INTRODUCTION: Hypomethylating agents continue to be the standard treatment for higher-risk MDS. However, in cases of failure or resistance to azacitidine (AZA) ± venetoclax (VEN), novel therapies are imperative. Preclinical studies demonstrated that granulocyte colony-stimulating factor (G-CSF) promoted the differentiation of MDS stem cells, thereby increasing their sensitivity to AZA + VEN. In this study, we retrospectively evaluated the safety and efficacy of G-CSF combined with AZA and VEN (VAG) in adults (≥18 years old) with higher-risk MDS.

METHODS: Between November 2023 and July 2025, VAG regimen was consistently employed for treating all higher-risk MDS patients, defined by the Revised International Prognostic Scoring System (IPSS-R) score of >3 with an Eastern Cooperative Oncology Group performance status of ≤2, and bone marrow blasts <20% at baseline, at Beijing Chao-Yang Hospital. During the first cycle, patients received escalated doses of oral VEN, starting at 100 mg on Day 1, 200 mg on Day 2, and 400 mg on Days 3-14. From the second cycle onwards, a consistent dose of 400 mg on Days 1-14 was administered. Intravenous AZA 75 mg/m² and subcutaneous G-CSF 300 μg were administered on Days 1-7 of each 28-day cycle. Up to 8 cycles were administered. Responses were assessed using the International Working Group (IWG) 2023, MDS response criteria.

RESULTS: A total of n=17 higher-risk MDS patients received VAG regimen, with median age 73 years (range: 55-84). At baseline, n=11 patients (65%) were red blood cell (RBC) and/or platelet (PLT) transfusion-dependent. According to the WHO 2022 criteria, five (29%) cases were diagnosed with MDS with increased blasts-1 (MDS-IB1), while seven (41%) had MDS-IB2. Cytogenetic/molecular risks were very adverse: (1) eight patients (47%) showed ≥intermediate-risk cytogenetics; (2) six (35%) and eight (47%) had high and very-high risk by IPSS-R, respectively; (3) the median IPSS-M score was very high (2.23, range: 0.51-3.88); (4) and six (35%) patients had TP53 mutations, six (35%) had DNMT3A mutations and five (29%) had RUNX1 mutations. All patients received a median of 3 (range: 1-8) cycles of VAG. Notably, none proceeded to hematopoietic stem cell transplantation.

According to the IWG 2023 criteria, n=12 (71%) patients achieved a best response of complete remission (CR), while three (18%) achieved a best response of CR bilineage (CRbi). The objective response rate (ORR) was 88% (15/17). 88% (14/16) of patients showed non-detectable minimal residual disease by flow cytometry. Besides, following the first cycle the ORR was 88%, with 35% (6/17) achieving CR, 6% (1/17) achieving CR unilineage (CRuni), and 47% (8/17) achieving CRbi. Among n=9 patients who achieved CRuni/CRbi after the first cycle, six (67%) eventually converted to CR. The median time to CR was 2.2 months (range, 1.5-6.0). None had a partial remission. Two patients (12%) exhibited progressive disease as their best response; both harbored TP53 mutations. Among n=11 patients who were transfusion-dependent at baseline, nine (82%) became transfusion-independent during therapy. The median overall survival among responders (CR/CRbi) was 8.8 months (range, 2.0-20.2). In particular, among n=11 patients without TP53 mutations nine (82%) achieved CR and two (18%) achieved CRbi. The ORR was 100%. Among n=6 patients harboring TP53 mutations, three (50%) achieved CR and one achieved CRbi.

All patients experienced treatment-emergent adverse events (AEs), predominantly cytopenias. Grade ≥3 hematologic AEs were very common: neutropenia and anemia in 94% of patients, leukopenia in 88%, and thrombocytopenia in 82%. Febrile neutropenia occurred in 24%. Common non-hematologic AEs (any grade) included fever (59%), hyponatremia (53%), hypokalemia (41%), and infections (41% with bacterial infection; 35% with pneumonia). Seven patients (41%) experienced serious AEs, but no treatment-related mortality was observed.

CONCLUSIONS: The 14-day venetoclax plus 7-day azacitidine and G-CSF (VAG) combination was well tolerated and demonstrated high efficacy in higher-risk MDS, with CR in over 70% of patients and an ORR of 88%. These outcomes suggested that G-CSF priming may further enhance remission depth. Clinically, the high CR rate translated into improved hematologic function, with >80% of previously dependent patients achieving transfusion independence. A prospective phase 2 trial is ongoing to confirm these findings and evaluate long-term outcomes.

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2025
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