Remissions in Newly Diagnosed, High-Risk/Secondary AML Appear Deeper With CPX-351

Deeper remissions in patients with newly diagnosed, high-risk/secondary acute myeloid leukemia (AML) may be achieved with CPX-351 treatment and lead to improvement in overall survival, according to post hoc analyses of a phase 3 study (NCT01696084) published in Blood.

CPX-351 is a liposomal encapsulation of daunorubicin and cytarabine which was designed to promote better efficacy in the AML subgroup compared with standard chemotherapy. The success of this hypothesis was demonstrated in the study’s primary analysis through the achievement of the primary end point, overall survival (OS). In patients treated with CPX-351, the median OS was 9.56 versus 5.95 months with standard chemotherapy (HR, 0.69; 95% CI, 0.52-0.90; 1-sided P = .003). the experimental agent also led to a higher complete remission (CR) rate or CR with incomplete neutrophil or platelet recovery (CRi). The CR or CRi rate in the CPX-315 arm was 48% compared with 33% with standard chemotherapy (2-sided P = .016).

The primary analysis suggested that in patients who achieved a CR, there is potential for CPX-351 to deepen response even further, thus leading to the exploratory post hoc analyses investigating how treatment with CPX-351 impacted the achievement of CRs in comparison with standard chemotherapy, getting patients to hematopoietic cell transplantation (HCT), as well as safety outcomes in older patients with newly diagnosed high-risk/secondary AML.

For the analyses, patients were randomized 1:1 to receive induction therapy with CPX-351 or chemotherapy according to a 7 + 3 dosing schedule. Two cycles of CPX-351 were administered at 100 units/m^2, consisting of daunorubicin 44 mg/m² plus cytarabine 100 mg/m² were administered via 90-minute infusion on days 1, 3, and 5 in the chemotherapy arm, or patients received a 7 + 3 chemotherapy regimen of cytarabine 100 mg/m² per day continuous infusion for 7 days plus daunorubicin 60 mg/m² on days 1, 2, and 3. Investigators recommended a second induction for those with a documented reduction in leukemia burden followed the first induction. The second induction was required for patients who achieved a reduction of 50% or greater in blast count at day 14. However, patients with evidence of aplasia/hypoplasia or equivocal bone marrow assessments.

Moreover, patients included in the analyses who achieved a CR or CRi were able to receive up to 2 cycles of consolidation with CPX-351 dosed at 65 units/m² administered as a 90-minute infusion on days 1 and 3, or a 5 + 2 regimen chemotherapy regimen of cytarabine 100 mg/m² per day via continuous infusion for 5 days plus daunorubicin 60 mg/m² on days 1 and 2. Patients underwent HCT according to the physician’s discretion.

For the post hoc analyses, investigators assessed duration of remission relapse-free survival, and OS in the population of patients with newly diagnosed, high-risk/secondary AML who achieved a CR or CRi during the primary study analysis. Overall, 125 patients were included in the post hoc investigations, including 73 in the CPX-351 arm and 52 in the 7 + 3 arm. The baseline characteristics of the patients were well-balanced between the 2 arms. In terms of age, patients ranged from 48 to 75 years, and the population was predominantly male. Most patients in both arms have an ECOG performance status of 2.

Among all patients who had a CR/CRi from treatment, the median duration of remission was 6.93 months for the CPX-351 arm compared with 6.11 months with 7+3 (HR, 0.77; 95% CI, 0.47-1.26). Looking only at patients who achieved a CR, the median DOR was 7.89 versus 6.54 months, respectively (HR, 0.90; 95% CI, 0.54-1.49). Finally, when investigators looked at patients who achieved a CRi only, the median duration of remission was 5.32 versus 3.09 months, respectively (HR, 0.46; 95% CI, 0.17-1.20). The median recurrence-free survival among the CR achievers was longer with CPX-3512 compared with 7 + 3 at 11.24 months versus 8.82 months (HR, 0.65; 95% CI, 0.39-1.06).

In terms of OS, CPX-351 outperformed 7 + 3 achieved a median OS of 25.43 months compared with 10.41 months (HR, 0.49; 95% CI, 0.31-0.77) in those who achieved either a CR or CRi. In the group of patients who achieved a CR only, the median OS was similar to the overall population at 25.43 months for the CPX-351 arm compared with 10.97 months in the 7 + 3 arm (HR, 0.49; 95% CI, 0.29-0.83). Finally, among those who had a CRi, the median OS was 13.70 months versus 8.97 months, respectively (HR, 0.48; 95% CI, 0.19-1.26).

HCT was received by 52 patients in the CPX-351 arm and 39 in the 7 +3 arm. The majority of those who underwent HCT were in a CR or CRi at the time. The HCT rate was much higher among those treated with CPX-351 at 55 compared with 7 + 3 at 46% (Odds ratio [OR], 0.71; 95% C, 0.35-1.44).

To determine safety, patients were evaluated for the number of treatment-emergent adverse events (TEAEs). In the post hoc analysis for safety, the profile of CPX-351 appeared to be consistent with the primary analysis. The most common TEAEs of any grade reported in the experimental arm and the 7 +3 arm respectively included febrile neutropenia (82% vs. 77%, respectively) and nausea (52% vs. 54%). The most frequently observed grade 3 or higher TEAEs were febrile neutropenia (79% vs. 77%, respectively), hypertension (14% vs 6%), pneumonia (12% vs 15%), bacteremia (11% vs 2%), sepsis (6% vs 10%), and pulmonary edema (3% vs 10%). Febrile neutropenia was also the most common serious TEAE observed in the study.

Cardiac failure was the one TEAEs that led to treatment discontinuation in the study.

“CPX-351 has demonstrated longer median OS, a higher rate of patients undergoing HCT, longer median OS landmarked from the date of HCT, and comparable safety to that of conventional 7+3 chemotherapy among patients who achieved CR or CRi in this population of older adults with newly diagnosed high-risk/secondary AML. Although it was not possible to evaluate the depth of remission via MRD assessments, results of the current analyses suggest the remissions achieved with CPX-351 treatment may permit more patients to proceed to HCT and lead to prolonged survival,” wrote the study authors led by Tara Lin, MD, associate professor of Medicine at the University of Kansas Medical Center.

A subsequent study was recommended by the authors to further test the treatment strategy and how achievement of CR/CRis impact overall outcomes in patients with newly-diagnosed, high-risk/secondary AML.

_Reference:

_{Lin TL, Rizzieri DA, Ryan DH, et al. Older adults with newly diagnosed high-risk/secondary AML who achieved remission with CPX-351: phase 3 post hoc analyses. Blood Adv. 2021; 5 (6): 1719–1728. doi: 10.1182/bloodadvances.2020003510}