番茄社区

ORLANDO -- Patients with acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) lived significantly longer if they achieved a complete remission (CR) with liposomal cytarabine-daunorubicin (CPX-351, Vyxeos) as induction therapy as compared with conventional 7+3 chemotherapy, according to a study reported here.

Patients treated with CPX-351 had a median overall survival (OS) of 19.15 months versus 11.58 months with 7+3 (seven days of cytarabine plus three days of daunorubicin). A complete remission with CPX-351 was associated with longer OS in patients with de novo AML with myelodysplastic syndrome (MDS) karyotype and those with antecedent MDS.

The findings, which came from an exploratory analysis of a randomized trial, were consistent with those from patients without AML-MDS, as reported at the Transplantation and Cellular Therapy Meetings.

"CPX-351 improved median overall survival and median overall survival landmarked from the date of hematopoietic cell transplantation versus conventional 7+3," said Stefan Faderl, MD, of Jazz Pharmaceuticals, filling in for the scheduled speaker who was unable to attend the conference. "The longer overall survival with CPX-351 in this subgroup of patients with AML-MRC suggests potentially deeper responses may be achieved with CPX-351. The safety profile of CPX-351 in this subgroup was consistent with that of the overall safety population and the known safety profile of 7+3."

The World Health Organization as patients with AML and a history of MDS or MDS/MPN (myeloproliferative neoplasia), an MDS-related cytogenetic abnormality, or multilineage dysplasia in more than 50% of cells in two or more cell lineages in the absence of NPM1 or biallelic CEBPA mutations. AML-MRC is associated with poor prognosis and a lower rate of complete remission after standard induction chemotherapy, as compared with other AML subtypes, Faderl noted.

CPX-351 has FDA approval and European Medicines Agency approval for adults with newly diagnosed therapy-related AML or AML-MRC. A randomized phase III trial showed that CPX-351 significantly improved median OS versus 7+3 in older patients with newly diagnosed high-risk secondary AML. The trial involved a total of 309 patients, 246 of whom met criteria for AML-MRC.

The post hoc analysis focused on the subgroup of patients with AML-MRC who achieved a CR (including CRi, incomplete hematologic recovery). CPX-351 led to a total CR rate of 48% (11% CRi) versus 33% (8% CRi) with conventional therapy. The difference represented an 83% increase in the odds ratio for CR/CRi with the liposomal therapy.

CPX-351 outperformed 7+3 in patients with prior exposure to hypomethylating agents (36% vs 29%) and without prior exposure (58% vs 36%). Faderl pointed out that the results were similar to those for patients without AML-MRC (47% with CPX-351 vs 36%).

The analysis of OS in the CR/CRi subgroup showed that treatment with CPX-351 was associated with a 42% reduction in the hazard ratio versus 7+3 (95% CI 0.34-0.96). Other survival analyses also favored treatment with CPX-351:

• 1-year OS: 64% vs 43%
• 2-year OS: 48% vs 31%
• Median OS, de novo AML with MDS karyotype: 25.43 vs 14.03 months
• Median OS, antecedent MDS: 18.53 vs 10.87 months

Among patients without AML-MRC, CR/CRi was associated with a median OS not yet reached in the CPX-351 group versus 9.15 months with 7+3 (HR 0.19, 95% CI 0.06-0.62).

Patients who achieved CR/CRi with CPX-351 were more likely to undergo stem-cell transplantation (54% vs 43%, HR 1.18, 95% CI 0.79-1.76). The pattern was similar for patients with de novo AML and MDS karyotype (57% vs 50%) and those with antecedent MDS (53% vs 44%). Median OS from the date of transplantation also was longer in the CPX-351 group (not reached vs 14.09 months, HR 0.61, 95% CI 0.27-1.40).

The median time to neutrophil and platelet recovery was 6 to 12 days longer in the CPX-351 group, depending on whether a patient received one or two cycles of induction therapy.

During a discussion that followed the presentation, Faderl acknowledged that all of the survival curves from the analysis did not reflect statistically significant differences and reiterated the unplanned, post hoc nature of the analysis. An unidentified speaker noted that patients who received a second cycle of induction therapy in the control arm received less therapy (5+2). Faderl said the lower dose for re-induction represented a compromise among investigators and noted the older age of the study population, among other considerations.

In response to another question, Faderl said analysis of patient specimens at baseline did not show substantive differences in mutational patterns or burdens that could explain the improved survival with CPX-351. However, post-treatment samples were not analyzed for presence of residual disease or mutations in patients who achieved CR/CRi.

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