PF264 TREATMENT INTENSIFICATION WITH FLAG‐IDA MAY IMPROVE DISEASE CONTROL IN YOUNGER PATIENTS WITH SECONDARY AML WHICH MANIFESTS ITSELF WITH LONGER FOLLOW‐UP: LONG‐TERM ANALYSIS OF THE MRC AML15 TRIAL
Authors: Russell N. , Hills R. , Kjeldsen L. , Spearing R. , Burnett A. 
Published: June 2019

Background:

Typically patients with Secondary AML do badly, even with intensive chemotherapy (typically Ara‐C + anthracycline). A recent phase 3 trial of CPX‐351, a liposomal daunorubicin/ara‐C combination, found significant benefit compared to standard DA 3+7 chemotherapy in a secondary AML population age 60–75 with prior MDS or CMML, therapy related AML, or an MDS‐related karyotype (mOS 9.6 vs 6.0 m p = 0.005). It is unclear whether DA is an appropriate comparator for younger patients or if they do better with more intensive chemotherapy such as FLAG‐Ida.

Aims:

To evaluate the outcomes of secondary AML patients aged 16–59 enrolled in the UK MRC AML15 trial which randomized 1736 patients between DA/DAE (daunorubicin, araC  ±  etoposide) and FLAG‐Ida.

Methods:

Patients aged 16–59 with secondary AML were included, with performance status of ≤2. In AML15 patients were randomised between 2 courses of either DAE/DA (3+10/3+8) or FLAG‐Ida (Burnett et al JCO, 2013). Survival was evaluated using the Kaplan‐Meier method and compared using stratified logrank tests and Cox regression for multivariate analyses. Median follow‐up was 115.6 months (range 8.4–145.2). Outcomes are reported at 5 years. An odds ratio or hazard ratio <1 indicates better outcomes for FLAG‐Ida.

Results:

A total of 115 patients were identified (73 DA/DAE, 42 FLAG‐Ida). Median age was 52 (range 16–59) y; 52% were male; median WBC was 6.4x109/L (range 0.2–260.0); 10%, 65% and 25% had favourable, intermediate and adverse karyotype. There was some evidence that patients given FLAG‐Ida had worse risk karyotype (p = 0.10): analyses are presented both raw and stratified by cytogenetics. CR/CRi rate was 80% (DAE/DA 79%, FLAG‐Ida 81%, unadj. OR 0.91 (0.35–2.34) p = 0.8; strat. OR 0.54 (0.19–1.55) p = 0.3). 5‐year survival was better for patients treated with FLAG‐Ida (median OS 20.2 m/5‐y OS 27% vs 20.6 m/37%, unadj. HR 0.81 (0.52–1.26) p = 0.4) which was significant in stratified analyses (strat HR 0.54 (0.33–0.90) p = 0.02). RFS was improved with FLAG‐Ida (22% vs 41%; unadj. HR 0.70 (0.43–1.15) p = 0.16; strat HR 0.54 (0.31–0.96) p = 0.04). In a multivariable analysis of RFS, only cytogenetic group (HR 2.06 (1.21–3.51) p = 0.03) and FLAG‐Ida (HR 0.52 (0.29–0.95) p = 0.03) emerged as significant prognostic factors. Allografts in first CR occurred in 24% of cases (21% vs 31% p = 0.2). In a landmark analysis at 120 days post remission, survival in the transplanted group was better than the non‐transplanted group after adjustment for cytogenetics (43% vs 32%, unadj. HR 0.80 (0.45–1.44) p = 0.3, strat HR 0.48 (0.23–0.98) p = 0.04).

Summary/Conclusion:

Outcomes in this group of patients are poor with DA/DAE chemotherapy, with median OS of 20.2 m and 5‐y/10‐y survival of 27%/21%. Despite similar median OS (20.6 m) FLAG‐Ida showed a significant improvement in survival in analyses adjusted for the imbalance in cytogenetic risk group with 5‐y/10‐y survival of 37%/31%. While numbers are small, and a greater number of patients received an allograft in first remission in the FLAG‐Ida arm than in the DA/DAE group, there is a suggestion that recipients of an allograft had better outcomes, after adjustment for cytogenetic risk. The emergence of a survival difference after 2 years shows the need for long‐term follow‐up when considering questions of treatment intensification. The improved results with FLAG‐Ida show that DA may not be an appropriate standard of care in younger patients with secondary AML, and that thought should be given to FLAG‐Ida as comparator in this younger population. The NCRI AML19 is currently randomising CPX‐351 versus FLAG‐Ida.

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