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]

Cytogenetics and age are major determinants of outcome in intensively treated acute myeloid leukemia patients older than 60 years: results from AMLSG trial AML HD98-B

Blood ◽  
2006 ◽  
Vol 108 (10) ◽  
pp. 3280-3288 ◽  
Author(s):  
Stefan Fröhling ◽  
Richard F. Schlenk ◽  
Sabine Kayser ◽  
Martina Morhardt ◽  
Axel Benner ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Elderly Patients ◽  
Myeloid Leukemia ◽  
Proportional Hazards ◽  
Proportional Hazards Model ◽  
Normal Karyotype ◽  
Prognostic Impact ◽  
Factors Affecting ◽  
Acute Myeloid

Abstract To assess the prognostic impact of cytogenetics in elderly patients with acute myeloid leukemia (AML) receiving intensive induction and consolidation treatment according to a single protocol specifically designed for patients above age 60, pretreatment samples from 361 patients registered for the AML HD98-B trial of the German-Austrian AML Study Group were analyzed by chromosome banding and fluorescence in situ hybridization, and cytogenetic findings were correlated with outcome. Using a proportional hazards model with backward selection, 3 prognostic subgroups were identified based on the influence of cytogenetic abnormalities on overall survival (OS): low-risk, t(15;17), and inv(16) in 25 of 361 patients (7%); standard-risk, normal karyotype, t(8;21), t(11q23), +8 within a noncomplex karyotype, and +11 within a noncomplex karyotype in 208 of 361 patients (58%); high-risk, all other aberrations in 128 of 361 patients (35%). On multivariate analysis, high-risk cytogenetics (hazard ratio [HR], 2.24) and age above 70 years (HR, 2.34) were independent prognostic factors affecting OS, and stratification according to these parameters demonstrated that a large subgroup of patients (55%), characterized by age 70 or older or high-risk cytogenetics, or both, had very unfavorable treatment results despite intensive chemotherapy. Thus, karyotype and age are major determinants of outcome in elderly patients with AML.

Characterization of Acute Myeloid Leukemia with PTPN11 Mutation - The Mutation Is Closely Associated with NPM1 Mutation but Inversely Related to FLT3/ITD.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3490-3490 ◽  
Author(s):  
Hsin-An Hou ◽  
Wen-Chien Chou ◽  
Chien-Yuan Chen ◽  
Liang-In Lin ◽  
Jih-Luh Tang ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Tyrosine Phosphatase ◽  
Normal Karyotype ◽  
Receptor Protein ◽  
Missense Mutations ◽  
Npm1 Mutation ◽  
Ptpn11 Mutation ◽  
Acute Myeloid

Abstract The development of acute myeloid leukemia (AML) is a multistep process. Recently, somatic mutations of PTPN11, the gene encoding non-receptor protein tyrosine phosphatase SHP-2, were observed in some hematological malignancies. However, the characteristics of adult AML with PTPN11 mutations have not been comprehensively studied, and the specific genetic alteration cooperative with a PTPN11 mutation in the leukemogenesis remains largely unknown. In this study, PTPN11 mutation and its association with other gene aberrations were analysed for 272 adult patients with de novo AML. Missense mutations were identified in 14 individuals (5.1%). The PTPN11 mutation was closely associated with old age (P=0.036), FAB M4/M5 subtypes (P=0.049), CD14 expression (P=0.026), a normal karyotype (P=0.044) and NPM1 mutation (P=0.037), but negatively associated with FLT3/ITD (P = 0.025). In addition, four patients revealed simultaneous mutations of PTPN11 and AML1 (n=3) or MLL (n=1). We observed a shorter overall survival for patients with PTPN11 mutation than those without amongst NPM1-wild patients (P=0.001), but not amongst NPM1-mutated patients (P=0.738). Our findings provide evidence that AML patients with PTPN11 mutations had some distinct biological and clinical characteristics, and the mutation may cooperate with other gene alterations to lead to AML in a subset of patients.

Tailored Temozolomide Therapy for Elderly Patients with Acute Myeloid Leukemia.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 954-954
Author(s):  
Bruno C. Medeiros ◽  
Jason R. Gotlib ◽  
Steven E. Coutre ◽  
Angela Mignea ◽  
James Zehnder
Keyword(s):  
Acute Myeloid Leukemia ◽  
Elderly Patients ◽  
Promoter Methylation ◽  
Myeloid Leukemia ◽  
Methylation Status ◽  
Normal Karyotype ◽  
Neutropenic Fever ◽  
Treatment Modalities ◽  
Neutropenic Sepsis ◽  
Acute Myeloid

Abstract Alternative treatment modalities are greatly needed for elderly patients with acute myeloid leukemia (AML). Previous preclinical data and clinical observations show that only patients lacking expression of O6-alkylguanine-DNA alkyltransferase (AGAT) in leukemic blasts are sensitive to temozolomide. Furthermore, AGAT enzymatic activity can be significantly decreased by protracted exposure to low doses of temozolomide. Based on these data, we have designed a phase II clinical trial tailoring temozolomide therapy to elderly patients with AML according to AGAT status. AGAT promoter methylation status was determined in pretreatment leukemic samples. Patients demonstrating evidence of AGAT promoter methylation were stratified to conventional doses of temozolomide at 200mg/m2 orally x 7 days. Patients demonstrating lack of AGAT promoter methylation (unmethylated) were stratified to receive protracted doses of temozolomide (100mg/m2 orally x 14 days) followed by conventional doses of temozolomide. Those patients who achieved CR were given up to 5 similar consolidation treatments. Eleven patients have been treated to date. The median age was 78 (71–83) and 6 were male. Seven patients were newly diagnosed and 6 patients had a normal karyotype. Nine patients had an unmethylated AGAT promoter in their leukemic blasts. Correlative AGAT protein expression in leukemic blasts will be presented at the meeting. All patients had an intact mismatch repair pathway. Median HCT-CI score was 1 (0–5). Four patients (4/10) achieved a complete remission after 1 cycle of therapy (1/2 for patients with methylated AGAT promoter and 3/8 for patients with unmethylated AGAT promoter). Nonhematologic toxicities attributed were minimal. Drug-related hematologic toxicities were difficult to distinguish from disease-related cytopenias. Six patients developed neutropenic fever (four patients developed neutropenic fever before the start of therapy). Three (3/10) patients remain alive with a median duration of remission of 4.5 months (4–5 months). Four patients have died from disease progression. And two patients died of neutropenic sepsis. One patient who achieved a CR, experienced prolonged marrow aplasia (47 days) following consolidation cycle #1 and withdrew from the study. The trial is ongoing with an accrual goal of 36 patients. These preliminary results suggest that temozolomide therapy may be individually tailored to elderly patients with AML according to AGAT promoter status.

Incidence and Prognostic Value of FLT-3 and NPM1 Genes Abnormalities in Acute Myeloid Leukemia in the Côte D’or Population, France

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4873-4873
Author(s):  
Marc Maynadié ◽  
Martine Courtois ◽  
Morgane Mounier ◽  
Ines Janoray-Manivet ◽  
Ingrid Lafon ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Prognostic Value ◽  
De Novo ◽  
Relative Survival ◽  
Normal Karyotype ◽  
Npm1 Mutation ◽  
Clinical Series ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Context: In acute myeloid leukemia (AML), the recently described FLT-3 and NPM1 genes abnormalities were found to have a prognostic value in AML with normal karyotype and a specific therapeutic strategy was proposed according to these abnormalities. We look for the incidence and prognostic value of these abnormalities in cases diagnosed on a well defined population. Material and Methods: AML diagnosed according to WHO classification between 01/01/2001 and 31/12/2006 in the population of the Côte d’Or department, were included. Karyotype analyses were performed in 81% of the cases. The FLT3 D835 mutation, the FLT3 internal duplication (ITD) and the NPM1 mutation were systematically studied on the biological material of the diagnosis cryopreserved in the Ferdinand Cabanne Biobank of Burgundy, by PCR and DNA sequencing techniques. The vital status of the patients was update on 31/10/2007. The relative survival was calculated with the STATA (V9) software. Results: 100 de novo AML and 47 secondary AML (sAML) were registered (72 females and 75 males). The world standardized incidence rate was 2.4 in men and 1.5 in women for de novo AML instead of what it was respectively of 1.1 and 0.6 in sAML. The urban predominance was present in both type of AML. The karyotype was normal in 38% (45/119) of cases (35% of de novo AML and 21% of sAML). It was abnormal in 62% of cases (74/119)(51% of de novo AML and 49% of sAML). Molecular analyses were performed in 78 de novo AML and in 24 sAML. FLT3 ITD was present in 19% (15/78) de novo AMl and in any sAML. The FLT3 D835 mutation was present in 6.5% of de novo AML and in 8% of sAML. NPM1 was mutated respectively in 26% and 4% of the cases. There was a significantly higher WBC count and proportion of blast cells in peripheral blood in FLT3 ITD cases. Overall and relative survivals of FLT3 ITD cases were decreased compared to FLT3 wild type cases. No difference according to NPM1 status was found. Conclusions: These data confirm the bad prognostic value of FLT3 ITD status in AML observed in clinical series. Furthermore their particular interest lies in the fact that they are the first molecular data in AML produced on a population-based series indicating the feasibility of such epidemiological studies.

FLT3 mutations have no prognostic impact in elderly patients with acute myeloid leukemia and normal karyotype

2009 ◽  
Vol 84 (8) ◽  
pp. 532-534 ◽  
Author(s):  
Felicetto Ferrara ◽  
Clelia Criscuolo ◽  
Cira Riccardi ◽  
Tiziana Izzo ◽  
Mariangela Pedata ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Elderly Patients ◽  
Myeloid Leukemia ◽  
Normal Karyotype ◽  
Prognostic Impact ◽  
Flt3 Mutations ◽  
Acute Myeloid

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.

scholarly journals Cytogenetic profile of minimally differentiated (FAB M0) acute myeloid leukemia: correlation with clinicobiologic findings [see comments]

Blood ◽  
1995 ◽  
Vol 85 (12) ◽  
pp. 3688-3694 ◽  
Author(s):  
A Cuneo ◽  
A Ferrant ◽  
JL Michaux ◽  
M Boogaerts ◽  
H Demuynck ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Normal Karyotype ◽  
Clinical Findings ◽  
Trisomy 13 ◽  
Professional Exposure ◽  
Cytogenetic Profile ◽  
Acute Myeloid ◽  
Clonal Abnormalities

Cytogenetic data were studied in 26 patients with de novo acute myeloid leukemia (AML) with minimal myeloid differentiation, corresponding to the M0 subtype of the French-American-British classification, in correlation with cytoimmunologic and clinical findings. Clonal abnormalities were detected in 21 cases (80.7%), 12 of which had a complex karyotype. Partial or total monosomy 5q and/or 7q was found, either as the sole aberration or in all abnormal metaphases, in 11 patients; in 8 cases, additional chromosome changes were present, including rearrangements involving 12p12–13 and 2p12–15 seen in 3 cases each. Five patients had trisomy 13 as a possible primary chromosome change; in 5 cases, nonrecurrent chromsome abnormalities were observed. Comparison of these findings with chromosome data from 42 patients with AML-M1 shows that abnormal karyotypes, complex karyotypes, unbalanced chromosome changes (-5/5q- and/or -7/7q- and +13) were observed much more frequently in AML-M0 than in AML-M1. Patients with abnormalities of chromosome 5 and/or 7 frequently showed trilineage myelodysplasia and low white blood cell count. Despite their relatively young age, complete remission was achieved in 4 of 11 patients only. Patients with +13 were elderly males with frequent professional exposure to myelotoxic agents. Unlike patients with clonal abnormalities, most AML-M0 patients with normal karyotype showed 1% to 2% peroxidase-positive blast cells at light microscopy and frequently achieved CR. It is concluded that (1) AML-M0 shows a distinct cytogenetic profile, partially recalling that of therapy-related AML, (2) different cytogenetic groups of AML-M0 can be identified showing characteristic clinicobiologic features, and (3) chromosome rearrangements may partially account for the unfavorable outcome frequently observed in these patients.

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