scholarly journals Integrated Genomic Analysis Identifies UBTF Tandem Duplications As a Subtype-Defining Lesion in Pediatric Acute Myeloid Leukemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 2) ◽  
pp. LBA-4-LBA-4
Author(s):  
Masayuki Umeda ◽  
Jing Ma ◽  
Benjamin J. Huang ◽  
Kohei Hagiwara ◽  
Tamara Westover ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Research Funding ◽  
De Novo ◽  
Screening Method ◽  
Normal Karyotype ◽  
Rna Seq ◽  
Trisomy 8 ◽  
De Novo Aml ◽  
Pediatric Aml ◽  
Tandem Duplications

Abstract Children with acute myeloid leukemia (AML) have a dismal prognosis due to a high relapse rate; however, the molecular basis leading to relapsed pediatric AML has not yet been fully characterized. To define the spectrum of alterations common at relapse, we performed integrated profiling of 136 relapsed pediatric AML cases with RNA sequencing (RNA-seq), whole-genome sequencing, and target-capture sequencing. In addition to well-characterized fusion oncoproteins, such as those involving KMT2A (n=36, 26.5%) or NUP98 (n=18, 13.2%), we also identified somatic mutations in UBTF (upstream binding transcription factor) in 12 of 136 cases (8.8%) of this relapsed cohort. Somatic alterations of the UBTF gene, which encodes a nucleolar protein that is a component of the RNA Pol I pre-initiation complex to ribosomal DNA promoters, have rarely been observed in AML. In our cohort, all alterations can be described as heterozygous in-frame exon 13 tandem duplications (UBTF-TD), either at the 3' end of exon 13 of UBTF or of the entire exon 13 (Fig. A). As we noticed limited detection in our pipeline as a result of complex secondary indels alongside the duplications, we established a soft-clipped read-based screening method to detect UBTF-TD more efficiently. Applying the screening to RNA-seq data of 417 additional pediatric AMLs from previous studies and our clinical service, we identified 15 additional UBTF-TDs, many of which have not been previously reported. At the amino acid level, UBTF-TDs caused amino acid insertions of variable sizes (15-181 amino acids), duplicating a portion of high mobility group domain 4 (HMG4), which includes short leucine-rich sequences. UBTF-TD AMLs commonly occurred in early adolescence (median age: 12.6, range: 2.4-19.6), and 19 of the total 27 cases had either normal karyotype (n=12) or trisomy 8 (n=7). UBTF-TD is mutually exclusive from other recurrent fusion oncoproteins, such as NUP98 and KMT2A rearrangements (Fig. B), but frequently occurred with FLT3-ITD (44.4%) or WT1 mutations (40.7%). The median variant allele fraction (VAF) of the UBTF-TD was 48.0% (range: 9.7-66.7%). In four cases with data at multiple disease time points, the identical UBTF-TDs were present at high allele fractions at all time points, suggesting that UBTF-TD is a clonal alteration. tSNE analysis of the transcriptome dataset showed that UBTF-TD AMLs share a similar expression pattern with NPM1 mutant and NUP98-NSD1 AML subtypes, including NKX2-3 and HOXB cluster genes (Fig. C) . Altogether, these findings suggest that UBTF-TD is a unique subtype of pediatric AML. To address the impact of UBTF-TD expression in primary hematopoietic cells, we introduced UBTF-TD and UBTF wildtype expression vectors into cord blood CD34+ cells via lentiviral transduction. UBTF-TD expression promotes colony-forming activity and cell growth, yielding cells with a persistent blast-like morphology (Fig. D). Further, transcriptional profiling of these cells demonstrated expression of HOXB genes and NKX2-3, similar to UBTF-TD AMLs in patients, indicating that UBTF-TD is sufficient to induce the leukemic phenotype. To investigate the prevalence of UBTF-TDs in larger de novo AML cohorts, we applied the above UBTF-TD screening method to the available de novo AML cohorts of TCGA (n=151, adult), BeatAML (n=220, pediatric and adult), and AAML1031 (n=1035, pediatric). We identified UBTF-TDs in 4.3% (45/1035) of the pediatric AAML1031 cohort, while the alteration is less common (0.9%: 3/329, p=0.002) in the adult AML cohorts (Fig. E). In the AAML1031 cohort, UBTF-TDs remain mutually exclusive with known molecular subtypes of AML and commonly occur with FLT3-ITD (66.7%) and WT1 (40.0%) mutations and either normal karyotype or trisomy 8. The presence of UBTF-TDs in the AAML1031 cohort is associated with a poor outcome (Fig. F, median overall survival, 2.3 years) and MRD positivity; multivariate analysis revealed that UBTF-TD and WT1 are independent risk factors for overall survival within FLT3-ITD+ AMLs. In conclusion, we demonstrate UBTF-TD defines a unique subtype of AMLs that previously lacked a clear oncogenic driver. While independent of subtype-defining oncogenic fusions, UBTF-TD AMLs are associated with FLT3-ITD and WT1 mutations, adolescent age, and poor outcomes. These alterations have been under-recognized by standard bioinformatic approaches yet will be critical for future risk-stratification of pediatric AML. Figure 1 Figure 1. Disclosures Iacobucci: Amgen: Honoraria; Mission Bio: Honoraria. Miller: Johnson & Johnson's Janssen: Current Employment. Mullighan: Pfizer: Research Funding; Illumina: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Amgen: Current equity holder in publicly-traded company.

scholarly journals Clinical, morphologic, and cytogenetic characteristics of 26 patients with acute erythroblastic leukemia

Blood ◽  
1992 ◽  
Vol 80 (11) ◽  
pp. 2873-2882 ◽  
Author(s):  
OI Olopade ◽  
M Thangavelu ◽  
RA Larson ◽  
R Mick ◽  
A Kowal-Vern ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
De Novo ◽  
Chromosomal Abnormalities ◽  
Normal Karyotype ◽  
Intensive Chemotherapy ◽  
Trisomy 8 ◽  
Cytogenetic Abnormalities ◽  
Favorable Prognosis ◽  
Multiple Abnormalities ◽  
French American British

Abstract We have performed a retrospective analysis of the clinical, morphologic, and cytogenetic findings in 26 patients diagnosed between January 1969 and September 1991 with acute erythroblastic leukemia de novo (EL or AML-M6). Clonal chromosomal abnormalities were found in 20 (77%) patients (95% confidence interval [CI], 61% to 93%). Loss of all or part of the long arm (q) of chromosomes 5 and/or 7 was observed in 17 (65%) patients (95% CI, 47% to 83%). In addition, the karyotypes were often complex, with multiple abnormalities and subclones. Among the remaining nine patients, six had a normal karyotype and one each had trisomy 8, t(3;3), or t(3;5). The overall frequency of abnormalities of chromosomes 5 and/or 7 observed in our M6 patients is similar to that observed in our patients with therapy-related acute myeloid leukemia (t-AML; 99 of 129 patients, 77%), but substantially higher than that noted in our other patients with AML de novo (French- American-British [FAB] subtypes M1-M5: 52 of 334 patients, 16%). Our M6 patients with abnormalities of chromosomes 5 and/or 7 were older and had a shorter median survival (16 v 77 weeks [P = .005]) than did the M6 patients without these abnormalities. We found no correlation between morphologic features and either cytogenetic abnormalities or clinical outcome. Of note was the finding that the percentage of myeloblasts, which may account for only a small fraction of the total marrow elements when the revised FAB criteria are applied, had no bearing on prognosis. We conclude that acute erythroblastic leukemia, when defined by morphologic criteria, consists of two distinctive subgroups: one group tends to be older, has complex cytogenetic abnormalities, especially of chromosomes 5 and/or 7, and shares biologic and clinical features with t-AML; the other group, with simple or no detectable cytogenetic abnormalities, has a more favorable prognosis when treated with intensive chemotherapy.

FLT3 Internal Tandem Duplications in Adults with De Novo Acute Myeloid Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4430-4430
Author(s):  
Sandra G. Xavier ◽  
Rocío Hassan ◽  
Nelma C.D. Clementino ◽  
Daniel G. Tabak ◽  
Nelson Spector ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Tandem Duplication ◽  
De Novo ◽  
Univariate Analysis ◽  
Internal Tandem Duplication ◽  
Hematopoietic Stem ◽  
Proliferation And Differentiation ◽  
Polymerase Chain ◽  
De Novo Aml ◽  
Tandem Duplications

Abstract FLT3 is a receptor tyrosine kinase involved in the proliferation and differentiation of hematopoietic stem cells. Recently, internal tandem duplication (ITD) mutations of the FLT3 gene have been described in patients with AML and associated with a poor prognosis. The aim of this study was to analyze the prevalence of FLT3-ITD in a series of 90 adults with de novo AML and correlate the presence of this mutation with biological characteristics and clinical response. We analyzed diagnostic peripheral blood or bone marrow specimens from 43 women and 47 men, with a median age of 38 years (16–83). Polymerase chain reaction was performed on genomic DNA using previously published primers for exons 11 and 12. An FLT3-ITD was found in 22/89 patients (25%). It was present in 37% (9/24) of the patients with acute promyelocytic leukemia (APL) and in only 20% (13/65) of the patients with non-M3-AML (p=0.07). The FLT3-ITD was not detected in patients with M6 (n=1) and M7-AML (n=3), nor in patients with the AML1-ETO (n=2) or with the CBFb-MYH11 (n=4) fusion genes. The median WBC counts were higher in FLT3-ITD patients than in those without the mutation (37 X 109/L vs. 27 X 109/L, p=0.43). In APL, FLT3-ITD was found in 5 out of 6 patients with the short PML-RARa isoform, but in only 4 out of 18 patients with the non-short isoform (p=0.01). Univariate analysis showed an association between the presence of FLT3-ITD and both a lower complete remission (CR) rate (41% vs. 64%; p=0.05) and a shorter overall survival (14% vs. 34%; p=0.03). However, FLT3-ITD was not associated with the CR rate (p=0.18) or the OS (p=0.07) in the multivariate analysis. The clinical significance of FLT3-ITD in adult AML remains uncertain, and further investigation is clearly warranted.

High Frequency of AML1/RUNX1 Mutations in Specific Cytogenetic Subgroups in De Novo Acute Myeloid Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 986-986
Author(s):  
Frank Dicker ◽  
Claudia Haferlach ◽  
Wolfgang Kern ◽  
Torsten Haferlach ◽  
Susanne Schnittger
Keyword(s):  
Trisomy 21 ◽  
De Novo ◽  
Normal Karyotype ◽  
Clinical History ◽  
Trisomy 13 ◽  
Complex Karyotype ◽  
Trisomy 8 ◽  
Cytogenetic Aberrations ◽  
De Novo Aml ◽  
Acute Myeloid

Somatic mutations in the DNA-binding domain, the socalled Runt homology domain, of the AML1/RUNX1 gene have been identified to occur in acute myeloid leukaemia (AML) with the highest incidence in AML M0, in therapy-related myelodysplastic syndrome (t-MDS), in therapy-related AML (t-AML) and AML after MDS (s-AML). Cytogenetic aberrations that are associated with RUNX1 mutations (RUNX1mut) have been reported to be trisomy 13 in AML and trisomy 21 in myeloid malignancies, but also loss of chromosome 7q, mainly in t-MDS but rarely in t-AML. So far the majority of RUNX1mut have been described in secondary or therapy-related cases. Thus, we characterized a cohort of 119 patients (pts) with de novo AML and compared these results to 19 MDS and s-AML, 2 t-MDS (n=2) and 8 t-AML. The cohort was selected for specific cytogenetics with high reported frequencies of RUNX1mut: trisomy 13 (n=17), trisomy 21 (n=9), −7/7q- (n=34). In addition pts with normal karyotype (NK) (n=42), inv(3)/t(3;3) (n=12), trisomy 8 (n=11), complex karyotype (n=13) and 10 pts with various other cytogenetic aberrations (other) were analyzed. The incidence of RUNX1mut in the different cytogenetic subgroups was: 94% (16/17) in +13, 56% (5/9) in +21, 29% (10/34) in −7/7q-, 10% (4/42) in NK, 17% (2/12) in inv(3)/t(3;3), 18% (2/11) in +8, 0% (0/13) in complex karyotype and 20% (2/10) in other, respectively. Based on clinical history we observed RUNX1 mutations in: 6/19 (32%) in MDS/s-AML, 1/10 (10%) in t-MDS/t-AML and 34/119 (29%) in de novo AML. Of the 6 RUNXmut cases with MDS/s-AML the karyotypes were heterogeneous NK (n=1), −7 (n=2) +13 (n=1), +21 (n=1), and inv(3) (n=1). The only recurrent cytogenetic aberration in MDS/s-AML was −7, thus the frequency of RUNXmut in the MDS/s-AML group with −7 was 2/8 (25%). Also the only RUNX1mut case with t-AML revealed a −7. These data correspond to those reported in the literature. We further focussed on the analyses of RUNX1 in de novo AML which is rarely reported so far. In the de novo AML group only we detected RUNX1mut with the highest frequency in +13 (16/16; 100%) followed by +21 (4/8; 50%) −7 (7/21; 33%), + 8 (2/10, 20%), inv(3) (1/8; 12.5%), and NK (3/33; 9.1%). In addition, in the group with “other” aberration 2/8 were mutated. Interestingly, these 2 mutated cases displayed a high number of trisomies including +8 and +13. No RUNX1mut were detected in AML with complex karyotype (n=10). These data for the first time show that RUNX1mut are not strongly correlated to MDS, s-AML or t-AML. With almost the same frequency they can be observed in de novo AML if specific cytogenetic groups are considered. Thus the RUNXmut seem to be more related to these cytogenetic subgroups than to the MDS, s-AML or t-AML.

Cytogenetic Diagnostics and Outcome in a Series of Thirty Three Greek Pediatric Acute Myeloid Leukemia Patients

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4889-4889
Author(s):  
Kalliopi N Manola ◽  
Agapi Parcharidou ◽  
Vassilios Papadakis ◽  
Maria Kalntremtziou ◽  
Chryssa Stavropoulou ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Bone Marrow Cells ◽  
Normal Karyotype ◽  
Acute Leukemias ◽  
Early Treatment Response ◽  
Pediatric Aml ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) accounting for approximately 17% of all childhood acute leukemias, arises either de novo or from a backround of myelodysplasia or previous chemotherapy. Cytogenetics is considered one of the most valuable prognostic determinants in AML while current risk–group classification in the limited cases of pediatric AML, is mainly based on cytogenetics and early treatment response. We reviewed the clinical and cytogenetic characteristics and the outcomes of 33 cases of childhood AML between 1997 and 2007 in order to investigate the incidence of the main FAB subtypes, the incidence of primary AML compared to secondary AML (s-AML) and the correlation between specific chromosome abnormalities and outcome in greek pediatric AML patients. Chromosome studies were performed on unstimulated bone marrow cells, derived from 33 pediatric AML patients, who were <18 years of age at the time of diagnosis. Eighteen patients were male and 15 were female. According to FAB classification one patient was classified as M0 (3%), 13 patients as M2 (39.4%), 4 as M3 (12.12%), 4 as M5 (12.12%), 2 as M6 (6.1%) and 4 as M7 (12.12%). No patient was classified as M4 while 5 patients with s-AML (15.15%) could not be classified. The median follow-up of all patients was 57.95 months (0.03–132.47). Overal survival and event free survival were 66,7% and 75,8% respectively. Eight patients with s-AML and 25 patients with primary AML were identified. The median age of patients with s-AML at diagnosis was 9.15 years while the median age of patients with primary AML was 7.2 years. Six out of 8 patients with s-AML died at a median follow up of 11.03 months. Nineteen out of 25 patients with primary AML are alive in complete remission (CR). Cytogenetic analysis was performed at diagnosis in 32 patients and results were obtained in 30 of them. The karyotype was abnormal in 21 out of 30 patients (70%). Normal karyotype was found in 9 patients, t(8;21)(q22;q22) in 5, t(15;17)(q22;q21) in 3, t(9;11)(p22;q23) in 3, −7/del(7q) in 5, del(9q) in 3, and complex karyotype in 4 patients. Three out of 4 patients with M3 are alive in CR with a median follow-up of 98.6 months while one with s-AML-M3 died 13 days post diagnosis. Three out of five patients with M2 and t(8;21), including 1 patient with s-AML, died at a median follow-up of 4.35 months. Three out of 5 patients with −7/del(7q) had s-AML and died in less than 4 years, while the two others are alive for more than 5 years, in CR. Although all patients with M7 had complex karyotypes, they are alive after a median follow-up of 96.73 months, 3 of them in CR and 1 in relapse. These results indicate that in greek patients, the main FAB subtypes show a distribution similar to that reported in the literature with the exception of M4 which is absent in our study but with a reported incidence of 20%. Pediatric patients with s-AML are older and their outcome is poor and is related to a higher probability of poor cytogenetic features compared to primary AML patients. Interestingly all patients with M7 had a good clinical course although they exhibited complex karyotypes.

scholarly journals Clinical, morphologic, and cytogenetic characteristics of 26 patients with acute erythroblastic leukemia

Blood ◽  
1992 ◽  
Vol 80 (11) ◽  
pp. 2873-2882
Author(s):  
OI Olopade ◽  
M Thangavelu ◽  
RA Larson ◽  
R Mick ◽  
A Kowal-Vern ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
De Novo ◽  
Chromosomal Abnormalities ◽  
Normal Karyotype ◽  
Intensive Chemotherapy ◽  
Trisomy 8 ◽  
Cytogenetic Abnormalities ◽  
Favorable Prognosis ◽  
Multiple Abnormalities ◽  
French American British

We have performed a retrospective analysis of the clinical, morphologic, and cytogenetic findings in 26 patients diagnosed between January 1969 and September 1991 with acute erythroblastic leukemia de novo (EL or AML-M6). Clonal chromosomal abnormalities were found in 20 (77%) patients (95% confidence interval [CI], 61% to 93%). Loss of all or part of the long arm (q) of chromosomes 5 and/or 7 was observed in 17 (65%) patients (95% CI, 47% to 83%). In addition, the karyotypes were often complex, with multiple abnormalities and subclones. Among the remaining nine patients, six had a normal karyotype and one each had trisomy 8, t(3;3), or t(3;5). The overall frequency of abnormalities of chromosomes 5 and/or 7 observed in our M6 patients is similar to that observed in our patients with therapy-related acute myeloid leukemia (t-AML; 99 of 129 patients, 77%), but substantially higher than that noted in our other patients with AML de novo (French- American-British [FAB] subtypes M1-M5: 52 of 334 patients, 16%). Our M6 patients with abnormalities of chromosomes 5 and/or 7 were older and had a shorter median survival (16 v 77 weeks [P = .005]) than did the M6 patients without these abnormalities. We found no correlation between morphologic features and either cytogenetic abnormalities or clinical outcome. Of note was the finding that the percentage of myeloblasts, which may account for only a small fraction of the total marrow elements when the revised FAB criteria are applied, had no bearing on prognosis. We conclude that acute erythroblastic leukemia, when defined by morphologic criteria, consists of two distinctive subgroups: one group tends to be older, has complex cytogenetic abnormalities, especially of chromosomes 5 and/or 7, and shares biologic and clinical features with t-AML; the other group, with simple or no detectable cytogenetic abnormalities, has a more favorable prognosis when treated with intensive chemotherapy.

scholarly journals Transcriptome Analysis Revealed the Entire Genetic Understanding of Pediatric Acute Myeloid Leukemia with a Normal Karyotype

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2850-2850
Author(s):  
Norio Shiba ◽  
Kenichi Yoshida ◽  
Yuichi Shiraishi ◽  
Shiraishi Yuichi ◽  
Yusuke Hara ◽  
...  
Keyword(s):  
Rna Sequencing ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Normal Karyotype ◽  
Gene Rearrangements ◽  
Pediatric Leukemia ◽  
Pediatric Acute Myeloid Leukemia ◽  
Recurrent Mutations ◽  
Pediatric Aml ◽  
Acute Myeloid

Abstract Background: Pediatric acute myeloid leukemia (AML) comprises approximately 20% of pediatric leukemia, representing one of the major therapeutic challenges in pediatric oncology with a current overall survival rate of less than 70%. The pathogenesis of AML is heterogeneous and can be caused by various chromosomal aberrations, gene mutations/epigenetic modifications, and deregulated/overregulated gene expressions, leading to increased proliferation and decreased hematopoietic progenitor cell differentiation. Recurrent chromosomal structural aberrations [e.g., t(8;21), inv(16), and MLL-rearrangements] have been well established as diagnostic and prognostic markers of AML. Furthermore, recurrent mutations in FLT3, KIT, NPM1, and CEBPA have been reported in both adult and pediatric AML. Recently, massively parallel sequencing enabled the discovery of recurrent mutations in DNMT3A, TET2, and IDH, which are clinically useful for the prediction of the prognosis. However, these mutations are rare in pediatric AML, suggesting that other genetic alterations exist in pediatric AML. In contrast, recent reports have described NUP98-NSD1 fusion as an adverse AML prognostic marker and PRDM16 (also known as MEL1) as the representative overexpressed gene in patients harboring NUP98-NSD1 fusion. Intriguingly, PRDM16 overexpression occurs in nearly one-quarter of all children, with AML involving NUP98-NSD1-negative patients. Moreover, this overexpression is enriched in specimens with other high-risk lesions (e.g., FLT3-ITD, NUP98-NSD1, and MLL-PTD). Patients and Methods: To reveal a complete registry of gene rearrangements and other genetic lesions in pediatric AML with a normal karyotype, we performed transcriptome analysis (RNA sequencing) of 61 of 70 de novo pediatric AML patients with a normal karyotype using Illumina HiSeq 2000. We could not perform RNA sequencing in nine patients because of a lack of RNA quantity or quality. Among the 70 AML patients with a normal karyotype, 33 patients overexpressed PRDM16, which was found to be strongly associated with a poor prognosis in our previous studies. All patients were enrolled and treated with AML-05 in the study conducted by the Japan Pediatric Leukemia/Lymphoma Study Group (JPLSG). We also analyzed the known genetic mutations associated with these patients using the data derived from RNA sequencing. Results: A total of 144 candidate gene rearrangements, which were not observed in normal samples, were identified in 51 of 61 samples. Many of the recurrent gene rearrangements identified in this study involved previously reported targets in AML, including NUP98-NSD1, NUP98-JARID1A, CBFA2T3-GLIS2, MLL-MLLT10, and MLL-MLLT3. However, several gene rearrangements were newly identified in the current study, including MLL-SEPT6, HOXA10-HOXA-AS3, PRDM16-SKI, and CUL1-EZH2. We have also performed the validation of these novel gene rearrangements using Sanger sequencing. Most of these gene rearrangements were found in patients with a high expressionof PRDM16. In contrast, CEBPA mutations were frequently observed in patients with a low expression of PRDM16. Known gene alterations, such as FLT3-ITD and MLL-PTD, and mutations of the RAS, KIT, CEBPA, WT1, and NPM1genes were also detected using RNA sequencing. Conclusion: RNA sequencing unmasked a complexity of gene rearrangements and mutations in pediatric AML genomes. Our results indicate that a subset of pediatric AML represents a discrete entity that could be discriminated from adult counterparts, regarding the spectrum of gene rearrangements and mutations. In the present study, we identified at least one potential gene rearrangement or driver mutation in nearly all AML samples, including some novel fusion genes. These findings suggest that gene rearrangements in conjunction with mutations also play essential roles in pediatric AML. Disclosures Ogawa: Kan research institute: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy, Research Funding; Sumitomo Dainippon Pharma: Research Funding.

Treatment of Elderly Acute Myeloid Leukemia (AML) Patients with the Combination of Mitoxantrone and Cytarabine (MAC).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4624-4624
Author(s):  
Theodoros Marinakis ◽  
Athanasios G. Galanopoulos ◽  
Athanasios Zomas ◽  
Euridiki Michalis ◽  
George Gortzolidis ◽  
...  
Keyword(s):  
De Novo ◽  
Normal Karyotype ◽  
Blood Dyscrasia ◽  
Trisomy 8 ◽  
Total Response Rate ◽  
Elderly Aml ◽  
Resistant Patient ◽  
De Novo Aml ◽  
Clinical Dilemma ◽  
Improvement In Survival

Abstract The value and exact type of intensive chemotherapy of unselected elderly AML patients in terms of overall survival (OS) and quality of life remains controversial. The lack of large randomized trials comparing intensive to low dose treatment or to just supportive care as well as the selection bias observed in smaller studies in AML patients over 60 years contribute significantly to the clinical dilemma. Despite recent improvements in supportive measures during cytotoxic therapy, elderly AML patients continue to exhibit lower remission rates, higher toxicity, more relapses and eventually a worse survival. The present analysis evaluates in a retrospective manner the outcome of 39 homogeneously treated AML patients >60yrs during a period of 44 months (Nov 2001 to Aug 2005). The protocol schedule included an initial course of mitoxantrone + cytarabine 3+5 (12mg/m2/d and 100mg/m2 q12h respectively) followed by a second abbreviated course of mitoxantrone + cytarabine 2+5, followed by a final course of idarubicin + cytarabine + thioguanine 2+7+7 (10mg/m2/d, 100mg/m2 q12h and 100mg/m2/d respectively). G-CSF at 5μg/Kg was added to all courses to accelerate hematopoietic recovery. Our patient population consisted of 22 cases of de novo AML and 17 cases of secondary AML (MDS 16, NHL 1) classified according to FAB as follows: M0 (5), M1 (4), M2 (19), M4 (3), M5 (2), M6 (5), hybrid-leukemia (1). Their median age was 70 yrs (range 63–80 yrs) and M/F ratio was 27/12. Cytogenetic analysis was performed in 33/39 cases: 6/33 cases failed to produce metaphases, 20/33 cases revealed standard risk abnormalities (seventeen normal karyotype, three trisomy 8) and 7/33 cases had poor risk abnormalities by MRC cytogenetic criteria. Leukocytosis >50X109/L was noted in 6/39 and leukopenia<5X109/L was noted in 19/39 patients. After a median observation period of 9 months (range 1–40) the following results are available: 19/39 (48,7%) patients entered CR (13 de novo, 7 secondary) post-course 2 and their median OS is 15,5 months (range 2–40). An additional 6/39 (15,3%) cases returned to a myelodysplastic phase without excess of blasts achieving thus partial hematological remission. The remaining 14/39 (35,8%) patients proved primary resistant and deceased after a median of 2,5 months (range 1–20) with one resistant patient surviving 20 months with on-going disease. Within the group of remitters 3/19 deceased from complications (MI, fungal infection, sepsis) before the next chemotherapy course. The remaining 11/19 remitters relapsed after a median of 7,5 months (range 1–30); nine of them deceased and two are alive as a result of salvage treatment. Finally 5/19 cases remain alive and disease-free (two interrupted after the second course). Conclusion: Combination chemotherapy with mitoxantrone and cytarabine is well-tolerated and reasonably effective in elderly AML patients fit enough to undergo chemotherapy regardless of karyotype and antecedent blood dyscrasia. With a total response rate of 64% (CR+PR) and an induction death rate of 5,1% (2/39), the current schedule deserves further evaluation in a larger AML population. Furthermore, our data validate the improvement in survival of those patients achieving CR as suggested by other studies.

Mitoxantrone and Cytarabine Combination in Untreated Elderly Patients with Acute Myeloid Leukemia (AML): A Retrospective Single-Centre Analysis.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4372-4372
Author(s):  
Theodore Marinakis ◽  
Vasilios Xanthopoulos ◽  
Athanasios Galanopoulos ◽  
Evrydiki Michalis ◽  
George Gortzolidis ◽  
...  
Keyword(s):  
De Novo ◽  
Normal Karyotype ◽  
Trisomy 8 ◽  
Total Response Rate ◽  
Elderly Aml ◽  
De Novo Aml ◽  
Improvement In Survival ◽  
Standard Risk

Abstract The value and exact type of intensive chemotherapy of unselected elderly AML patients in terms of overall survival (OS) and quality of life remains controversial. Despite recent improvements in supportive measures during cytotoxic therapy, elderly AML patients continue to exhibit lower remission rates, higher toxicity, more relapses and eventually a worse survival. The present analysis evaluates in a retrospective manner the outcome of 57 homogeneously treated AML patients >60yrs during a period of 70 months (Nov 2001 to Aug 2007). The protocol schedule included an initial course of mitoxantrone+ cytarabine 3+5 (12mg/m2/d and 100mg/m2 q12h respectively) followed by a second abbreviated course of mitoxantrone+ cytarabine 2+5, followed by a final course of idarubicin+cytarabine+ thioguanine 2+7+7 (10mg/m2/d, 100mg/m2 q12h and 100mg/m2/d respectively). G-CSF at 5μg/Kg was added to all courses to accelerate hematopoietic recovery. Our patient population consisted of 30 cases of de novo AML and 27 cases of secondary AML (MDS 26, NHL 1) classified according to FAB as follows: M0 (6), M1 (7), M2 (25), M4 (7), M5 (4), M6 (6), hybrid-leukemia (2). Their median age was 70 yrs (range 63–80, mean 70,3 yrs) and M/F ratio was 35/22. Cytogenetic analysis was performed in 52/57 cases: 6/57 cases failed to produce metaphases, 32 cases revealed standard risk abnormalities (twenty six normal karyotype, six trisomy 8) and 7/52 cases had poor risk abnormalities. Leukocytosis >50X109/L was noted in 12/57 and leukopenia<5X109/L was noted in 22/57 patients. After a median observation period of 9 months (range 1–70) the following results are available: 26/57(45,6%) patients entered CR (15 de novo, 11 secondary) post-course 2 and their median OS is 15 months (range 2–63). An additional 6/57(10,5%) cases returned to a myelodysplastic phase without excess of blasts achieving thus partial hematological remission. The remaining 25/57(43,8%) patients proved primary resistant and deceased after a median of 3 months (range 1–22). One resistant case survive in remission attained off protocol. Within the group of remitters 3/26 deceaced from complications (MI, fungal infection, sepsis) before the next chemotherapy course. The remaining 16/26 remitters relapsed after a median of 8 months (range 1–12,5); fourteen of them deceaced and two are alive for 63 and 16 months respectively (one as a result of salvage treatment and the other with on going disease). Finally 7/26 cases remain alive and disease-free. Due to the short follow up, median OS for the whole cohort was estimated to date at 7,5 months. Conclusion: Combination chemotherapy with mitoxantrone and cytarabine is well-tolerated and reasonably effective in elderly AML patients. With a total response rate of 56,1% (CR+PR) and an induction death rate of 3,4%(2/57), the current schedule deserves further evaluation in a larger AML population. Furthermore, our data validate the improvement in survival of those patients achieving CR as suggested by other studies.

FLT3, NPM1 and MLL Mutations Help Risk Stratification in Pediatric Acute Myeloid Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1574-1574
Author(s):  
Shuhong Shen ◽  
Yin Liu ◽  
JingYan Tang ◽  
Long-Jun Gu
Keyword(s):  
Acute Myeloid Leukemia ◽  
Risk Stratification ◽  
Myeloid Leukemia ◽  
Tandem Duplication ◽  
De Novo ◽  
Genetic Alterations ◽  
Npm1 Mutation ◽  
De Novo Aml ◽  
Pediatric Aml ◽  
Acute Myeloid

Abstract Abstract 1574 Poster Board I-600 Introduction Acute myeloid leukemia (AML) is a heterogeneous disease which harbors various genetic alterations. Among theses genetic events, Mutations of FLT3, NPM1, MLL and other genes often predict prognosis, particularly in cases cytogenetic normal (CN-AML). Could these be criteria for risk stratification in Pediatric AML ? Patients and Methods 155 cases of de novo AML were diagnosed routinely according to morphology, immunology, cytogenetics, and molecular biology examination on bone marrow (BM) aspirates between Jan. 2002 and Dec. 2008. All patients received chemotherapy according to the AML-XH-99 protocol, which consist of Daunorubicin, Cytosine arabinoside, Etoposide, Homoharringtonine. For acute promyelocytic leukemia, all-trans retinoic acid and Arsenic trioxide were also included. Meanwhile, total RNA of leukemic cells form all diagnostic BM samples were extracted, and then reverse transcribed. MLL partial tandem duplication (MLL/PTD) fusion transcripts were screened by real-time quantitative polymerase chain reaction. FLT3 internal tandem duplication (FLT3/ITD), FLT3 tyrosine kinase domain mutation (FLT3/TKD) and NPM1 mutation were examined by High resolution melting analysis. Results Of the 155 children with de novo AML, 121(78.1%) had received chemotherapy for more than one week with data available for analysis. Among them, 55(45.5%) was cytogenetically normal (CN-AML). In this total cohort of patients 49(27.09%) had FLT3/ITD (32.70% in CN-AML), 14 (9.03%) had FLT3/TKD (7.30% in CN-AML), 62 (40%) had NPM1 mutation (49% in CN-AML), and additional 8 (5.16%) had MLL/PTD (5.50% in CN-AML). In this cohort of patients 98 (63.22%) had at least one mutation. The clinical outcomes were listed in table 1. Generally, patients with FLT3 mutation (ITD or TKD mutation) usually have worse results after chemotherapy, as reported previously by other researchers. Meanwhile, NPM1 mutations usually predict better prognosis in our cohort of AML patients. MLL/PTD always predicts the worst outcome in AML as other MLL rearrangements in leukemia. Among CN-AML patients, 5-year EFS and OS were similar to whole cohort of patients according to those mutations. Cox regression analysis in a univariate model revealed that the presence of FLT3/ITD and NPM1 was significant prognostic factor of EFS, (P<0.05). We therefore proposed a molecular-risk classification of pediatric AML patients based on the data we got in this study. For the newly classified groups of low, medium and high risk groups, EFS rate was 62.03%±8.42%, 45.42%±4.52%, and 14.85%±2.99%, respectively, P=0.00. CRD for the 3 groups was 27.69±21.34 months, 22.62±19.64 months, 13.26±11.95 months, respectively, p=.022. Our results indicate that combinations of these couple of molecular events may be the useful tool for further classify AML in children. Disclosures No relevant conflicts of interest to declare.

IDH1 and IDH2 Mutations in Therapy-Related Acute Myeloid Leukemia Are Associated with a Normal Karyotype or Der(1;7)(q10;p10) Combined with RUNX1 Mutations,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3514-3514
Author(s):  
Maj K. Westman ◽  
Morten T. Andersen ◽  
Jens Pedersen-Bjergaard ◽  
Mette K. Andersen
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Normal Karyotype ◽  
Chromosome 7 ◽  
Previous Therapy ◽  
Idh Mutations ◽  
Idh1 And Idh2 Mutations ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Abstract 3514 Isocitrate dehydrogenase (IDH) is a metabolic enzyme that catalyzes a reaction in the tricarboxylic acid cycle. Gain of function mutations in the IDH1/2 genes have been reported in different malignancies and are observed in 15–30% of de novo AML with association to a normal karyotype and to NPM1 mutations. The exact role of IDH1/2 mutations in leukemogenesis remains to be determined. IDH mutations have not previously been studied in a cohort of therapy-related myelodysplasia (t-MDS) and therapy-related acute myeloid leukemia (t-AML). To evaluate the frequency of IDH1/2 mutations in t-MDS and t-AML, and their possible association to type of previous therapy and to other genetic abnormalities, DNA from 140 well-characterized patients with t-MDS (n=89) and t-AML (n=51) were analyzed with high-resolution melting followed by sequencing. All patients have previously been examined cytogenetically and investigated for mutations in 12 other genes: FLT3(ITD, TKD), KIT, JAK2, KRAS, NRAS, BRAF, PTPN11, RUNX1, MLL(ITD), CEBPA, NPM1, and TP53. In total, IDH mutations were detected in 12 of 140 patients (9%). 3 patients had a mutation in IDH1 and 9 patients had a mutation in IDH2 (Table 1), all mutations previously reported in de novo AML. No patients had concurrent IDH1 and IDH2 mutations. IDH mutations were not related to previous therapy with alkylating agents, topoisomerase II inhibitors or radiotherapy, but were significantly associated with other types of therapy not firmly established to be leukemogenic (p=0.004). The latency period to development of t-MDS/t-AML was not different between IDH1/2 positive (+) cases and cases with IDH (wt) (64 and 48 months, respectively, p=0.118). 4/5 cases with t-MDS and IDH+ progressed to AML compared to 27/84 t-MDS cases with IDHwt (p=0.048).Table 1:Characteristics of 12 patients with t-MDS/t-AML and mutations in IDH1/2CaseAge/sext-AML/t-MDSPrevious therapyKaryotypeOther mutationsIDH Mutation1974/FAMLAlk45,XX,-7/48,XX,der(1;7)(q10;p10),+11, +13/46,XX–IDH1 R132G2963/FAMLRT46, XXNPM1 FLT3-ITDIDH1 R132G3663/FAMLAlk46,XX,+2,+8/47,XX,der(6)t(1;6) (q?25;p21),+8N-RASIDH2 R172K4472/MMDSAlk46,XY,+1,der(1;7)(q10;p10)/46,XY–IDH2 R140Q5562/FMDS→AMLRT46, XXRUNX1IDH2 R140L7272/FMDS→AMLAlk, T II, RT46,XX,+1,der(1;7)(q10;p10)/50,XX,idem, +8,+9,14+21RUNX1IDH2 R140Q8178/MMDS→AMLAlk46,XY,der(17)t(11;17)(q13;p13),i(13) (q10)/47,idem,+der(13)t(11;13) (q13;p11)IDH2 R172K10443/FMDS→AMLAlk47,XX,+1,der(1;7)(q10;p10),+8RUNX1IDH1 R132C10944/FAMLMtx, Aza46, XXIDH2 R140Q11952/FAMLAlk, T II, RT46, XXNPM1IDH2 R140Q13325/MAMLVCR, MTX, Asp,6-MP46, XXIDH2 R140Q18060/MMDS→AMLMtx46, XXMLL-ITDIDH2 R140Q6-MP, 6 mercaptopurine; Alk, alkylating agent; Asp, l-asparaginase; Aza, azathioprine; Mtx, methotrexate; RT, radiotherapy, T II, topoisomerase inhibitor, VCR, vincristine. IDH mutations were significantly associated with a normal karyotype (6/12 cases with IDH+ vs. 18/128 with IDHwt, p=0.006) and der(1;7)(q10;p10) resulting in trisomi 1q and loss of 7q (4/12 cases with IDH+ vs. 7/128 with IDHwt, p=0.008), but was inversely correlated to other chromosome 7 abnormalities (1/12 cases with IDH+ vs. 54/128 with IDHwt, p=0.03). No patient with mutated IDH had chromosome 5 abnormalities, TP53 mutations or recurrent balanced translocations. 7/12 patients with mutated IDH1/2 had other gene mutations characteristic of AML (Table 1). The frequency of each of these other mutations were not different from patients with wildtype IDH1/2 (RUNX1, p=0.4; NPM1, p=0.2; FLT3, p=1.0; MLL, p=0.165; N-RAS, p=1.0). In conclusion, mutations of IDH1/2 were observed in 9% of patients with t-MDS/t-AML. They were not related to any specific type of therapy but perhaps associated with transformation from MDS to AML. IDH mutations clustered in the genetic pathway characterized by a normal karyotype and mutations of NPM1, and the pathway characterized by 7q−/−7 and RUNX1 point mutations. The significant association observed between IDH1/2 mutations and der(1;7)(q10;p10) may indicate that this cytogenetic aberration represents a specific entity, biologically distinct from other chromosome 7 abnormalities. This is also supported by the different clinical outcome between cases with der(1;7) and other cases with -7/7q- (Sanada et al, Leukemia 2007). Disclosures: No relevant conflicts of interest to declare.

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