Tailored Temozolomide Therapy for Elderly Patients with Acute Myeloid Leukemia.

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.

Download Full-text

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

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.7052 ◽

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]

Download Full-text

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

American Journal of Hematology ◽

10.1002/ajh.21458 ◽

2009 ◽

Vol 84 (8) ◽

pp. 532-534 ◽

Cited By ~ 11

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

Download Full-text

Methylation of ESR1 and Tumour Suppressor Genes Together Constitute an Independent Outcome Predictor in Acute Myeloid Leukemia.

Blood ◽

10.1182/blood.v108.11.803.803 ◽

2006 ◽

Vol 108 (11) ◽

pp. 803-803 ◽

Cited By ~ 3

Author(s):

Corine J. Hess ◽

Johannes Berkhof ◽

Fedor Denkers ◽

Gert J. Ossenkoppele ◽

Gerrit Jan Schuurhuis ◽

...

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Promoter Methylation ◽

Myeloid Leukemia ◽

Total Population ◽

Risk Group ◽

Methylation Status ◽

Methylation Index ◽

Group B ◽

Acute Myeloid

Abstract In acute myeloid leukemia (AML) promoter methylation has been observed for the estrogen receptor (ESR1) as well as for a number of Tumor Suppressor Genes (TSGs). These individual aberrancies were suggested to be part of a general methylation defect in subsets of AML patients, rather than random events. The objective of this study was to assess whether aberrant promoter methylation of multiple genes, as observed in AML samples, are associated and whether such associations render impact on clinical outcome. By Methylation-Specific Multiplex Ligation Probe Amplification (MS-MLPA) the methylation status of 26 TSGs was determined in bone marrow samples of 119 primary AML patients and 5 control individuals. No promoter methylation was detected in any of the controls, while at least one TSG was methylated in 59/119 patients. Methylation was observed in 12 out of 26 assessed sites, most frequently for ER, CDKN2B/p15, and IGSF4 (28–36% of all patients). A substantial intra-class correlation of 0.38 existed between methylation of different TGSs. ESR1 methylation (34/119) strongly predicted concurrent methylation of TSGs, OR 7.33 (95%CI 4.13–12.99). A regression model that included both the ESR1 methylation status and the number of methylated TSGs (methylation index), showed both parameters to be independent oppositely directed predictors for overall survival (OS), HR 0.06 (95%CI 0.01–0.33; p=.001) and HR 1.92 (95%CI 1.19–3.10; p=.007), respectively. In line with this observation, a higher methylation index was found to yield a significant negative effect on patient OS in both the ESR1 methylated (ESR1+) and ESR1 unmethylated (ESR1−) subgroups. Combining ESR1 methylation status with the absence or presence of promoter methylation of other TSGs (TSG+ or TSG−); yielded 4 patient subgroups with large differences in OS in univariate analysis (p=.0001, figure 1A). In multivariate analysis that included, FLT3-status, age at diagnosis, cytogenetics and achievement of CR, the predictive impact of the 4-group division on OS was maintained, HR 2.12 (95%CI 1.04–4.29; p=.037). Moreover, the combination identified a good prognostic patient subgroup (n=15, median OS 39 month) within the intermediate cytogenetic risk group (n=54, median OS 8.3 month), figure 1B. In conclusion, concurrent methylation occurs frequent in AML and is best predicted by ESR1 methylation. Methylation of ESR1 and methylation of other TSGs represent processes with independent predictivity. When combined, they constitute a unique and powerful factor for predicting overall survival, both in the total AML population as well as within the intermediate cytogenetic risk group. Figure 1. Overall Survival based on the methylation status of ER (ER+/ER) combined with the absence or presence of methylation of TSGs (TSG+/TSG−) for the total population (A) and confined to the intermediate cytogenetic risk group (B) Figure 1. Overall Survival based on the methylation status of ER (ER+/ER) combined with the absence or presence of methylation of TSGs (TSG+/TSG−) for the total population (A) and confined to the intermediate cytogenetic risk group (B)

Download Full-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 ◽

10.1182/blood-2006-04-014324 ◽

2006 ◽

Vol 108 (10) ◽

pp. 3280-3288 ◽

Cited By ~ 197

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.

Download Full-text

Addition of bevacizumab to chemotherapy in acute myeloid leukemia at older age: a randomized phase 2 trial of the Dutch-Belgian Cooperative Trial Group for Hemato-Oncology (HOVON) and the Swiss Group for Clinical Cancer Research (SAKK)

Blood ◽

10.1182/blood-2012-04-420596 ◽

2012 ◽

Vol 120 (24) ◽

pp. 4706-4711 ◽

Cited By ~ 40

Author(s):

Gert J. Ossenkoppele ◽

Georg Stussi ◽

Johan Maertens ◽

Kees van Montfort ◽

Bart J. Biemond ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Elderly Patients ◽

Myeloid Leukemia ◽

Treatment Modalities ◽

Phase 2 ◽

Standard Chemotherapy ◽

Clinical Cancer Research ◽

Phase 2 Trial ◽

New Treatment ◽

Acute Myeloid

Abstract An urgent need for new treatment modalities is emerging in elderly patients with acute myeloid leukemia (AML). We hypothesized that targeting VEGF might furnish an effective treatment modality in this population. Elderly patients with AML were randomly assigned in this phase 2 study (n = 171) to receive standard chemotherapy (3 + 7) with or without bevacizumab at a dose of 10 mg/kg intravenously at days 1 and 15. In the second cycle, patients received cytarabine 1000 mg/m2 twice daily on days 1-6 with or without bevacizumab. The complete remission rates in the 2 arms were not different (65%). Event-free survival at 12 months was 33% for the standard arm versus 30% for the bevacizumab arm; at 24 months, it was 22% and 16%, respectively (P = .42). The frequencies of severe adverse events (SAEs) were higher in the bevacizumab arm (n = 63) compared with the control arm (n = 28; P = .043), but the percentages of death or life-threatening SAEs were lower in the bevacizumab arm (60% vs 75% of SAEs). The results of the present study show that the addition of bevacizumab to standard chemotherapy does not improve the therapeutic outcome of older AML patients. This trial is registered as number NTR904 in The Nederlands Trial Register (www.trialregister.nl).

Download Full-text