HIGHER DOSE DAUNORUBICIN APPEARS BENEFICIAL IN PATIENTS HARBOURING A FLT3-ITD MUTATION: UPDATED RESULTS OF THE UK NCRI AML17 TRIAL
(Abstract release date: 05/19/16)
EHA Library. Russell N. 06/12/16; 135302; S808
Prof. Nigel Russell
Contributions
Contributions
Abstract
Abstract: S808
Type: Oral Presentation
Presentation during EHA21: On Sunday, June 12, 2016 from 08:00 - 08:15
Location: Hall C13
Background
The use of anthracycline and ara-C has been standard induction therapy for Acute Myeloid Leukaemia for at least 30 years. Several trials have compared 90mg/m2 of daunorubicin with 45mg/m2 and found benefit either overall or in subgroups. In the NCRI AML17 trial we compared 90mg/m2 with the more commonly used control arm of 60mg/m2 in the first course of chemotherapy. Our preliminary findings showed no benefit for increasing the dose of daunorubicin, with increased early mortality (Burnett et al, Blood 2015,125, 3878).However, follow-up was short at only 14.8 months, and there was a suggestion of heterogeneity, with FLT3-ITD mutant patients potentially benefitting. We present here an updated analysis with a median follow up of 28 months
Aims
To establish whether high dose daunorubicin in induction therapy for AML patients predominantly aged 18-60 years improved survival overall or in any cytogenetic or genetic subgroup.
Methods
Between 09/2011 and 10/2013, 1206 patients were randomised in 1:1 to daunorubicin 90mg/m2 or 60mg/m2 (d1,3,5) in course 1, then 50mg/ m2 (d1,3,5) in course 2, with Ara-C 100mg/m2 12-hourly d1-10 (course 1) and d1-8 (course 2). The median age was 53yrs (16-72); 54% were male; 84% had de novo AML, 10% secondary, and 6% high risk MDS; median presenting WBC was 8.5 (0.3-430); 10% had favourable cytogenetics; 72% intermediate and 18% adverse.
Results
Overall, 60-day mortality remained higher with DA90 (10% vs 5%, p=0.002), and 3-year overall survival did not differ (50% vs 47%, p=0.7) suggesting that no overall survival benefit has emerged for DA90. However, analysis stratified by FLT3-ITD showed significant heterogeneity (p=0.02). In ITD WT patients, DA90 did not improve outcome (51% vs 49%, p=0.3), but in ITD mutant patients a survival significant benefit (54% vs 34%, p=0.03) has emerged with longer follow up. 60-day mortality was not different (7% vs 6%, p=0.8). Although numbers were small the benefit appeared greater with higher allelic ratio (p=0.01 for trend). We did not observe a benefit related to age, cytogenetic group, NPM1 mutation status, nor in patients with a FLT3 TKD mutation.
Conclusion
These results indicate a potential role for higher doses of daunorubicin in patients with FLT3-ITD mutations. Such therapy could complement the use of FLT3-inhibitors, but its delivery is dependent on early knowledge of mutation status or possibly delivery of the escalated dose in the second course of induction therapy
Session topic: Treatment in Specific AML Subgroups
Keyword(s): Anthracycline, Clinical trial, Flt3-ITD
Type: Oral Presentation
Presentation during EHA21: On Sunday, June 12, 2016 from 08:00 - 08:15
Location: Hall C13
Background
The use of anthracycline and ara-C has been standard induction therapy for Acute Myeloid Leukaemia for at least 30 years. Several trials have compared 90mg/m2 of daunorubicin with 45mg/m2 and found benefit either overall or in subgroups. In the NCRI AML17 trial we compared 90mg/m2 with the more commonly used control arm of 60mg/m2 in the first course of chemotherapy. Our preliminary findings showed no benefit for increasing the dose of daunorubicin, with increased early mortality (Burnett et al, Blood 2015,125, 3878).However, follow-up was short at only 14.8 months, and there was a suggestion of heterogeneity, with FLT3-ITD mutant patients potentially benefitting. We present here an updated analysis with a median follow up of 28 months
Aims
To establish whether high dose daunorubicin in induction therapy for AML patients predominantly aged 18-60 years improved survival overall or in any cytogenetic or genetic subgroup.
Methods
Between 09/2011 and 10/2013, 1206 patients were randomised in 1:1 to daunorubicin 90mg/m2 or 60mg/m2 (d1,3,5) in course 1, then 50mg/ m2 (d1,3,5) in course 2, with Ara-C 100mg/m2 12-hourly d1-10 (course 1) and d1-8 (course 2). The median age was 53yrs (16-72); 54% were male; 84% had de novo AML, 10% secondary, and 6% high risk MDS; median presenting WBC was 8.5 (0.3-430); 10% had favourable cytogenetics; 72% intermediate and 18% adverse.
Results
Overall, 60-day mortality remained higher with DA90 (10% vs 5%, p=0.002), and 3-year overall survival did not differ (50% vs 47%, p=0.7) suggesting that no overall survival benefit has emerged for DA90. However, analysis stratified by FLT3-ITD showed significant heterogeneity (p=0.02). In ITD WT patients, DA90 did not improve outcome (51% vs 49%, p=0.3), but in ITD mutant patients a survival significant benefit (54% vs 34%, p=0.03) has emerged with longer follow up. 60-day mortality was not different (7% vs 6%, p=0.8). Although numbers were small the benefit appeared greater with higher allelic ratio (p=0.01 for trend). We did not observe a benefit related to age, cytogenetic group, NPM1 mutation status, nor in patients with a FLT3 TKD mutation.
Conclusion
These results indicate a potential role for higher doses of daunorubicin in patients with FLT3-ITD mutations. Such therapy could complement the use of FLT3-inhibitors, but its delivery is dependent on early knowledge of mutation status or possibly delivery of the escalated dose in the second course of induction therapy
Session topic: Treatment in Specific AML Subgroups
Keyword(s): Anthracycline, Clinical trial, Flt3-ITD
Abstract: S808
Type: Oral Presentation
Presentation during EHA21: On Sunday, June 12, 2016 from 08:00 - 08:15
Location: Hall C13
Background
The use of anthracycline and ara-C has been standard induction therapy for Acute Myeloid Leukaemia for at least 30 years. Several trials have compared 90mg/m2 of daunorubicin with 45mg/m2 and found benefit either overall or in subgroups. In the NCRI AML17 trial we compared 90mg/m2 with the more commonly used control arm of 60mg/m2 in the first course of chemotherapy. Our preliminary findings showed no benefit for increasing the dose of daunorubicin, with increased early mortality (Burnett et al, Blood 2015,125, 3878).However, follow-up was short at only 14.8 months, and there was a suggestion of heterogeneity, with FLT3-ITD mutant patients potentially benefitting. We present here an updated analysis with a median follow up of 28 months
Aims
To establish whether high dose daunorubicin in induction therapy for AML patients predominantly aged 18-60 years improved survival overall or in any cytogenetic or genetic subgroup.
Methods
Between 09/2011 and 10/2013, 1206 patients were randomised in 1:1 to daunorubicin 90mg/m2 or 60mg/m2 (d1,3,5) in course 1, then 50mg/ m2 (d1,3,5) in course 2, with Ara-C 100mg/m2 12-hourly d1-10 (course 1) and d1-8 (course 2). The median age was 53yrs (16-72); 54% were male; 84% had de novo AML, 10% secondary, and 6% high risk MDS; median presenting WBC was 8.5 (0.3-430); 10% had favourable cytogenetics; 72% intermediate and 18% adverse.
Results
Overall, 60-day mortality remained higher with DA90 (10% vs 5%, p=0.002), and 3-year overall survival did not differ (50% vs 47%, p=0.7) suggesting that no overall survival benefit has emerged for DA90. However, analysis stratified by FLT3-ITD showed significant heterogeneity (p=0.02). In ITD WT patients, DA90 did not improve outcome (51% vs 49%, p=0.3), but in ITD mutant patients a survival significant benefit (54% vs 34%, p=0.03) has emerged with longer follow up. 60-day mortality was not different (7% vs 6%, p=0.8). Although numbers were small the benefit appeared greater with higher allelic ratio (p=0.01 for trend). We did not observe a benefit related to age, cytogenetic group, NPM1 mutation status, nor in patients with a FLT3 TKD mutation.
Conclusion
These results indicate a potential role for higher doses of daunorubicin in patients with FLT3-ITD mutations. Such therapy could complement the use of FLT3-inhibitors, but its delivery is dependent on early knowledge of mutation status or possibly delivery of the escalated dose in the second course of induction therapy
Session topic: Treatment in Specific AML Subgroups
Keyword(s): Anthracycline, Clinical trial, Flt3-ITD
Type: Oral Presentation
Presentation during EHA21: On Sunday, June 12, 2016 from 08:00 - 08:15
Location: Hall C13
Background
The use of anthracycline and ara-C has been standard induction therapy for Acute Myeloid Leukaemia for at least 30 years. Several trials have compared 90mg/m2 of daunorubicin with 45mg/m2 and found benefit either overall or in subgroups. In the NCRI AML17 trial we compared 90mg/m2 with the more commonly used control arm of 60mg/m2 in the first course of chemotherapy. Our preliminary findings showed no benefit for increasing the dose of daunorubicin, with increased early mortality (Burnett et al, Blood 2015,125, 3878).However, follow-up was short at only 14.8 months, and there was a suggestion of heterogeneity, with FLT3-ITD mutant patients potentially benefitting. We present here an updated analysis with a median follow up of 28 months
Aims
To establish whether high dose daunorubicin in induction therapy for AML patients predominantly aged 18-60 years improved survival overall or in any cytogenetic or genetic subgroup.
Methods
Between 09/2011 and 10/2013, 1206 patients were randomised in 1:1 to daunorubicin 90mg/m2 or 60mg/m2 (d1,3,5) in course 1, then 50mg/ m2 (d1,3,5) in course 2, with Ara-C 100mg/m2 12-hourly d1-10 (course 1) and d1-8 (course 2). The median age was 53yrs (16-72); 54% were male; 84% had de novo AML, 10% secondary, and 6% high risk MDS; median presenting WBC was 8.5 (0.3-430); 10% had favourable cytogenetics; 72% intermediate and 18% adverse.
Results
Overall, 60-day mortality remained higher with DA90 (10% vs 5%, p=0.002), and 3-year overall survival did not differ (50% vs 47%, p=0.7) suggesting that no overall survival benefit has emerged for DA90. However, analysis stratified by FLT3-ITD showed significant heterogeneity (p=0.02). In ITD WT patients, DA90 did not improve outcome (51% vs 49%, p=0.3), but in ITD mutant patients a survival significant benefit (54% vs 34%, p=0.03) has emerged with longer follow up. 60-day mortality was not different (7% vs 6%, p=0.8). Although numbers were small the benefit appeared greater with higher allelic ratio (p=0.01 for trend). We did not observe a benefit related to age, cytogenetic group, NPM1 mutation status, nor in patients with a FLT3 TKD mutation.
Conclusion
These results indicate a potential role for higher doses of daunorubicin in patients with FLT3-ITD mutations. Such therapy could complement the use of FLT3-inhibitors, but its delivery is dependent on early knowledge of mutation status or possibly delivery of the escalated dose in the second course of induction therapy
Session topic: Treatment in Specific AML Subgroups
Keyword(s): Anthracycline, Clinical trial, Flt3-ITD
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