Liposomal cytarabine CPX-351 in patients with AML

The breakdown of CPX-351, a liposome encapsulating cytarabine and daunorubicin used for the treatment of patients with acute myeloid leukemia (AML), is carried out by the enzyme cytidine deaminase (CDA). How pharmacokinetics (PK) of the catabolism of cytarabine is affected by individual variations in CDA activity so far is unclear.

CPX-351 received attention earlier this year as the U.S. Food and Drug Administration (FDA) increased its indication to allow for the treatment of pediatric patients with AML.

In a study by Mélanie Donnette and colleagues,¹ nine patients with AML were treated with CPX-351 and the PK was compared with respect to the patient’s classification as a poor metabolizer (PM) or extensive metabolizer (EM), depending on CDA activity.

Study design

Patients were included in this study if they were ≥18 years old and due to be treated with CPX-351 for AML with myelodysplastic-related changes or therapy-related AML.

The primary endpoint in this study was to estimate the PK parameters and exposure. Secondary endpoints were to estimate the buildup of CPX-351 in the bone marrow, and to ascertain if the PK parameters of CPX-351 could be associated with clinical outcome.

Results

Patient characteristics

The age of the patients in the whole cohort was 64 ± 12 years. Of the nine patients in the study, seven were classified as PM with only two as EM. The threshold for determining if a patient was a PM was CDA < 2 U/mg; CDA activity ≥ 2 U/mg resulted in a classification as EM. CDA activity was increased in the EM group (4.43 ± 2.06) compared with the PM group and this was approaching significance (p = 0.056; Table 1).

Table 1. Patient baseline characteristics*

Genotyping of CDA was performed in seven patients. While single nucleotide variations were found in the first and fourth exons, there were no differences in genotypes between the two CDA groups.

Plasma concentration and exposure of cytarabine

The time to reach Cmax (Tmax) came later with the liposomal form of cytarabine compared with total and released cytarabine. There was considerable variation between patients in terms of cytarabine concentrations across all categories:

• Released cytarabine concentration: 47−75%
• Liposomal cytarabine concentration: 14−90%
• Total cytarabine concentration: 31−74%

The exposure level had to be estimated graphically using the mean area under the curve (AUC). For free cytarabine the mean AUC was lower (682 ± 403 h.mg/L) compared with the mean AUC for CPX-351 (942 ± 305 h.mg/L).

Liposomal cytarabine nanoparticles in the bone marrow

Lipidic nanoparticles were transiently visible on bone marrow smears at Day 15 but were not present in smears from Day 30. These nanoparticles were only present at Day 15 in patients who had been treated with CPX-351 and not found in the negative control patients.

Individual PK and total cytarabine plasma exposure

When investigating the PK parameters, it was found that systemic clearance was 0.164 L/h and the central volume of distribution was 5.39 L. Variability between patients ranged from 20−61%. The mean AUC was 4,465 h.mg/L.

CDA status clearly impacted the PK parameters of cytarabine. Compared with PM patients:

• Total cytarabine clearance was 142% greater in EM patients
• Plasma half-life was reduced by 60%
• Exposure was reduced as a result with a 77% decrease in trough level
• 66% lower cumulative area under the plasma concentration-time curve from time zero to infinity (AUC_0–inf)

The ratio released/total cytarabine according to AUC was 47% for PM patients and 18% for EM patients. Variability for the whole cohort was 63%, whereas when considering the PM or the EM group alone the variability decreased to 33 and 39%, respectively.

The results for Cmax and free cytarabine were only available for seven patients and the results are shown in Figure 1. In both cases, patients who were classified as PM showed greatly increased values compared with EM patients. PM patients also demonstrated increased exposure for the encapsulated form at 988 ± 307 h.ng/mL compared with 668 h.ng/mL for EM patients.

Figure 1. Differences in plasma exposure of cytarabine between EM and PM patients*

AUC, area under the plasma concentration-time curve; CDA, cytidine deaminase; Cmax, maximum observed plasma concentration; EM, extensive metabolizer; PM, poor metabolizer.
*Adapted from Donnette et al.¹

 AUC, area under the plasma concentration-time curve; CDA, cytidine deaminase; Cmax, maximum observed plasma concentration; EM, extensive metabolizer; PM, poor metabolizer.
*Adapted from Donnette et al.¹

Survival outcomes

The overall response rate (ORR) was 75% with:

• Complete response (CR) = 62.5%
• Partial response (PR) = 12.5%
• Progressive disease (PD) = 25%

After showing PD following induction and not responding to consolidation, two patients died. Patients who responded to treatment showed no difference in total cytarabine AUC_0–inf at 3,855 ± 2,418 compared with 4,739 ± 1,010 h.mg/L for non-responders (p = 0.64).

All patients experienced febrile neutropenia. Grade 3−5 adverse events were seen in 56% of patients, with a trend where patients who had higher exposure to cytarabine showed non-hematologic severe toxicities. Due to the small sample size and high level of variability between patients this was not statistically significant.

One patient died 40 days after starting CPX-351 as a result of colonic obstruction, and this was classified as a toxic death. This patient had the PM phenotype and demonstrated the longest cytarabine elimination half-life, of 43.9 days, of the whole cohort.

For released cytarabine the same trend was seen between exposure and toxicities; however, this was not significant.

Conclusion

While this study is limited in terms of the number of patients included, CDA status was shown to impact the metabolism of liposomal CPX-351 and led to a large inter-patient variation in clearance. Patients categorized as EM with respect to CDA status showed clearance values 142% greater than PM patients and a 60% shorter half-life. As patients with PM made up 78% of the cohort this may explain why the ORR was so high at 75%. In addition, this may also explain the high level of toxicity experienced by patients, with all patients experiencing febrile neutropenia. These results show that using CDA status to tailor the dose of CPX-351 for patients with AML may be beneficial and allows greater personalization of treatment regimens.