Genome-Wide Genotype-Based Risk Model for Survival in Acute Myeloid Leukemia Patients with Normal Karyotype.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2526-2526
Author(s):  
Hyeoung-Joon Kim ◽  
Hangseok Choi ◽  
Yeo-Kyeoung Kim ◽  
Sang Kyun Sohn ◽  
Joon Ho Moon ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Risk Model ◽  
Conflicts Of Interest ◽  
Snp Array ◽  
Normal Karyotype ◽  
P Value ◽  
Genome Wide ◽  
Acute Myeloid

Abstract Abstract 2526 Introduction: Single nucleotide polymorphism (SNP) is an inter-individual genetic variation which could explain inter-individual differences of response/survival to chemotherapy. The present study was attempted to build up risk model of survival for acute myeloid leukemia (AML) patients with normal karyotype (AML-NK). Methods and materials: A total of 247 patients with AML-NK was included into the study. Genome-wide SNP array (Affymetrix SNP-array 6.0) was performed in the discovery set (n=118), and genotypes were analyzed for overall survival (OS). After identifying significant SNPs for OS in single SNP analyses, risk model was constructed. Replication was performed in an independent validation cohort (n=129). Results: Out of 632,957 autosomal SNPs meeting genotype data filtration criteria, a total of 82 SNPs were selected and passed into the next step of validation in an independent cohort. In the risk model generation step, finally 4 SNPs (rs2826063, rs12791420, rs11623492 and rs2575369) were meeting stringent criteria for SNP selection as follows: 1) p-value < 0.10 from Cox proportional hazards regression model in adjustment with age and WBC counts at diagnosis; 2) minor allele frequency > 0.05; 3) call rate > 95.0%; 4) high linkage disequilibrium r2 < 0.8. These 4 SNPs were introduced into the risk model, and patients was grouped into 2 groups according to the number of deleterious variables including 4 SNPs and 2 clinical variables (i.e. age and WBC counts at presentation): risk score 0–2 as a low risk (n=80) and 3–6 as a high risk (n=38). The risk model could stratify the patients according to their OS in discovery (p=1.053656•10−4) and in validation set (p=5.38206•10−3). The risk model showed a higher AUC than those being incorporated only clinical or only 4 SNPs, suggesting improved prognostic stratification power of combined model. Conclusion: Genome-wide SNP based risk model obtained from 247 patients with AML-NK can identify high risk group of patients with poor survival using genome wide SNP data. (Clinicaltrials.govIdentifier:NCT01066338) Disclosures: No relevant conflicts of interest to declare.

Genome-Wide Micro-Deletions and Amplifications Acquired at Relapse in Acute Myeloid Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 166-166 ◽  
Author(s):  
Manoj Raghavan ◽  
Manu Gupta ◽  
Tracy Chaplin ◽  
Sabah Khalid ◽  
T. Andrew Lister ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Copy Number ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Snp Array ◽  
Uniparental Disomy ◽  
Normal Karyotype ◽  
P Value ◽  
Copy Number Changes ◽  
Acute Myeloid

Abstract Abstract 166 Recurrence of acute myeloid leukemia AML has a poor prognosis with only 20% of adults surviving to 5 years. Therefore it is of importance to identify molecular changes that explain the pathogenesis of relapsed AML. Previous studies had not identified consistently acquired cytogenetic changes at relapse. Recently, acquired uniparental disomy due to mitotic recombination was described in 40% of relapsed AML (Raghavan et al 2008). Most of the events lead to homozygosity for FLT3 mutations. This study aimed to discover if there are further genetic abnormalities acquired at disease recurrence that cannot be identified by conventional cytogenetics, i.e. microdeletions or gains. Twenty-one presentation and relapse paired AML patient blood and marrow samples were stored with consent at St Bartholomew's Hospital, London. Eleven patient samples had a normal karyotype at diagnosis, two had favourable prognosis cytogenetics (inv(16) and t(8;21)) and others had varying numerical cytogenetic abnormalities and rearrangements associated with an intermediate prognosis. DNA from the samples was analysed by array based high-resolution single nucleotide polymorphism (SNP) genotyping (Affymetrix Human SNP array 6.0). Data was analysed using Partek Genome Browser (Partek, MO). In all cases, the leukemia infiltrate of the marrow or blood was greater than 60% and most cases were greater than 90% allowing accurate identification of DNA copy number changes. Abnormalities of a size that would be identified by cytogenetics were disregarded. Using segmentation analysis using a p-value less than 0.001, over 400 microdeletions and gains were detected that were acquired at relapse in the 21 pairs. Each of the copy number changes was less than 2 megabases in size. One AML sample with a normal karyotype at diagnosis and trisomy 8 and add(9)(q34) at relapse had not acquired any microdeletions or gains. In contrast, in other samples as many as 69 microdeletions/gains were detected. There was no correlation between increased complexity of the karyotype of the leukemia and the number of microdeletions/gains. Several of the acquired microdeletions/gains were in regions containing genes known to be involved in AML, including a deletion of 234Kb at 13q12.2 involving FLT3 and CDX2, and an acquired deletion at 21p11.2 of 150Kb involving exons encoding the runt domain of RUNX1. Another copy number gain was detected at the MLL locus, suggestive of partial tandem duplication. Other detected locations are in Table 1.Table 1Location by cytobandCopy number changeSize / KbP valueGene13q12.2Deletion23410−33FLT3, CDX221q22.12Deletion15010−13RUNX111q23.3Gain5.10.0099MLL11p15.4Gain830.00001NUP9817q21.31Deletion8.00.0007BRCA1The results indicate that recurrent AML may be associated with the deletion or gain of several genes involved in leukaemogenesis. Many other locations are involved throughout the genome, suggesting at least some of these are also involved in the clonal evolution of the leukaemia at recurrence. Further studies should identify novel genes from these regions involved in the pathogenesis of AML. Disclosures: No relevant conflicts of interest to declare.

Selective and Titratable Effects On AML Genome Wide Methylation Patterning, Transcription and Clonogenicity Using Very Low Concentrations of 5-Aza-2'deoxycytidine.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2385-2385
Author(s):  
Elisabeth Heuston ◽  
Jason E. Farrar ◽  
Timothy Triche ◽  
Jonathan Buckley ◽  
Poul Sorensen ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Cellular Reprogramming ◽  
Transcription Profiles ◽  
Genome Wide ◽  
Low Concentrations ◽  
Xenograft Models ◽  
Methylation Patterns ◽  
Acute Myeloid

Abstract Abstract 2385 Poster Board II-362 5-Aza-2'deoxycytidine (5AzadC) has significantly contributed to the treatment of myelodysplatic syndromes (MDS) and acute myeloid leukemia (AML). But while the cytotoxic effects of 5AzadC have been well characterized, its influence on methylation-induced cellular reprogramming remains poorly understood. We have treated several AML cell lines at extremely low concentrations of 5AzadC (0 nM to 1.0 nM) over the course of three days, followed by the determination of genome wide methylation changes, alterations in transcription profiles as well as cell viability, proliferation, apoptosis and changes in clonogenicity. The results demonstrate titratable responses on both genomic methylation and transcriptional patterns as well as a selective effect on clonogenicity compared to cytotoxicity. An alternative chemotherapeutic cytosine analog, cytosine arabinofuranoside (AraC), does not show the same selective depletion of clonogenic cells, suggesting that 5AzadC's effects are likely due to altered epigenetic changes associated with cellular reprogramming rather than a direct cytotoxic effect. We are currently evaluating 5AzadC and AraC effects on this population using immunophenotyping methods as well as xenograft models of tumorigenicity. These findings describe a potential role for very low concentrations of 5AzadC in treating acute myeloid leukemia through a selective affect on genome wide methylation patterns leading to altered transcription that differentially effects the clonogenic, leukemic stem cell compartment. Disclosures: No relevant conflicts of interest to declare.

Patterns of Infection in Patients with Myeloid Malignancies Receiving 5-Azacytidine: identification of Candidates for Antifungal Prophylaxis

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4955-4955
Author(s):  
Cristina Calderón ◽  
Jose F Falantes ◽  
Francisco Márquez-Malaver ◽  
Jose González ◽  
Maria Luz Martino ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myelodysplastic Syndrome ◽  
Fungal Infection ◽  
Myeloid Leukemia ◽  
Hospital Admissions ◽  
Conflicts Of Interest ◽  
Infectious Complications ◽  
Febrile Episodes ◽  
Acute Myeloid

Abstract Abstract 4955 Introduction Infectious complications are among the most recurrent causes of mortality in patients (pts) with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) undergoing intensive chemotherapy (IC). These pts routinely receive anti-infective prophylaxis (AIP) with flourquinolones and antifungals. 5-azacytidine has recently been incorporated to treatment options for AML and MDS. However, the evidence of the effectiveness of AIP in patients treated with 5 azacytidine (AZA) is limited [1–3]. Objectives To analyze the incidence of episodes of infectious fever (IF), type of microbiological isolation and clinical relevance of infectious complications in AML and MDS pts treated with AZA who did not received prophylaxis. Identification a subgroup of pts who may benefit from AIP in this setting. Material/methods We retrospectively analyzed 48 pts with AML and MDS who received AZA from 2008, with a total of 365 cycles administered. Median age was 68 years (29–83y). Distribution: LMA (n=17) and MDS (n=31). One third of these pts had an absolute neutrophil count (ANC)<0. 5×10e9/L at time of starting AZA. Another 33% of pts had received prior IC, being all refractory to previous treatment. Baseline characteristics in table 1. Results Forty-eight febrile episodes were recorded (13% of IF/cycles of AZA). There was no difference in IF in pts with ANC<0. 5×109/L vs ANC>0. 5×10e9/L (p=0. 53). A total of 17 pts suffered at least one episode of IF (35% of the pts). Hospital admission was required in 14 of these 17 pts with a median time of hospitalization of 14 days (4–80). Mortality attributed to infectious complications ocurred only in 3/48 pts (6%). Twelve microbiological isolations were documented, the most common being: Gram negative bacilli (E Coli=4) and aspergillus reported as probable (n=4) and shown in table 1. Upon comparing pts who received prior IC (n=16; 33%) vs AZA as first line treatment, a higher risk for IF per cycle was observed in first group (18% vs 11. 5%; p=0. 06). Double of these pts developed fever (56% vs 25%; p=0. 03), required more hospital admissions (44% vs 22%; p=0. 21) and had longer duration of hospital stay (22 vs 14 days; p=0. 71). Finally, the group of patients that underwent previous IC, had higher rate of fungal infection by aspergillus and candida (5/9 isolations; 55% vs 0/5; 0%. P <0. 001), although no difference was observed in terms of mortality attributed to infection (6% each group) because of the reduced number of pts who died of this complication overall (3/48). Conclusions To our knowledge, this is the first study to evaluate the frequency and impact of IF in pts treated with AZA not receiving routinely AIP. Overall, the incidence of IF is lower than the reported in similar series. These results allow to identify pts that previously were treated with IC as those at highest risk of fungal infection. Thus, prophylaxis should be considered in this group. Prospective studies are needed to assess the requierement of prophylaxis during treatment with 5 azacytidine. Jain N et al. Benefit of Anti-infectious Prophylaxis in Patients with Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome receiving Frontline “Targeted Therapy”. Blood (ASH) 2007, 110:Abstract 2858 Je-Hwan Lee et al. Decreased incidence of febrile episodes with antibiotic prophylaxis in the treatment of decitabine for myelodysplastic syndrome. Leuk Res 35 (2011):499–503 Merkel D et al. Predictive Parameters for Infections During Azacitidine Therapy in High Risk MDS Patients. Blood (ASH) 2011, 118:Abstract 3811 Disclosures: No relevant conflicts of interest to declare.

Interim results of protracted low doses of temozolomide in high-risk acute myeloid leukemia

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 7052-7052
Author(s):  
B. C. Medeiros ◽  
J. R. Gotlib ◽  
S. E. Coutre ◽  
C. Jones ◽  
S. A. Khan ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Elderly Patients ◽  
Promoter Methylation ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Normal Karyotype ◽  
Low Doses ◽  
Npm1 Mutation ◽  
Acute Myeloid

7052 Background: High treatment-related mortality and low response rates often discourage elderly patients with acute myeloid leukemia from receiving treatment. Previous data demonstrate that only patients lacking expression of O6-alkylguanine-DNA alkyltransferase (AGAT) in leukemic blasts are sensitive to temozolomide. Protracted exposure to low doses of temozolomide can significantly inhibit AGAT enzymatic activity. Methods: Phase II clinical trial of tailored temozolomide therapy to high-risk AML patients according to AGAT methylation promoter status. Patients demonstrating evidence of AGAT promoter methylation were stratified to conventional doses of temozolomide at 200 mg/m2 orally x 7 days. Patients demonstrating lack of AGAT promoter methylation (unmethylated) received protracted doses of temozolomide (100 mg/m2 orally x 14 days) followed by conventional doses of temozolomide. Patients who achieved CR were given up to 5 consolidation treatments. Results: Fifteen patients have completed treatment to date. The median age was 78 (68–83) and nine were male. De novo AML was diagnosed in eight patients and five patients had s-AML. Nine patients had a normal karyotype and three patients had a complex karyotype. Two patients had only a NPM1 mutation and one had NPM1mut/FLT3-ITD. In 13 patients, the AGAT promoter was found to be unmethylated. AGAT protein was present in 5/11 patients. All patients had an intact mismatch repair pathway. Thirteen patients had HCT-CI scores of 0–2. Six patients (6/13) achieved a complete remission (CR) after 1 cycle of therapy (1/2 for patients with methylated and 5/11 for patients with unmethylated AGAT promoter). Nonhematologic toxicities were minimal. Drug-related hematologic toxicities were difficult to distinguish from disease-related cytopenias. Three patients remain in CR with a median duration of 22 weeks (14–36 weeks). Seven patients have died from disease progression, while two patients died of neutropenic sepsis (early deaths). With a median follow-up of 38 weeks (10–48), the median overall survival for the entire population is 12 weeks (3.5 - 38) weeks (responders 26.5 weeks). Conclusions: These preliminary results suggest that temozolomide therapy may be individually tailored to elderly patients with AML according to AGAT promoter status. [Table: see text]

scholarly journals A Phase 2 Randomized Study of Low Dose Ara-C with or without Glasdegib (PF-04449913) in Untreated Patients with Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 99-99 ◽  
Author(s):  
Jorge E. Cortes ◽  
Florian H. Heidel ◽  
Michael Heuser ◽  
Walter Fiedler ◽  
B. Douglas Smith ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Low Dose ◽  
P Value ◽  
Employment Equity ◽  
Equity Ownership ◽  
Acute Myeloid

Abstract Background: The Hedgehog signaling pathway (HhP) is aberrantly activated in leukemias and myelodysplastic syndrome (MDS), promoting cancer stem cell maintenance. HhP inhibition reduces leukemic stem cells. Glasdegib is a potent, selective, oral HhP inhibitor, with activity in pre-clinical and clinical studies. The addition of glasdegib to standard chemotherapy (CT) has an acceptable safety profile and appears to have clinical activity in MDS and acute myeloid leukemia (AML). Methods: In this study (NCT01546038), previously untreated AML or high-risk MDS patients (pts) ineligible for intensive CT were randomized 2:1 to receive low-dose cytarabine (LDAC) 20 mg subcutaneously twice a day x 10 days q28 days + oral glasdegib 100 mg daily or LDAC alone for as long as pts received clinical benefit. The primary endpoint was overall survival (OS). The final analysis was conducted after completion of recruitment (Oct 2015) and at least 92 OS events. Results: As of Apr 2016, 132 pts (116 AML, 16 MDS) were randomized to LDAC + glasdegib (n = 88) or LDAC alone (n = 44) (stratified as good/intermediate [int.] vs poor risk) (Table). Demographic and baseline characteristics were similar between arms in median age, baseline cytogenetic risk, and diagnosis. Eighty-four pts received LDAC + glasdegib and 41 pts LDAC alone (7 randomized/not treated pts were followed for survival). Median treatment duration was 83 days for LDAC + glasdegib and 47 days for LDAC alone; median follow up was 14.3 months and 12.4 months, respectively. In the glasdegib arm, 12 pts were continuing treatment and 25 were in follow up; in the LDAC arm, 1 pt was on treatment and 5 in follow up. Cytopenias and gastrointestinal toxicities were the adverse events (AEs) occurring more frequently in the LDAC + glasdegib arm. Hh-associated AEs in the glasdegib arm included dysgeusia (23.8%), muscle spasms (20.2%) and alopecia (10.7%). Serious AEs of febrile neutropenia were more frequent in the glasdegib arm, but sepsis rates were lower and pneumonia rates were similar. The most common cause of death was disease progression in both arms. Grade 2-4 QTcF prolongation was more frequent in the LDAC arm. Investigator-reported complete response (CR) rates were numerically higher for LDAC + glasdegib (n = 17, 15%) vs LDAC alone (n = 1, 2.3%), p-value 0.0142. Based on intent to treat analysis of 96 events, median OS (mOS) for LDAC + glasdegib was 8.3 (80% confidence interval [CI] 6.9, 9.9) vs 4.9 months (80% CI 3.5, 6.0) for LDAC alone (HR 0.511, 80% CI 0.386, 0.675; one-sided log rank p-value 0.0020 stratified by cytogenetic risk). For good/int. risk, mOS for LDAC + glasdegib was 12.2 vs 6.0 months for LDAC alone (HR 0.464, p-value 0.0035). For poor risk, mOS for LDAC + glasdegib was 4.4 vs 2.3 months (HR 0.575, p-value 0.0422). In AML pts, mOS for LDAC + glasdegib was 8.3 vs 4.3 months for LDAC alone (HR 0.462, p-value 0.0004). Conclusions: The addition of glasdegib to LDAC for AML and high-risk MDS pts improved OS compared with LDAC alone. The improvement was consistent among subgroups, particularly in good/int. risk pts. Treatment was associated with an acceptable safety profile. The addition of glasdegib to LDAC may be a treatment option for pts with AML or high-risk MDS. Disclosures Cortes: ARIAD: Consultancy, Research Funding; Bristol-Myers Squib: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Heuser:Tetralogic: Research Funding; Celgene: Honoraria; Bayer Pharma AG: Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Research Funding; Karyopharm Therapeutics Inc: Research Funding; BerGenBio: Research Funding. Fiedler:Gilead: Other: Travel; Novartis: Consultancy; Ariad/Incyte: Consultancy; Teva: Other: Travel; Pfizer: Research Funding; Kolltan: Research Funding; Amgen: Consultancy, Other: Travel, Patents & Royalties, Research Funding; GSO: Other: Travel. Smith:Actinium Pharmaceuticals, Inc.: Research Funding. Robak:Pfizer: Research Funding. Montesinos Fernandez:Gamida Cell: Consultancy. Ma:Pfizer: Employment, Equity Ownership. Shaik:Pfizer: Employment, Equity Ownership. Zeremski:Pfizer: Employment, Equity Ownership. O'Connell:Pfizer: Employment, Equity Ownership. Chan:Pfizer: Employment, Equity Ownership.

Loss of Heterozygosity Identified in Acute Myeloid Leukemia with Normal Karyotype Using SNP Microarrays.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 760-760
Author(s):  
Christine Steudel ◽  
Sofia Traikov ◽  
Uta Oelschlägel ◽  
Markus Schaich ◽  
Gerhard Ehninger ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
Loss Of Heterozygosity ◽  
Myeloid Leukemia ◽  
Normal Karyotype ◽  
Snp Analysis ◽  
Genome Wide Analysis ◽  
Genome Wide ◽  
Free Material ◽  
Acute Myeloid

Abstract Loss of heterozygosity (LOH) is detectable in many forms of cancer including leukemia and contributes to tumorigenesis through the deletion of tumor suppressor genes. It derives from the loss of one of the two alleles at a given locus caused by deletion or uniparental disomy (UPD). In this study we describe the genome wide analysis of LOH in purified leukemic blasts from acute myeloid leukemia (AML) samples with normal karyotype using a novel technique based on single nucleotide polymorphisms (SNP). In total we selected 50 peripheral blood samples of de novo AML patients with normal karyotype at the time of diagnosis. Patients were treated according to the AML-96 multi-center protocol of the DSIL. Pure leukemic cells and tumor free material (T cells) from each patient were obtained using FACS-Vantage cell-sorting (BD Sciences, Germany). DNA was isolated from sorted cells. Genome wide SNP analysis was carried out according to the standard GeneChip Mapping Assay protocol (Affymetrix, USA) with pre-amplified DNA (Repli-g™ Kit; Molecular Staging Inc. USA) using the Human Mapping 10K Arrays XbaI 131 (Affymetrix). Individual regions of potential LOH identified by the Affymetrix® GeneChip® Chromosome Copy Number Analysis tool were confirmed by microsatellite analysis of short tandem repeat (STR) markers using the matched non-manipulated original DNA samples. Genome wide analysis of SNP in pre amplified DNA of FACS sorted cells from AML samples with normal karyotype detected long stretches of hemizygosity, indicative of LOH in 8/49 evaluable patients (16%). In 6 of these cases STR-analysis of T cells representing the corresponding tumor free material confirmed the regions of partial UPD. UPD affected four different chromosomes (chromosome 2p and 11q, in each case twice; chromosome 8q, and 13q) and covered between 11.5 and 88 Mb. To our surprise in the healthy material of the remaining two cases no heterozygote loci were identified at the affected chromosomal regions (chromosome 3 14.5 Mb; chromosome 20 29.3 Mb) and consequently identified as unusual long stretches of homozygosity present in both the malignant and the healthy cells. These cases might reflect genotypes with high susceptibility to malignant mutations. No differences were observed for any clinical factors, including age, WBC-counts, sex and FAB-subtype. Also, several of the mutations frequently identified in patients with normal karyotype (FLT3-ITD, MLL-PTD, NPM1) had a comparable prevalence in patients with and without UPD. Interestingly, although 5/6 patients with UPD achieved complete remission after induction chemotherapy, 4/5 (80%) relapsed within the first 6 months. In contrast the rate of relapse in patients without UPD was only 54% (15/28). The only patient positive for UPD and alive in remission received an allogeneic stem cell transplantation. In conclusion, the combination of whole genome amplification method and SNP array technology allows the identification and mapping of LOH in AML patients with normal karyotype. Our data also point to the necessity to analyze tumor free material to confirm the somatic origin of the alteration. Although small numbers of patients were investigated, our data might indicate that patients with UPD have a high rate of treatment failure. This should be further investigated in larger cohorts of patients.

Analysis of Loss of Heterozygosity in Adult Patients with De Novo Acute Myeloid Leukemia and Normal Karyotype.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 806-806 ◽  
Author(s):  
Christian Schon ◽  
Lars Bullinger ◽  
Frank G. Rucker ◽  
Konstanze Dohner ◽  
Hartmut Dohner
Keyword(s):  
Acute Myeloid Leukemia ◽  
Signal Intensity ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Snp Array ◽  
Uniparental Disomy ◽  
Normal Karyotype ◽  
Intensity Data ◽  
Chromosome 13 ◽  
Acute Myeloid

Abstract A large proportion of acute myeloid leukemia (AML) exhibits a normal karyotype in which the underlying pathomechanisms still have to be determined. Novel techniques like arrayCGH or single nucleotide polymorphism (SNP) chip analysis allow the identification and characterization of molecular rearrangements at the sub-megabase level. Recently, the application of genome-wide SNP array technology revealed frequent uniparental disomy (UPD) in approximately 20% of AML suggesting that UPD represents a nonrandom event in leukemogenesis. Uniparental disomy is acquired by somatic recombination and therefore not accessible by conventional cytogenetic methods or arrayCGH. In this study we analyzed DNA from AML patients with normal karyotype for the presence of LOH. SNP analysis was performed on the Mapping 100k GeneChip (Affymetrix, Santa Clara, CA). DNA was extracted from paired samples of 56 de novo AML patients with normal karyotype at diagnosis and in complete remission, respectively. Signal intensity data were analyzed by the GCOS GeneChip analysis software and statistical analysis of SNP call data was performed by the dChipSNP software. In addition, standard mutation screening of the genes encoding NPM1, FLT3, CEBPA, MLL and NRAS was performed in all cases. Using the 100k SNP array, a mean SNP call rate of 98.2% was reached, resulting in &gt; 110,000 SNP genotype calls per sample. Signal intensity data analysis revealed submicroscopic chromosomal deletions resulting in hemizygosity in three patients. Patient 1 had a single 2 Mb deletion in chromosomal band 3p14.1, patient 2 had two small deletions affecting chromosome 12q23 and 12p13, the latter encompassing the ETV6 locus, and patient 3 had two small deletions within the long arm of chromosome 8. Besides these small chromosomal regions of copy number alterations, we found 4 large stretches of somatically acquired homozygosity without numeric alterations, affecting chromosome 6 (6p21 to 6 pter and 6q26 to 6 qter), chromosome 11 (11p12 to 11pter) and chromosome 13 (13q11 to 13qter). Noteworthy, in the case with uniparental disomy of chromosome 13, we could detect a homozygous FLT3-ITD mutation, supporting the findings that acquired isodisomy for chromosome 13 is common in AML, and associated with FLT3-ITD mutations (Griffiths et al., Leukemia, 2005). In summary, high resolution SNP assay technology in AML patients with normal karyotype allowed the identification of distinct chromosomal regions affected by UPD, supporting the postulated nonrandom mechanism of acquired mitotic recombination events in AML. Besides known chromosomal regions known to be affected by genomic aberrations in AML, we found additional submicroscopic chromosomal aberrations in cases with normal karyotype. Analysis of larger patient series will allow the identification of novel regions of interest harboring genes that might be involved in the pathogenesis of AML.

Adoptive Immunotherapy with Haploidentical Kir Ligand-Mismatched Natural Killer Cells In Elderly High Risk Acute Myeloid Leukemia Patients: Biological and Clinical Results of A Pilot Study

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4287-4287
Author(s):  
Antonio Curti ◽  
Loredana Ruggeri ◽  
Alessandra D'Addio ◽  
Andrea Bontadini ◽  
Valeria Giudice ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Nk Cells ◽  
Natural Killer ◽  
Myeloid Leukemia ◽  
Nk Cell ◽  
Conflicts Of Interest ◽  
Interleukin 2 ◽  
Active Disease ◽  
Acute Myeloid

Abstract Abstract 4287 Purpose: To evaluate safety, feasibility and anti-leukemia potential of haploidentical KIR-L mismatched natural killer (NK) cell infusion in elderly high risk acute myeloid leukemia (AML) patients. Patients and Methods: Thirteen patients (5 active disease, 2 molecular relapse and 6 complete remissions) with median age 62 years (range 53–73) received NK cell infusion after immunosuppressive chemotherapy (fludarabine/cyclophosphamide), followed by interleukin-2. Highly purified CD56+CD3- NK cells from haploidentical KIR-L mismatched donors were used. The median number of infused NK cells was 2.74 × 106/Kg. T cells were less than 105/Kg. NK cell chimerism, phenotyping, and functional assays were performed. Results: No significant toxicity, including graft versus host disease, related to NK cell infusion was observed. Among patients with active disease, 1/5 obtained transient complete remission (CR), whereas 4/5 patients had no clinical benefit. Both patients in molecular relapse obtained CR, which lasted 9 and 4 months. Three/6 patients in morphologic CR are disease-free after 34, 32 and 18 months. Donor NK cells were demonstrated in the peripheral blood (PB) of all evaluable patients with a peak at day 10 after infusion and, in some cases, also in the bone marrow (BM). NK alloreactivity was demonstrated in vivo by the detection of donor-derived postinfusion NK clones capable of killing recipient targets. Conclusion: Infusion of purified CD56+CD3- NK cells is feasible and safe in elderly high risk AML patients. Adoptively transferred NK cells, which can be detected in PB and BM after infusion, are alloreactive against recipient cells and may induce an anti-leukemic activity. Disclosures: No relevant conflicts of interest to declare.

Karyotypic Complexity In Acute Myeloid Leukemia In The Context Of Adverse Prognosis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 489-489 ◽  
Author(s):  
Friedrich Stölzel ◽  
Brigitte Mohr ◽  
Michael Kramer ◽  
Christoph Röllig ◽  
Tilmann Bochtler ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Normal Karyotype ◽  
Control Group ◽  
Cytogenetic Aberrations ◽  
First Remission ◽  
The Uk ◽  
Acute Myeloid

Abstract Introduction Cytogenetic analysis is a mandatory component in the diagnostic evaluation of acute myeloid leukemia (AML) providing information regarding the biology of the disease including response or resistance to therapy. One of the cytogenetic markers which reflect an adverse outcome in conventional chemotherapy regimens is the complex aberrant karyotype consisting of multiple unrelated cytogenetic abnormalities. In AML two definitions have been established which differ in the perception of unbalanced aberrations as well as the number of single aberrations. The ELN classification scheme adopts three unrelated abnormalities while the UK MRC recently recommended four abnormalities as the most informative cut-off of complexity in the context of an adverse prognosis. The aim of this work was to study the best cut-off defining complexity (3 vs. 4) in AML with other cytogenetic high-risk markers. Methods The databases of three clinical multicentric, randomized, and prospective SAL trials (NCT 00180115, 00180102, and 00180167) were analyzed for AML patients with multiple cytogenetic aberrations as well as normal karyotypes (control group). Unbalanced abnormalities were counted as two aberrations according to the recommendations of the MRC (i.e. a single unbalanced translocation leading to gain and loss of chromosomal material as two unique abnormalities). The following single aberrations associated with an adverse prognosis according to ELN as well as UK MRC recommendations were included: inv(3), t(3;3), abn(3q), -5, del(5q), t(5q), t(6;9), -7, add(7q)/del(7q), t(11;v)(q23;v) (except t(9;11)), and abnl(17p). Results Complete data were analyzed from 2056 patients: normal karyotype (NK) n=1590, three aberrations (K3) n=65, ≥ four aberrations (K4) n=355, t(8;21)/inv(16)/t(16;16) and at least two additional aberrations n=46. All four groups differed significantly in 5–year overall survival (OS): 35% [95% CI 32–37], 19% [95% CI 9–29], 7% [95% CI 4–10], 67% [95% CI 53–81], respectively, p≤0.001. The K4 group had a significant inferior 5–year OS as compared to the K3 group, 19% [95% CI 9–29] and 7% [95% CI 4–10], p≤0.001. HSCT was performed in first remission in 25% of patients with K3 (n=16) and 17% of patients with K4 (n=59) (p=n.s.). As demonstrated earlier, multiple aberrations additional to the good risk anomalies (t(8;21), inv(16), or t(16;16)) did not impact on the favourable prognosis of the respective group. In the K3 and K4 groups single adverse risk abnormalities were found in 55% (abnl(17p) 12%) and 83% (abnl(17p) 37%) in these patients, respectively. A hyperdiploid karyotype (HDK) with gains of whole chromosomes without any structural aberration or monosomy was present in 14% of K3 and 3% of K4-patients. Interestingly, HDK with three trisomies as well as ≥ four trisomies led to a survival similar to K4 patients without HDK. Therefore, the K3 group lost its inferior survival as compared to NK when patients with adverse risk, which induce a worse prognosis per se, as well as HDK were excluded (5y–OS: 29% [9–44] vs. 35%, [95% CI 32–37], p=n.s.). HDK patients or patients with additional single adverse risk abnormalities had a worse survival compared to NK (5y–OS: 11%, [95% CI 0–32], p=0.012; and 15%, [95% CI 3–28], p=0.004 vs. 35%, [95% CI 32–37], respectively). In contrast, when comparing the K4 group after exclusion of adverse risk and HDK patients to NK, the K4 group remained its inferior OS as compared to NK, p<0.001. Conclusions Hence, our investigation confirms and therefore favors the ≥4 cut-off of complexity in the context of an adverse prognosis as proposed by the MRC with the exception of HDK patients. HDK patients should be considered as high-risk independent of the level of complexity. Whether K3 patients without single adverse risk abnormalities and HDK should be treated as intermediate risk, as suggested by our results, needs to be investigated prospectively in clinical trials. Disclosures: Platzbecker: Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

Azacitidine Use in a Low Income Country, Effectiveness of a 100mg Fixed Dose

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5555-5555
Author(s):  
Jorge Carlos Torres ◽  
Nidia Zapata ◽  
Eduardo Cervera ◽  
Sergio Sanchez ◽  
Manuel Aguilar
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Low Income ◽  
Survival Data ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Public Institution ◽  
Fixed Dose ◽  
Median Income ◽  
Acute Myeloid

Abstract Azacitidine, a pyrimidine nucleoside analog of cytidine, causes hypomethilation of DNA. Currently FDA approved for treatment of low and intermediate MDS with complete responses around 50%. And Acute myeloid leukemia (AML) in the eldery In the CALGB studies, the usual dose is 75mg/m2 in 28 day cycles, with dose modifications according to toxicity. In low income countries such as Mexico, one course of Azacitidine is around 500 dollars, median income in Mexico is 4,910 PPP (purchasing power parity); vs 30,616 in the USA. So, azacitidine treatment is far from reach for most of the common population, particularly those who do not have insurance. This is a retrospective observational study, of a compassionate use program of a fixed dose of Aza at 100mg. We analyzed data from patients that were treated with Aza between 2012 and 2016, and collected data in 2016. The aim of the study was to assess the effectivity of the fixed dose. For that purpose, we collected information from the physical and electronic file. We analyzed: Hemoglobin level before and after treatment, independence of transfusion, ANC recovery, number of courses, and overall survival. We conducted our research in a public institution in Mexico (Instituto Nacional de Cancerología) and a private institution (Medica Sur). We included acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients, regardless of age, previous treatment and comorbidities (we included patients with renal failure, hypertension etc.) We included 8 patients in our study, 6 males and 2 females, with a mean age of 69.9 years (49-87). We had 2 AML and 6 MDS. We had 2 high risk AML and according to IPSS-R: 1 very low, 2 low, 1 intermediate, 1 high and 1 very high risk MDS. As for the Karyotype we had 1 complex KT, 4 normal KT and 1 Del 7q Del 5q +8. All patients received at least one dose of Aza, with mean number of cycles of 4. We have a mean survival of 439 days (110-1385). 6/8 patients achieved transfusion independency within 3 doses of Aza. 6/8 patients achieved ANC but lost eventually lost response. 5/8 patients are alive in follow up. 3 patients died of infectious complications. 2 patients never achieved transfusion independence or ANC. The information recovered suggests that a fixed dose of 100mg is as feasible as a higher dose, at least when no other treatment or higher dose can be administered. We still are analyzing the survival data in order to find other bad prognosis factor within this population. Disclosures No relevant conflicts of interest to declare.

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