In a letter to the Editor of Haematologica, Roland B. Walter [member of the AGP North American Steering Committee] , from the Fred Hutchinson Cancer Research Center, Seattle, WA, and colleagues reported results from a phase II randomized study (NCT01804101), which evaluated attenuated doses of CPX-351, a liposomal formulation of daunorubicin and cytarabine co-encapsulated at a molar ratio of 1:5, in medically less fit patients with untreated AML with a Treatment Related Mortality (TRM) score of > 13.1.
The main objective of this phase II study was to estimate whether 32 units/m2 or 64 units/m2 or both dose levels of CPX-351 could improve TRM rate (versus the historical rate of 30%) while keeping Complete Remission (CR) rate constant in AML patients with high risk of TRM.
In total, 48 patients with a median age of 70.5 years (range, 39.1 –91.1 years) were enrolled in this study between May 2013 and November 2016. Patients were randomized 1:1 to receive either 32 or 64 units /m2 of CPX-351 on Days 1, 3 and 5 for up to four identical induction/re-induction courses. Patients received a median of two (range: 1 – 6) cycles of CPX-351 therapy. Due to the small sample size, randomization was stratified using a dynamic allocation scheme based on TRM score, cytogenetic risk and presence/absence of secondary disease.
Initially, the first 20 patients enrolled in this study were randomized to receive either doses of CPX-351.
Key findings in the 64 units/m2/dose arm (n = 10):
- CR and CR with Incomplete Blood Count Recovery (CRi) was achieved in two patients respectively
- Both patients relapsed (after 27 and 251 days) and died on Day 320 and 364
- Early death occurred in four (40%) patients by Day 28 due to infections with TRM scores of 14.7, 24.1, 33.4, and 58.1 respectively
- Median Overall Survival (OS): 6 months
- Due to early death, accrual in the 64 units/m2/dose arm was terminated
The remaining patients (n = 28) enrolled in this study were administered 32 units/m2 CPX-351
Key findings in the 32 units/m2/dose arm (n = 38):
- CR was achieved in 10 patient
- CRi was achieved in one patient
- Resistant disease was observed in 21 patients
- Early death rate: 28.9% (11/38)
- Six patients died due to indeterminate causes
- Median OS: 3 months
- Median relapse free survival in responders (n = 11): 7 months
In summary, the optimal treatment dosage of CPX-351 for less-fit AML patients remains unidentified. The authors concluded that this study demonstrates that CPX-351 at 32 or 64 units/m2 failed to lower the TRM rate to 15% compared to the historical control while maintaining CR rate of 30% in patients with high-risk of AML.