Clinical trialPhase 3Blood cancers (leukaemia, lymphoma and myeloma)Leukaemia

CPX-351 (cytarabine and daunorubicin) Liposome for Injection Versus Conventional Cytarabine Plus Daunorubicin in Older Patients With Newly Diagnosed Secondary Acute Myeloid Leukemia

J Clin Oncol · 2018309 patients (153 CPX-351 and 156 7+3)

Lancet JE, Uy GL, Cortes JE, Newell LF, Lin TL, Ritchie EK, et al. J Clin Oncol. 2018. 36:2684-2692

Study type: Clinical trial
Study name: CPX-351
Phase: Phase 3
Design: Randomised (1:1, stratified by age and AML subtype), open-label, multicentre trial at 39 academic and regional cancer centres in the United States and Canada
Sample size: 309 patients (153 CPX-351 and 156 7+3)
Source: J Clin Oncol · 2018
Trial registration: NCT01696084

In plain words

In older people with a type of acute myeloid leukaemia called "secondary" or high-risk (for example leukaemia caused by earlier cancer treatment or leukaemia with myelodysplasia-related changes), the results of usual chemotherapy are poor; in this study median survival with the usual "7+3" treatment was about 6 months. CPX-351 contains the same two familiar drugs, cytarabine and daunorubicin, packed in a fixed ratio inside very tiny fat particles (liposomes) so that more of them reach the leukaemia cells. In this study of 309 patients aged 60 to 75, CPX-351 raised median survival to about 9.5 months and more patients went into remission (about 48% versus 33%); at five-year follow-up, 18% of patients in the CPX-351 group were alive versus 8% in the usual-treatment group. After this treatment, white blood cells and platelets take a little longer to recover, so regular blood tests and watching for infection are important during this time.

Key results

9.56 vs 5.95 months

Median overall survival

HR 0.69 (95% CI 0.52–0.90); one-sided P=0.003

47.7% vs 33.3%

Overall remission rate

Two-sided P=0.016

5.9% vs 10.6%

Early mortality to day 30

Two-sided P=0.149

13.7% vs 21.2%

Early mortality to day 60

Two-sided P=0.097

Dose and schedule cards

CPX-351 (liposomal daunorubicin and cytarabine)

Newly diagnosed therapy-related AML or AML with myelodysplasia-related changes (age 60 to 75 in the trial)On the page “Acute myeloid leukaemia (AML): 2022 classification, ELN genetic risk and treatment” · Induction and consolidation in patients fit for intensive treatment

Newly diagnosed therapy-related AML or AML with myelodysplasia-related changes (age 60 to 75 in the trial)

Drug	Dose	Route	Schedule
First induction
CPX-351	Daunorubicin 44 mg/m² and cytarabine 100 mg/m² (liposomal)	IV, 90-minute infusion	Days 1, 3 and 5
Second induction (if not in remission)
CPX-351	Daunorubicin 44 mg/m² and cytarabine 100 mg/m²	IV, 90 minutes	Days 1 and 3
Consolidation (up to 2 cycles)
CPX-351	Daunorubicin 29 mg/m² and cytarabine 65 mg/m²	IV, 90 minutes	Days 1 and 3

Cycle length: Second induction 2 to 5 weeks after the first; consolidation 5 to 8 weeks after the start of the last induction
Duration: 1 to 2 induction cycles and up to 2 consolidation cycles

Before each cycle, calculate the previous cumulative anthracycline exposure and assess cardiac, hepatic and renal function; give prophylactic antiemetics. Start consolidation only after neutrophils exceed 0.5 and platelets 50×10⁹/L. CPX-351 is not interchangeable with conventional daunorubicin or cytarabine products. In the phase 3 trial, neutrophil and platelet recovery took longer with CPX-351.

On the page “Acute myeloid leukaemia (AML): 2022 classification, ELN genetic risk and treatment” · Induction and consolidation in patients fit for intensive treatment

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1CPX-351 (liposomal daunorubicin and cytarabine)

Induction (up to 2 cycles): CPX-351 100 units/m² as a 90-minute IV infusion on days 1, 3 and 5; in the second induction on days 1 and 3.

Consolidation (up to 2 cycles, for patients with complete remission or complete remission with incomplete neutrophil or platelet recovery): CPX-351 65 units/m² as a 90-minute infusion on days 1 and 3.

Dose expression in the FDA label (Vyxeos): first induction: daunorubicin 44 mg/m² and cytarabine 100 mg/m² (liposomal) on days 1, 3 and 5; second induction: the same dose on days 1 and 3; consolidation: daunorubicin 29 mg/m² and cytarabine 65 mg/m² (liposomal) on days 1 and 3.

2Cytarabine + daunorubicin 7+3 (control group)

First induction ("7+3"): cytarabine 100 mg/m² per day as a continuous IV infusion for 7 days with daunorubicin 60 mg/m² IV on days 1, 2 and 3.

Second induction ("5+2"): cytarabine for 5 days and daunorubicin on days 1 and 2.

Consolidation (up to 2 cycles, for patients with complete remission or complete remission with incomplete neutrophil or platelet recovery): "5+2" at the same dose as the second induction cycle. Further details in the full text of the paper.

Source of the regimen details: Abstract of the five-year report of the same trial, PMID 34171279 (Lancet Haematol 2021), for the dose and schedule of both groups, and the FDA label for Vyxeos for expressing the CPX-351 dose in mg of daunorubicin and cytarabine

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients aged 60 to 75 years with newly diagnosed high-risk or secondary acute myeloid leukaemia (AML). According to the abstract of the five-year report of the same trial (Lancet Haematol 2021): pathological diagnosis of AML according to the 2008 World Health Organization (WHO) criteria, no previous induction therapy for AML and ECOG performance status 0 to 2. The exact definitions of the high-risk and secondary subgroups are given in the full text of the paper.

Endpoints

Primary endpoint: overall survival (in all randomised patients).

Other outcomes reported in the abstract: overall remission rate, early mortality to day 30 and 60, time to neutrophil and platelet count recovery, and adverse events.

Safety and side effects

The incidence of non-haematological adverse events was comparable in the two groups, although with CPX-351 the treatment phase was longer and neutrophil and platelet count recovery occurred later. Early mortality with CPX-351 versus "7+3": to day 30, 5.9% versus 10.6% (P=0.149), and to day 60, 13.7% versus 21.2% (P=0.097). In the five-year report, 6 (5%) of 124 deaths in the CPX-351 group and 7 (5%) of 140 deaths in the "7+3" group were considered related to study treatment. The percentage of grade 3 or higher adverse events is not reported in the abstracts (details in the full text of the paper).

Clinical significance and place in guidelines

According to the abstract of the five-year report, the primary analysis of this trial supported the approval of CPX-351 by the FDA and the European Medicines Agency (EMA). Indication in the FDA label (Vyxeos): treatment of newly diagnosed therapy-related acute myeloid leukaemia or AML with myelodysplasia-related changes in adults and children aged one year and older. At the final five-year follow-up (Lancet Haematol 2021; median follow-up about 60 months), the survival advantage was maintained: median overall survival 9.33 versus 5.95 months (HR 0.70; 95% CI 0.55–0.91) and five-year overall survival 18% (95% CI 12–25) versus 8% (4–13). The most common cause of death in both groups was progression of leukaemia.

Limitations

The trial was open-label. Only patients aged 60 to 75 years with high-risk or secondary AML were enrolled, and the results cannot be directly generalised to younger patients or other types of AML. Despite the significant benefit, median overall survival in both groups was less than one year. With CPX-351 the treatment phase was longer and neutrophil and platelet count recovery was later. The study was funded by the manufacturer (Jazz Pharmaceuticals).

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.