Both acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are associated with poor outcomes, particularly in patients with high-risk disease: 5-year survival rates for AML and MDS are 28.7% and 8%, respectively. Currently, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only putative cure for these patients, though the 70% relapse and 10% long-term survival rates are rather dismal. This, combined with a lack of robustly effective salvage regimens, has led to renewed efforts to prevent relapse.

Both venetoclax, a BCL2 inhibitor, and hypomethylating agents, such as decitabine, have shown promise in the treatment of AML and MDS, even in high-risk disease, though there is a lack of information regarding these treatments in the post-transplant setting. Yunxiong Wei et al. recently published a prospective study in Cancer Science to investigate the efficacy and tolerability of low dose decitabine and venetoclax as post-transplant maintenance therapy in patients with high-risk AML and MDS.¹

Study design

This was a prospective study that included 20 patients, aged ≥18 years and ≤70 years, with high-risk AML (n = 17) and high-risk MDS (n = 3), who underwent allo‑HSCT (within 2 months). All patients had an Eastern Cooperative Oncology Group (ECOG) score of ≤2, an absolute neutrophil count ≥500/µL, a platelet count ≥50,000/µL, and no uncontrolled active infections. Patients with active acute or chronic graft-versus-host disease (GvHD), or impaired renal or hepatic function were excluded. Results reported herein are from the past 3 years, and recruitment is ongoing.

Patients with AML were considered high risk if they were ≥60 years of age or had:

• A history of MDS or a myeloproliferative neoplasm
• Treatment-related or secondary AML
• White blood cell count ≥100 × 10⁹/L
• Combined central nervous system leukemia
• Gene mutations with poor prognosis of complex karyotypes
• Two courses of standard induction chemotherapy without complete remission

Patients with MDS were considered high risk if they had ≥3 World Health Organization Prognostic Scoring System points or >4.5 International Prognostic Scoring System-Revised points.

Treatment plan

The treatment regimen consisted of 15 mg/m² decitabine on Day 1 to Day 3 and 200 mg venetoclax on Day 1 to Day 21, beginning at about Day 100 post-transplant. There were ten treatment cycles, with a cycle interval of 2 months.

Endpoints

Primary endpoints included:

• Overall survival (OS)
• Event-free survival (EFS)

Secondary endpoints included:

• Adverse events (AEs), which were graded using the Common Terminology Criteria for Adverse Events version 4.03
• Cumulative incidence of relapse
• Non-relapse mortality
• Incidences of acute GvHD (aGvHD) and chronic GvHD
• Incidences of viral infection after transplant

Baseline characteristics

There were 20 patients meeting the eligibility criteria, with a median age of 35.5 years (range, 21‒64 years). Of the 17 patients with high-risk AML, two had a prior diagnosis of MDS. Baseline characteristics are shown in Table 1.

Table 1. Baseline characteristics*

AML, acute myeloid leukemia; CR, complete remission; HLA, human leukocyte antigen; IPSS-R, International Prognostic Scoring System-Revised; MDS, myelodysplastic syndromes; MRD, minimal residual disease; PCR, polymerase chain reaction; PR, partial remission; WBC, white blood cell; WPSS, World Health Organization Prognostic Scoring System. *Adapted from Wei, et al.1 †Molecular characteristics with poor prognosis were defined as DNMT3A, TP53, FLT3-ITD, MLL, c-KIT, ASXL1, and WT-1 overexpression.
Patient characteristics, % unless otherwise stated	Total patients (N = 20)
Male gender	40
Disease type
AML	75
MDS	15
MDS transformed to AML	10
CR1	35
CR2	30
Others	35
MRD detection method
Flow cytometry	100
PCR	75
Disease status at transplant
CR	85
MRD negative	25
MRD positive	60
PR	15
High-risk factor
Primary refractory/relapsed	60
>60 years old	15
Complex cytogenetic aberrations	35
Molecular characteristics with poor prognosis†	65
WBC >100 x 109/L	10
WPSS points ≥3 or IPSS-R points >4.5	15
Median CD34+ cells at transplant, 106 (range)	4.79 (3.0‒8.25)
Donor type
Haploidentical HLA-matched donor	85
Matched sibling donor	15
Median days of neutrophils ≥0.5 × 109/L	12 (10‒16)
Median days of platelets ≥20 × 109/L	17 (10‒29)
Median follow-up time, days (range)	598 (149‒1,072)

Results

Each of the 20 patients received the low dose decitabine + venetoclax maintenance regimen ~100 days after allo-HSCT. The median number of treatment cycles was five, with 13 patients receiving at least five cycles, and two patients who received all ten cycles.

Toxicity

Tumor lysis syndrome is a concern for patients with high tumor burden who are treated with venetoclax, though no cases of tumor lysis syndrome were reported in this study. Grade ≥2 AEs occurred in 55% of patients and are reported in Table 2. The most common AEs were neutropenia (n = 7), anemia (n = 6), thrombocytopenia (n = 4), diarrhea (n = 4), fatigue (n = 2), and neutropenic fever (n = 1).

Table 2. Grade ≥2 adverse events occurring during maintenance with low dose decitabine and venetoclax*

*Adapted from Wei, et al.1
Event	Grade 2	Grade 3	Grade 4	Grade 5
Neutropenia	6	3	0	0
Anemia	5	3	0	0
Thrombocytopenia	4	2	0	0
Neutropenic fever	1	1	0	0
Diarrhea	4	1	0	0
Fatigue	2	1	0	0

All reported toxicities were tolerable and reversible, though one patient had a dose reduction for one cycle due to persistent severe neutropenia. There were no treatment-related deaths.

Clinical outcomes

At a median follow up of 598 days (range, 149‒1,072 days), median EFS was 525 days. In total, 17 patients still had EFS at the time of publication. Regarding the remaining three patients:

• Patient 7 relapsed on Day 274, continued treatment, and had a second allo-HSCT. This patient was continuously MRD positive after the first allo-HSCT and achieved complete remission but remained MRD positive and eventually relapsed after the second transplant. This patient’s treatment is ongoing.
• Patient 8 relapsed on Day 516 and died of relapse.
• Patient 9 died of a lung infection on Day 309 after transplantation.

Results after low dose decitabine + venetoclax maintenance are as follows:

• Two-year OS was 85.2%
• Two-year EFS was 84.7%
• Two-year cumulative incidence of relapse was 15.3%
• Two-year non-relapse mortality was 6.1%

GvHD

Patients were treated with a prophylactic GvHD regimen (cyclosporin A, methotrexate, and mycophenolate mofetil); patients who developed GvHD were treated with cyclosporin A and glucocorticoids (except for three patients who received tacrolimus instead of cyclosporin A).

Nine patients had aGvHD prior to receiving low dose decitabine + venetoclax maintenance, and two patients had aGvHD after maintenance therapy; four patients had chronic GvHD after maintenance therapy. There were no GvHD-related deaths, and maintenance therapy was not found to increase any of the side effects of GvHD treatment (namely increased blood pressure and increased blood glucose). There was no difference noted in the occurrence of GvHD between patients who did or did not receive a hypomethylating agent prior to transplantation.

Conclusion

This prospective study demonstrated that low dose decitabine + venetoclax is as safe and efficacious as maintenance therapy following allo-HSCT in patients with high-risk AML/MDS. There were no reported irreversible regimen-related toxicities, likely owing to the extended cycle interval (2 months vs 4 weeks) and reduced daily dosage of venetoclax (200 mg vs 400 mg) used in this study. The reduction in the venetoclax dose did not appear to impact the regimen’s efficacy, with 2-year OS and EFS rates of 85.2% and 84.7%, respectively. One important note is that the authors hypothesized that decitabine + venetoclax may influence the graft-versus-leukemia effect, though no evidence of this was observed, potentially due to the small sample size. Further investigation of this maintenance regimen in larger cohorts is required.