between samples and variant allele frequencies of germline single nucleotide polymorphisms (SNPs). CNAs in TP53 and CDKN2A/2B are frequently found in various types of leukemias. TP53 loss was reported to be a frequent CNA with poor prognosis in adult AML, and CDKN2A/2B alterations were found to be frequent in adult and pediatric acute lymphoblastic leukemia. However, the molecular and clinical profiles of the CNAs of these genes remain unclear in pediatric AML. [Patients and Methods] We analyzed clinical samples from 331 pediatric AML patients in the AML-05 trial, which was conducted by the Japanese Pediatric Leukemia/Lymphoma Study Group. Targeted sequencing was performed using a 343-gene custom panel and next-generation sequencer. These 343 genes are reportedly associated with hematopoietic malignancy or solid tumor pathogenesis. Copy number analysis was performed using the in-house pipeline CNACS. Additionally, a SNP array was performed for 40 of the 331 patients, including 34 patients with complex karyotype, to detect CNAs of TP53. [Results] TP53 alterations were identified in 7 (2.1%) of 331 patients. TP53 losses and mutations were detected in 7 and 4 patients, respectively, and all the patients with TP53 mutations concurrently had TP53 losses. Seven patients with TP53 losses were identified by CNACS, although only 4 patients with TP53 losses were found by SNP array. As for the cytogenetics of 7 patients with TP53 losses, six carried a complex karyotype, lacking FAB-M7 morphology. Accordingly, 6 (28.6%) of 21 non-FAB-M7 patients with complex karyotype had TP53 losses. Fusion genes and gene mutations were rare in patients with TP53 losses (NUP98-KDM5A, n=1; KIT, n=1; NRAS, n=1; CEBPA, n=1; ASXL1, n=1), and no patients with core-binding factor AML (CBF-AML) or KMT2A-rearrangements had TP53 losses. In survival analyses, patients with TP53 losses had significantly worse overall survival, event-free survival, and cumulative incidence of relapse rates than patients with wildtype TP53 (14.3% vs 71.4%, p<0.001, 0% vs 54.4%, p<0.001, and 100% vs 43.1%, p<0.001, respectively) (Figure). Among the 7 patients with TP53 losses, 2 had induction failure, and the remaining 5 relapsed. As a result, 6 patients died. CDKN2A/2B alterations were identified in 10 patients (3.0%) (9 losses and 1 mutation). Three patients with CDKN2A/2B losses had simultaneous TP53 alterations. Unlike TP53 alterations, CDKN2A/2B alterations were found in patients with CBF-AML and those with FAB-M7. In survival analyses, no significant difference was observed between patients with or without CDKN2A/2B alterations. [Discussion] TP53 losses were identified in approximately 2% of patients with pediatric AML. However, these alterations were found to be frequent in patients with complex karyotypes, particularly in those with non-FAB-M7 (28.6%). Furthermore, patients with TP53 losses had very poor prognosis. These findings indicate the necessity of risk stratification using TP53 status for pediatric AML. The efficacy of hematopoietic stem cell transplantation (HSCT) for the treatment of patients with TP53 losses remains unclear because 6 of 7 patients with TP53 losses received HSCT in this study. Moreover, because some of the identified TP53 mutations were possible germline mutations, HSCT may increase the incidence rate of the secondary cancer in patients with TP53 mutations. Thus, the efficacy of new agents (e.g., azacitizine and gemtuzumab ozogamicin) should be evaluated in future clinical trials for the intensification of chemotherapy for these patients. Meanwhile, the clinical and molecular profiles of CDKN2A/2B alterations were not fully identified in this study. However, the high incidence of CDKN2A/2B alterations in patients with TP53 losses indicates that the correlation between these gene alterations is essential for oncogenesis in a subset of pediatric AML patients. Figure Disclosures Ogawa: ChordiaTherapeutics, Inc.: Consultancy, Equity Ownership; Kan Research Laboratory, Inc.: Consultancy; RegCell Corporation: Equity Ownership; Asahi Genomics: Equity Ownership; Qiagen Corporation: Patents & Royalties; Dainippon-Sumitomo Pharmaceutical, Inc.: Research Funding.

scholarly journals TP53 Abnormality in Myelodysplastic Syndrome

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5410-5410
Author(s):  
Fei Huang ◽  
Yu Chen ◽  
Yuxing Zhu ◽  
Chun Qiao ◽  
Sixuan Qian ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Disease Progression ◽  
Tp53 Mutation ◽  
Conflicts Of Interest ◽  
Multiple Time ◽  
Complex Karyotype ◽  
Newly Diagnosed ◽  
Tp53 Mutations ◽  
Molecular Abnormalities ◽  
Highly Correlated

TP53 (tumor suppressor gene P53), one of the most important tumor suppressor genes, plays an important role in cell cycle arrest, cell senescence, apoptosis, differentiation and metabolism. The TP53 gene is located on 17p13.1, its encoded product is the transcription factor P53 protein, which is known as the "the guardian of the genome". Alterations of TP53 include mutations and deletions and are generally associated with advanced stages of disease, insufficient therapy-response and poor prognosis. The main purpose of our study was to comprehensively analyze the TP53 mutation and 17p deletion in MDS in our single center. To better understand the relationship between TP53 abnormality and clinical phenotype, prognosis, leukemia transformation, therapeutic response of MDS. Next generation sequencing (NGS) method combining with cytogenetics analysis were used, 36 common related AML/MDS/MPN related genes such as TP53, TET2, WT1, ASXL1, U2AF1, RUNX1, etc were covered. According to the 2016 WHO classification and prognosis score system and from June 2011 to June 2017, 88 newly diagnosed MDS patients including 17 MDS-SLD, 32 MDS-MLD,6 MDS-RS,19 MDS-EB-1,11 MDS-EB-2 and 2 MDS-U, 1 5q- syndrome were enrolled. TP53 mutation/deletions were found in twenty-two (25%) of the 88 newly diagnosed MDS patients, among them,7 MDS-SLD, 4 MDS-MLD, 2 MDS-RS, 1 5q-, 6 MDS-EB-1 and 6 MDS-EB-2. TP53 mutation/deletions cases had a higher proportion of bone marrow blasts compared with TP53 negative cases (P=0.009), At the same time, TP53 positive were highly correlated with MDS-EB-2 subtype (P=0.025), complex karyotype (P<0.001). Based on a median follow-up time of 21(1-267) months in all pts, 13 patients (14.8%) progressed to AML and pts with TP53 mutation/deletions tended to progress to AML (P=0.056) with a shorter OS (P=0.005) and PFS (P=0.001). NGS data of accompanying mutation in other classical leukemia genes shown that compound TP53 and U2AF1 mutations were significantly associated with disease progression. For TP53 mutation/deletion group (n=22), we further sequenced the TP53 status at multiple time point of pre and after DAC treatment, results shown that all patients had persistent TP53 positive status before and after treatment. In conclusion, our results indicate that in MDS TP53 mutation/deletions is highly correlated with MDS-EB-2 subtype, IPSS high-risk group, and complex karyotype. TP53 mutations that occur in the early stages of MDS may contribute to disease progression and leukemia transformation in conjunction with other molecular abnormalities. DAC improves outcomes in patients with TP53 mutation/deletion but may not clear TP53 mutations. Disclosures No relevant conflicts of interest to declare.

Azacitidine in Older Patients with Acute Myeloid Leukemia (AML) and Adverse Karyotype. Subanalisis from the Alma Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 945-945
Author(s):  
Jose Falantes ◽  
Guillermo Deben ◽  
Violeta Martinez Robles ◽  
Joan Bargay ◽  
Olga Salamero ◽  
...  
Keyword(s):  
Overall Survival ◽  
Multivariate Analysis ◽  
Complete Remission ◽  
Performance Status ◽  
Complex Karyotype ◽  
Newly Diagnosed ◽  
Off Label Use ◽  
Ecog Performance Status ◽  
Off Label ◽  
Monosomal Karyotype

Abstract Background Adverse karyotype and age are associated with poor prognosis in older AML patients (pts). Although complete remission (CR) can be achieved with intensive chemotherapy (IC) in pts with adverse cytogenetics, overall survival (OS) and leukemia free-survival (LFS) are poor (Knipp S, et al. Cancer 2007). In addition, low doses of ARA-C (LDAC) did not offer survival benefit in older pts with poor cytogenetics as compared to hydroxyurea and best supportive care (BSC) (Burnett A, et al. Cancer 2007). Azacitidine has shown a survival advantage in older pts with newly diagnosed AML in a recent phase 3 trial, as compared to conventional care regimens (BSC/LDAC/IC)(Dombret H, et al. EHA 2014). Aim To evaluate the role of azacitidine and factors associated with OS in pts with newly diagnosed AML and adverse karyotype from the ALMA study (Ramos F, et al. Blood 2012;120:abstract 3593). Methods Retrospective, multicenter study, of pts with newly diagnosed AML and adverse karyotype who received front-line azacitidine in Spain. Response to azacitidine was evaluated by ELN-2010 criteria. Overall survival was evaluated by Kaplan-Meier method and log-rank test. Results Thirty-nine pts were identified. Median age: 71y (52-83). Baseline characteristics are shown in table 1. All pts received azacitidine (75 mg/m2 sc x7 days) as first line treatment. Median time from AML diagnosis to therapy was 16 days (1-88). 56% of pts had bone marrow (BM) blasts >30% at diagnosis (median: 32%; range: 20-90). Five out of 39 (13%) pts had leucocyte count (WBC) >15x109/L and 20/39 (51%) had ECOG performance status >1. Complex karyotype (CK) and monosomal karyotype (MK) was present in 18/39 pts each (46%). Within the subset showing CK, 14/18 (78%) had MK. Complete remission (CR) and CRi was 23.1% and 5.1% respectively (ORR=28.2%). Median courses of therapy to best response: 3 (1-11). After 17m median follow-up, median OS (95% CI) was 7m (3.1-8.8). Estimated 1-year survival was 29.8%. There were no differences in median OS in pts with MK vs. rest of pts with CK (median OS 9m [95% CI: 5.3-12.6] vs. 6.5m [3.1-8.8], respectively; p=0.854). Monosomal karyotype, CK with >5 abnormalities, BM blasts >30% and ECOG status >1 did not achieve statistically significance in multivariate analysis. Only WBC at baseline (>10x109/L or >15x109/L; threshold not relevant) had an impact on OS in both univariate (3m [95% CI: 4.9-13] vs. 9m [4.9-13] if WBC <10x10e /L; p=0.014) and multivariate analysis (HR=3.3, [95% CI 1.1-9.5], p=0.025; Table 2). Most frequent causes of death were disease progression and infection (82%).Table 2Multivariate analysis for survivalParameterHR95% CIp-valueWBC >10x109/L3.341.17-9.580.025BM blast >30%1.080.46-2.540.855MK0.950.33-2.740.919CK1.610.58-4.510.361ECOG >11.840.81-4.170.144 Conclusion Albeit retrospective and non-comparative, azacitidine seems to improve median and 1y survival as compared to historic AML data in pts with adverse cytogenetics. An elevated WBC >10x109/L at diagnosis was the only parameter associated to adverse outcome in this set of pts.Table 1Baseline characteristicsAge, median (range)71 (52-83)ECOG performance status 0-1 2-319 (48.7%) 20 (51.3%)WBC (x109/L), median (range) WBC >10x109/L, N (%)2.2 (0.9-89.2) 5 (12.8%)BM blasts, median; (range) BM blasts >30%, N (%)32 (20-90) 22(56.4%)Complex karyotype (CK), N (%)18 (46.2)Monosomal karyotype (MK), N (%)18 (46.2%)Both CK and MK, N (%)14/18 (77.8%)Prior MDS, N (%)11 (28.2%)Karyotype, N (%) Complex >3 Complex >5 Chrom 7 abn Chrom 3 abn -7 only Chrom 5 and 7 abn Chrom 5 abn Other6 (15.4%) 11 (28.2%) 4 (10.3%) 4 (10.3%) 8 (20.5%) 2 (5.1%) 2 (5.1%) 2 (5.1%)*Excludes pts with chromosome 5 and 7 abnormality Disclosures Falantes: Celgene: Consultancy. Off Label Use: Use of azacitidine in AML with blast count >30% This paper deals with both on-label and off-label use of azacitidine in AML. Xicoy:Celgene: Honoraria. Ramos:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Monosomal Karyotype in Acute Myeloid Leukemia: A Better Indicator of Poor Prognosis Than a Complex Karyotype

2008 ◽  
Vol 26 (29) ◽  
pp. 4791-4797 ◽  
Author(s):  
Dimitri A. Breems ◽  
Wim L.J. Van Putten ◽  
Georgine E. De Greef ◽  
Shama L. Van Zelderen-Bhola ◽  
Klasien B.J. Gerssen-Schoorl ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
Prognostic Impact ◽  
Complex Karyotype ◽  
Single Chromosome ◽  
Cytogenetic Abnormalities ◽  
Poor Outcome ◽  
Monosomal Karyotype ◽  
Acute Myeloid

Purpose To investigate the prognostic value of various cytogenetic components of a complex karyotype in acute myeloid leukemia (AML). Patients and Methods Cytogenetics and overall survival (OS) were analyzed in 1,975 AML patients age 15 to 60 years. Results Besides AML with normal cytogenetics (CN) and core binding factor (CBF) abnormalities, we distinguished 733 patients with cytogenetic abnormalities. Among the latter subgroup, loss of a single chromosome (n = 109) conferred negative prognostic impact (4-year OS, 12%; poor outcome). Loss of chromosome 7 was most common, but outcome of AML patients with single monosomy −7 (n = 63; 4-year OS, 13%) and other single autosomal monosomies (n = 46; 4-year OS, 12%) did not differ. Structural chromosomal abnormalities influenced prognosis only in association with a single autosomal monosomy (4-year OS, 4% for very poor v 24% for poor). We derived a monosomal karyotype (MK) as a predictor for very poor prognosis of AML that refers to two or more distinct autosomal chromosome monosomies (n = 116; 4-year OS, 3%) or one single autosomal monosomy in the presence of structural abnormalities (n = 68; 4-year OS, 4%). In direct comparisons, MK provides significantly better prognostic prediction than the traditionally defined complex karyotype, which considers any three or more or five or more clonal cytogenetic abnormalities, and also than various individual specific cytogenetic abnormalities (eg, del[5q], inv[3]/t[3;3]) associated with very poor outcome. Conclusion MK enables (in addition to CN and CBF) the prognostic classification of two new aggregates of cytogenetically abnormal AML, the unfavorable risk MK-negative category (4-year OS, 26% ± 2%) and the highly unfavorable risk MK-positive category (4-year OS, 4% ± 1%).

scholarly journals TP53 mutation in newly diagnosed acute myeloid leukemia and myelodysplastic syndrome

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Pimjai Niparuck ◽  
Pornnapa Police ◽  
Phichchapha Noikongdee ◽  
Kanchana Siriputtanapong ◽  
Nittaya Limsuwanachot ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndrome ◽  
Myeloid Leukemia ◽  
Tp53 Mutation ◽  
De Novo ◽  
Complex Karyotype ◽  
Newly Diagnosed ◽  
Secondary Aml ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Objectives TP53 mutation is found frequently in therapy related acute myeloid leukemia (AML)/ myelodysplastic syndrome (MDS), AML and MDS patients with monosomy or complex karyotype. However, the prevalence and treatment outcome in TP53 mutated AML/MDS patients in Asian population are scarce. We therefore conducted this study to analyze the prevalence and the treatment outcomes of TP53 mutation in AML and MDS-EB patients. Methods Patients with newly diagnosed AML and MDS-EB were recruited, extraction of deoxyribonucleic acid from bone marrow samples were done and then performing TP53 mutation analysis, using MassArray® System (Agena Bioscience, CA, USA). Results A total of 132 AML/MDS patients were recruited, patients with de novo AML, secondary AML, MDS-EB1, MDS-EB2 and T-AML/MDS were seen in 66, 13, 9, 9 and 3%, respectively. TP53 mutation was found in 14 patients (10.6%), and prevalence of TP53 mutation in T-AML/MDS, secondary AML, de novo AML and MDS-EB patients were 50, 17.6, 9.2 and 8%, respectively. Three patients had double heterozygous TP53 mutation. Mutated TP53 was significantly detected in patients with monosomy and complex chromosome. Common TP53 mutation were R290C, T220C, A249S and V31I which V31I mutation was reported only in Taiwanese patients. Most variant allele frequency (VAF) of TP53 mutation in the study were greater than 40%. Three year-overall survival (OS) in the whole population was 22%, 3y-OS in AML and MDS-EB patients were 22 and 27%, respectively. The 1y-OS in patients with TP53-mutant AML/MDS were shorter than that in TP53 wild-type patients, 14% versus 50%, P = 0.001. In multivariate analysis, factors affecting OS in 132 AML/MDS patients was mutant TP53 (P = 0.023, HR = 1.20–7.02), whereas, WBC count> 100,000/μL (P = 0.004, HR = 1.32–4.16) and complex karyotype (P = 0.038, HR = 1.07–9.78) were associated with shorter OS in AML patients. Discussion In this study, the prevalence of TP53 mutation in de novo AML and MDS-EB patients were low but it had impact on survival. Patients with monosomy or complex karyotype had more frequent TP53 mutation.

scholarly journals PHF6 Mutations Are Mutually Exclusive to TP53 Mutations, and Define a Distinct Subgroup of Secondary Acute Myeloid Leukemia Associated with a Primitive Stem/Progenitor Immunophenotype, Absent Complex Karyotype and Relatively Better Outcomes

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2788-2788
Author(s):  
Wenbin Xiao ◽  
Aaron D Goldberg ◽  
Brian Ball ◽  
Christopher Famulare ◽  
Friederike Pastore ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Poor Prognosis ◽  
Advisory Board ◽  
Complex Karyotype ◽  
Tp53 Mutations ◽  
Secondary Acute Myeloid Leukemia ◽  
Equity Ownership ◽  
Acute Myeloid

Abstract Introduction Secondary acute myeloid leukemia (s-AML) includes AML with myelodysplasia-related changes (AML-MRC) transformed from an antecedent diagnosis of myelodysplastic syndrome (MDS) or from myeloproliferative and myelodysplastic overlap syndrome (MPN/MDS), as well as therapy-related AML (t-AML) arising in patients with prior exposure to leukemogenic therapies. S-AML has a dismal prognosis. Although the genomic profiling of AML has been well studied, few studies have focused on the molecular aberrations of s-AML. A recent study has demonstrated shared genomic aberrations by AML-MRC and t-AML including mutations in TP53, SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, or STAG2. Another recent study has shown that AML patients with mutations in TP53 and chromatin-splicesosome confer poor prognosis and likely represent s-AML. As such, further characterization of the genomic landscape of s-AML is needed. Recurrent somatic PHF6 mutations are rare in de novo AML (~3%), but the frequency and characteristics of PHF6 mutated s-AML are largely unknown. Patients and Methods AML-MRC and t-AML patients were searched from the patient database at the MSKCC between 1/2014 and 12/2016. All the patients were reviewed and the diagnosis was confirmed. Only patients with genomic sequencing studies (a targeted NGS panel comprising 30 genes with mutations enriched in AML) performed at diagnosis were included. Results 152 patients were identified. There were 7 t-AML patients with favorable cytogenetic abnormalities that likely represent a distinct biological subgroup; therefore these cases were excluded from further analysis. AML-MRC (N=75) and t-AML (N=70) patients had similar clinical characteristics including ages, gender distribution, cytogenetic risk, treatment and survival (median survival: 8 months in t-AML and 10 months in AML-MRC, p=0.4); The mutational profiles of AML-MRC and t-AML cohorts were also comparable with recurrent TP53, PHF6, RAS, and RUNX1 mutations, albeit with different frequencies (Figure 1; Red represents t-AML and blue AML-MRC). Therefore we combined AML-MRC and t-AML cohorts for further analysis. 43 (29.7%) patients had TP53 mutations, 17 (11.7%) patients had PHF6 mutations, and 85 (58.6%) patients had neither mutation (non-TP53/non-PHF6). TP53 and PHF6 mutations were mutually exclusive. TP53 mutations were nearly exclusively associated with adverse cytogenetic abnormalities including alterations involving chromosomes (chr) 5p and/or 7q (41/43, 95.3%) with the majority being complex karyotype (30/43, 70%). By contrast, only 18% PHF6 mutated s-AML patients had chr 5p/7q abnormalities and none of them had complex karyotype. Among the patients with non-TP53/non-PHF6 mutations, 30% had chr 5p/7q abnormalities and 6% had complex karyotype. Although secondary AML has very poor prognosis, PHF6 mutated patients had better overall survival than the other two groups (Log rank test, p=0.0095; median survival: PHF6 vs TP53 vs. non-TP53/non-PHF6: 24 vs. 7 vs. 9 months). Immunophenotypically, the blasts from PHF6 mutated patients showed a high frequency of loss of CD38 (44% vs 17%, p=0.04) and CD33 expression (69% vs 28%, p=0.004) compared to PHF6 unmutated cases, indicative of a less mature, stem-cell derived phenotype Conclusion PHF6 mutations define a unique subset of s-AML that is associated with a more primitive stem/progenitor immunophenotype, absent complex karyotype and relatively better outcomes. PHF6 mutations are mutually exclusive to TP53 mutations. Studies are needed to further define the genomic classification of s-AML patients in an unbiased way and to elucidate the role of PHF6 mutations in s-AML. Figure 1 Figure 1. Disclosures Goldberg: AROG: Research Funding; Abbvie: Research Funding; Pfizer: Research Funding; Celgene: Research Funding. Tallman:Orsenix: Other: Advisory board; AbbVie: Research Funding; Cellerant: Research Funding; BioSight: Other: Advisory board; AROG: Research Funding; Daiichi-Sankyo: Other: Advisory board; ADC Therapeutics: Research Funding. Arcila:Invivoscribe, Inc.: Consultancy, Honoraria. Levine:Loxo: Consultancy, Equity Ownership; Gilead: Honoraria; Roche: Consultancy, Research Funding; Epizyme: Patents & Royalties; Imago: Equity Ownership; Qiagen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; C4 Therapeutics: Equity Ownership; Novartis: Consultancy; Janssen: Consultancy, Honoraria; Isoplexis: Equity Ownership; Prelude: Research Funding.

scholarly journals TP53 Mutation in Newly Diagnosed Acute Myeloid Leukemia and Myelodysplastic Syndrome

2021 ◽  
Author(s):  
Pimjai Niparuck ◽  
Pornnapa Police ◽  
Phichchapha Noikongdee ◽  
Kanchana Siriputtanapong ◽  
Nittaya Limsuwanachot ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndrome ◽  
Myeloid Leukemia ◽  
Tp53 Mutation ◽  
De Novo ◽  
Complex Karyotype ◽  
Newly Diagnosed ◽  
Secondary Aml ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Objectives: TP53 mutation is found frequently in therapy related acute myeloid leukemia (AML)/ myelodysplastic syndrome (MDS), AML and MDS patients with monosomy or complex karyotype. However, the prevalence and treatment outcome in TP53 mutated AML/MDS patients in Asian population are scarce. We therefore conducted this study to analyze the prevalence and the treatment outcomes of TP53 mutation in AML and MDS-EB patients. Methods: Patients with newly diagnosed AML and MDS-EB were recruited, extraction of deoxyribonucleic acid from bone marrow samples were done and then performing TP53 mutation analysis, using MassArray® System (Agena Bioscience, CA, USA). Results: A total of 132 AML/MDS patients were recruited, patients with de novo AML, secondary AML, MDS-EB1, MDS-EB2 and T-AML/MDS were seen in 66%, 13%, 9%, 9% and 3%, respectively. TP53 mutation was found in 14 patients (10.6%), and prevalence of TP53 mutation in T-AML/MDS, secondary AML, de novo AML and MDS-EB patients were 50%, 17.6%, 9.2% and 8%, respectively. Three patients had double heterozygous TP53 mutation. Mutated TP53 was significantly detected in patients with monosomy and complex chromosome. Common TP53 mutation were R290C, T220C, A249S and V31I which V31I mutation was reported only in Taiwanese patients. Most variant allele frequency (VAF) of TP53 mutation in the study were greater than 40%. Three year-overall survival (OS) in the whole population was 22%, 3y-OS in AML and MDS-EB patients were 22% and 27%, respectively. In multivariate analysis, factors affecting OS in 132 AML/MDS patients was mutant TP53 (P= 0.023, HR= 1.20- 7.02), whereas, WBC count> 100,000/μL (P= 0.004, HR= 1.32- 4.16) and complex karyotype (P= 0.038, HR= 1.07- 9.78) were associated with shorter OS in AML patients. Discussion: In this study, the prevalence of TP53 mutation in de novo AML and MDS-EB patients were low but it had impact on survival. Patients with monosomy or complex karyotype had more frequent TP53 mutation.

Sign in / Sign up

Export Citation Format

Share Document