Clinical Outcomes Based on Treatment Approach in Secondary AML with Prior Hypomethylating Agent Exposure

Treated secondary acute myeloid leukemia (ts-AML) is a high-risk malignancy and patients are often administered chemotherapy or hypomethylating agents (HMAs) plus venetoclax (VEN) in clinical practice, with the impact of prior HMA exposure remaining unknown to date. A retrospective, single-institution, observational study was conducted to assess the impact of chemotherapy or HMA + VEN frontline treatment approaches on clinical outcomes in patients with ts-AML and prior HMA exposure.

This study included patients with AML secondary to myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML) who received their first antileukemic therapy between June 2004 and January 2021, and who had prior HMA exposure for their antecedent disease. Patients were classified into 3 treatment cohorts: intensive chemotherapy (IC), low-intensity chemotherapy (LIC), or HMA + VEN. Clinical outcomes assessed included complete response (CR)/CR with incomplete hematologic history (CRi) rate, overall response rate (ORR; defined as CR + CRi + morphologic leukemia-free state [MLFS]), overall survival (OS), and relapse-free survival (RFS).

A total of 562 patients with ts-AML were included in the analysis; of these, 271 (47%) patients received IC, 237 (41%) received LIC, and 54 (9%) received HMA + VEN. In the overall cohort, patients had received a median of 1 prior therapy for their previous MDS/CMML diagnosis. Baseline characteristics were generally similar among the 3 treatment cohorts, except that the IC cohort was significantly younger than the LIC or HMA + VEN cohorts.

In the overall cohort, the CR/CRi rate was 26% and ORR was 34%; median OS was 4.8 months, and RFS was 5.9 months. In comparison to the IC/LIC therapies, patients who were treated with HMA + VEN achieved significantly higher CR/CRi rates (39% vs 25%; P = .03) and ORR (54% vs 33%; P = .002), which translated into significant improvement in OS (median OS, 5.8 months vs 4.7 months; 1-year OS, 34% vs 17%; P = .05) and RFS (median RFS, 12.9 months vs 5.3 months; 1-year RFS, 55% vs 22%; P = .04). Efficacy outcomes in terms of CR/CRi rate, ORR, and OS were similar in the IC or LIC cohorts. Treatment did not have an impact on early mortality (60-day mortality: IC, 14%; LIC, 9%; HMA + VEN, 13%). Overall, 13% of patients treated with IC underwent allogeneic stem-cell transplant, compared with 5% of those treated with IC and 9% of patients treated with HMA + VEN.

Subgroup analysis by risk karyotype indicated poor outcomes in patients with adverse risk karyotype regardless of treatment received (IC/LIC vs HMA + VEN: ORR, 24% vs 28%, P = .66). However, in the non─adverse risk karyotype cohort, HMA + VEN therapy was associated with significantly higher CR/CRi rates (57% vs 30%; P = .008) and ORR (78% vs 39%; P = .0003) compared with IC/LIC without VEN; and superior OS (5.0 vs 6.3 vs 13.7 months; 1-year OS, 217% vs 30% vs 54%; P = .05) compared with IC or LIC.

When the impact of age in the IC (aged <60 and ≥60 years) and HMA + VEN (any age) treatment cohorts was evaluated, patients treated with HMA + VEN had significantly higher OS compared with IC-treated patients aged ≥60 years (5.8 months vs 4.1 months; 1-year OS, 35% vs 12%; P = .009) and showed a trend toward superior OS compared with IC-treated patients aged <60 years (5.8 months vs 5.0 months; 1-year OS, 35% vs 16%; P = .16).

Based on these results, it was concluded that patients with ts-AML and prior HMA exposure derived significant clinical benefit from HMA + VEN therapy compared with chemotherapy-based approaches, particularly in patients with non─adverse risk karyotype and aged ≥60 years.

Source: Venugopal S, et al. ASH 2021; abstr 794.

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