CPX-351 as first-line treatment in AML: Real-world data

CPX-351, a liposomal formulation of cytarabine + daunorubicin, is approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of newly diagnosed patients with acute myeloid leukemia (AML) with myelodysplasia-related changes (AML-MRC) or therapy-related AML (t-AML). This approval was based on results from a phase III trial (NCT01696084) that demonstrated a survival benefit with CPX-351 vs conventional 7+3 chemotherapy in older patients with high-risk secondary AML (sAML).

Additionally, findings from the phase III UK AML19 trial (ISRCTN78449203) suggest a relapse-free survival benefit from CPX-351 vs fludarabine + cytarabine + granulocyte-colony stimulating factor + idarubicin (FLAG-Ida) in younger patients with high-risk AML or myelodysplastic syndromes (MDS), and an overall survival (OS) benefit in patients with AML with MDS-related mutations. However, real-world studies are needed to confirm the efficacy of CPX-351 when followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT),¹ to determine the optimal duration of treatment with CPX-351 and timing of allo-HSCT,² and to fully elucidate the prognostic impact of unfavorable gene mutations.^3,4

In addition, the updated 5th edition of the World Health Organization (WHO) Classification of Haematolymphoid Tumours and the 2022 International Consensus Classification (ICC) of Myeloid Neoplasms and Acute Leukemias now include MDS-related mutations in the criteria for AML myelodysplasia-related (AML-MR, formerly AML-MRC).⁵ Further data are necessary to determine the efficacy of CPX-351 in younger patients with AML-MR and whether patients with mutation-defined AML-MR (AML-MRmut) have similar responses to other AML-MR subgroups.⁵ Below, we summarize several posters presented during the European Hematology Association (EHA) 2024 Hybrid Congress, by Avenoso¹, Guolo², Todisco, ³Riva⁴, and Peters,⁵ which discuss real-world outcomes of patients with AML treated with CPX-351.

Real-world outcomes of CPX-351 followed by allo-HSCT¹

Study design and patient population

This analysis included patients with AML-MRC (n = 92) and t-AML (n = 18) who received upfront CPX-351 induction at five centers, between 2018 and 2023. The median age was 64 years, with 68% of patients aged ≥60 years. The primary endpoint was OS.

Key findings

• After a median follow-up of 10 months, the overall response rate (ORR) was 69%.
• Neutropenic fever occurred in 60% of patients, leading to 6 deaths.
• Median OS was higher in patients who received allo-HSCT (n = 52) vs no allo-HSCT (n = 52; p < 0.0001) and in patients aged ≤60 vs ≥60 years (p = 0.008; Figure 1).
  • In patients who received allo-HSCT, median OS was not reached for either age group.
  • Multivariable analysis confirmed that patients who did not receive allo-HSCT had a lower OS (p < 0.0001).
• In patients with a TP53 mutation (n = 17), median OS was 6 months, and 21 months vs 5 months in patients who received allo-HSCT vs did not receive allo-HSCT, respectively.
• Overall relapse rate was 20%, with a median time to relapse of 11 months.

Figure 1. OS in patients who received CPX-351 induction* 

Allo-HSCT, allogeneic hematopoietic stem cell transplantation; NR, not reached OS, overall survival.
*Data from Avenoso.¹

 These real-world data further confirm the efficacy of CPX-351 in patients with high-risk AML and highlights the survival benefit of allo-HSCT consolidation in patients with AML-MRC or t-AML.

Optimal duration of CPX-351 treatment, timing of allo-HSCT, and impact of TP53 mutations on response to CPX-351^2,3

Study design and patient population

This study included 513 patients with sAML (t-AML, n = 108; AML-MRC, n = 405) who were treated with CPX-351 in 38 centers in Italy, from January 2019. The median age was 65.6 years, and 6% and 4.6% of patients had NPM1 and FLT3-internal tandem duplication (ITD) mutations, respectively. Of, 335 patients evaluated for the presence of TP53 mutations, 15% were TP53 mutation-positive, and 33% of these had a concomitant complex karyotype (CK). Patients were stratified by 2017 European LeukemiaNet (ELN) risk, with 5.2%, 34.5%, and 60.3% of patients having favorable, intermediate, and adverse risk, respectively.  

Key findings: CPX-351 consolidation cycles and allo-HSCT²

• The complete remission (CR) rates after induction Cycles 1 and 2 were 58% and 66.3%, respectively, and 48.8% of patients received allo-HSCT in first CR.
  • The CR rates were higher in patients with mutated NPM1 vs NPM1 wild type (wt) (p < 0.05), and also in favorable risk patients (p < 0.05).
• After a median follow-up of 23.66 months, the median OS was 16.23 months.
  • The median OS was higher in patients with mutated NPM1 vs NPM1-wt (24.6 months; p < 0.05) and in patients with favorable risk (not reached; p < 0.05).
• In the landmark analysis of patients alive and in CR at Day 90, allo-HSCT was the strongest predictor of OS (median OS not reached vs 16.3 months for allo-HSCT vs no allo-HSCT, respectively; p < 0.05).
• Receiving 2 cycles of CPX-351 consolidation was beneficial vs <2 cycles in patients not proceeding to allo-HSCT (p < 0.05) but not in patients who received allo-HSCT (Table 1).

Table 1. Impact of CPX-351 consolidation cycles on median OS in patients who received and did not receive allo-HSCT*

 These results confirm the effectiveness of CPX-351 in sAML, including in patients with NPM1 mutations or ELN 2017 favorable risk. They also imply that allo-HSCT should be performed as soon as CR is achieved, and for patients who are ineligible for allo-HSCT further consolidation with CPX-351 is beneficial.

Key findings: Prognostic impact of TP53 mutations³

• CR rate after induction Cycle 1 was similar in patients with mutated TP53 vs TP53-wt but was lower in patients with mutated TP53 with concomitant CK vs TP53-wt (p < 0.05; Figure 2).

Figure 2. CR rate after induction Cycle 1 in patients evaluated for TP53 mutations* 

CK, complex karyotype; CR, complete remission; wt, wild-type.
*Data from Todisco.³

•  Patients with mutated TP53 had a similar OS when compared with patients with TP53-wt; however, OS was poorer in patients with concomitant TP53 mutation and CK vs those with either TP53 mutation and no CK (p < 0.05) or those with TP53-wt (p < 0.05).
• • Among patients with CK, the presence of TP53 was associated with a shorter OS compared with TP53-wt (p < 0.05).
• In patients who received allo-HSCT, those with concomitant mutated TP53 and CK had worse outcomes (Table 2; p < 0.05).

Table 2. Landmark analysis of patients alive and in CR at Day 90 according to TP53 mutational status and CK*

This analysis confirms the efficacy of CPX-351 in patients with TP53-mutated AML and additionally found that concomitant CK had worse outcomes. Consolidation with allo-HSCT may improve survival outcomes in these patients.

Prognostic impact of high-risk mutations in elderly patients⁴

Study design and patient population

This single-center study included 80 patients with sAML, including t-AML, treated with CPX-351, with a median age of 70 years. Mutational analysis was performed using next-generation sequencing, and MRD testing was performed in all patients achieving CR with multicolor flow cytometry (MFC).

Key findings

• The most frequently observed mutations are shown in Figure 3.

Figure 3. Most frequently observed mutations* 

*Adapted from Riva.⁴

•  62.5% and 76% of patients showed molecular features linked to venetoclax or 7+3 chemotherapy resistance, respectively.
• After Cycle 1, 80% of patients achieved CR, of which 67% were MFC-MRD negative.
• At median follow-up of 39.3 months, median OS was 18 months, and 2-year OS rate was 31.8%.
• CR, MRD negativity, and OS were not affected by any of the high-risk mutations or high mutational burden, and OS was also not impacted by presence of a hypomethylating agent + venetoclax resistance profile; median OS was 13 vs 14 months for patients with vs without, respectively.
• Multivariate analysis showed that MRD negativity was the strongest prognostic factor for OS (p < 0.05).
• In landmark analysis of patients alive and in CR at Day 90, allo-HSCT (n = 23) within 3 months of achieving CR (n = 8) was associated with better outcomes vs no allo-HSCT (n = 41) or allo-HSCT after 3 months (n = 15; p < 0.03).

These results demonstrate that treatment with CPX-351 can induce MRD-negative CR in elderly patients with sAML, regardless of mutational burden or resistance to hypomethylating agent + venetoclax. In addition, early allo-HSCT consolidation was associated with improved long-term survival.

CPX-351 vs 7+3 in patients aged <60 years with AML-MR⁵

Study design and patient population

This study included 61 younger patients, aged 18–59 years, with AML-MR based on the 2022 WHO/ICC criteria, who were treated with CPX-351 as a first-line therapy, as part of the Myeloid Malignancy Association of Rapid Research Outcomes Working Group (MARROW). Outcomes were compared to a 1:2 matched retrospective cohort of 122 patients aged 18–59 years with AML-MR who received conventional 7+3 chemotherapy first-line therapy through protocols of the Cancer and Leukemia Group B (CALGB)/Alliance for Clinical Trials in Oncology (Alliance). Patients with mutated FLT3-ITD were excluded, and no patients in the Alliance cohort received allo-HSCT in first CR. The four subgroups of AML-MR were evenly matched between cohorts, with 25%, 30%, 72%, and 26% of patients with t-AML, antecedent MDS/chronic myelomonocytic leukemia (CMML), AML-MRC, and AML-MRmut, respectively.

Key findings

• In patients treated with CPX-351, the CR rate was 48% and composite CR (CRc) rate was 59%.
• In total, 18% and 19% of patients in the CPX-351 and 7+3 cohorts had TP53 mutations, respectively.
  • In TP53-wt patients, CR rates (62% vs 55%; p = 0.60) and median OS (1.2 vs 1.2 years; p = 0.91) were similar between the CPX-351 and 7+3 cohorts.
• CRc rates and median OS were similar overall and in patients with AML-MRmut, regardless of treatment with CPX-351 or 7+3 (Figure 4).
• There were no significant differences in CRc rates and median OS across each AML-MR subgroup when comparing CPX-351 vs 7+3.
• In total, 25% of patients in the CPX-351 cohort received allo-HSCT in first CR, with a 3-year OS rate of 72%.

Figure 4. Comparison of A CRc rates and B median OS in patients with AML-MR and AML-MRmut treated with CPX-351 vs 7+3 chemotherapy* 

AML-MR, AML myelodysplasia-related; AML-MRmut, mutation-defined AML-MR; CRC, composite complete remission; OS, overall survival.
*Data from Peters.⁵ 

Based on these results, further clarification is needed to determine the impact of CPX-351 in the treatment of AML-MR and particularly in patients aged <60 years.

Conclusion

These real-world findings presented at EHA 2024 confirm the efficacy of CPX-351 in patients with sAML.^1-5 First-line treatment with CPX-351 was associated with high response rates, regardless of mutational profile,^3,4 although patients with mutated TP53 and concomitant CK did have poor outcomes.³ Several studies highlighted the survival benefit of allo-HSCT consolidation, particularly in patients with mutated TP53;^1-4 however, in patients ineligible for allo-HSCT, consolidation with CPX-351 improved outcomes.² Further analyses are needed to confirm whether treatment with CPX-351 confers a survival advantage over conventional 7+3 chemotherapy in patients aged <60 years within the updated subclass AML-MR.⁵ Taken together, these findings highlight the benefit of first-line treatment with CPX-351 in patients with sAML, and the importance of timely allo-HSCT in eligible patients in order to optimize outcomes.^1–4

This educational resource is independently supported by Jazz Pharmaceuticals. All content is developed by SES in collaboration with an expert steering committee; funders are allowed no influence on the content of this resource.