scholarly journals tinguishing AML from MDS: A fixed blast percentage may no longer be optimal

Blood ◽  
2021 ◽  
Author(s):  
Elihu H Estey ◽  
Robert P Hasserjian ◽  
Hartmut Döhner
Keyword(s):  
Myeloid Leukemia ◽  
De Novo ◽  
Performance Status ◽  
Independent Effect ◽  
Approval Process ◽  
Allogeneic Transplant ◽  
Secondary Aml ◽  
Transplant Patients ◽  
De Novo Aml ◽  
Genetic Signatures

Patients with acute myeloid leukemia (AML) have conventionally received more "intense" therapy than patients with myelodysplastic syndromes (MDS). Although less intense therapies are being used more often in AML, the AML-MDS dichotomy remains, with the presence of ≥ 20% myeloblasts in marrow or peripheral blood generally regarded as defining AML. Consequently, patients with 19% blasts are typically ineligible for AML studies, with patients with 21% blasts ineligible for MDS studies. Here we cite biologic and clinical data to question this practice. Biologically, abnormalities in chromosome 3q26,and mutations in NPM1, and FLT3, regarded as AML-associated, also occur in MDS. The genetic signatures of MDS, particularly cases with 10-19% blasts (MDS-EB2), resemble those of AML following a preceding MDS ("secondary AML"). Mutationally, secondary AML appears at least as similar to MDS-EB2 as to de novo AML. Patients presenting with de novo AML but with secondary-type AML mutations, appear to have the same poor prognoses associated with clinically defined secondary AML. Seattle data indicate that after accounting for European LeukemiaNet (ELN) 2017 risk, age, performance status, clinically secondary AML, and treatment including allogeneic transplant, patients with WHO-defined AML (n=769) have similar rates of OS, EFS and CR/CRi as patients with MDS-EB2 (n=202). We suggest defining patients with 10-30% blasts ("AML/MDS") as eligible for either AML or MDS studies. This would permit empirical testing of the independent effect of blast percentage on outcome, allow patients access to more therapies, and potentially simplify the regulatory approval process.

Etiology and Management of Therapy-Related Myeloid Leukemia

Hematology ◽  
2007 ◽  
Vol 2007 (1) ◽  
pp. 453-459 ◽  
Author(s):  
Richard A. Larson
Keyword(s):  
Myeloid Leukemia ◽  
Hematopoietic Cell Transplantation ◽  
De Novo ◽  
Performance Status ◽  
Direct Consequence ◽  
Cytotoxic Therapy ◽  
Prognostic Features ◽  
Similar Disease ◽  
Primary Disorder ◽  
De Novo Aml

Abstract The diagnosis of therapy-related myeloid leukemia (t-MDS/t-AML) identifies a group of high-risk patients with multiple and varied poor prognostic features. These neoplasms are thought to be the direct consequence of mutational events induced by cytotoxic therapy. Their outcomes have historically been poor compared with those of people who develop acute myeloid leukemia (AML) de novo. The question arises whether a diagnosis of t-AML per se indicates a poor prognosis, or whether their bad outcomes result from other clinical and biologic characteristics. Because of lingering damage from prior cytotoxic therapy and, in some cases, the persistence of their primary disorder, patients with t-AML are often poor candidates for intensive AML therapy. The spectrum of cytogenetic abnormalities in t-AML is similar to de novo AML, but the frequency of unfavorable cytogenetics, such as a complex karyotype or deletion or loss of chromosomes 5 and/or 7, is higher in t-AML. Survival varies according to cytogenetic risk group, with better outcomes observed in patients with t-AML with favorable-risk karyotypes. Treatment recommendations should be based on performance status and karyotype. Patients with t-AML should be enrolled on front-line chemotherapy trials, appropriate for de novo AML patients with similar disease characteristics. Allogeneic hematopoietic cell transplantation can cure some patients with t-AML. Most important , the molecular and genetic differences that appear to determine the phenotype and the outcome of these patients need to be investigated further.

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

Blood ◽  
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.

Prognostic Significance Of TP53 mutations and Single Nucleotide Polymorphisms In Acute Myeloid Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4971-4971
Author(s):  
Simon B. Zeichner ◽  
Sarah Alghamdi ◽  
Gina Elhammady ◽  
Robert Poppiti ◽  
Amilcar Castellano-Sanchez
Keyword(s):  
Myeloid Leukemia ◽  
Tp53 Mutation ◽  
De Novo ◽  
Performance Status ◽  
Nucleotide Polymorphisms ◽  
Complex Karyotype ◽  
Single Nucleotide ◽  
Tp53 Mutations ◽  
Significant Difference ◽  
De Novo Aml

Abstract Background The response to treatment and overall survival (OS) of patients with acute myeloid leukemia (AML) is variable, with a median OS ranging from several months to more than 10 years. Age at diagnosis, performance status (PS), and karyotype expression have long been established in prognostication. Loss of TP53, a tumor suppressor gene located on the short arm of chromosome 17, is one of the most frequent genetic abnormalities in human cancer and is one of the more promising prognostic markers for AML. Studies have shown that TP53 mutations are present in 5-25% of all AML patients, in 70% of those with complex karyotypes, and are associated with old age, chemotherapy resistance, and worse OS. Single nucleotide polymorphisms (SNPs), changes in DNA seen in an appreciable amount of the population, have been examined in AML and studies have suggested a possible correlation with worse outcomes. Using genetic sequencing, we set out to look at our own experience with AML, and hypothesized TP53 mutations and SNPs would mimic the literature, occurring in a minority of patients, and conferring a worse OS. Methods We performed a pilot study of randomly selected, newly diagnosed AML patients at Mount Sinai Medical Center, diagnosed from 2005-2008 (n =10). Immunohistochemical (IHC) analysis of bone marrows and peripheral blood smears was assessed via DO-1 antibody on paraffin embedded tissue. Conventional cytogenetic analyses were performed on short-term cultured bone marrow and peripheral blood cells with the use of the GTG-banding technique. TP53 PCR sequencing was performed using DNA from bone marrow smears using the Sanger sequencing platform and resolved by capillary electrophoresis. Analysis was performed using Mutation Surveyor software with confirmation of the variants using the COSMIC and dbSNP databases. Descriptive frequencies and median survivals were calculated for demographic information, prognostic factors, and treatment variables. A univariate analysis was performed. Results The majority of patients in our pilot study were older than age 60 (80%), male (60%), Hispanic (60%), and had a poor PS (ECOG 2-3: 60%). Most patients had de-novo AML (50%) with an intermediate (50%) non-complex (70%) karyotype and a TP53 P72R SNP (50%). Fewer than half of these patients harbored TP53 mutations (40%). There was no significant difference in OS based on sex, AML history, risk-stratified karyotype, or TP53 mutation. There was a trend toward improved survival among patients younger than age 60 (11, 4 mo, p = 0.09), of Hispanic ethnicity (8, 1 mo, p = 0.11), and those not harboring P72R (8, 2, p = 0.10). There was a significant improvement in survival among patients with a better PS (28, 4 mo, p = 0.01) and those who did not have a complex karyotype (8, 1 mo, p = 0.03). Among patients with a TP53-mutation, there were a larger number of individuals who were younger than age 60 (25.0, 16.7%), who were male (75.0, 50.0%), had a good performance status (ECOG 0-1: 50.0, 16.7%), had de-novo AML (50.0, 66.7%), and who had an adverse karyotype (50.0, 33%). Patients with a P72R SNP were more often male (80, 40%) and had a worse PS (ECOG 2-3: 80, 40%) with AML secondary to MDS (60, 20%) and a complex karyotype (40, 0%). The most commonly observed TP53 mutation was a missense N310K (40%) and the most commonly observed SNP was P72R (100.0%). Patients with more than one TP53 mutation had a worse clinical course than those with only a single mutation. Conclusion Our study demonstrated that poor PS and the presence of a complex karyotype were associated with a decreased OS. TP53 mutations were relatively uncommon, occurring more frequently in male patients with an adverse karyotype. Although there was no significant difference in survival between TP53 mutated and un-mutated patients, there was a trend toward worse OS among patients with a specific SNP. These results suggest that different TP53 mutations and SNPs should not be treated the same, and that some may confer a worse prognosis than others. Larger studies are needed to validate these findings. Disclosures: No relevant conflicts of interest to declare.

Gene Expression Profile Analysis of Pediatric MDS Patients Correlates with FAB Classification and Has Prognostic Relevance

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2695-2695
Author(s):  
Silvia Bresolin ◽  
Luca Trentin ◽  
Geertruy Kronnie ◽  
Laura Sainati ◽  
Marco Zecca ◽  
...  
Keyword(s):  
Gene Expression ◽  
Principal Component Analysis ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Gene Expression Signature ◽  
Principal Component ◽  
Component Analysis ◽  
Secondary Aml ◽  
Fab Classification ◽  
De Novo Aml

Abstract Myelodysplatic syndromes (MDS) are rare malignant haematopoietic stem cell disorders in children. They have the propensity to transform into acute myeloid leukemia and, for this reason they can be considered as a pre-leukemia condition. In this study we analyzed the gene expression profile (GEP) of a large cohort of pediatric patients: 14 MDS [6 refractory cytopenias (RC), 6 refractory anemias with excess blasts (RAEB) and 2 refractory anemias with excess blasts in transformation (RAEB-t)], 50 de-novo acute myeloid leukemia (AML) and 6 normal bone marrow (BM) aspirates. Furthermore, in 5 cases, samples were available for analysis both at diagnosis and at time of secondary AML progression. Gene expression analysis was performed on the Affymetrix HG U133 Plus 2.0 oligonucleotide microarrays using Partek software packages and the leukemia classifier version 7(LCver7). Statistical analyses were performed to determine the correlation between the gene expression signature and MDS subtype. Unsupervised hierarchical clustering analysis separated the majority of MDS cases from the diagnostic AML samples and placed the normal BM specimens into the MDS cluster. Remarkably, all the MDS cases that evolved into an AML within one year, except one, clustered together inside the diagnostic AML group. Performing principal component analysis (PCA) we observed that MDS samples were clustered between the group of normal BM and AML samples. Moreover the RC samples were located proximal to the cluster of normal BM samples while RAEB and RAEB-t specimens were nearest to the AML samples cluster (Fig 1). Further, we classified the MDS samples using the LCver7 classifier, an algorithm developed inside the MILE (Microarray Innovation In LEukemia) study that gives an overall cross-validation accuracy of &gt;95% for distinct sub-classes of pediatric and adult leukemias using gene expression profiles. The 14 MDS samples had 57.2 % and 42.8 % AML and non AML-like signatures, respectively. The Fisher exact test showed that there was a statistical concordance (p=0.008) between the FAB classification and the gene expression signature. In fact, 83% of RC patients had a non AML-like signature whereas only 17% had an AML-like signature. On the contrary 85% of the RAEB and RAEB-t patients had an AML-like signature. In conclusion, the results of unsupervised analysis not only demonstrated that gene expression technology is able to distinguish between MDS, AML and normal BM samples but, in addition, GEP can identify an AML-like signature in samples at diagnosis of MDS, with a higher risk of AML-evolution, allowing to identify a group of patients that could be eligible for a more intensive treatment. Fig.1. Principal component analysis (PCA) of MDS, AML and normal BM samples. Red: MDS samples, Blue: de novo AML, Green: secondary AML, Violet: normal BM. RC samples are placed closer to the normal BM specimens. The three MDS patients that will evolve into secondary AML are included into the green ellipsoids. Fig.1. Principal component analysis (PCA) of MDS, AML and normal BM samples. Red: MDS samples, Blue: de novo AML, Green: secondary AML, Violet: normal BM. RC samples are placed closer to the normal BM specimens. The three MDS patients that will evolve into secondary AML are included into the green ellipsoids.

Poor Outcome in Secondary Acute Myeloid Leukemia (AML): A First Report From the Population-Based Swedish Acute Leukemia Registry

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 130-130 ◽  
Author(s):  
Soren Lehmann ◽  
Vladimir Lazarevic ◽  
Ann-Sofi Hörstedt ◽  
Erik Hulegårdh ◽  
Christer Nilsson ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Performance Status ◽  
Population Based ◽  
Induction Treatment ◽  
Secondary Aml ◽  
Male Predominance ◽  
Hematological Disorder ◽  
De Novo Aml

Abstract Abstract 130 Secondary AML comprises AML patients with an antecedent hematological disorder (AHD) or previous exposure to chemotherapy and/or radiation (therapy-related AML; tAML). Population-based data on this patient group are scarce. Here, we report for the first time, data on secondary AML from the Swedish Acute Leukemia Registry covering 98% of all AML cases diagnosed in Sweden between 1997 and 2006. In total, 3372 AML patients were registered during this period. Of these, 949 (28%) had secondary AML; 655 (19%) had a history of AHD and 294 (8.7%) had tAML. The proportion of secondary AML increased from 8% in patients below the age of 40 years to 36% in patients between 70–79 years. Of patients with AHD, 423 (65%) had previously been diagnosed with myelodysplastic syndrome (MDS) and 227 (35%) with various types of myeloproliferative disorders (MPN). AML with AHD showed male predominance (57%), whereas tAML showed female predominance (64%). This distribution was significantly different (p<0.001) compared to de novo AML with an equal gender distribution. Median and mean ages for patients with AML with antecedent hematological disorder were 73 and 71 years, which differed significantly from de novo AML with 70 and 66 years, respectively (p<10−11). For tAML, median and mean ages were 71 and 67 years, respectively, not significantly different from de novo AML. Patients with secondary AML had slightly worse WHO/ECOG performance status (WHO PS) with lower incidence of WHO PS 0 (10%: 14%: 18% for AML with AHD:tAML:de novo AML) and a higher incidence of WHO PS 3–4 (27%: 24%: 20%). The proportion of patients with PS 1 and PS2 was similar for secondary AML and de novo AML. Intensive induction treatment was given to 45% of all patients with AHD, to 57% of patients with tAML compared to 68% for patients with de novo AML. In patients below the age of 65, the proportion of intensively treated patients was 76, 85 and 98%, respectively. CR rates for in patients including all ages were 40% for AML with AHD, 54% for tAML and 72 % for de novo AML (p-values<0.0001 for all calculations). CR rates were lower in all cytogenetic risk groups in both AML with AHD and tAML compared to de novo AML (Low risk NA: 70%: 91%; intermediate risk 53%: 56%: 89%; high risk 30%: 43%: 76%). CR rates were lower for both secondary leukemia types within all WHO PS groups, despite similar early death rates in secondary and de novo AML. Median survival for all patients regardless of age or type of treatment was 4 mo, 4 mo and 9 mo respectively for patients with AML with AHD, tAML and de novo AML, respectively. For all patients receiving intensive induction treatment, corresponding figures were 7 mo, 9 mo and 17 mo, and for patients below 65 years of age 7 mo, 9 mo and 38 mo. We conclude that secondary AML is less common in younger patients and that the proportion increases to a third of patients above 70. Patients with AHD and tAML less often receive intensive induction treatment than those with de novo AML and treatment responses are poor regardless of cytogenetic risk group or performance status also in intensively treated patients. Disclosures: No relevant conflicts of interest to declare.

Fusion Gene Detection Using Whole Transcriptome Analysis in Patients with Chronic Myeloproliferative Neoplasms and Secondary Acute Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4093-4093 ◽  
Author(s):  
Fiorella Schischlik ◽  
Jelena D. Milosevic Feenstra ◽  
Elisa Rumi ◽  
Daniela Pietra ◽  
Bettina Gisslinger ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Research Funding ◽  
De Novo ◽  
Fusion Gene ◽  
Myeloproliferative Neoplasms ◽  
Chronic Phase ◽  
Loss Of Function ◽  
Secondary Aml ◽  
De Novo Aml ◽  
Whole Transcriptome

Abstract Fusion oncogenes resulting from chromosomal aberrations are common disease drivers in myeloid malignancies. The most prominent example is BCR-ABL1 fusion present in chronic myeloid leukemia, which together with essential thromobocythemia (ET), primary myelofibrosis (PMF) and polycythemia vera (PV) belongs to the classic myeloproliferative neoplasms (MPN). The BCR-ABL1 negative MPNs are driven by somatic mutations in JAK2, MPL and CALR. MPN patients can progress to acute myeloid leukemia (AML) but the transformation process is not well understood. Studies using standard karyotyping and SNP microarrays have shown that disease progression is characterized by an increase in karyotype complexity. We aimed to identify novel fusion oncogenes in patients with BCR-ABL1 negative MPN during chronic phase and disease progression in high-throughput and cost-efficient manner using RNA-seq technology. In addition this approach enabled us to perform RNA-seq variant calling for identification of gene mutations on the same cohort of patients. Whole transcriptome sequencing was performed on 121 patients (112 chronic phase MPN and 9 secondary AML samples) and 23 healthy controls in a 100 base pair paired-end manner. The cohort consisted of 44% PMF, 22% ET, 12% PV and 6% secondary AML patients. The output of three fusion detection tools (Defuse, Tophat-fusion and SOAPfuse) was combined in order to increase sensitivity. Extensive filtering steps were applied in order to enrich for cancer specific fusion events, including filtering for fusions appearing in healthy individuals, filtering for read-throughs and false positives with external databases and manual inspection of sequencing reads. The outcome of analysis for Defuse, Tophat-fusion and SOAPfuse resulted in the total of 52, 54 and 38 candidate fusions, respectively. Candidate fusions were Sanger-sequenced and for Tophat-fusion and Defuse the validation rate was 60%, while for SOAPfuse only 20% could be validated. Approximately 70% of the fusion candidates were not shared among the 3 tools which underlines the importance of selecting the union of all calls from each tool rather than the intersect. We did not observe clustering of breakpoints along the genome. Most fusion candidates could be detected in PMF which corresponds to the disease entity that was most represented in the cohort (44% of patients). No enrichment for fusions was found in 7 triple negative (no JAK2, CALR, MPL mutations) cases. 42% of chromosomal aberrations were translocations, followed by duplication (31%), inversion (14%) and deletion events (11%). Among the intragenic fusions, approximately half had genomic breakpoints less than 1 Mb apart. 70% of validated fusions were out of frame, while 28% were in frame. In the leukemic samples a higher abundance of fusions was found (4/9). Typical fusions for de novo AML were not detected within secondary AML (sAML) samples. We did not detect a recurrent fusion oncogene in our patient cohort. In a PMF patient with JAK2-V617F mutation we identified a BCR-ABL1 fusion, indicating a clonal exchange which was consistent with patient's phenotype. Another PMF patient exhibited an inversion event involving the first exon of CUX1, causing a CUX1 loss of function. Other fusions in chronic MPN patients affected genes involved in histone modifications (SMYD3-AHCTF1, KDM4B-CYHR1). In post-MPN AML patients we identified a somatic in frame-fusion involving INO80D and GPR1 and a fusion truncating the first 3 exons of RUNX2 (XPO5-RUNX2). The high quality of RNA sequencing data, allowed us to set up a variant detection workflow that will be compared with matched samples that have been exome sequenced. Preliminary results could demonstrate that mutations in the JAK2 gene in a cohort of 96 patients were all correctly recalled, emphasizing its sensitivity. Fusion events among patients in chronic phase MPN are rare and the majority of these events imply loss of function of both fusion gene partners. This approach adds valuable information on the true frequency of inactivation of genes such as CUX1 in patients, as small inversions like the one described above would not be detectable by other methods. Detection of a subclone with BCR-ABL1 fusion underlines the strength of the fusion detection workflow for diagnostic purposes. Typical de novo AML fusions were not found in sAML and further suggests that de novo AML and sAML are distinct disease entities on a genetic level. Disclosures Gisslinger: Janssen Cilag: Honoraria, Speakers Bureau; Sanofi Aventis: Consultancy; AOP ORPHAN: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Geron: Consultancy. Kralovics:AOP Orphan: Research Funding; Qiagen: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Acute myeloid leukemia ontogeny is defined by distinct somatic mutations

Blood ◽  
2015 ◽  
Vol 125 (9) ◽  
pp. 1367-1376 ◽  
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.

scholarly journals 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 ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4013-4013 ◽  
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.

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

Blood ◽  
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.

SET-NUP214 Fusion Gene at Chromosome 9q34 Contributed to the Development of Not Only T-ALL, but Also Primary and Secondary AML.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4696-4696
Author(s):  
Myung-Geun Shin ◽  
Da-Woon Kim ◽  
Hye-Ran Kim ◽  
Duck Cho ◽  
Seung-Jung Kee ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
De Novo ◽  
Fusion Gene ◽  
Direct Sequencing ◽  
Leukemic Cells ◽  
Rt Pcr ◽  
Hoxa Cluster ◽  
Secondary Aml ◽  
Chromosome 9Q34 ◽  
De Novo Aml

Abstract Abstract 4696 SET-NUP214 rearrangement at chromosome 9q34 is an extremely rare recurrent cryptic deletion resulting from del(9)(q34.11q34.13) mainly found in T-cell acute lymphoblastic leukemia (T-ALL). A multiplex RT-PCR system (HemaVision; DNA Technology) covering 28 leukemic fusion transcripts was applied to 271 bone marrow (BM) samples obtained from acute leukemia patients at initial diagnosis to investigate new pathophysiologic role of SET-NUP214 fusion gene. Out of 271 samples, we identified three cases (1.1%) harboring SET-NUP214 rearrangement – each case of adult T-ALL, pediatric acute myeloid leukemia (AML) from chronic myeloid leukemia (CML) and adult de novo AML with minimal differentiation (M0). Adult T-ALL occurred in 38-year-old man presented with dizziness and hepatomegaly. Conventional cytogenetic study disclosed normal karyotype and existence of SET-NUP214 fusion gene generated by del(9)(q34.11q34.13) was confirmed by RT-PCR, FISH and direct sequencing. Hematological remission was achieved after treatment of induction chemotherapy but during 7 months follow-up, SET-NUP214 fusion gene was steadily detected by RT-PCR. 13-year-old female with AML M0 converted from CML after treatment of imatinib for 2 months was the second case. Leukemic cells showed negative myeloperoxidase (MPO) and sudan-black B (SBB) staining, positive reaction against CD13, CD33, CD117 and MPO monoclonal antibodies by flowcytometry-based immunophenotyping. Major BCR-ABL1 rearrangement and SET-NUP214 fusion genes were simultaneously detected by RT-PCR, FISH and direct sequencing. She died at 38 days after diagnosis during the chemotherapy. The fusion protein contributed to the leukemogenesis by promoting expression of HOXA cluster genes. Last case was a de novo AML M0 in 39-year-old male. Cytochemical stains of leukemic cells on MPO and SBB were negative and immunophenotyping studies were positive for CD34, HLA-DR, CD13 and CD33. SET-NUP214 rearrangement was detected by multiplex RT-PCR. After treatment of induction and consolidation chemotherapy, he received allogeneous sibling stem cell transplantation (SCT), then complete chimerism was achieved. In clonclusion, SET-NUP214 rearrangement is associated with the development of not only T-ALL, but also primary and secondary AML via aberrant expression of HOXA cluster genes. Disclosures: No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document