Upfront CPX-351 Induction at 8 Spanish Hospital. Efficacy of CPX-351 in Everyday Clinical Practice and Increased Insight into Its Use in Younger Adults
Authors: Fernández Villalobos Manuel Jorge , Ortiz Javier , Figuera Alvarez Angela , De Laiglesia Almudena , De Miguel Carlos , Pradillo Fernandez Virginia , Esteve Jordi , Diaz Beya Marina , Polo Marta , Olave Mayte , Moles Maria del Mar , Pimentel Amparo , Garcia-Sanz Ramon , Rodriguez Macias Gabriela 
Published: December 2024

INTRODUCTION:
CPX-351 is a liposomal formulation of daunorubicin and cytarabine approved for the treatment of acute myeloid leukemia (AML). In the pivotal study, only older patients (pts) (≥60-75 y) with newly diagnosed of high-risk secondary AML were included. The updated classification of AML (5th WHO and ICC2022) now include myelodysplasia (MDS) related gene mutations in the criteria for AML-MDS-related (AML-MR). Currently pts &lt; 60y and/or with mutations in MDS-related genes (MDG) have been treated with CPX-351 in the real-life setting.
The aim of this study was to investigate the efficacy of CPX-351 in real life, and its potential benefit in pts excluded from the pivotal study, such as young pts and AML patients with other mutational profiles (as AML-MR) and the impact of response in proceedings to the ASCT.
METHODS:
We retrospectively reviewed data from 87 AML pts treated with CPX-351 from June 2018 to June 2024 in 8 hospitals from Spain. Only 74 pts of them were included as they had received all CPX-351 pre-programmed cycles to avoid short follow up. We use the ELN2022 criteria to evaluate the response: complete remission (CR) or CR with incomplete hematologic recovery (CRi), morphologic leukemia free state (MLFS) and partial response (PR). The statistical analysis was performed using IBM SPSS v. 26
RESULTS:
A total of 74 pts treated with CPX-351 were included. Median age was 65y (20-78) of which 21(28%) were &lt; 60y. Forty-seven male and 27 female. The median (IQR) leucocytes and platelets was 3.4·109/L (1.5-12-3) and 62·109/L (25-121) and blast in baseline BM 28% (20-53). Up to 40% of pts had at least one major comorbidity at diagnosis. Karyotype was normal in 28(37%) and complex in 11(15%). Prior MDS or MDS/MPN was described in 22 pts. According to the alterations that defining MDS, 23 had cytogenetic alterations (MDC) and 31 had MDG. Seven (9%) pts had NPM1 mutated (with MDS alterations associated). The majority of pts had adverse risk according to ELN2022 criteria: 50(68%) adverse risk,18(24%) intermediate and 6(8%) favorable. Of note, the cytogenetic characteristics and mutational profile of the 21 young pts were as follows: complex karyotype 2 and normal 5, cytogenetic alterations of myelodysplasia 6, TP53 mutated 4, mutations in genes related to myelodysplasia 6, NPM1 4.
Median time (days, IQR) to neutrophil (ANC &gt;500 /µL) and platelet (&gt;20000/µL) recovery was 35 (28-49) and 35 (27-44) respectively. The safety profile of CPX-351 was similar as previously described in the literature. Early mortality at 30 and 60 days was 6(8%) and 9 (12%) respectively.
With a median follow up of 8 months (IQR 5-21), the overall response rate (ORR) was 57%: 39 CR/CRi, 3 PR. Thirteen pts received 2 cycles for induction, and only 23% showed response. Thirty pts received a second line (2L) after CPX-351(16 Azacitidine (AZA) + Venetoclax (VEN), 5 AZA, 4 FLAG-IDA, 5 others).
Overall survival (OS) at 1y and 3y was 67% and 48% respectively. Response to CPX-351 defined 3 groups of different OS-12m (by Kaplan Meier): response after 1 cycle 74%, after 2 cycles 67% and no response 34%; p&lt;0,05). Of note, non-responders who went to reinduction (n=13) had similar OS12m (46.6 vs 33%) and reached ASCT (33 vs 26.6%) at a similar rate to those who switched lines.
Interestenly, the 7 NPM1mutated pts treated with CPX-351, showed an OS-3y of 86%, and 5 (71%) proceeding to ASCT. The other 2 pts are alive in treatment (one with oral AZA and the other with AZA + VEN).
Regarding ASCT data: 37pts (50%) reach ASCT, 16 of 21 (76%) young pts (&lt;60y) and 21of 53(41%) older pts (&gt;60y). As expected, a higher number of young pts reach ASCT. Data at ASCT: 30 in response after CPX-351, although 5 with 2nd line (2L) as a bridge to ASCT for different reasons (such as MRD positive or waiting for ASCT) and 7 after 2L: 1 CR (AZA +VEN), 4 in aplasia (2 with AZA + VEN and 2 with AZA),1 with leukemia (direct to ASCT), 1 after FLAG-ida (status prior to ASCT unknow). The ASCT, are an independent factor for OS-3y vs. non-ASCT (76 vs 38%). Our results confirm the benefit of ASCT in both older and younger patients with OS-3y 62% vs 28% (≥60y) and 75%vs20%(≤60y).
CONCLUSION
Despite the relatively low number of patients, our results confirm the benefit of first line treatment with CPX-351 in younger patients with high-risk AML and appears to advance an excellent response in patients NPM1 mutated (with MDS alterations). Further data are necessary to address the efficacy of CPX-351 in AML-MR and in younger patients with AML.