Safety and effectiveness of DEC plus VEN as a maintenance therapy in patients with high-risk AML and MDS

Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are typically associated with poor outcomes, especially in high-risk patients. Allogenic hematopoietic stem cell transplantation (allo-HSCT) is the only curative option for patients with AML/MDS but is associated with high relapse rates leading to treatment failure. Additionally, patients receiving allo-HSCT have reduced long-term survival and salvage regimens have limited anti-leukemic effects, meriting new methods to prevent relapse. Venetoclax (VEN), a B-cell lymphoma-2 inhibitor, in combination with the hypomethylating agent decitabine (DEC) has previously shown promising anti-tumor effects and effective salvage treatment in patients with AML/MDS, including high risk patients. An early phase study also demonstrated that DEC could ameliorate graft-versus-host-disease (GvHD) without forfeiting graft-versus-leukemia effect, prolonging overall survival (OS) and disease-free progression in patients. However, there is limited data on the safety and efficacy of DEC for preventing relapse after allo-HSCT.

The AML Hub has previously reported on the efficacy of VEN in combination with DEC or azacitidine in elderly patients with AML. Recently, Wei, et al.¹ published in Cancer Science, a prospective study of low-dose DEC (LDEC) plus VEN, as a prophylactic treatment for relapse in patients with high-risk AML/MDS following allo-HSCT. The key findings are summarized here.

Study design

A prospective study (ChiCTR1900025374) was conducted in patients aged ≥18 and ≤70 years of age, diagnosed with high-risk AML or MDS (2016 World Health Organization (WHO) guidelines); who had undergone allo-HSCT within 2 months, had an Eastern Co-operative Oncology Group (ECOG) score ≤2, an absolute neutrophil count ≥500/µL, a platelet count of ≥50,000/µL, and no uncontrolled active infectious diseases. Treatment schedule began at approximately Day 100 post-HSCT and is shown in Figure 1.

Figure 1. Treatment schedule*

D, day; DEC, decitabine; VEN, venetoclax.
*Adapted from Wei, et al.¹

The primary endpoints were rate of OS (measured from the time of transplantation to death from any cause) and event-free survival (EFS) (time from transplantation to recurrence, progression, or death). The secondary endpoints included adverse events (AEs), cumulative incidence of relapse, non-relapse mortality, incidences of acute GvHD (aGvHD), chronic GvHD (cGvHD), and viral infection.

Results

Baseline characteristics

Overall, 20 patients with high-risk AML (n = 17) and high-risk MDS (n = 3) were enrolled with a median age of 36 years (range, 21–64 years) and 60% of these patients were female. The median follow-up time was 598 days (range, 149–1072 days) and the conditioning regimens included busulfan/fludarabine/cyclophosphamide/cytarabine/anti-thymocyte globulin thymoglobulin. Table 1 summarizes the baseline characteristics.

Table 1. Baseline characteristics*

Efficacy

The clinical outcomes for the last three years were reported. The median 2-year EFS time was 525 days (range, 149–1072 days) and 17 patients still had EFS. Two patients experienced disease progression, one died, and one was still alive after the second transplant. The 2-year OS and EFS after LDEC + VEN was 85% each (Table 2). In total, 19 patients achieved minimal residual disease (MRD) negative complete response after allo-HSCT, while one continued to be MRD-positive after second transplantation. The 2-year cumulative incidence of relapse was 15% and non-relapse mortality was 6%. Two patients completed all 10 cycles and were still alive with no AEs.

Safety

• No tumor lysis syndrome was observed during the study, potentially due lack of tumor burden in patients 100 days after transplantation.
• A total of 55% of patients showed Grade ≥2 AEs and no Grade >3 AEs were observed. The most common AEs were neutropenia, anemia, thrombocytopenia, diarrhea, neutropenic fever, and fatigue and these were all tolerable and reversible.
• The 100-day incidence of aGvHD and cGvHD was 55% and 20%, respectively (Table 2). There were no GvHD related deaths.
• At least one bacterial and one invasive fungal infection was observed in 15% and 10% of patients, respectively. Bacterial infections included Escherichia coli (n = 1), Enterococcus faecium (n = 2), and Pseudomonas aeruginosa (n = 2). All patients responded to antibiotics.

Table 2. Efficacy and safety*

Conclusion

This prospective, ongoing study demonstrated that the combination of LDEC and VEN as a maintenance treatment nearly 3 months after allo-HSCT was efficacious, with a tolerable safety profile and good long-term disease control. The maintenance therapy of LDEC plus VEN did not impact on GvHD. However, the impact of LDEC plus VEN on graft-versus-leukemia effect needs to be further explored. The current study is limited by the small number of patients and therefore, the efficacy of LDEC plus VEN in larger cohorts with a longer-term follow-up needs further investigation.