Abstract 484

On behalf of the NCRI AML Working Group, United Kingdom

There is a general acceptance that survival in younger patients (<60 years) with AML has improved over the last 20 years, the majority still fail treatment. While the induction rate is satisfactory at >75% relapse remains a problem. Optimisation of induction and defining the schedule and duration of post-induction chemotherapy remains important even as novel approaches such as antibody directed therapy or small molecule therapy are added. The MRC AML15 compared 3 induction chemotherapy schedules and 4 post induction options. In induction patients were randomised to two course of DA or ADE or FLAG-Ida. In each case patients were also eligible to be randomised to receive Gemtuzumab Ozogamicin (GO) or not, which has been separately reported. In consolidation patients were randomised to MRC schedule (MACE/MidAC) or two courses of High Dose Ara-C and for those randomised to Ara-C to a dose of 3g/m2 or 1.5g/m2. Finally patients could be randomised to receive, or not, a 5th course comprising Ara-C.

Between October 2002 and January 2009, 1982 patients were randomised between DA (n=994) and ADE (n=988); up to May 2007, patients could also be randomised to FLAG-Ida; the randomised comparison with ADE recruited 1266 patients (FLAG-Ida n=635, ADE n=631). For part of the trial patients could be randomised to GO or not (306 patients in the DA v ADE and 297 in the FLAG-Ida v ADE comparisons were randomised). The median age of patients in the randomised comparisons was 49 years. Overall the ORR was 85% (CR 80%, CRi 5%) and the OS at 5 years is 43%. The randomisations were balanced for age, sex, performance status, de Novo/secondary disease, cytogenetics, white cell count, and GO allocation.

Induction outcomes

CRCRi30-day mortality5 year relapse5 year RFS5 year OS
DA 76% 7% 6% 56% 38% 42% 
ADE 80% 6% 5% 53% 35% 39% 
OR/HR, 95% CI 1.27 (1.03-1.58) ORR: 1.26 (0.99-1.61)  1.00 (0.85-1.18) 1.01 (0.88-1.17) 1.03 (0.90-1.18) 
p-value 0.03 0.06  1.0 0.8 0.7 
FLAG-Ida 84% 2% 6% 42% 48% 46% 
ADE 81% 4% 6% 54% 37% 41% 
OR/HR, 95% CI 0.84 (0.63-1.13) ORR:0.95 (0.69-1.29)  0.69 (0.58-0.84) 0.82 (0.69-0.96) 0.95 (0.82-1.11) 
p-value 0.3 0.7  0.0001 0.02 0.5 
CRCRi30-day mortality5 year relapse5 year RFS5 year OS
DA 76% 7% 6% 56% 38% 42% 
ADE 80% 6% 5% 53% 35% 39% 
OR/HR, 95% CI 1.27 (1.03-1.58) ORR: 1.26 (0.99-1.61)  1.00 (0.85-1.18) 1.01 (0.88-1.17) 1.03 (0.90-1.18) 
p-value 0.03 0.06  1.0 0.8 0.7 
FLAG-Ida 84% 2% 6% 42% 48% 46% 
ADE 81% 4% 6% 54% 37% 41% 
OR/HR, 95% CI 0.84 (0.63-1.13) ORR:0.95 (0.69-1.29)  0.69 (0.58-0.84) 0.82 (0.69-0.96) 0.95 (0.82-1.11) 
p-value 0.3 0.7  0.0001 0.02 0.5 
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With the exception of a suggestion of greater benefit on ORR with FLAG-Ida among patients given GO, overall outcomes were not affected by GO treatment. In consolidation 1445 patients were randomised between MRC (n=723) and HD Ara-C (n=722). Of the 723 Ara-C patients, 328 were randomised to 3g/m2 and 329 to 1.5g/m2: 227 of the 1619 patients who received 4 courses were randomised for a 5th course with 112 allocated 5 courses.

Post-induction outcomes

5-year death in CR5 year relapse5 year RFS5 year OS
Ara-C 10% 53% 42% 54% 
MRC 15% 51% 42% 52% 
OR/HR, 95% CI 0.66 (0.44-0.98) 1.07 (0.90-1.26) 0.99 (0.85-1.16) 0.89 (0.74-1.07) 
p-value 0.04 0.5 0.9 0.2 
Ara-C 1.5g 9% 58% 38% 54% 
Ara-C 3g 14% 51% 43% 52% 
OR/HR, 95% CI 0.62 (0.32-1.18) 1.17 (0.92-1.49) 1.09 (0.87-1.36) 0.94 (0.72-1.24) 
p-value 0.14 0.2 0.5 0.7 
5 courses 0% 58% 42% 60% 
4 courses 1% 53% 46% 58% 
OR/HR, 95% CI 1.25 (0.02-6.30) 1.02 (0.70-1.50) 1.00 (0.68-1.47) 0.91 (0.56-1.47) 
p-value 1.0 0.9 1.0 0.7 
5-year death in CR5 year relapse5 year RFS5 year OS
Ara-C 10% 53% 42% 54% 
MRC 15% 51% 42% 52% 
OR/HR, 95% CI 0.66 (0.44-0.98) 1.07 (0.90-1.26) 0.99 (0.85-1.16) 0.89 (0.74-1.07) 
p-value 0.04 0.5 0.9 0.2 
Ara-C 1.5g 9% 58% 38% 54% 
Ara-C 3g 14% 51% 43% 52% 
OR/HR, 95% CI 0.62 (0.32-1.18) 1.17 (0.92-1.49) 1.09 (0.87-1.36) 0.94 (0.72-1.24) 
p-value 0.14 0.2 0.5 0.7 
5 courses 0% 58% 42% 60% 
4 courses 1% 53% 46% 58% 
OR/HR, 95% CI 1.25 (0.02-6.30) 1.02 (0.70-1.50) 1.00 (0.68-1.47) 0.91 (0.56-1.47) 
p-value 1.0 0.9 1.0 0.7 
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Conclusions:

There were no significant differences in the response rate between induction treatments. FLAG-Ida resulted in a reduced relapse rate but this was balanced by increased myelosuppression and deaths in CR resulting in no overall benefit in survival. No survival differences were seen in any of the post induction comparisons, but the MACE/MidAc arm produced more myelosuppression and required more supportive care, and led to increased death in remission.

Disclosures:

No relevant conflicts of interest to declare.

Topics:
chemotherapy regimen, leukemia, myelocytic, acute, magnetic resonance cholangiography, medical reserve corps, cytarabine, myelosuppression, antibodies, chemotherapy, neoadjuvant, disease remission, gemtuzumab

Author notes

*

Asterisk with author names denotes non-ASH members.

© 2009 by The American Society of Hematology
2009
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