Background: Patients with higher-risk myelodysplastic syndromes (MDS) experience poor overall survival (OS). Standard of care hypomethylating agents (HMAs) require burdensome and prolonged parenteral administration. Allogeneic stem cell transplantation (alloSCT) remains the only curative therapy but is only applicable to a small subset of patients. The addition of the BCL-2 inhibitor venetoclax to an HMA has resulted in improved response rates and OS in acute myeloid leukemia (AML) and is an emerging strategy in higher-risk MDS. Recently, a new oral formulation of an HMA (oral decitabine/cedazuridine; ASTX727) has been FDA approved for the treatment of MDS.
Aims: Determine safety, tolerability and overall response rate (ORR) of ASTX727 in combination with venetoclax in patients with treatment-naïve higher-risk MDS or chronic myelomonocytic leukemia (CMML).
Methods: We conducted a phase 1/2 open-label, single center clinical trial (NCT04655755). Eligibility criteria included a confirmed diagnosis of treatment-naïve MDS or CMML (IPSS intermediate-2 or high) and bone marrow blasts > 5%. The phase 1 portion (dose escalation) used the standard 3 + 3 study design to identify the recommended phase 2 dose. In the phase 2 dose expansion, we evaluated the efficacy of this combination with ORR as the primary objective.
Results: Between 01/2021 and 01/2023, 37 patients were enrolled. The median age was 71 years old (27-94), with 26 (70%) male patients. The WHO 2016 diagnoses were MDS with excess-blasts 1 (n=6, 16%), MDS with excess-blasts 2 (n=24, 65%), CMML-2 (n=6, 16%) and atypical chronic myeloid leukemia (n=1, 3%). The cytogenetic risk according to IPSS was good in 11 patients (30%), intermediate in 12 (32%), and poor in 14 (38%). The median number of mutations per patient was 3 (1-14). The most common mutations were ASXL1 (n=18, 49%), RUNX1 (n=14, 38%), SRSF2 (n=11, 30%), TET2 (n=8, 22), and TP53 (n=7, 19%).
Nine patients were enrolled in the phase 1 portion. All patients received ASTX727 100/35mg on days 1-5. 3 patients received venetoclax 200mg on days 1-14 and 6 patients received 400mg on days 1-14. No dose-limiting toxicities were recorded and therefore the phase 2 dose was established as ASTX727 100/35mg on days 1-5 plus venetoclax 400mg on days 1-14.
Grade 3 and 4 TEAEs were observed in 34 (92%) and 31 (84%) patients, respectively. The most common grade 3-4 TEAEs were decreased platelet count (n=30, 81%), decreased neutrophil count (n=26, 70%), febrile neutropenia (n=7, 19%), and anemia (n=6, 16%). Grade 3-4 infectious complications included lung infection (n= 4, 11%), skin infection (n=3, 8%), sepsis (n=2, 5%), and SARS-Cov-2 infection (n=2, 5%). 3 deaths occurred on study (2 from sepsis and 1 from pneumonia). The 4-week and 8-week mortality were 0% and 3%, respectively. At the time of data cutoff, 9 patients were remained on study. Reasons for discontinuation were undergoing alloSCT (n=18, 49%), patient or physician decision (n=4, 11%), AML progression (n=2, 5%) and lack of response without transformation (n=1, 3%).
The median number of cycles given was 2 (1-13). The ORR was 94.5%: 13 (35.1%) complete remission (CR), 11 (29.7%) marrow CR (mCR) with hematological improvement (mCR-HI), and 11 (29.7%) mCR alone. The median number of cycles to achieve first response and best response was 1 (1-2) and 1 (1-6), respectively. In patients with cytogenetic abnormalities at diagnosis, 53% achieved cytogenetic response. The median duration of response was 23 months. After a median follow-up 9.6 months, the median OS was not reached and the median progression-free survival (PFS) was 23 months.
Summary/Conclusion: The combination of ASTX727 plus venetoclax is a promising, fully oral combination that is well-tolerated and demonstrates a high response rate in higher-risk MDS
Keywords: Myelodysplastic syndrome, decitabine, Venetoclax, Oral