Low dose azacitidine + venetoclax as maintenance therapy for patients with AML in remission

Relapse with chemorefractory disease is common in patients with acute myeloid leukemia (AML) and is a major cause of therapy failure and death.¹ Maintenance approaches with low-toxicity regimens to delay or prevent relapse after consolidation is an emerging area.¹ One promising combination is low-dose azacitidine (Aza) + venetoclax (Ven).

Recently, Bazinet et al.¹ published results from a phase II trial (NCT04062266) evaluating the safety and efficacy of low-dose Aza + Ven as maintenance therapy in patients with AML remission after either intensive or low-intensity induction in The Lancet Haematology. We summarize the key results below.

Study design¹

• This was a single center, single arm phase II study with two patient cohorts based on previous induction intensity
  • Cohort 1: intensive induction
  • Cohort 2: low-intensity induction
• Aza (50 mg/m²) was administered on Days 1–5.
• Ven (400 mg) was administered on Days 1–14.
• The primary endpoint was relapse-free survival (RFS).
• Secondary endpoints were modified RFS, duration of remission, overall survival, event-free survival, measurable residual disease (MRD), and safety.

Key findings¹

• N = 35
  • Cohort 1: n = 25
  • Cohort 2: n = 10

Efficacy

• The primary endpoint of median RFS was not reached in either patient cohort (Table 1).

Table 1. Survival endpoints for patients with AML remission after intensive or low-intensity induction and treated with low-dose Aza + Ven*

Survival endpoint	Cohort 1 (n = 25)	Cohort 2 (n = 10)
Median RFS, months	Not reached	30.3
2-year RFS rate, %	71	52
Median modified RFS, months†	Not reached	23.5
2-year modified RFS rate, %	64	34
Median DOR, months	Not reached	30.3
2-year DOR rate, %	71	52
Median OS, months	Not reached	Not reached
2-year OS rate, %	77	60
Median EFS, months	Not reached	23.5
2-year EFS rate, %	59	34
Aza, azacitidine; AML, acute myeloid leukemia; DOR, duration of remission; EFS, event-free survival; OS, overall survival; RFS, relapse-free survival; Ven, venetoclax.  *Adapted from Bazinet, et al.1 †Modified RFS defined as time from enrolment into maintenance to relapse or death from any cause.

• Of the 24% of patients who had positive MRD at enrolment; 25% of patients cleared MRD during treatment and a further 25% cleared MRD only after transitioning to transplant.

Safety

• Overall, 69% of patients experienced ≥1 treatment emergent adverse events (TEAE)
• The most common Grade 3–4 TEAE were decreased platelet count (17%), lung infection (11%), decreased white blood cell count (11%), and decreased neutrophil count (9%).
• Infectious TEAE were experienced by 29% of patients.
• Treatment discontinuation due to adverse events occurred in 3% of patients.
• Deaths were reported in 26% of patients and occurred following AML relapse or from transplant related complications.

Key learnings

Results from this trial highlight the feasibility and safety of low-dose Aza + Ven maintenance therapy in patients with AML in remission following intensive and low-intensity induction. Larger, randomized studies are needed to further evaluate the efficacy of Aza + Ven as maintenance therapy. An ongoing trial (NCT05010772) is evaluating a personalized maintenance approach using decitabine plus physician’s choice of a molecularly targeted second agent.