CPX-351 Offers Potential Bridge to Transplant for Secondary AML

Jeffrey E. Lancet, MD

More patients with acute myeloid leukemia (AML) could proceed to transplant following treatment with CPX-351 (Vyxeos) compared with the traditional 7+3 chemotherapy regimen, according to an exploratory analysis presented at the 2017 BMT Tandem Meetings.

The exploratory analysis was conducted on data from a phase III study comparing CPX-351 with 7+3 for patients with secondary untreated AML. Overall, 34 of the 52 patients (65%) in the CPX-351 arm who proceeded to transplant remained alive after a median follow-up of 521 days. In the 7+3 arm, after 442 days of follow-up, 13 of 39 patients remained alive (33%).

From the time of transplant, the median overall survival (OS) was not reached in the CPX-351 arm versus 10.25 months for 7+3, representing a 54% reduction in the risk of death (HR, 0.46; P = .0046). Furthermore, 100 days after transplant, the rate of mortality from any cause was 53% lower in the CPX-351 arm versus 7+3.

"A greater proportion of patients treated with CPX-351 versus 7+3 in both age subgroups eventually went on to receive an allogeneic transplant," said Jeffrey E. Lancet, MD, from the Moffitt Cancer Center, during the presentation. "We believe that these results may indicate CPX-351 could provide a potential bridge to successful allogeneic transplant in an otherwise poor-risk group of AML patients, keeping in mind that these results should be interpreted with caution as they do represent an exploratory analysis of a non-randomized subgroup of a larger phase III trial."

CPX-351 is a liposomal bound coformulation of cytarabine and daunorubicin which delivers the two medications in a 5:1 molar ratio. The phase III trial consisted of 309 patients aged 60 to 75 who were stratified evenly between each arm into groups aged 60 to 69 (n = 198) or from 70 to 75 (n = 111). Patient characteristics were well-balanced between the 2 arms and groups.

Findings from the full cohort of patients in the study showed a 3.61-month improvement in OS for CPX-351 versus 7+3 (HR, 0.69; P = .005). The complete response (CR) or CR with incomplete platelet or neutrophil recovery (CRi) rate was 47.7% versus 33.3% for CPX-351 and 7+3, respectively (OR, 1.77; 95% CI, 1.11-2.81; P = .016).

"In this phase III trial, CPX-351 was associated with a significantly longer median OS and higher response rates compared with 7+3 in patients over age 60 with newly diagnosed, high-risk or secondary AML," noted Lancet.

More patients in the CPX-351 arm went on to receive a stem cell transplant (34% versus 25%); however, this difference was not statistically significant (OR, 1.54; 95% CI, 0.92-2.56; P = .098). When looking at age demographics for those who received transplant, significantly more patients aged 70 to 75 years could proceed to transplant in the CPX-351 arm versus 7+3 (28.1% vs 11.1%; OR, 3.12; 95% CI, 1.12-3.72).

Overall, in the age 60 to 69 group, there were 36 patients in the CPX-351 arm and 33 in the 7+3 arm who proceeded to transplant. In those aged 70 to 75, there were 16 in the CPX-351 arm and 6 in the 7+3 group. In the younger group, approximately 55% of patients were male and most had an ECOG performance status of 0 to 1 (94%). In the older age group, the population consisted more heavily of males (77%). AML subtypes and karyotypes were well balanced between the groups.

"Overall, the survival of transplanted patients was longer in patients treated with CPX-351 versus 7+3, although in the 70 to 75 subgroup this difference did not quite reach statistical significance," noted Lancet.

Those with FLT3 mutations appeared to respond better to treatment with CPX-351. In this population, those treated with CPX-351 (n = 22) had a CR or CRi of 68.2%, and 45% went on to receive a transplant. In the 7+3 group of FLT3-mutant AML (n = 20), the CR plus CRi rate was 25% and 10% proceeded to transplant.

"Of those patients who had a FLT3 mutation, a higher percentage achieved a CR or CRi with CPX-351 versus 7+3. Not surprisingly, probably because of this, a higher proportion of patients with FLT3 went on to transplant, if they received CPX-351 as their initial therapy," said Lancet.

The analysis looked at the safety profiles prior to transplant for those in the CPX-351 arm (n = 52) and 7+3 (n = 38). There were differences in infection and bleeding events in the CPX-351 arm that delayed recovery from myelosuppression, Lancet noted. Eighty-five percent of those in the CPX-351 arm experienced febrile neutropenia versus 71% of those in the 7+3 group. Additionally, the epistaxis rates were 38% versus 24%, for CPX-351 and 7+3, respectively.

The adverse events for each agent remained consistent in the 60 to 69 age group and those aged 70 to 75. "When we did the same analysis based on the age breakdown, there really was no significant difference in the safety profile for CPX-351 in the transplant patients in the different age subgroups," said Lancet.

Based on data from the full study, the FDA granted CPX-351 a breakthrough therapy designation in May 2016 as a treatment for patients with therapy-related AML or AML with myelodysplasia-related changes. Final OS data from the phase III study were initially presented at the 2016 ASCO Annual Meeting. The company developing the treatment, Jazz Pharmaceuticals, is working to complete a new drug application.

Lancet JE, Uy GL, Cortes J, et al. Analysis of Transplantation Rate and Overall Treatment Efficacy By Age for Patients Aged 60 to 75 with Untreated Secondary Acute Myeloid Leukemia (AML) Given CPX-351 Liposome Injection Versus Conventional Cytarabine and Daunorubicin in a Phase III Trial. Presented at: BMT Tandem Meetings; February 22-26, 2017; Orlando, FL. Abstract 19.

In the age 60 to 69 group, the median OS from the time of transplant was not reached in the CPX-351 arm versus 12.16 months with 7+3 (HR, 0.49; 95% CI, 0.24-0.98; P = .02). In the aged 70 to 75 arm, the median OS was not reached with CPX-351 versus 6.64 months with 7+3 (HR, 0.22; 95% CI, 0.04-1.23; P = .033).