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A COMPARISON OF LIMITED CONSOLIDATION CHEMOTHERAPY THERAPY OR NOT, AND DEMETHYLATION MAINTENANCE OR NOT IN OLDER PATIENTS WITH AML AND HIGH RISK MDS: LONG TERM RESULTS OF THE UK NCRI AML16 TRIAL.
Author(s): ,
Alan Burnett
Affiliations:
Blackwaterfoot,Isle of Arran,United Kingdom
,
Nigel Russell
Affiliations:
Department of Haematology,Nottingham University Hospitals,Nottingham,United Kingdom
,
Sylvie Freeman
Affiliations:
University of Birmingham,Birmingham,United Kingdom
,
Lars Kjeldsen
Affiliations:
Rigshospitalet,Copenhagen,Denmark
,
Donald Milligan
Affiliations:
Birmingham Heartlands Hospital,Birmingham,United Kingdom
,
Christopher Pocock
Affiliations:
Kent and Canterbury Hospital,Canterbury,United Kingdom
,
Paul Cahalin
Affiliations:
Blackpool Victoria Hospital,Blackpool,United Kingdom
,
Jonathan Kell
Affiliations:
Department of Haematology,University Hospital of Wales,Cardiff,United Kingdom
,
Mike Dennis
Affiliations:
Department of Haematology,Christie Hospital,Manchester,United Kingdom
Robert Hills
Affiliations:
HCTU, Department of Haematology,Cardiff University School of Medicine,Cardiff,United Kingdom
(Abstract release date: 05/21/15) EHA Library. Burnett A. 06/13/15; 103225; S513
Dr. Alan Burnett
Dr. Alan Burnett
Contributions
Abstract
Abstract: S513

Type: Oral Presentation

Presentation during EHA20: From 13.06.2015 16:15 to 13.06.2015 16:30

Location: Room C2

Background
In older patients (>60yrs) with AML or high risk MDS (>10% marrow blasts), the UK NCRI AML16 trial compared two induction courses of DA vs DClo +/- gemtuzumab ozogamicin (GO). The benefit of GO has been reported (Burnett et al J Clin. Oncol 30(32); 3924-31, 2012). The trial also compared adding etoposide or ATRA to DA induction in a 2x2 design, and considered the optimal number of courses of treatment and the use of maintenance therapy.

Aims

Following 2 courses of induction patients with at least a partial remission (<15% marrow blasts) after course 1, and in CR after course 2 were eligible to be randomised to one course of consolidation (Dauno 50mg/m2 d 1, 2 + ara-C 100mg/m2 bid d 1-5) or not; patients in remission after course 2 could be randomised to maintenance (Azacitidine 75mg/m2 for 5 d x9 every 6 wks) or not.



Methods

From 8/2006-5/2012, 1880 patients entered the intensive induction options: 573 patients were randomised between 3 vs 2 courses in total, and 530 between maintenance and not. Of those randomised for consolidation 474 entered CR after course 1 and 99 achieved PR after course 1 and were in CR after course 2. Of the 530 patients entering the maintenance randomisation, 421 were in CR post course 1. A total of 453 patients entered both questions. Randomisations were stratified by induction chemotherapy and other demographics to ensure balance. The demographics of those entering the post induction options were: median age 67y (53-84); 77% de novo, 14% secondary, 8% high risk MDS; 4%, 82%, 14% favourable, intermediate, poor risk cytogenetics: 18% FLT3-ITD and 30% NPM1 mutant: 32%, 40%, 28% Wheatley good, standard, poor risk. Follow-up is complete to 1st January 2014 (median 50.4 months).



Results

For all trial entrants the overall response rate was 69% (CR 59%, CRi 10%) and 5-yr OS was 14%. There were no significant outcome differences between induction arms.

There was no difference in 5-year survival by consolidation randomisation (consolidation 25% vs not 22% HR 0.92 (0.75-1.12) p=0.4). Similarly, there was no difference in 5-year OS in those who did (24%) or did not (20%) receive maintenance (HR 0.93 (0.76-1.14) p=0.5). In the 226 patients allocated consolidation there was no difference in 5 year survival whether they received maintenance (26%) or not (21%) (p=0.7). Of 227 patients allocated no consolidation there was a non-significant benefit of maintenance (5yr OS 27% vs 18%, p=0.15), but no significant interaction (p=0.5).

During the study marrow samples were tested for MRD by immuno-flow analysis (Freeman S. et al. J Clin. Oncol. 31; 4123-4131, 2013) with a sensitivity of 1 in 104. This showed that for patients in CR after course 1, MRD positivity was the most powerful predictor of survival in multivariable analysis. In the 74 MRD –ve patients who received consolidation or not, there was a trend for improved OS (36% vs 26%) for recipients of consolidation (p=0.09); however, in the 74 patients who were in CR but MRD +ve, survival was significantly inferior with consolidation (11% vs 27%; p=0.03). In the 73 MRD –ve patients in the maintenance randomisation, there was a significant survival benefit for maintenance (40% vs 13%, p= 0.003), but no difference for MRD +ve patients (20% vs 23%, p=0.9). There was no additional benefit from both consolidation and maintenance irrespective of MRD status. 



Summary

Overall, neither a 3rd course nor demethylation maintenance improved survival. However in the ~50% of patients who achieved CR with course 1 who were MRD –ve, OS was improved by consolidation or maintenance but not incrementally by both. MRD appears to identify chemo-sensitive patients who benefit from additional treatment whereas the chemo-insensitive do not.

Acknowledgements: This study received research support from Cancer Research UK. Celgene provided Azacitidine for the trial.



Keyword(s): Clinical trial, Consolidation, Maintenance

Session topic: AML outcome and clinical trials
Abstract: S513

Type: Oral Presentation

Presentation during EHA20: From 13.06.2015 16:15 to 13.06.2015 16:30

Location: Room C2

Background
In older patients (>60yrs) with AML or high risk MDS (>10% marrow blasts), the UK NCRI AML16 trial compared two induction courses of DA vs DClo +/- gemtuzumab ozogamicin (GO). The benefit of GO has been reported (Burnett et al J Clin. Oncol 30(32); 3924-31, 2012). The trial also compared adding etoposide or ATRA to DA induction in a 2x2 design, and considered the optimal number of courses of treatment and the use of maintenance therapy.

Aims

Following 2 courses of induction patients with at least a partial remission (<15% marrow blasts) after course 1, and in CR after course 2 were eligible to be randomised to one course of consolidation (Dauno 50mg/m2 d 1, 2 + ara-C 100mg/m2 bid d 1-5) or not; patients in remission after course 2 could be randomised to maintenance (Azacitidine 75mg/m2 for 5 d x9 every 6 wks) or not.



Methods

From 8/2006-5/2012, 1880 patients entered the intensive induction options: 573 patients were randomised between 3 vs 2 courses in total, and 530 between maintenance and not. Of those randomised for consolidation 474 entered CR after course 1 and 99 achieved PR after course 1 and were in CR after course 2. Of the 530 patients entering the maintenance randomisation, 421 were in CR post course 1. A total of 453 patients entered both questions. Randomisations were stratified by induction chemotherapy and other demographics to ensure balance. The demographics of those entering the post induction options were: median age 67y (53-84); 77% de novo, 14% secondary, 8% high risk MDS; 4%, 82%, 14% favourable, intermediate, poor risk cytogenetics: 18% FLT3-ITD and 30% NPM1 mutant: 32%, 40%, 28% Wheatley good, standard, poor risk. Follow-up is complete to 1st January 2014 (median 50.4 months).



Results

For all trial entrants the overall response rate was 69% (CR 59%, CRi 10%) and 5-yr OS was 14%. There were no significant outcome differences between induction arms.

There was no difference in 5-year survival by consolidation randomisation (consolidation 25% vs not 22% HR 0.92 (0.75-1.12) p=0.4). Similarly, there was no difference in 5-year OS in those who did (24%) or did not (20%) receive maintenance (HR 0.93 (0.76-1.14) p=0.5). In the 226 patients allocated consolidation there was no difference in 5 year survival whether they received maintenance (26%) or not (21%) (p=0.7). Of 227 patients allocated no consolidation there was a non-significant benefit of maintenance (5yr OS 27% vs 18%, p=0.15), but no significant interaction (p=0.5).

During the study marrow samples were tested for MRD by immuno-flow analysis (Freeman S. et al. J Clin. Oncol. 31; 4123-4131, 2013) with a sensitivity of 1 in 104. This showed that for patients in CR after course 1, MRD positivity was the most powerful predictor of survival in multivariable analysis. In the 74 MRD –ve patients who received consolidation or not, there was a trend for improved OS (36% vs 26%) for recipients of consolidation (p=0.09); however, in the 74 patients who were in CR but MRD +ve, survival was significantly inferior with consolidation (11% vs 27%; p=0.03). In the 73 MRD –ve patients in the maintenance randomisation, there was a significant survival benefit for maintenance (40% vs 13%, p= 0.003), but no difference for MRD +ve patients (20% vs 23%, p=0.9). There was no additional benefit from both consolidation and maintenance irrespective of MRD status. 



Summary

Overall, neither a 3rd course nor demethylation maintenance improved survival. However in the ~50% of patients who achieved CR with course 1 who were MRD –ve, OS was improved by consolidation or maintenance but not incrementally by both. MRD appears to identify chemo-sensitive patients who benefit from additional treatment whereas the chemo-insensitive do not.

Acknowledgements: This study received research support from Cancer Research UK. Celgene provided Azacitidine for the trial.



Keyword(s): Clinical trial, Consolidation, Maintenance

Session topic: AML outcome and clinical trials

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