Influence of Molecular Abnormalities on Treatment Response of Venetoclax Plus Azacytidine and Homoharringtonine Versus Venetoclax Plus Hypomethylating Agent in Relapsed/Refractory Acute Myeloid Leukemia

Purpose: Aim to explore the impact of molecular and cytogenetic abnormalities on the response of venetoclax (VEN)-based therapies in relapsed/refractory acute myeloid leukemia (R/R-AML).

Method: 231 patients with RR-AML were included from an exploratory study (n=29), an prospective single-arm study (n=40) and a randomized controlled trial study (n=162) and analyzed the influence of molecular and cytogenetic abnormalities on the response of VEN-based therapies.

Results: 98 patients received VEN+hypomethylating agent (HMA) therapy. 138 cases were treated with VEN+azacytidine and homoharringtonine (VAH). There was not significantly different in the clinical characteristics and the treatment after acquiring response, except for remarkably higher rate of prior allogeneic hematopoietic stem cell transplantation and higher incidence of ASXL1 and RUNX1 mutation, -5/5q- and -7/7q- in VAH group versus VEN+HMA group. VAH group had significantly higher rate of complete remission (CR)/CR with incomplete count recovery (CRi) (63.8% vs 40.9%, P=0.003), overall survival (OS) (no reach vs 16.0 months, P=0.023) and event-free survival (EFS) (7.1 vs 2.3 months, P<0.001) than VEN+HMA group. Patients with TET2 (P=0.041), NPM1 (P=0.039), ASXL1 (P=0.044), FLT3-ITD/TKD (P=0.008), DNMT3A (P<0.001) or RAS (P=0.006) mutation or co-mutation of DNMT3A and FLT3 (P=0.020, DNMT3A and NPM1 (P=0.020) or DNMT3A and IDH/2 (P=0.016) acquired statistically higher rate of CR/CRi with VAH therapy as compared with VEN+HMA trerapy. AML1-ETO-positive AML patients poorly responded to VEN+HMA therapy (0/7), but responded much better to VAH treatment (5/7, P=0.005). Patients with complex chromosome had low CR/CRi rate with either VEN+HMA or VAH therapy (1/10 vs 6/17, P=0.148).

Conclusion: Combination of HHT with VEN+HMA could significantly improve the treatment response and long time survival in the patients with R/R-AML, especially benefit more in those with some special molecular and cytogenetic abnormalities.

Key words: relapsed/refractory acute myeloid leukemia, venetoclax, HHT, molecular mutation, cytogenetic abnormalities

No relevant conflicts of interest to declare.