TP53 mutation in newly diagnosed acute myeloid leukemia and myelodysplastic syndrome

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.

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TP53 Mutation in Newly Diagnosed Acute Myeloid Leukemia and Myelodysplastic Syndrome

10.21203/rs.3.rs-148593/v1 ◽

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.

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The Size of the Dendritic Cell Population At Diagnosis Worsens Prognosis in Acute Myeloid Leukemia – Bigger Is Not Better

Blood ◽

10.1182/blood.v118.21.4870.4870 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4870-4870

Author(s):

Marta I Pereira ◽

Ana I Espadana ◽

Emília Cortesão ◽

Gilberto P Marques ◽

Catarina Geraldes ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

De Novo ◽

World Health ◽

Biological Behavior ◽

Newly Diagnosed ◽

Secondary Aml ◽

De Novo Aml ◽

Dc Component ◽

Acute Myeloid

Abstract Abstract 4870 Background: Dendritic cells (DC) are a heterogeneous population of lineage-negative antigen-presenting cells derived from CD34+ hematopoietic progenitors, present in tissue, blood and bone marrow (BM), where plasmacytoid DC (pDC) are a normal finding, representing 0.2 ± 0.1% of cell populations (Matarraz et al, 2010). DC neoplasms include solid tumors (such as DC sarcomas) and an entity classified by the World Health Organization (2008) as an acute myeloid leukemia (AML)-related precursor neoplasm: blastic pDC neoplasm/leukemia, an aggressive disease with poor prognosis, with no clinical trials to orient consensus regarding the most effective treatment; it is usually chemo-resistant, although some cases respond to AML-like regimens and allogeneic hematopoietic stem cell transplant. It is not clear if the presence of an increased DC population in non-DC AML confers pDC neoplasm-like biological characteristics to the former. Aims: This study aims to evaluate whether an increase in the size of DC populations in newly-diagnosed non-DC AML affects the latter's biological behavior, as represented by the overall survival (OS) of patients with the disease. Methods: We reviewed all AML diagnosed in our Hospital between January 1st 2008 and December 31st 2010, identifying 146 patients. We excluded 9 patients who had no flow cytometry immunophenotyping (IP) performed, and 7 whose first IP was performed after treatment was instituted. In that time frame, we also diagnosed 4 pDC neoplasms. Of the 130 patients included, 91 had their presenting IP performed on BM aspirate, while the remaining 39 were phenotyped on blood samples. The size of the DC populations and blastic DC maturation were determined on these samples. Patients were classified into 2 groups according to the size of the DC component; one (the Non-DC Group) had a DC component of up to 0.3% (in practice, the highest value in this group was 0.2%); the other (DC Group) had a percentage over this limit (the lowest value being 1.0%). OS data was determined for both groups; special consideration was given to age strata, separating patients under 65 years of age (Under-65) from those 65 or older (Over-65) and etiology (distinguishing de novo AML from AML secondary to therapy, myelodysplasia or myeloproliferative diseases). The percentage of DC identified by IP did not influence nor alter the type of treatment instituted. Results: We found that the presence of a DC component above the normal BM interval (as determined by Matarraz et al) was associated with a significantly decreased OS, with patients with DC components over 0.3% presenting with a median OS of 2.4 months (mean: 6.4 ± 1.6) and those with a component under 0.3% with a median OS of 8.6 months (mean: 17.0 ± 1.9) (p = 0.033). In our series, patients Over-65 had a median OS of 2.9 months (mean = 6.9 ± 1.0) and those Under-65 a median of 21.3 months (mean = 22.5 ± 2.5), p < 0.001. The differences in OS according to DC component were attenuated in patients Over-65 (median = 1.8 vs. 3.9 months, p = NS), whereas in patients Under-65 the median survival was 2.7 months (mean: 8.7 ± 2.9) for the DC Group and 24.4 months (mean: 24.3 ± 2.7) for the non-DC Group (p = 0.035). The differences in OS were also significant for de novo AML (median = 2.4 vs. 16.0 months, mean = 4.7 ± 1.9 vs. 20.5 ± 2.6, p = 0.017), but not statistically relevant for secondary AML (median = 4.4 vs. 5.5 months, mean = 8.4 vs. 10.8, p = NS). Discussion: In this study, we found that an increase in the size of the DC component as determined by IP at diagnosis on newly-diagnosed AML had a negative impact on prognosis, with a significant decrease in median and mean OS in patients with a percentage of DC over the upper limit of the normal interval. We also determined that the decreased survival was primarily attributed to the better-prognosis groups (patients under 65 and with de novo AML), whereas the effect of the worsened prognosis was attenuated in those patients with a bad prognosis at the outset (patients over 65 and with secondary AML). If data from DC neoplasms could be extrapolated, we could suggest that AML with increased DC components are less chemo-sensitive, which would explain the OS differences found in the Under-65 group, as well as the no-difference found in the Over-65 Group, which is frequently undertreated due to comorbidities. Conclusion: Our study suggests that the size of the DC component at diagnosis as determined by IP is a new prognostic marker predictive of decreased survival. Disclosures: No relevant conflicts of interest to declare.

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Acute myeloid leukemia ontogeny is defined by distinct somatic mutations

Blood ◽

10.1182/blood-2014-11-610543 ◽

2015 ◽

Vol 125 (9) ◽

pp. 1367-1376 ◽

Cited By ~ 347

Author(s):

R. Coleman Lindsley ◽

Brenton G. Mar ◽

Emanuele Mazzola ◽

Peter V. Grauman ◽

Sarah Shareef ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Somatic Mutations ◽

De Novo ◽

Clinical Heterogeneity ◽

Secondary Aml ◽

Key Points ◽

De Novo Aml ◽

Secondary Type ◽

Acute Myeloid

Key Points The presence of a mutation in SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, or STAG2 is highly specific for secondary AML. Secondary-type mutations define an s-AML–like disease within t-AML and elderly de novo AML that underlies clinical heterogeneity.

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De Novo and Secondary Acute Myeloid Leukemia, Real World Data on Outcomes from the French Nord-Pas-De-Calais Picardie Acute Myeloid Leukemia Observatory

Blood ◽

10.1182/blood.v128.22.4013.4013 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4013-4013 ◽

Cited By ~ 3

Author(s):

Loïc Renaud ◽

Olivier Nibourel ◽

Celine Berthon ◽

Christophe Roumier ◽

Céline Rodriguez ◽

...

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Supportive Care ◽

Real World ◽

Myeloid Leukemia ◽

De Novo ◽

Secondary Aml ◽

Secondary Acute Myeloid Leukemia ◽

De Novo Aml ◽

Acute Myeloid

Abstract Background. Population-based registries may provide data complementary to that from clinical intervention studies. Registries with high coverage of the target population reduce the impact of selection on outcome and the subsequent problem with extrapolating data to nonstudied populations like secondary Acute Myeloid Leukemia (AML). Actually, secondary AML are frequently excluded from clinical trials so the registries constitute the only way to fine data for establishing recommendations for the management of these patients in the real world. Method. The French Nord-pas-de-calais Picardie AML observatory containing 1 582 AML patients diagnosed between 2000 and 2015. We compared 974 primary AML to 514 Secondary AML include AML arising from a pre-existing myelodysplastic (n=211), myeloproliferative (n=88) or myelodysplastic/myeloproliferative (n=57) disease and therapy related AML (t-AML) (n=158). Results. Median survival and 5 years overall survival were respectively 420 days [95%IC: 349-491] and 32% for patients with de novo AML; 157 days [95%IC: 118-196] and 7% for patients with secondary AML. 1101 patients were classified according to the MRC as favorable, intermediate and unfavorable, respectively 18(5.2%), 178(51.9%) and 147(42.9%) patients with secondary AML including 100(29.2%) complexes karyotypes and 117(15.4%), 468(61.7%) and 173(22.8%) patients with de novo AML including 121 (15.9%) complexes karyotypes. 987 patients were classified according to the ELN as favorable, intermediate-1, intermediate-2 and unfavorable for respectively 35(11.7%), 53(17.7%), 67(22.%) and 144(48.2%) patients with secondary AML and 219(31.8%), 167(24.%), 136(19.8%) and 166(24.1%) patients with de novo AML. The age at diagnosis was significantly different (p < 10-3) with a median of 72.6 years for secondary AML and 63.2 for de novo AML. 206 (40.4%) patients with secondary AML received demethylating agents versus 184 (19%) for de novo AML and 152(29%) received high dose chemotherapy (HDC) versus 619 (63.9%) patients with de novo AML. Best supportive care was the only treatment for 170 (17.5%) de novo AML and 164 (31.9%) secondary AML patients. For patients over than 60 years old, median survival and 5 years overall survival were respectively 182 days [95%IC: 136.5-127.4] and 12.9% for 559 patients with de novo AML; 128 days [95%IC: 95.0-161.0] and <4% for 413 patients with secondary AML. Conclusion. The poor prognosis of secondary and t- AML is confirmed by this registry study. Possible explanations for this worse outcome could be older age at diagnosis and increased frequency of complex karyotypes which lead to less intensive therapy or supportive care only. In this specific population, the choice of demethylating agent therapy was frequently made because of the weak efficacy of HDC and increased frequency of side effects in this vulnerable group. Disclosures No relevant conflicts of interest to declare.

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Leukemic Stem Cell Phenotype Is Associated with Mutational Profile in Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2019-126373 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3852-3852

Author(s):

Ja Min Byun ◽

Dong-Yeop Shin ◽

Youngil Koh ◽

Sung-Soo Yoon ◽

Junshik Hong ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Stem Cell ◽

Genomic Dna ◽

Myeloid Leukemia ◽

Research Funding ◽

De Novo ◽

Leukemic Stem Cell ◽

Secondary Aml ◽

De Novo Aml ◽

Acute Myeloid

Background: Understanding leukemic stem cell (LSC) is important for acute myeloid leukemia (AML) treatment. As such, understanding the relationship between LSC and genetically defined sub-clones can, in turn, help to understand the heterogeneity of AML. However, to date, there are only a few reports specifically focusing on this topic. To this end, we conducted this study to (1) examine the phenotypic diversity of AML-LSC, (2) explore the association between AML-LSC phenotypes and gene mutations, and (3) investigate the prognostic implications of AML-LSCs. Methods: Mononuclear cells (MNCs) were isolated from the patient's bone marrow aspirates by ficoll gradient centrifugation and cryopreserved in serum-free medium. Stored cells were thawed to Iscove's Modified Dulbecco's Medium (IMDM) and washed with fluorescence-activated cell sorting (FACS) buffer [1% FBS, Dulbecco's Phosphate-Buffered Saline (DPBS)]. Cells were stained with following anti-human monoclonal antibodies: CD45-APC/cy7, CD34-APC, CD38-BV421, CD90-PE, CD123-PE/Cy7, CD45RA-PerCP/Cy5.5. Analyses were performed on a FACSCanto II (HTS) (BD Bioscience) and FlowJo V 10.0 (BD Bioscience) program. For sequencing, the DNA capture probes for 76 target genes were designed using the Agilent SureDesign web-based application. The target regions included protein coding exons with 10 bp intron flanking regions and hot spot regions of the 20 genes involved in recurrent translocations. DNA was extracted on a Chemagic 360 instrument (Perkin Elmer, Baesweiler, Germany). The genomic DNA was sheared using Covaris S220 focused‐ultrasonicator (Covaris, Woburn, MA). We used 50ng of total input genomic DNA. A library preparation was performed according to Agilent's SureSelectQXT Target Enrichment protocol. Paired-end 150-bp sequencing was using NextSeq 550 Dx platform (Illumina, San Diego, CA). Targeted sequencing raw data was obtained in FASTQ format. Results: In secondary AML patients, MPP-like LSC was significantly higher than de-novo AML (p=0.0037), and was higher in MPN-AML than in MDS-AML (p=0.0485). There was no correlation between age and LSC phenotype, though CD34+CD38- subpopulation was enriched in younger patients (<65 yrs). Mutations of KRAS and NRAS were frequently observed in MPP-like LSC dominant patients (3/14 and 4/14), TP53 and ASXL1 mutations in LMPP-like LSC dominant patients (4/12 and 4/12) , and CEBPA, DNMT3A and IDH1 (6/12, 4/12, and 3/12) mutations in GMP-like LSC dominant patients. Furthermore, as shown in Figure, KRAS mutation was significantly associated with the percentage of MPP-like LSC phenotype (p=0.0540), and TP53 mutation with the percentage of LMPP-like LSC phenotype (p=0.0276). When the patients were separated according to the combined risk including next generation sequencing data, the poorer the prognosis, the higher the LMPP-like LSC expression (p=0.0052). The importance of our study lies in that we showed for a given AML patients there is a dominant LSC phenotype and LSCs are associated with clinical outcomes, supporting the significance of cancer stem cell model for human AML. First of all, based on detailed characterization of the surface immunophenotype of AML LSCs we found that AML show evidence of a hierarchical cellular organization. We also recognized that the composition of LSC phenotypes is associated with AML phenotypes. For example, secondary AML patients showed higher fraction of MPP-like LSCs compared to de novo AML patients. In this regard, the higher expression of MPP-like LSCs could explain the poor response to standard treatments traditionally associated with secondary AML. Furthermore, the higher expression of MPP-like LSCs in post-MPN AML compared to post-MDS AML could explain the dismal prognosis associated with post-MPN AML, despite the relative indolent clinical course in their chronic phase and the presence of druggable target. Conclusion: In conclusion, our findings provide better insights into the characteristics and clinical implications of LSC. Although in a small scale, we provide evidence that specific LSC phenotypes are associated with certain mutations thus should be in the AML risk stratification process. Figure Disclosures Yoon: Janssen: Consultancy; Kyowa Hako Kirin: Research Funding; Genentech, Inc.: Research Funding; Yuhan Pharma: Research Funding; MSD: Consultancy; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria.

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Methylation of the RIZ1 Gene In Myelodysplastic Syndrome and Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v116.21.5112.5112 ◽

2010 ◽

Vol 116 (21) ◽

pp. 5112-5112

Author(s):

Naoki Mori ◽

Kentaro Yoshinaga ◽

Mari Ohwashi ◽

Toshiaki Kondoh ◽

Hanae Shimura ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Promoter Region ◽

Myeloid Leukemia ◽

De Novo ◽

Methylation Status ◽

Leukemia Cells ◽

Pcr Analysis ◽

Secondary Aml ◽

De Novo Aml ◽

Acute Myeloid

Abstract Abstract 5112 Inactivation of a tumor suppressor gene is often caused by a mutation, small deletion of one allele accompanied by loss of the second allele. Methylation in a promoter CpG of several tumor suppressor genes has recently been reported and has been associated with loss or decreased expression in many tumors. We previously reported frequent loss of heterozygosity on the short arm of chromosome 1 (1p) in the progression of myelodysplastic syndrome (MDS) to acute myeloid leukemia (AML). The retinoblastoma protein-interacting zinc finger gene RIZ maps to 1p36. Mouse gene knockout models show that RIZ1 inactivation can cause tumor susceptibility. Inactivation of the RIZ1 gene by promoter hypermethylation has been reported in breast, liver, and gastric carcinoma. Previous study showed altered expression of the RIZ1 gene in human leukemia. However, methylation status of the RIZ1 gene has not been well studied in hematological neoplasms. To determine the relevance of the RIZ1 methylation, we performed methylation specific-polymerase chain reaction (PCR) analysis on the RIZ1 gene in 34 patients with MDS and 17 with AML evolved from MDS (secondary AML) as well as 55 patients with de novo AML. The 34 MDS samples consisted of 13 refractory anemia (RA), 1 RA with ringed sideroblasts (RARS), 10 RA with excess of blasts (RAEB), 6 RAEB in transformation (RAEB-t), and 4 chronic myelomonocytic leukemia. The 55 de novo AML consisted of 1 M0, 12 M1, 17 M2, 7 M3, 8 M4, 7 M5, 1 M6, and 2 M7. Written informed consent was obtained from the patients. Methylation of the RIZ1 gene was detected in 17 of the 34 MDS (50%) and 22 of 72 de novo and secondary AML (31%) (p=0.053). Methylation was detected in 7 of 14 low risk MDS (50%) and 10 of 20 high risk MDS (50%). Patients with MDS were classified using the IPSS score. Frequency of methylation was not statistically different among IPSS subgroups (p=0.419). No statistical differences were observed between methylation and overall survival (3 years) or progression to AML. In AML patients, methylation was more frequent in secondary AML (11/17, 65%) than in de novo AML (11/55, 20%) (p=0.0005). To define the methylation status of the CpG in the RIZ1 promoter region, we performed bisulfite sequence in several samples with methylation. Bisulfite sequence analysis revealed methylation at many CpG sites in the promoter region. Expression of the RIZ1 gene was examined by quantitative real time reverse transcriptase-PCR analysis in 22 samples of MDS and AML. RIZ1 expression (mean) was not statistically different in secondary AML and de novo AML (2.026 vs. 1.900, p=0.815). RIZ1 expression (mean) was not statistically different in methylation-positive group and methylation-negative group (1.996 vs. 1.810, p=0.728). In comparison with expression of normal bone marrow cells, decreased RIZ1 expression was accompanied by methylation in 6 of 9 samples examined, while it was also observed in 7 of 13 without methylation. HL-60 myeloid leukemia cells with RIZ1 methylation were cultivated for 3 days in the presence of various concentrations of 5-Aza-dC. Treatment of the leukemia cells with 5 Aza-dC induced growth suppression with RIZ1 restoration. Our results suggest that the RIZ1 gene was inactivated in MDS and AML in part by methylation, whereas another mechanism of inactivation should be involved in others. Disclosures: No relevant conflicts of interest to declare.

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Therapy-related acute myeloid leukemia and myelodysplastic syndrome: a clinical and morphologic study of 65 cases

Blood ◽

10.1182/blood.v65.6.1364.bloodjournal6561364 ◽

1985 ◽

Vol 65 (6) ◽

pp. 1364-1372 ◽

Cited By ~ 213

Author(s):

SD Michels ◽

RW McKenna ◽

DC Arthur ◽

RD Brunning

Keyword(s):

Acute Myeloid Leukemia ◽

Myelodysplastic Syndrome ◽

Median Survival ◽

Myeloid Leukemia ◽

De Novo ◽

Poor Response ◽

Significant Difference ◽

Multiple Cell ◽

De Novo Aml ◽

Acute Myeloid

Abstract This study consists of 65 patients (pts) who developed a myelodysplastic syndrome (MDS) (39 pts) or acute myeloid leukemia (AML) (26 pts) following chemotherapy and/or radiotherapy; the interval from the onset of therapy to bone marrow abnormality ranged from 11 to 192 months (median, 58). Thirty-three patients had been previously treated for lymphoproliferative diseases, 29 for carcinoma, and three for a nonneoplastic disorder. Approximately 30% of the cases presenting in the MDS phase evolved to AML in one to 12 months (median, 3.5). The AML in 49% of the cases was not readily classified according to French- American-British (FAB) criteria; the primary difficulty in classification related to the involvement of multiple cell lines. Among the cases that could be classified, all FAB types were represented except for M1; M2 was the most frequent type. Clonal chromosome abnormalities were found in marrow specimens from 22 of 24 (92%) patients studied with G banding; 11 had abnormalities of chromosomes 5 and/or 7. The median survival for all patients was four months with no significant difference between those treated and not treated with antileukemic therapy. The median survival was three months for the patients presenting with AML, six months for the patients with AML following an MDS, and four months for the patients with an MDS that did not evolve to AML. The findings in the present study suggest that there are three stages of therapy-related panmyelosis: (1) pancytopenia with associated myelodysplastic changes, (2) a frank MDS, and (3) overt AML. Many patients will present in the stage of overt AML that differs from de novo AML primarily by the high incidence of trilineage involvement, difficulty in classification, frequent cytogenetic abnormalities, and poor response to antileukemic therapy. The myelodysplastic phase, with or without evolution to acute leukemia, is a highly lethal disease with a median survival comparable to that of the patients who present with AML.

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Expression of mast cell tryptase by myeloblasts in a group of patients with acute myeloid leukemia

Blood ◽

10.1182/blood.v98.7.2200 ◽

2001 ◽

Vol 98 (7) ◽

pp. 2200-2209 ◽

Cited By ~ 94

Author(s):

Wolfgang R. Sperr ◽

John-Hendrik Jordan ◽

Mehrdad Baghestanian ◽

Hans-Peter Kiener ◽

Puchit Samorapoompichit ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Messenger Rna ◽

Myeloid Leukemia ◽

De Novo ◽

Elevated Serum ◽

Leukemia Cell ◽

Acute Leukemias ◽

Secondary Aml ◽

De Novo Aml ◽

Acute Myeloid

α- and β-tryptase genes encode serine proteases that are abundantly expressed by mast cells. Under physiologic conditions other myeloid cells are virtually tryptase negative. However, tryptases are also expressed in several myeloid leukemia cell lines. In this study, serum total tryptase levels were determined in 150 patients with acute leukemias (de novo acute myeloid leukemia [AML], n = 108; secondary AML, n = 25; acute lymphoid leukemia [ALL], n = 17) by fluoroenzyme immunoassay. In healthy subjects (n = 30), tryptase levels ranged between 2.0 and 12.6 ng/mL. Elevated tryptase levels (> 15) were detected in 42 (39%) of 108 patients with de novo AML and in 11 (44%) of 25 patients with secondary AML. No elevated tryptase levels were found in patients with ALL. In de novo AML, elevated tryptase levels were frequently detected in patients with French-American-British classification M0 (6 of 9), M2 (9 of 14), M3 (4 of 6), and M4eo (7 of 7), and less frequently in M1 (7 of 20), M4 (6 of 26), M5 (2 of 18), M6 (0 of 5), or M7 (1 of 3). The highest tryptase levels were found in M4eo. Immunohistochemical staining of bone marrow sections with anti-tryptase antibody as well as immunoelectron microscopy revealed tryptase expression in the cytoplasm of myeloblasts. As assessed by Northern blotting and reverse transcriptase–polymerase chain reaction, AML cells expressed α-tryptase messenger RNA (mRNA) but little or no β-tryptase mRNA. In AML patients with elevated serum tryptase before chemotherapy, who entered complete remission, tryptase levels returned to normal or near normal values. Blast cell persistence or regrowth was associated with a persistently elevated level or recurrent increase of tryptase. Together, tryptase is expressed in myeloblasts in a group of AML and may serve as a useful disease-related marker.

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Outcomes of Haploidenitical Stem Cell Transplants for De Novo Acute Myeloid Leukemia, Myelodysplastic Syndrome and Acute Myeloid Leukemia Arising from MDS: The MD Anderson Experience

Blood ◽

10.1182/blood.v126.23.3225.3225 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3225-3225

Author(s):

Reshma Ramlal ◽

Sameh Gaballa ◽

Julianne Chen ◽

Gabriela Rondon ◽

Betul Oran ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Stem Cell ◽

Myelodysplastic Syndrome ◽

Myeloid Leukemia ◽

De Novo ◽

De Novo Aml ◽

Disease Free ◽

Active Disease ◽

Acute Myeloid

Abstract Background Outcomes of haploidentical stem cell transplantation (haploSCT) have improved since the introduction of post-transplantation cyclophosphamide (PTCy) to the extent that survival is comparable to HLA matched donor transplantation. Here, we report the outcomes of 80 patients treated at our institution for de novo acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and AML arising from MDS treated with melphalan, fludarabine conditioning. Methods We retrospectively analyzed data from 80 patients (60 [75%] with de novo AML and 20 [25%] with MDS or MDS/AML who received a haploSCT between 2009 to April 2015. Twenty-nine patients (38%) in total had adverse cytogenetics while 12/18 (66%) of MDS, MDS/AML patients had adverse cytogenetics. Fifty one patients (64%) were in a complete response (CR) at the time of transplant. Thirty-seven patients (46.3%) were conditioned with fludarabine 40 mg/m2 (day -6 to -3), melphalan 100 mg/m2 (day -8), thiotepa 5 mg/kg (day -7), 26 (32.5%) with fludarabine and melphalan 140 mg/m2 and 13 (16%) with fludarabine, melphalan and total body irradiation (TBI) at 200 cGy. Graft vs host disease (GvHD) prophylaxis consisted of PTCy on day +3 and +4 after haploSCT and tacrolimus and mycophenolate for 6 and 3 months, respectively. Donors included children (48%), siblings (41%) and parents (10%). Seventy six patients (95%) received a bone marrow graft and the remaining 4 (5%) received peripheral blood. Results Median age was 50 years (range, 15-69 years), 54% were male. Three patients had early death: 2 from infection and 1 from multiorgan failure. Of the 77 evaluable patients, 76 engrafted (99% primary engraftment). The median times to neutrophil and platelet engraftment were 18 days (range, 6-40 days) and 25 days (range, 10-54 days), respectively. The rates of grade II-IV and III- IV acute GvHD at day 100 were 30% and 3%, respectively. Chronic GvHD occurred in 8 of 60 patients (13%): 3 with extensive and 5 with limited stage. At the last follow-up, 40 patients (50%) were alive and disease-free. Relapse occurred in 17 of the 60 patients with de novo AML (28.3%) and 6 of 20 patients with MDS, MDS/AML (30%). The 1-year and 2-year overall survival rates were 56% and 47.5%, respectively, with 64.6% of patients in CR1 or 2 at the time of transplant and 42.3% of patients with active disease or greater than CR2 alive at 1 year (log rank p= 0.030). On univariate analysis, cytogenetic risk and disease status prior to transplant were found to have a statistically significant influence on progression free survival (PFS) (Figure 1B, C) All 17 patients with active disease at the time of transplant attained a CR and 7 (41%) remained disease free and alive at the median time of follow-up. The cumulative incidence of non-relapse mortality (NRM) at day 100 and 1 year were 13.8% and 27.4% respectively. Of the 34 deaths; 18 (53%) were due to relapsed disease, 7(20%) infection, 3 GvHD, 5 organ failure and 1 graft failure. Conclusion HaploSCT using a fludarabine, melphalan backbone for conditioning is safe and effective not only for patients with de novo AML, but also with MDS and AML arising from MDS. Improvement in relapse rate for patients with high-risk disease and those not in remissions at transplant is warranted. Figure 1. Figure 1. Figure 2. Figure 2. Figure 3. Figure 3. Disclosures No relevant conflicts of interest to declare.

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Chromothripsis in Acute Myeloid Leukemia Is Strongly Associated with Poor Prognosis and TP53 Alterations

Blood ◽

10.1182/blood.v128.22.1678.1678 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1678-1678

Author(s):

Maria Chiara Fontana ◽

Giovanni Marconi ◽

Jelena D. Milosevic Feenstra ◽

Cristina Papayannidis ◽

Marco Manfrini ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Genomic Instability ◽

Copy Number ◽

Driving Force ◽

Myeloid Leukemia ◽

Poor Prognosis ◽

Tp53 Mutation ◽

Complex Karyotype ◽

Newly Diagnosed ◽

Acute Myeloid

Abstract Introduction Genomic instability and complex karyotype are linked to chemoresistance, poor prognosis and early relapse rate in Acute Myeloid Leukemia (AML). Chromothripsis, a one-step catastrophic mechanism of genomic instability, could represent a driving force in the development and progression of hematological diseases and could be identified by high throughput technologies as Single Nucleotide Polymorphism (SNP) Array. We investigate the mechanisms involved in chromothripsis in newly diagnosed non M3-AML patients (patients) in order to better characterize a class of very high risk patients that could be candidate to innovative therapies. Methods We performed classical cytogenetic and microarray analysis (SNP Arrays 6.0 or Cytoscan HD Arrays, Affymetrix) in 418 AML samples. Data were analyzed by Nexus Copy Number™ and R Core Team. Chromothripsis-like patterns were confirmed by CTLP Scanner (Log Ratio ≥ 8, ≥ 10 switches, minimum segment size of 10 kb, distance between adjacent fragments ≤ 10% and 0.3 as variation from different copy number (CN) states). Overall survival was analyzed by Kaplan-Meier method and Mantel-Cox test. Results Twenty-six/418 patients (6.2%) showed chromothripsis involving different chromosomes. Chromosome 12 (23%), 17 (19%) and 5 (19%) were the most affected, followed by chromosomes 3, 6, 7, 8, 10, 11, 13, 15 and 20. Patients harboring chromothripsis had a higher median age compared with chromothripsis-negative ones (70.4 vs. 55 years, respectively, p<.001) and a lower white blood cells (WBC) count at diagnosis (4,395 vs. 30,000, respectively, p =.019). The group of patients with chromothripsis presented a prevalence of complex karyotype (p<.001) and high risk (HR) disease according to ELN definition (p<.001). Furthermore, we found a significantly higher incidence of TP53 mutation (p<.001) in chromothripsis-positive patients: 16/26 patients had an heterozygous loss of 17p13 (p<.001) and 21/24 harbored a TP53 mutation (2 samples were not evaluated) . TP53 loss and mutation co-occurred in 20 cases. Chromothripsis-positive patients showed an extremely poor prognosis compared with chromothripsis-negative ones (median survival of 120 vs. 526 days, respectively, p<.001) and a 3.4 risk of death at Cox-hazard ratio analysis (C.I. 95%: 1.85-6.27). Moreover, chromothripsis showed to predict a lower response rate independently of age at diagnosis, de novo/secondary AML, FLT3 mutational status and type of induction therapy (p=.044). Of note, chromothripsis was associated with worst prognosis even if compared with HR karyotype features without chromothripsis (median survival of 120 and 265 days, respectively, p<.001, Figure 1). Finally, by comparing patients with and without chromothripsis, we identified several genes and pathways differentially altered between the 2 groups (p<0.001). Chromothripsis was particularly associated with loss of RAD50, FANCA, MARCH3, WNT8A, SHH, BCL2, USP34, CTNNA1, with 5q being the main altered chromosomic region, while ZFPM2 was the main amplified gene. Conclusion Our results demonstrate that chromothripsis is a recurrent event in adult AML and independently defines a group of patients with poor prognosis. Chromothripsis is strongly associated with TP53 alterations in AML and for the first time, we define incidence and survivals of chromothripsis in a set of 418 newly diagnosed consecutive AML patients. Chromosomal abnormalities like chromothripsis could be a driving force in the development of cancer as well in hematological disease like AML, in which the genomic instability represent the main scenario. Since TP53 is known to deregulate Fanconi Anaemia genes, the deregulation of DNA double-strand break repair could sustain the maintenance of catastrophic mechanism like chromothripsis. Acknowledgment ELN, AIL, AIRC, PRIN, Progetto Regione-Università 2010-12 (L. Bolondi), FP7 NGS-PTL project. MCF and GM equal contribution Disclosures Kralovics: Qiagen: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Research Funding. Martinelli:Novartis: Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; MSD: Consultancy; Genentech: Consultancy; Pfizer: Consultancy, Speakers Bureau; Ariad: Consultancy, Speakers Bureau; BMS: Speakers Bureau; Roche: Consultancy, Speakers Bureau.

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