Highlights
– In 439 patients ≥60 years without adverse‑risk cytogenetics enrolled to NCRI AML18, DAGO2 produced higher post‑course‑1 CR/CRi and MRD‑negative CR rates than CPX‑351.
– Three‑year event‑free survival (EFS) and overall survival (OS) favored DAGO2: 3‑yr EFS 34% vs 27% (HR 0.73, p=0.012) and 3‑yr OS 52% vs 35% (HR 0.62, p=0.001).
– CPX‑351 did not improve outcomes in patients with MDS‑related mutations and was associated with worse survival in patients with NPM1 and FLT3 mutations compared with DAGO2.
Background
Older adults with acute myeloid leukemia (AML) represent a heterogeneous population in which patient fitness, disease biology and prior hematologic history (including myelodysplasia‑related changes) critically influence outcomes. In recent years, two different strategies have become important in the management of newly diagnosed older patients who are deemed fit for intensive therapy: (1) reformulated cytotoxic combinations such as CPX‑351 (a fixed‑ratio liposomal formulation of daunorubicin and cytarabine), developed to optimize drug synergy and pharmacokinetics for secondary and therapy‑related AML; and (2) incorporation of targeted antibody–drug conjugates such as gemtuzumab ozogamicin (GO) added to conventional daunorubicin+cytarabine backbones, particularly in non‑adverse risk disease where benefit has been shown.
Choosing between these approaches is a common clinical dilemma. The National Cancer Research Institute (NCRI) AML18 trial compares two commonly used intensive strategies in older adults without adverse‑risk cytogenetics: daunorubicin/cytarabine with fractionated gemtuzumab (DAGO2) versus CPX‑351.
Study design
The analysis comes from a randomized comparison embedded in the NCRI AML18 (version 2) trial (NCT02272478). Between arms, patients were randomized 1:2 to receive either DAGO2 or CPX‑351. Key features:
- Population: 439 patients aged ≥60 years (median 68 years) with newly diagnosed AML and without known adverse‑risk cytogenetics.
- Interventions: DAGO2 — conventional daunorubicin + cytarabine with fractionated dosing of gemtuzumab ozogamicin; CPX — liposomal daunorubicin/cytarabine (CPX‑351) per trial dosing.
- Randomization: 1:2 (DAGO2:CPX‑351).
- Follow‑up: median 35 months.
- Post‑induction strategy: Patients not achieving MRD‑negative remission after course‑1 could enter a second randomization between standard versus intensified chemotherapy.
- Endpoints: Response rates (CR/CRi), MRD‑negative CR, event‑free survival (EFS), overall survival (OS), transplant rates and post‑transplant survival; subgroup analyses by mutation status (e.g., NPM1, FLT3, MDS‑related mutations).
Key findings
Primary response and MRD
After the first course of therapy, the DAGO2 arm had significantly higher overall remission rates (CR + CRi) compared with CPX‑351: 60.0% versus 47.5% (OR 0.61, 95% CI 0.41–0.91; P=0.016). Importantly, DAGO2 yielded more MRD‑negative CRs after course‑1: 47% versus 29% for CPX (OR 0.46, 95% CI 0.29–0.72; P=0.004). MRD negativity after induction is a potent prognostic marker in AML and is increasingly used to guide consolidation and transplant decisions; higher early MRD clearance with DAGO2 may plausibly contribute to downstream survival differences.
Responses after course‑2
Following a second course of therapy the overall response rate (CR+CRi) was numerically higher with DAGO2 (85%) than with CPX‑351 (78%), but this difference did not reach statistical significance (OR 0.64, 95% CI 0.39–1.09; P=0.095).
Survival outcomes
Survival outcomes favored DAGO2. Three‑year EFS was 34% with DAGO2 versus 27% with CPX‑351 (HR 0.73, 95% CI 0.57–0.93; P=0.012). Three‑year OS showed a more pronounced benefit: 52% for DAGO2 versus 35% for CPX‑351 (HR 0.62, 95% CI 0.46–0.83; P=0.001). These differences are clinically meaningful in a population where long‑term survival is limited.
Subgroup analyses by mutation status
Stratified analyses revealed heterogeneity of treatment effect by molecular subgroup. CPX‑351 did not provide a survival benefit in patients with MDS‑related mutations (HR 1.40, 95% CI 0.97–2.03) relative to DAGO2. Notably, CPX‑351 was associated with poorer survival compared with DAGO2 for patients harboring NPM1 mutations (HR 2.83, 95% CI 1.17–6.82) and showed a signal toward worse survival in patients with FLT3 mutations (HR 2.14, 95% CI 0.98–4.68). These findings suggest that disease biology (mutational profile) may materially influence which intensive regimen is preferable.
Transplantation
Approximately 37% of patients proceeded to allogeneic hematopoietic cell transplantation in first remission, with no difference in transplant rates between the randomized arms. Survival after transplant did not differ by induction randomization, indicating that the survival advantage with DAGO2 was not solely a consequence of higher transplant rates.
Second randomization (intensified CPX dosing)
Among the subset entering the course‑2 randomization (n=107), outcomes were equivalent between standard and intensified CPX doses (P=0.565), suggesting dose intensification of CPX‑351 in this setting did not alter survival.
Safety and tolerability
The published summary emphasized efficacy and survival endpoints; detailed comparative safety data (grade ≥3 toxicities, early mortality, infection rates, cytopenia durations) were not provided in the summary data here. Safety remains a critical consideration when selecting between intensive regimens in older adults and should be evaluated in the full manuscript to inform risk–benefit decisions.
Expert commentary and interpretation
The randomized comparison in a non‑adverse cytogenetic cohort provides timely, pragmatic evidence for regimen selection in older, fit AML patients. Key interpretive points:
- Biology matters: The differential effect by mutational subgroup highlights that CPX‑351 is not universally superior and, in fact, may be less effective than an anthracycline/cytarabine backbone with fractionated GO in patients with NPM1 or FLT3 mutations — groups often considered chemo‑sensitive and in whom MRD clearance is prognostically important.
- MRD as an early surrogate: The higher rate of MRD‑negative remission after a single course with DAGO2 likely translated into improved long‑term outcomes. This reinforces the concept that early depth of response is a meaningful intermediate endpoint in older patients treated intensively.
- Transplant‑neutral survival benefit: Equivalent transplant rates and post‑transplant survival suggest that the survival advantage with DAGO2 was established pre‑transplant and sustained irrespective of consolidation strategy.
- Mechanistic hypotheses: CPX‑351 was designed to optimize the molar ratio of daunorubicin and cytarabine and has shown benefit in secondary/therapy‑related AML in prior studies. However, in a cohort selected for non‑adverse cytogenetics, the addition of antibody‑drug conjugate therapy (fractionated GO) may enhance leukemic cell targeting — particularly in CD33‑expressing, molecularly favorable/intermediate disease — leading to superior MRD clearance and survival. These mechanistic explanations remain hypotheses that require further translational study.
- Generalizability and limitations: The trial population excluded patients with adverse‑risk cytogenetics, so results should not be extrapolated to that higher‑risk group where CPX‑351 has been prioritized based on earlier trials. Additionally, full toxicity, quality‑of‑life and comorbidity‑adjusted analyses are needed to guide regimen choice in older adults with varying fitness levels.
Clinical implications
For older adults (≥60 years) with newly diagnosed AML and without adverse‑risk cytogenetics, DAGO2 should be strongly considered as an induction strategy when patients are fit for intensive therapy, particularly for those with NPM1 or FLT3 mutations. CPX‑351 may still have a role in patients with clear secondary or therapy‑related features and adverse biology, but its routine use in non‑adverse cytogenetic disease is not supported by this comparison.
Conclusion
The NCRI AML18 randomized comparison demonstrates that DAGO2 yields higher early remission and MRD‑negative rates and superior 3‑year EFS and OS versus CPX‑351 in older adults without adverse‑risk cytogenetics. Molecular subgroups (NPM1, FLT3, MDS‑related mutations) showed differential benefit, underlining the importance of integrating mutation profiling into induction‑selection decisions. These findings should influence guideline discussions and shared decision‑making in fit older patients, though safety, tolerability and patient preferences remain central to regimen selection.
Funding and clinicaltrials.gov
The analysis reported derives from the NCRI AML18 trial (NCT02272478). Funding sources for the parent trial are reported in the primary publication. Readers should consult the full manuscript for detailed funding and conflict‑of‑interest declarations.
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, Wei AH, Appelbaum FR, et al. Diagnosis and management of AML in adults: 2022 ELN recommendations from an international expert panel. Blood. 2022;140(12):1200–1228. (European LeukemiaNet 2022 recommendations)
Note: Readers are encouraged to consult the full NCRI AML18 manuscript for comprehensive methodology, safety data and subgroup tables required to apply these findings to clinical practice.