Patients with poor risk cytogenetics and TP53wt treated with venetoclax and HMA show increases in overall survival compared to treatment with azacitidine only

Patients with acute myeloid leukemia (AML) with poor-risk cytogenetics show sub optimal responses to conventional therapies. Patients carrying a TP53 mutation are highly correlated with poor risk cytogenetic profiles and is independently associated with adverse outcomes when treated with venetoclax. The treatment option of venetoclax plus azacitidine is the standard regimen for patients who are unsuitable for intensive induction chemotherapy. However, the outcome of using hypomethylating agents (HMA) and venetoclax to treat patients with AML who have poor-risk cytogenetics and who harbour either TP53^mut or TP53^wt, is unknown.

During the 63rd American Society of Hematology (ASH) Annual Meeting and Exposition, Daniel Pollyea, University of Colorado School of Medicine, Aurora, US, presented results from a study where the safety and efficacy of venetoclax plus azacitidine or HMA were assessed in patients with treatment-naïve AML, who had poor-risk cytogenetics and who harboured either TP53^mut or TP53^wt.¹ We summarize key results below.

Study design¹

Treatment-naïve patients with AML who were not suitable for chemotherapy due to co-morbidities or being ≥75 years, were enrolled.

Data were combined from the ongoing phase III VIALE-A trial (NCT02993523) comparing venetoclax + azacitidine and placebo + azacitidine, and a phase Ib study (NCT02203773) where patients were treated with venetoclax + HMA (azacitidine or decitabine). Treatment was organized into a 28-day cycle; 400 mg venetoclax was administered daily, 75 mg/m² azacitidine on Days 1–7, and 20 mg/m² decitabine on Days 1–5.

Cytogenetics risk was determined pre-treatment as per the National Comprehensive Cancer Network (NCCN) criteria, with several abnormalities found to be associated with poorer outcomes. These included three or more clonal chromosomal abnormalities, monosomal karyotype, and chromosomal band 11q23 translocation. TP53 status was also assessed at screening and analyzed using MyAML panel assays. Patients with inconclusive or missing results were excluded.

Key endpoints were complete remission (CR) + CR with incomplete hematologic remission (CRi), duration of remission (DoR), and overall survival (OS).

Results

The pooled data included 546 patients, of which 353 were treated with venetoclax + azacytidine, and 145 with azacitidine only. A total of 127 patients in the venetoclax + azacitidine treatment group were found to have poor cytogenetics versus 56 patients in the azacitidine treatment group. A further 401 patients were treated with venetoclax + HMA; of these, 152 were found to have poor cytogenetics. The median variant allele frequency for TP53 was 42.9% for both venetoclax + azacitidine and azacitidine alone.

In patients with poor-risk cytogenetics and TP53^wt, the composite complete remission (CRc) rate in the venetoclax + azacitidine group was 70% compared to 23% in the azacitidine group. The median DoR was 18.37 months for patients treated with venetoclax + azacitidine, and 8.51 months for those treated with azacitidine alone. The median OS for the venetoclax + azacitidine treatment group was 23.43 months compared to 11.29 months in the azacitidine group. Results were similar for patients treated with venetoclax + HMA; the CRc rate was found to be 74%, the median DoR was 16.72 months, and the median OS was 21.13 months. These results were also comparable to those patients with intermediate-risk cytogenetics and TP53^wt.

For patients with poor-risk cytogenetics and TP53^mut, the CRc rate in the venetoclax + azacitidine group was 41% versus 17% for patients in the azacitidine group. The median DoR was 6.54 months for patients treated with venetoclax + azacytidine, and 6.7 months for those treated with azacitidine alone. The median OS was 5.17 months for patients in the venetoclax + azacitidine group compared to 4.9 months in the azacitidine group. Patients treated with venetoclax + HMA were found to have a CRc rate of 47%, and a median DoR and OS of 6.54 and 5.42 months, respectively. CRc rate for each group can be seen in Figure 1, and median DoR and OS are shown in Figure 2.

Figure 1. CRc rates in patients with either TP53^wt or TP53^mut per treatment group*

CRc, composite complete remission.
*Adapted from Pollyea et al.¹

Figure 2. Median DoR and OS in patients with either TP53^wt or TP53^mut per treatment group*

DoR, duration of remission; OS, overall survival.
*Adapted from Pollyea et al.¹

Common Grade 3 adverse events (AEs) in patients with poor-risk cytogenetics and TP53^wt, treated with either venetoclax + azacitidine or azacitidine alone, included thrombocytopenia (36% in both groups), febrile neutropenia (32% and 14%, respectively), and pneumonia (18% and 23%, respectively). Patients with TP53^mut also experienced thrombocytopenia (28% for both groups), febrile neutropenia (43% and 22%, respectively), and pneumonia (26% and 53%, respectively). Patients treated with Ven + HMA also reported similar Grade 3 events.

Conclusion

Patients with poor-risk cytogenetics and TP53^wt treated with either venetoclax + azacitidine or venetoclax + HMA showed notable increases in remission rates, DoR, and OS compared with azacitidine only. In contrast, patients with poor-cytogenetic risk and TP53^mut did not show significant improvement in DoR or OS in any treatment group. No new toxicities were reported.