Highlight
– In the NCRI AML18 randomized comparison (n=439; median age 68), DAGO2 produced higher course‑1 CR/CRi and MRD‑negative CR rates than CPX‑351 (DAGO2 CR+CRi 60% vs CPX 47.5%; MRD‑neg CR 47% vs 29%).
– DAGO2 was associated with superior 3‑year event‑free survival (EFS 34% vs 27%; HR 0.73, 95% CI 0.57–0.93, P=0.012) and overall survival (OS 52% vs 35%; HR 0.62, 95% CI 0.46–0.83, P=0.001).
– CPX‑351 did not improve outcomes in patients with MDS‑related mutations (HR 1.40) and was associated with worse outcomes in NPM1‑mutated and FLT3‑mutated subgroups.
Background: clinical context and unmet need
Acute myeloid leukemia (AML) in older adults presents a therapeutic challenge: age‑related physiology, higher incidence of secondary AML or antecedent myelodysplastic syndromes, and adverse biology all reduce tolerance and response to intensive chemotherapy. CPX‑351 (a fixed‑molar ratio liposomal formulation of cytarabine and daunorubicin) was developed to improve delivery and preserve synergistic drug ratios and has regulatory approvals for therapy‑related AML and AML with myelodysplasia‑related changes. Gemtuzumab ozogamicin (GO), an anti‑CD33 antibody‑drug conjugate used in fractionated dosing, has demonstrated benefit when added to anthracycline‑cytarabine backbones in certain patient groups, improving remission rates and, in some trials, survival.
However, direct randomized comparisons of CPX‑351 against contemporary anthracycline/cytarabine regimens that include targeted agents such as fractionated GO have been lacking, particularly in patients who do not have adverse‑risk cytogenetics. The NCRI AML18 trial (version 2) sought to address this gap by randomizing older adults without known adverse cytogenetics to either DAGO2 (daunorubicin + cytarabine plus fractionated gemtuzumab) or CPX‑351.
Study design and methods
The comparison was embedded within the UK NCRI AML18 trial (NCT02272478). Key design elements:
- Population: 439 patients aged ≥60 years (median age 68 years) with newly diagnosed AML and no known adverse‑risk cytogenetics.
- Randomization: 1:2 allocation to DAGO2 (daunorubicin/cytarabine with fractionated gemtuzumab) versus CPX‑351.
- Treatment strategy: induction course‑1 followed by response assessment with MRD testing. Patients not achieving MRD‑negative remission after course‑1 could enter a second randomization examining standard versus intensified chemotherapy (including intensified CPX dosing for those randomized to CPX‑351 initially).
- Endpoints: primary comparative outcomes reported include response rates (CR/CRi), MRD‑negative CR rates after course‑1, event‑free survival (EFS), overall survival (OS), rates of transplant in first remission, and subgroup analyses by molecular features (e.g., MDS‑related mutations, NPM1, FLT3).
- Follow‑up: median 35 months.
Key findings
The trial produced several findings with potential immediate clinical relevance.
Response rates and MRD
After the first course of therapy, the DAGO2 arm had higher overall response rates (CR + CRi) than CPX‑351: 60.0% versus 47.5% (odds ratio 0.61, 95% CI 0.41–0.91; P=0.016). Importantly, MRD‑negative CR rates after course‑1 were substantially greater with DAGO2: 47% versus 29% for CPX‑351 (OR 0.46, 95% CI 0.29–0.72; P=0.004).
Following course‑2 (which included patients who received additional therapy per protocol), overall response rates converged and were not statistically different: 85% for DAGO2 versus 78% for CPX (OR 0.64, 95% CI 0.39–1.09; P=0.095).
Survival outcomes
DAGO2 produced superior long‑term outcomes in this cohort. At three years, EFS was 34% for DAGO2 versus 27% for CPX‑351 (hazard ratio 0.73, 95% CI 0.57–0.93; P=0.012). Overall survival favored DAGO2 more markedly: 3‑year OS was 52% versus 35% (HR 0.62, 95% CI 0.46–0.83; P=0.001).
Subgroup analyses by molecular features
Stratified analyses showed heterogeneous treatment effects by mutation subgroup. CPX‑351 showed no clear benefit over DAGO2 in patients with MDS‑related mutations (HR 1.40, 95% CI 0.97–2.03) and was associated with worse survival in patients with NPM1 mutations (HR 2.83, 95% CI 1.17–6.82) and in those with FLT3 mutations (HR 2.14, 95% CI 0.98–4.68). These hazard ratios indicate that, within this trial population, CPX‑351 was at best non‑superior and possibly harmful for certain molecular subgroups.
Transplantation and post‑transplant outcomes
Overall, 37% of patients underwent allogeneic stem cell transplantation in first remission (CR1), and the transplantation rate did not differ by randomized arm. Survival after transplant was similar between arms, indicating that the observed OS benefit with DAGO2 was not driven solely by differences in transplant frequency or post‑transplant outcomes.
Course‑2 intensification
Among the 107 patients who entered the course‑2 randomization comparing standard versus intensified CPX dosing, there was no difference in survival between standard and intensified dosing strategies (P=0.565), suggesting dose intensification of CPX‑351 within this context did not alter medium‑term outcomes.
Safety
The summary data provided did not present a detailed toxicity profile for each arm in this report excerpt. The primary efficacy and survival endpoints, MRD results, and transplant rates are reported. Safety should be reviewed in the full publication for grade‑specific toxicities, early mortality, and infection rates, which are critical when choosing therapy for older adults.
Expert commentary and interpretation
These randomized, contemporary data challenge the assumption that CPX‑351 broadly improves outcomes across older AML populations. In a cohort limited to patients without known adverse‑risk cytogenetics, DAGO2 achieved superior early MRD clearance and translated into better EFS and OS compared with CPX‑351. The magnitude of the survival difference (HR for OS 0.62) is clinically meaningful and strengthens the case for continuing to use anthracycline/cytarabine backbones with fractionated GO in selected older patients with non‑adverse cytogenetics.
Several mechanistic and practical considerations may explain the results. Fractionated GO delivery can increase CD33‑targeting efficacy while mitigating toxicity, potentially augmenting the cytotoxic backbone and promoting deeper remissions detectable by MRD. CPX‑351’s liposomal formulation alters pharmacokinetics and tumor exposure; it performed well in prior trials for therapy‑related and secondary AML but may not confer an advantage in patients without adverse cytogenetics or in those with certain molecular profiles. The discordant effects in molecular subgroups—particularly the worse outcomes among NPM1‑mutated and FLT3‑mutated patients treated with CPX‑351—warrant caution and further mechanistic study.
Limitations include that the trial population excluded patients with known adverse‑risk cytogenetics, so findings should not be generalized to unselected older AML populations or to those specifically defined by secondary AML biology. Subgroup analyses may be underpowered and hypothesis‑generating rather than definitive. Details on MRD methodology and cutpoints, complete safety data, and information on concurrent targeted therapy use (e.g., FLT3 inhibitors) are needed to fully contextualize the results in modern practice.
Clinical implications
For clinicians treating older patients with newly diagnosed AML who lack adverse cytogenetics, these data suggest that an anthracycline/cytarabine backbone plus fractionated gemtuzumab (DAGO2) should remain a strong therapeutic option and may provide superior survival compared with CPX‑351. CPX‑351 should continue to be considered for patients with therapy‑related AML or AML with myelodysplasia‑related changes where prior randomized evidence and approvals support its use, but its routine use in the non‑adverse cytogenetic older AML population now appears unsupported by this trial.
Molecular profiling remains essential: the interaction between treatment type and genomic subsets (NPM1, FLT3, MDS‑related mutation sets) highlights that personalization by both cytogenetic and molecular risk is crucial when selecting induction strategies. Integration with targeted agents (e.g., FLT3 inhibitors, IDH inhibitors) was not reported here and will be an important area for future trials and real‑world analyses.
Future directions and research gaps
Key priorities include:
- Detailed safety comparisons and quality‑of‑life analyses in older adults to guide shared decision‑making.
- Validation of the differential effects by molecular subgroup in independent datasets and mechanistic studies to understand why CPX‑351 underperformed in certain genotypes.
- Trials evaluating combinations of CPX‑351 or anthracycline/cytarabine + GO with targeted agents (FLT3, IDH inhibitors) and with MRD‑guided therapy intensification or de‑escalation strategies.
- Exploration of MRD dynamics and standardized MRD assays across trials to better translate MRD findings into treatment pathways.
Conclusion
In the NCRI AML18 comparison of DAGO2 versus CPX‑351 among older adults without adverse‑risk cytogenetics, DAGO2 produced higher early MRD‑negativity rates and superior 3‑year EFS and OS. CPX‑351 did not confer benefit in patients with MDS‑related mutations and was associated with worse outcomes in NPM1‑ and FLT3‑mutated subgroups. These results support the continued use of anthracycline/cytarabine plus fractionated gemtuzumab in appropriate older patients and underscore that CPX‑351 should not be assumed to be superior outside its established indications without careful consideration of cytogenetic and molecular features.
Funding and clinicaltrials.gov
The NCRI AML18 trial is registered at clinicaltrials.gov: NCT02272478. Funding sources for the trial are reported in the primary publication (see citation below).
References
1. Knapper S, Dillon LW, Babu M, et al. CPX‑351 versus daunorubicin, cytarabine plus gemtuzumab ozogamicin in older adults with non‑adverse risk AML: NCRI AML18. Blood. 2025 Nov 14:blood.2025031006. doi: 10.1182/blood.2025031006. Epub ahead of print. PMID: 41237344.
2. Döhner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations. Blood. 2017;129(4):424–447. (European LeukemiaNet recommendations; useful framework for risk‑stratified therapy.)
3. Castaigne S, Pautas C, Terré C, et al. Effect of gemtuzumab ozogamicin on survival of adult patients with de‑novo acute myeloid leukaemia (ALFA‑0701): a randomised, open‑label, phase 3 study. Lancet. 2012;380(9840):1508–1516.
Article information
Primary report: Knapper S et al., Blood (2025). ClinicalTrials.gov identifier: NCT02272478.
