Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML)

Blood ◽  
2006 ◽  
Vol 107 (10) ◽  
pp. 4011-4020 ◽  
Author(s):  
Christian Thiede ◽  
Sina Koch ◽  
Eva Creutzig ◽  
Christine Steudel ◽  
Thomas Illmer ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Disease Free Survival ◽  
Normal Karyotype ◽  
Clinical Impact ◽  
Prognostic Impact ◽  
Npm1 Mutation ◽  
Free Survival ◽  
High Bone ◽  
Acute Myeloid

Mutations of the nucleophosmin (NPM1) gene have recently been described in patients with acute myeloid leukemia (AML). To clarify the prevalence as well as the clinical impact of this mutation, we investigated 1485 patients with AML for NPM1 exon 12 mutations using fragment analysis. A 4 bp insert was detected in 408 of 1485 patients (27.5%). Sequence analysis revealed known mutations (type A, B, and D) as well as 13 novel alterations in 229 analyzed cases. NPM1 mutations were most prevalent in patients with normal karyotype (NK) (324 of 709; 45.7%) compared with 58 of 686 with karyotype abnormalities (8.5%; P < .001) and were significantly associated with several clinical parameters (high bone marrow [BM] blasts, high white blood cell [WBC] and platelet counts, female sex). NPM1 alterations were associated with FLT3-ITD mutations, even if restricted to patients with NK (NPM1-mut/FLT3-ITD: 43.8%; versus NPM1-wt/FLT3-ITD: 19.9%; P < .001). The analysis of the clinical impact in 4 groups (NPM1 and FLT3-ITD single mutants, double mutants, and wild-type [wt] for both) revealed that patients having only an NPM1 mutation had a significantly better overall and disease-free survival and a lower cumulative incidence of relapse. In conclusion, NPM1 mutations represent a common genetic abnormality in adult AML. If not associated with FLT3-ITD mutations, mutant NPM1 appears to identify patients with improved response toward treatment.

Clinical relevance of P-glycoprotein expression in de novo acute myeloid leukemia

Blood ◽  
1996 ◽  
Vol 87 (5) ◽  
pp. 1997-2004 ◽  
Author(s):  
G Del Poeta ◽  
R Stasi ◽  
G Aronica ◽  
A Venditti ◽  
MC Cox ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Survival Rates ◽  
Disease Free Survival ◽  
Normal Karyotype ◽  
Free Survival ◽  
Negative Phenotype ◽  
Acute Myeloid

Abstract Cytofluorimetric detection of the multidrug resistance (MDR)-associated membrane protein (P-170) was performed at the time of diagnosis in 158 patients with acute myeloid leukemia using the C219 monoclonal antibody (MoAb). In 108 of these cases the JSB1 MoAb was also tested. An improved histogram subtraction analysis, based on curve fitting and statistical test was applied to distinguish antigen-positive from antigen-negative cells. A marker was considered positive when more than 20% of the cells were stained. At onset, P-170 was detected in 43% of cases with C219 and in 73% of cases with JSB1. There was a strict correlation between C219 and JSB1 positivity, as all C219+ cases were also positive for JSB1 MoAb (P < .001). No relationship was found between sex, age, organomegaly, and MDR phenotype. Significant correlation was found between CD7 and both C219 and JSB1 expression (P < .001 and .001, respectively). C219-negative phenotype was more often associated with a normal karyotype (24 of 55 with P = .030). Rhodamine 123 (Rh123) staining and flow cytometry analysis showed a significantly decreased mean fluorescence in 51 C219+ and 38 JSB1+ patients compared to 42 MDR negative ones (P < .001). The rate of first complete remission (CR) differed both between C219+ and C219- cases and between JSB+ and JSB- ones (30.9% v 71.1% and 35.4% v 93.1%, respectively, P < .001). Of the 21 C219+ patients who had yielded a first CR, 19 (90.4%) relapsed, compared with 28 of 64 (43.7%) C219- patients (P < .001). Of the 28 JSB1+ patients in first CR, 17 (60.7%) relapsed relative to 8 (29.6%) of 27 JSBI- ones (P = .021). A higher rate of relapses among MDR+ compared with MDR- patients was observed both for C219 and JSB1 MoAbs taken separately (C219 80% v 44%; JSB1 52% v 27%), with no relationship to age. The survival rates (Kaplan-Meyer method) were significantly shorter both in C219+ patients and in JSB1+ cases (P < .001). Disease-free survival curves followed this same trend. The combination (C219- JSB1+) identified a subset of patients with an intermediate outcome compared to C219 positive cases. The prognostic value of both markers (C219 and JSB1) was confirmed in multivariate analysis. These results suggest that the assessment of MDR phenotype by flow cytometry may be an important predictor of treatment outcome.

The Detection of Multilineage Dysplasia (MLD) Has No Influence on Prognosis in NPM1 Mutated Acute Myeloid Leukemia (AML) with Normal Karyotype

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2518-2518
Author(s):  
Ulrike Bacher ◽  
Susanne Schnittger ◽  
Wolfgang Kern ◽  
Tamara Weiss ◽  
Claudia Haferlach ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Normal Karyotype ◽  
Biological Entity ◽  
Prognostic Impact ◽  
Npm1 Mutation ◽  
Cox Regression Analysis ◽  
Multilineage Dysplasia ◽  
Acute Myeloid

Abstract Acute myeloid leukemia with mutated nucleophosmin (AML NPM1mut) represents about one-third of all adult AML and shows distinctive biological and clinical features. For this reason, AML NPM1mut is planned to be included as a separate category in the revised WHO classification. A yet controversial issue, however, is whether AML NPM1mut with or without multilineage dysplasia (MLD) may differ biologically and clinically, as the presence of MLD might confer a negative prognostic impact. A further feature that was suggested to be typical for NPM1 mutated AML is “cup-like” morphology of blasts. We here analyzed 128 pts with AML NPM1mut and normal karyotype at first manifestation (59 females, 69 males; median age 60.5 years; 23.5–79.3 y). We investigated in parallel cytomorphology from bone marrow and/or peripheral blood, chromosome banding analysis, and molecular analyses. Presence of dysplasia was defined by dysplastic features in ≥50% of cells in the respective hematopoietic lineage as defined by the WHO. A 5% cut-off was taken for the presence of “cup-like” morphology of blasts. All cases were additionally analyzed for the FLT3-ITD, and in 122 pts for the FLT3-TKD. Statistical analysis was performed for overall survival (OS), and event-free survival (EFS) according to Kaplan-Meier using the 2-sided log-rank test. Cox regression analysis related OS and EFS with the analyzed parameters. We found a predominance of the FAB M1 (21.3% of all cases), M2 (33.9%), and M4 subtypes (28.3%). Cup-like morphology in ≥5% of all blasts was observed in 39 of 127 evaluable cases (31.3%) confirming previous observations of an association of the NPM1mut and this specific blast appearance. Molecular characterization detected NPM1 mutation subtype A (n=90/122; 73.8%), B (15/122; 12.3%), and D (7/122; 5.7%), which was in accordance to previous studies. In 56 cases (43.8%) there was a coincidence with an FLT3-ITD. Dysplasia of granulopoiesis was detected in 28/126 (22.2%), of erythropoiesis in 28/104 (26.9%), and of megakaryopoiesis in 57/87 (44.5%) cases in which the respective cell lineage could be analyzed. MLD (≥2 dysplastic hematopoietic lineages) was detected in 28 of 105 evaluable cases (21.9%). Clinical follow-up was available in 104 pts. (median follow-up 12,7 months). CR rate was 83.1% in 77 evaluable pts., and median EFS was 42.1 months in 104 evaluable pts (median OS not reached). An additional FLT3-ITD had a significantly inferior OS (p=0.003) and EFS (p=0.007), confirming the present series being representative. However, the presence of MLD was not significantly related to any endpoint such as CR rate, EFS, or OS. There was no association between MLD and the NPM1-subtype. Also, there was no significant correlation of MLD and the presence of a FLT3-ITD. In conclusion, the presence of MLD in AML NPM1mut with normal karyotype had no impact on CR rate and outcome, whereas coincidence of FLT3-ITD significantly worsened prognosis. These results give further evidence that AML with NPM1mut AML is a unique biological entity with clinical course mainly influenced by FLT3-ITD coincidence. These data do not support any additional prognostic influence of MLD in this AML subtype.

scholarly journals Clinical relevance of P-glycoprotein expression in de novo acute myeloid leukemia

Blood ◽  
1996 ◽  
Vol 87 (5) ◽  
pp. 1997-2004 ◽  
Author(s):  
G Del Poeta ◽  
R Stasi ◽  
G Aronica ◽  
A Venditti ◽  
MC Cox ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Survival Rates ◽  
Disease Free Survival ◽  
Normal Karyotype ◽  
Free Survival ◽  
Negative Phenotype ◽  
Acute Myeloid

Cytofluorimetric detection of the multidrug resistance (MDR)-associated membrane protein (P-170) was performed at the time of diagnosis in 158 patients with acute myeloid leukemia using the C219 monoclonal antibody (MoAb). In 108 of these cases the JSB1 MoAb was also tested. An improved histogram subtraction analysis, based on curve fitting and statistical test was applied to distinguish antigen-positive from antigen-negative cells. A marker was considered positive when more than 20% of the cells were stained. At onset, P-170 was detected in 43% of cases with C219 and in 73% of cases with JSB1. There was a strict correlation between C219 and JSB1 positivity, as all C219+ cases were also positive for JSB1 MoAb (P < .001). No relationship was found between sex, age, organomegaly, and MDR phenotype. Significant correlation was found between CD7 and both C219 and JSB1 expression (P < .001 and .001, respectively). C219-negative phenotype was more often associated with a normal karyotype (24 of 55 with P = .030). Rhodamine 123 (Rh123) staining and flow cytometry analysis showed a significantly decreased mean fluorescence in 51 C219+ and 38 JSB1+ patients compared to 42 MDR negative ones (P < .001). The rate of first complete remission (CR) differed both between C219+ and C219- cases and between JSB+ and JSB- ones (30.9% v 71.1% and 35.4% v 93.1%, respectively, P < .001). Of the 21 C219+ patients who had yielded a first CR, 19 (90.4%) relapsed, compared with 28 of 64 (43.7%) C219- patients (P < .001). Of the 28 JSB1+ patients in first CR, 17 (60.7%) relapsed relative to 8 (29.6%) of 27 JSBI- ones (P = .021). A higher rate of relapses among MDR+ compared with MDR- patients was observed both for C219 and JSB1 MoAbs taken separately (C219 80% v 44%; JSB1 52% v 27%), with no relationship to age. The survival rates (Kaplan-Meyer method) were significantly shorter both in C219+ patients and in JSB1+ cases (P < .001). Disease-free survival curves followed this same trend. The combination (C219- JSB1+) identified a subset of patients with an intermediate outcome compared to C219 positive cases. The prognostic value of both markers (C219 and JSB1) was confirmed in multivariate analysis. These results suggest that the assessment of MDR phenotype by flow cytometry may be an important predictor of treatment outcome.

The Amount of Mitochondrial Apoptosis Exerts Prognostic Impact on Normal Karyotype Acute Myeloid Leukemia.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1481-1481
Author(s):  
Giovanni Del Poeta ◽  
Maria Ilaria Del Principe ◽  
Francesco Buccisano ◽  
Luca Maurillo ◽  
Benedetta Neri ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Disease Free Survival ◽  
Normal Karyotype ◽  
Mitochondrial Proteins ◽  
Prognostic Impact ◽  
Mitochondrial Apoptosis ◽  
P Glycoprotein ◽  
The Impact ◽  
Acute Myeloid

Abstract The unbalance between anti-apoptotic (bcl-2) and pro-apoptotic mitochondrial proteins (bax) represents a critical mechanism explaining the high rate of resistance and treatment failure in acute myeloid leukemia (AML) (Del Poeta, 2003). Moreover, the availability of novel and effective pro-apoptotic compounds such as bortezomib (Attar, 2008) and gemtuzumab (Del Poeta, 2008) moved us to widely investigate the impact of mitochondrial proteins such as bcl-2, bax and 7A6 on AML prognosis. 7A6 antigen has been found to be exposed on the mitochondrial membrane during the early stages of apoptosis and is recognized by monoclonal antibody APO2.7. For this purpose, a large series of 420 non M3 AML patients (pts), median age 63 years, treated with intensive chemotherapy regimens, were tested. The aims of our research were: to correlate bax/bcl-2 and APO2.7/bcl-2 ratios, as measures of mitochondrial apoptosis, with other well-known prognostic factors such as age, cytogenetics, FLT3-ITD, P-glycoprotein; to evaluate whether mitochondrial apoptosis was able to dissect normal karyotype AML with regard to prognosis, and finally to confirm that mitochondrial apoptosis is an independent prognostic factor. Bcl-2, bax and 7A6 proteins were assessed by multicolor flow cytometry and bax/bcl-2 or APO2.7/bcl-2 ratios were obtained by dividing mean fluorescence intensity (MFI) of bax/MFI bcl-2 or MFI of APO2.7/MFI bcl-2. The thresholds of positivity were set at the median values &gt;0.35 and &gt;0.60, respectively. Fifty-nine percent of pts were bax/bcl-2 positive and 50% were APO2.7/bcl-2 positive. There were strict correlations between higher bax/bcl-2 or higher APO2.7/bcl-2 and FAB M2 or M4/M5 AML subgroups (p&lt;0.0001). Bax/bcl-2&gt;0.35 or APO2.7/bcl-2&gt;0.60 and CD34 negativity (p&lt;0.0001) or normal karyotype (p&lt;0.0001 and p=0.003) were closely associated. On the other hand, no significant relationships were found between bax/bcl-2 or APO2.7/bcl-2 and age, white blood cell count, P-glycoprotein or FLT3-ITD. A higher complete remission (CR) rate was found in pts either with higher bax/bcl-2 or higher APO2.7/bcl-2 (68% vs 32% and 60% vs 40%, p&lt;0.0001). Moreover, a shorter time to relapse was observed in pts with bax/bcl-2 &lt;0.35 (3.3 months vs 6 months, p=0.011). Overall survival (OS) and disease-free survival (DFS) were longer in pts with higher bax/bcl-2 (18% vs 0% at 3.5 years, p&lt;0.0001 and 19 vs 0% at 2.7 years, p=0.00007) or higher APO2.7/bcl-2 (14% vs 2% at 4 years, p&lt;0.0001 and 8% vs 0% at 4 years, p=0.02). Furthermore, in order to demonstrate the independent prognostic impact of the mitochondrial proteins, we investigated bax/bcl-2 and APO2.7/bcl-2 within the normal karyotype subgroup (243 pts). As a matter of fact, within this subset, higher bax/bcl-2 or higher APO2.7/bcl-2 were associated with higher CR rate (76% vs 24% and 64% vs 36%, p&lt;0.0001) and longer OS (16% vs 0% at 3.5 years, p=0.00001 and 14% vs 4 at 4 years, p=0.002). The independent prognostic value of bax/bcl-2 and APO2.7/bcl-2 was confirmed in multivariate analysis with regard to CR (p=0.00007 and p=0.0005) and OS (p=0.0009 and p=0.03). Therefore, the significant and independent prognostic role of mitochondrial apoptosis implies that therapeutic strategies for improving outcome in AML should be focused on apoptosis-inducing compounds combined with conventional chemotherapy.

Independent Prognostic Impact of CD15 for Achievement of Complete Remission in Patients with Acute Myeloid Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3687-3687
Author(s):  
Teresa Ceglie ◽  
Marta Chisini ◽  
Federico Vozella ◽  
Gioia Colafigli ◽  
Caterina Stefanizzi ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Univariate Analysis ◽  
Disease Free Survival ◽  
Multivariate Logistic Regression Model ◽  
Prognostic Impact ◽  
Prognostic Role ◽  
Free Survival ◽  
Acute Myeloid

Abstract The CD15 antigen is an adhesion molecule normally expressed on neutrophils that mediates phagocytosis and chemiotaxis: it is also expressed on blasts of patients with acute myeloid leukemia (AML). Its prognostic role has been tested in different studies, including or not acute promyelocytic leukemia (APL), with conflicting results and its significance still remains unclear. To address this issue, a cohort of 460 AML patients of all ages with, the exclusion of APL, [M/F 243/217, median age 50.6 years (range 0.9 – 81.2)] intensively treated at our Institute between 1/1999 and 12/2010 was retrospectively evaluated. Overall, 61 patients (13.3%) evolved from a documented myelodysplastic phase (MDS): AML-ETO, CBFβ-MYH11, FLT3-ITD and NPM were positive in 35/438 (8.2%), 30/427 (7.0%), 55/409 (13.4%) and 67/200 (14.6%) evaluable patients, respectively. A favorable karyotype was found in 90/436 patients (20.6%) while an unfavorable profile was documented in 60/436 cases (13.8%). CD15 positivity was found in 171/406 evaluable patients (42.1%): in particular, CD15 was positive in 13/42 evaluable patients evolved from MDS (31.0%) compared with 158/364 evaluable patients without previous MDS (43.4%) (p=0.123). Induction treatments consisted of anthracycline (ACY) + cytarabine (Ara-C) +/- etoposide in 448 patients and of a fludarabine-based regimen in 12 patients. A complete remission (CR) was achieved by 334 patients (72.6%), while 82 (17.8%) were resistant and 44 (9.6%) died during induction: the median CR duration was 15.5 months (range 0.6 – 176.0), with a 2-year disease-free survival (DFS) rate of 45.1% (95% CI 39.6 – 50.6). The median overall survival (OS) was 14.4 months (range 0.3 – 177.0), with a 2-year OS rate of 42.2% (95% CI 37.5 – 46.9). Among the several variables tested at univariate analysis for CR achievement, age <60 years (p<0.001), WHO classification (p=0.045), low-risk karyotype (p<0.001), no high-risk karyotype (p=0.006), positivity for AML-ETO (p=0.004)/CBFβ-MYH11 (p=0.003)/CD15 (p=0.006)/CD11b (p=0.013), negativity for FLT3-ITD (p=0.001), Hb >8 g/dl (p=0.020) and WBC <50 x 109/l (p=0.034) had a favorable impact. At a multivariate logistic regression model, CD15 positivity (p=0.002 – OR 2.96,95%CI 1.51 – 5.89), age <60 years (p=0.008 – OR 2.28, 95%CI 1.23 – 4.21), WBC <50 x 109/l (p=0.017 – OR 2.34, 95%CI 1.16 – 4.73) retained an independent prognostic role on CR achievement. In conclusion, the baseline assessment of CD15 positivity could have a role in the risk evaluation for CR achievement in non-APL AML patients undergoing intensive chemotherapy and should be assessed in prospective studies together with other clinical and biological features already reported. Disclosures Breccia: novartis: Consultancy; BMS: Consultancy; Celgene: Consultancy. Latagliata:Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Celgene: Consultancy; Shire: Consultancy.

scholarly journals High Throughput Molecular Characterization of Normal Karyotype Acute Myeloid Leukemia in the Context of the Prospective Trial 02/06 of the Northern Italy Leukemia Group (NILG)

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2242
Author(s):  
Silvia Salmoiraghi ◽  
Roberta Cavagna ◽  
Pamela Zanghì ◽  
Chiara Pavoni ◽  
Anna Michelato ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Throughput ◽  
Myeloid Leukemia ◽  
Prospective Trial ◽  
Disease Free Survival ◽  
Normal Karyotype ◽  
Molecular Profile ◽  
Remission Induction ◽  
Npm1 Mutation ◽  
Acute Myeloid

By way of a Next-Generation Sequencing NGS high throughput approach, we defined the mutational profile in a cohort of 221 normal karyotype acute myeloid leukemia (NK-AML) enrolled into a prospective randomized clinical trial, designed to evaluate an intensified chemotherapy program for remission induction. NPM1, DNMT3A, and FLT3-ITD were the most frequently mutated genes while DNMT3A, FLT3, IDH1, PTPN11, and RAD21 mutations were more common in the NPM1 mutated patients (p < 0.05). IDH1 R132H mutation was strictly associated with NPM1 mutation and mutually exclusive with RUNX1 and ASXL1. In the whole cohort of NK-AML, no matter the induction chemotherapy used, by multivariate analysis, the achievement of complete remission was negatively affected by the SRSF2 mutation. Alterations of FLT3 (FLT3-ITD) and U2AF1 were associated with a worse overall and disease-free survival (p < 0.05). FLT3-ITD positive patients who proceeded to alloHSCT had a survival probability similar to FLT3-ITD negative patients and the transplant outcome was no different when comparing high and low-AR-FLT3-ITD subgroups in terms of both OS and DFS. In conclusion, a comprehensive molecular profile for NK-AML allows for the identification of genetic lesions associated to different clinical outcomes and the selection of the most appropriate and effective treatment strategies, including stem cell transplantation and targeted therapies.

scholarly journals Characteristics and Survival of 927 Moroccan Adults with Acute Myeloid Leukemia: Monocentric Experience

2021 ◽  
Vol 6 (1) ◽  
pp. 5-13
Author(s):  
Oum kaltoum Ait boujmia ◽  
Mona Lamchahab ◽  
Nezha Hda ◽  
Asma Quessar
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Group Versus ◽  
Disease Free Survival ◽  
Normal Karyotype ◽  
P Value ◽  
Balanced Translocation ◽  
Free Survival ◽  
Disease Free ◽  
Acute Myeloid

Acute myeloïd leukemia (AML) is the most frequent form of acute leukemia among adults and the most aggressive type of leukemia, which is associated with the lowest survival rate. Patients with AML are treated with intensive chemotherapy and many factors could influence the survival of these patients, such as age, cytogenetic abnormalities; white blood cell (WBC) counts. The aim of this work was to study the epidemiological and response profiles of AML adults patients in Morocco.Patients and Methods: A prospective, descriptive study conducted in the Hematology and Pediatric Oncology department, 20 August Hospital Casablanca, and concerned adult patients diagnosed with AML through a period of seven years (January 2011 to December 2017). Statistical analysis was performed using SPSS version 20. The overall survival and disease-free survival were evaluated by using the Kaplan–Meier method. Results: A total of 927 patients diagnosed with AML during the 7 year period. 466 (50.3%) were males and 461 (49.7%) were females. The median age of patients was 46years.The most represented age group was between 18 and 60 years old with a percentage of 83.2%.The FAB subtype M2 occurred most frequently (27%) followed by M1 (24.8%). The cytogenetic study showed that the majority of patients had a normal karyotype. The t (8; 21) was the most detected balanced translocation in our series and the intermediate cytogenetic group was the most represented group (65.4%). A total of 461 patients (53.54%) were treated according to the protocol AML11. The Disease-free survival (DFS) was significantly better for favorable cytogenetic group as compared to other cytogenetic groups (median survival of 41.58 months for the favorable group versus 29.07 months for the adverse group; p-value = 0.02).Conclusion: The age of AML patients was younger compared to other populations. The majority of patients had a normal karyotype and the commonest balanced translocation was the t (8; 21). Survival was higher in patients with good prognosis.

Normal Karyotype-Acute Myeloid Leukemia With The CD4- CD7+ CD15+ CD34+ Immunophenotype Is a Clinically Distinct Entity With a Favorable Outcome

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2608-2608
Author(s):  
Noriyoshi Iriyama ◽  
Norio Asou ◽  
Toru Sakura ◽  
Tomoya Maeda ◽  
Hiroshi Handa ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Surface Antigen ◽  
Myeloid Leukemia ◽  
Disease Free Survival ◽  
Normal Karyotype ◽  
Antigen Expression ◽  
Free Survival ◽  
Surface Antigen Expression ◽  
Prognostic Implications ◽  
Acute Myeloid

Abstract Background Immunophenotyping is a standard diagnostic procedure in leukemia, but unlike cytogenetic classifications, which are reliable indicators for prognostic interpretation, immunophenotyping has, thus far, yielded inconsistent results. Recently, the presence of CEBPA, NPM1, or FLT3 mutations, as a molecular characteristic, was identified as an important prognostic factor for normal karyotype (NK)-acute myeloid leukemia (AML). Because AML with the CEBPA mutation is closely associated with specific surface antigen expression, we investigated the prognostic implications and characteristics of a certain immunophenotype in NK-AML. Design and Methods The frequency of CEBPA mutation according to cytogenetic classification in 318 AML patients was investigated, and then the surface antigen expression profile in NK-AML was assessed. Thereafter, the prognosis and patient characteristics of a specific immunophenotype was investigated in 329 NK-AML patients from the Japan Adult Leukemia Study Group (JALSG) AML97 study. Factor differences between groups of patients with and without this immunophenotype were compared by Fisher’s exact and Student’s t-tests. Complete remission (CR), disease-free survival (DFS), event-free survival (EFS) and overall survival (OS) was assessed using Fisher’s exact and log-rank tests. We used a multivariate Cox proportional hazard regression model to assess factors that could possibly affect the clinical outcome. Results The CEBPA mutation, including 12 monoallelic and 29 biallelic mutations, was detected in 41 of the 318 AML patients. AML with the CEBPA mutation was frequently observed in NK-AML and in cytogenetically intermediate-risk AML, but rare in favorable- or adverse-risk AML. NK-AML with the CEBPA mutation was closely associated with CD4 negativity as well as CD7 and CD34 positivity in 133 NK-AML cases. Furthermore, CD15 positivity is known to be associated with the CEBPA mutation. Therefore, we investigated the prognostic implications and characteristics of the CD4- CD7+ CD15+ CD34+ immunophenotype in NK-AML in the JALSG AML97 study. NK-AML with the CD4- CD7+ CD15+ CD34+ immunophenotype was classified as the CEBPA type, and NK-AML without this immunophenotype was considered as the non-CEBPA type. Of the 329 NK-AML patients analyzed, 39 and 243 were classified as having CEBPA and non-CEBPA type NK-AML, respectively. NK-AML patients with CEBPA type tended to have better EFS and OS than those with non-CEBPA type (5-year EFS, 48.4% vs 30.6%, P = 0.039; 5-year OS, 67.3% vs 35.7%, P = 0.0019). Multivariate analysis showed that the CEBPA type and white blood cell (WBC) counts of >20 × 109/L were independent prognostic factors for better EFS and OS. Compared to non-CEBPA type NK-AML, CEBPA type was associated with higher MPO-positive rates, frequent presentation with Auer rods, and a FAB classification of M1 or M2. Conclusions NK-AML with the CD4- CD7+ CD15+ CD34+ immunophenotype is a clinically discrete entity, indicating the presence of the CEBPA mutation, which may have a possible role in risk stratification. Disclosures: Taniwaki: Novartis: Honoraria.

A novel prognostic model in elderly patients with acute myeloid leukemia: results of 909 patients entered into the prospective AML96 trial

Blood ◽  
2010 ◽  
Vol 116 (6) ◽  
pp. 971-978 ◽  
Author(s):  
Christoph Röllig ◽  
Christian Thiede ◽  
Martin Gramatzki ◽  
Walter Aulitzky ◽  
Heinrich Bodenstein ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Risk Model ◽  
Cox Model ◽  
Prognostic Significance ◽  
Disease Free Survival ◽  
Intermediate Risk ◽  
Npm1 Mutation ◽  
Prognostic Groups ◽  
Acute Myeloid

Abstract We present an analysis of prognostic factors derived from a trial in patients with acute myeloid leukemia older than 60 years. The AML96 trial included 909 patients with a median age of 67 years (range, 61-87 years). Treatment included cytarabine-based induction therapy followed by 1 consolidation. The median follow-up time for all patients is 68 months (5.7 years). A total of 454 of all 909 patients reached a complete remission (50%). Five-year overall survival (OS) and disease-free survival were 9.7% and 14%, respectively. Multivariate analyses revealed that karyotype, age, NPM1 mutation status, white blood cell count, lactate dehydrogenase, and CD34 expression were of independent prognostic significance for OS. On the basis of the multivariate Cox model, an additive risk score was developed that allowed the subdivision of the largest group of patients with an intermediate-risk karyotype into 2 groups. We are, therefore, able to distinguish 4 prognostic groups: favorable risk, good intermediate risk, adverse intermediate risk, and high risk. The corresponding 3-year OS rates were 39.5%, 30%, 10.6%, and 3.3%, respectively. The risk model allows further stratification of patients with intermediate-risk karyotype into 2 prognostic groups with implications for the therapeutic strategy. This study was registered at www.clinicaltrials.gov as #NCT00180115.

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