Long-Term Follow-Up Confirm OS Advantage With CPX-351 in Newly Diagnosed AML

Jeffrey Lancet, MD

CPX-351 (Vyxeos) continued to showcase an overall survival (OS) benefit versus conventional 7+3 chemotherapy in patients with newly diagnosed high-risk/secondary acute myeloid leukemia (AML), as well as in those who achieved complete response (CR) or CR with incomplete neutrophil or platelet recovery (CRi) and in patients who underwent hematopoietic stem cell transplantation (HSCT), according to 5-year follow-up results from a phase 3 trial (NCT01696084) that were virtually presented during the 2020 European Hematology Association Annual Congress.

“The final 5-year follow-up results from this phase 3 study support the prior evidence that CPX-351 has the ability to produce or contribute to long-term remission and survival in older patients with newly diagnosed, high-risk or secondary AML,” the authors said in a virtual poster presentation during the meeting.

Older patients with AML and those with high-risk secondary AML have poor outcomes with conventional 7+3 chemotherapy. CPX-351 is a liposomal bound coformulation of cytarabine and daunorubicin that delivers the 2 medications in a 5:1 molar ratio. In 2017, the FDA approved the agent for the treatment of adults with newly diagnosed, therapy-related AML or AML with myelodysplasia-related changes.

The approval was based on findings from this phase 3 trial, in which patients with newly diagnosed high-risk/secondary AML between the ages of 60 to 75 were randomized to 1 to 2 cycles of induction with CPX-351 (n = 153) or 7+3 (n = 156). Patients were excluded from enrollment if they had acute promyelocytic leukemia t(15;17) or favorable cytogenetics at screening, prior treatment intended as induction therapy for AML (hydroxyurea permitted), active secondary malignancies, or central nervous system leukemia.

As part of the induction phase, patients in the investigational arm received 100 units/m2 of CPX-351 (100 mg/m² of cytarabine and 44 mg/m² of daunorubicin) over 90-minute infusions on days 1, 3, and 5 for the first cycle and days 1 and 3 for the second cycle. Patients in the control arm received 100 mg/m² daily of continuous cytarabine infusion for 7 days in the first cycle and 5 days in the second cycle and 60 mg/m² of daunorubicin on days 1, 2, and 3 in the first cycle and days 1 and 2 for the second cycle.

For consolidation, patients received up to 2 cycles of 65 units/m² of CPX-351 (65 mg/m² of cytarabine and 29 mg/m² of daunorubicin) or 5+2 chemotherapy for those who achieved CR/CRi. Patients could receive HSCT at the discretion of the treating physician.

Baseline characteristics were well balanced between arms. The majority of patients were between the ages of 60 to 69 (64%), male (61.5%), and had an ECOG performance status (PS) of 1 (61.5%).

After a median follow-up of 20.7 months, the median OS was 9.56 months with CPX-351 versus 5.95 months with 7+3 (HR, 0.69; 95% CI, 0.52-0.90; 1-sided P =.003). Additional findings showed that the overall safety profile of CPX-351 was consistent with the known safety profile of conventional 7+3 chemotherapy.

According to multivariate analysis, the factors that were associated with improved OS included an ECOG PS of 0 (HR, 0.53), non-poor karyotype (HR, 0.49), white blood cell count less than 20 x 10⁹/L (HR, 1.64), platelet count above 50 x 10⁹/L (HR, 0.64), and treatment with CPX-351 (HR, 0.70).

After a median follow-up of 60.65 months, the median OS was 9.33 months (95% CI, 6.37-11.86) and 5.95 months with CPX-351 and 7+3, respectively (HR, 0.70; 95% CI, 0.55-0.91). The estimated 3- and 5-year OS rates were also higher with CPX-351 versus 7+3, at 21% vs 9% and 18% vs 8%, respectively.

A total of 53 patients (35%) in the CPX-351 arm and 39 patients (25%) in the 7+3 arm underwent HSCT. The median OS from the time of HSCT was not reached in the CPX-351 arm versus 10.25 months (95% CI, 6.21-16.69) in the 7+3 arm (HR, 0.51; 95% CI, 0.28-0.90). The estimated 3- and 5-year OS rates from the time of HSCT were higher in the CPX-351 arm versus the 7+3 arm, at 56% vs 23% and 52% vs not estimable, respectively.

The percentage of patients who underwent HSCT and achieved CR/CRi was numerically higher in the CPX-351 arm (n = 41; 77%) versus the 7+3 arm (n = 24; 62%).

CR/CRi was achieved by 73 patients (48%) in the CPX-351 arm versus 52 patients (33%) in the 7+3 arm. Among all patients who achieved CR/CRi, the median OS was longer in the CPX-351 arm versus the 7+3 arm. The median OS was 21.72 months (95% CI, 13.01-29.70) and 10.41 months (95% CI, 7.82-15.21) in the CPX-351 and 7+3 arms, respectively (HR, 0.59; 95% CI, 0.39-0.88). Moreover, the estimated OS rates were higher for CPX-351 versus 7+3 at 3 and 5 years, at 36% versus 23% and 30% versus 19%, respectively.

A total of 23 patients received the full 2 cycles of consolidation with CPX-351 in the investigational arm versus 12 patients with 5+2 in the control arm.

Among patients who achieved CR/CRi, 41 patients (56%) in the CPX-351 arm and 24 patients (46%) in the 7+3 arm underwent HSCT. Here, the median OS was not reached in the CPX-351 arm versus 11.65 months (95% CI, 4.57-24.28) in the 7+3 arm (HR, 0.50; 95% CI, 0.26-0.97). Similarly, the estimated 3- and 5-year OS rates favored the use of CPX-351 versus 7+3, respectively, at 58% versus 29% and 52% versus not estimable.

At a minimum follow-up of 5 years, a total of 124 patients (81%) in the CPX-351 arm and 140 patients (93%) in the 7+3 arm had died, primarily due to progressive disease. The 30- and 60-day mortality rates for CPX-351 and 7+3, respectively, were 6% versus 11% and 14% versus 21%.

Reference

Lancet JE, Uy GY, Newell LF, et al. Five-year final results of a phase 3 study of CPX-351 versus 7+3 in older adults with newly diagnosed high-risk/secondary acute myeloid leukemia. Presented at: 2020 European Hematology Association Congress; June 11-21, 2020; Virtual. Abstract EP556.