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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.
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.
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.
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.
Table 1. Impact of CPX-351 consolidation cycles on median OS in patients who received and did not receive allo-HSCT*
Median, months |
OS |
p value |
---|---|---|
No allo-HSCT |
|
|
2 cycles of CPX-351 consolidation |
20.36 |
< 0.05 |
<2 cycles of CPX-351 consolidation |
12.2 |
|
Allo-HSCT |
|
|
2 cycles of CPX-351 consolidation |
28.4 |
Not significant |
1 cycle of CPX-351 consolidation |
35.0 |
|
0 cycles of CPX-351 consolidation |
Not reached |
|
Allo-HSCT, allogeneic hematopoietic stem cell transplantation; OS, overall survival. |
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.
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
Table 2. Landmark analysis of patients alive and in CR at Day 90 according to TP53 mutational status and CK*
Patients who received allo-HSCT |
Median OS, months |
---|---|
Mutated TP53, no CK + TP53-wt (n = 151) |
Not reached |
Mutated TP53, CK (n = 9) |
14.3 |
Mutated TP53 (n = 15) |
43.0 |
Mutated TP53, no CK (n = 6) |
Not reached |
CK, complex karyotype; CR, complete remission; OS, overall survival; wt, wild-type. |
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.
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).
Figure 3. Most frequently observed mutations*
*Adapted from Riva.4
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.
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.
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.
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.
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