No survival benefit of CPX-351 over FLAG-Ida in AML patients with adverse cytogenetics

CPX-351 does not improve response, overall survival, or event-free survival compared with FLAG-Ida in patients with acute myeloid leukaemia (AML) with adverse cytogenetics, but is associated with an improvement in duration of remission and relapse-free survival, results from the AML19 trial demonstrated.

AML patients with adverse cytogenetics have a poor prognosis; less than 10% will survive for 5 years or more following standard intensive chemotherapy [1]. Previous studies reported improved survival with FLAG-Ida (fludarabine/cytosine arabinoside, granulocyte-colony stimulating factor, and idarubicin) treatment in younger patients identified with high-risk AML following induction therapy and in patients with secondary AML [2]. On the other hand, CPX-351 (liposomal daunorubicin and cytarabine) has demonstrated an improved survival predominantly in older patients (>60 years) with secondary AML compared with standard chemotherapy [3].

To compare the efficacy of CPX-351 and FLAG-Ida, the AML19 trial (ISRCTN78449203) randomised 635 patients (mainly <60 years) with high-risk AML or myelodysplastic syndrome (>10% blasts) to CPX-351 or FLAG-Ida. Endpoints included overall and event-free survival, response, and the number of patients delivered to transplant with their post-transplant survival. Groups of high-risk patients were randomised with the aim of proceeding to allogeneic transplant:

• Group 1 (n=195) had known adverse-risk cytogenetics; they were randomised at diagnosis between 4 courses of CPX-351 and 2 courses of FLAG-Ida followed by MACE/MidAC consolidation.
• Group 2 (n=263) were determined high-risk by validated risk score, had FLT3-ITD without an NPM1 mutation, and had refractory disease; they were randomised after induction course 1.
• Group 3 (n=177) were randomised after course 2 if they had persisting minimal residual disease at the time of relapse.

Prof. Nigel Russell (Guy's and St Thomas' NHS Foundation Trust, UK) presented the results from Group 1 (n=88 FLAG-Ida, n=107 CPX-351) [4]. Overall response rate after course 2 was 75.6% and 63.8% for treatment with FLAG-Ida and CPX-351, respectively (HR 0.54; P=0.06). Complete response was observed in 51.2% in the FLAG-Ida arm versus 40.0% in the CPX-351 arm. The median duration of remission, however, numerically favoured CPX-351 (510 vs 391 days; P=0.24).

There was no significant difference in median overall survival (13.3 vs 11.4 months), median event-free survival (7.1 vs 6.0 months), and median relapse-free survival (22.1 vs 8.4 months) for CPX-351 and FLAG-Ida, respectively. Time to transplant was comparable in both arms (139 days vs 131 days), and slightly more patients receiving CPX-351 proceeded to transplant (50.5% vs 43.9%; P=0.41). Post-transplant survival was not different between treatments received.

“In this exploratory study of AML patients with adverse cytogenetics, CPX-351 did not improve response, overall survival, or event-free survival compared with FLAG-Ida, but was associated with an improvement in duration of remission and relapse-free survival,” summarised Prof. Russell.

1. Hills RK, et al. Lancet Oncol. 2014;15:986–996.
2. Burnett AK, et al. Leukemia. 2018;32:2693–2697.
3. Lancet JE, et al. J Clin Oncol. 2018;36:2684–2692.
4. Russell N, et al. A randomised comparison of CPX-351 and FLAG-IDA in high risk acute myeloid leukemia. Results from the NCRI AML 19 trial. Abstract S128. EHA2022 Hybrid Congress, 09–12 June.

 

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Posted on 1 July 2022