Doublet Therapy Shows Improved Outcomes vs Azacytidine Alone in MDS

The combination regimen delivered better overall survival and response rates among patients with myelodysplastic syndromes (MDS).

Although hypomethylating agents (HMAs) such as 5-azacytidine (AZA) are the standard of care in myelodysplastic syndromes (MDS), most patients do not experience durable remissions and will eventually fail therapy. Novel agents and combinations aim to change that, and a recent study explored granulocyte colony stimulating factor (G-CSF) in combination with AZA (GA) vs AZA alone in patients with MDS.

AZA is commonly used to treat patients with MDS that has progressed to the point it affects their survival, and it is either used as a bridge to transplantation or continuously in patients who are ineligible for transplantation. G-CSF, which is typically used for neutropenic complications, activates myeloid gene transcription in stem cells when administered prior to an HMA.

The current study, published in Blood Cancer Journal, enrolled 76 patients with high-risk MDS who were randomized to receive either AZA monotherapy or GA combination therapy. The final analysis included 70 enrollees: 39 patients in the GA arm and 31 patients in the AZA cohort. The median patient ages in each group were 73 and 74 years, respectively. The GA arm was 59% male, and the AZA group was 48% male.

The median number of AZA cycles was 8, and the GA cohort received G-CSF 2 days before the first AZA dose and 2 days prior to the sixth dose of AZA. Plasma G-CSF levels were measured after the first therapy cycle, and G-CSF efficacy was assessed using CD64 expression on granulocytes as a biomarker. Notably, 6 patients in the AZA monotherapy group (19%) received G-CSF due to febrile neutropenia.

The median overall survival (OS) in the GA arm was 14.8 months vs 13.4 months in the AZA monotherapy group. Male patients and those who did not experience grade 4 neutropenia showed longer survival rates compared with other patients, but patients on the GA regimen had a lower risk of death overall and prolonged OS compared with the AZA cohort.

The overall response rate was 77% in the GA cohort and 61% in the AZA monotherapy cohort. Thirty-one percent of patients in the GA cohort had complete responses (CRs) to therapy, while 23% had partial responses (PRs). In the AZA monotherapy cohort, the CR rate was 23% and the PR rate was 23%. In the GA cohort, 18% of patients had stable disease (SD) with hematological improvement (HI), and 8% achieved SD without HI. None of the monotherapy patients achieve SD with HI, but 13% achieved SD without HI. Progression-free survival was 9.7 months in the GA cohort vs 6.1 months in the AZA monotherapy group.

In the first 4 therapy cycles, twice as many patients in the combination treatment cohort responded with CR, PR, or HI than the monotherapy cohort (28 vs 14 patients).

“This is particularly important for those patients, who are at increased risk of infectious and other complications associated with cytopenias during the initial cycles of AZA; on the other hand, achieving a better response gives the chance of a longer OS,” the authors wrote.

The rates of progression to acute myeloid leukemia (AML) and time to progression to AML were notably similar between the groups. Toxicity assessments were also similar, although the GA group had less infection-related instances of mortality in the first 4 treatment cycles compared with the monotherapy group.

G-CSF therapy prior to AZA has demonstrated usefulness in early therapy stages and has shown more durable responses with less severe complications related to cytopenia. In this study, time to response and OS were improved with the addition of G-CSF prior to AZA, although both cohorts eventually failed therapy.

“Our primary objective of increasing treatment response and survival in the GA vs [AZA] arm was confirmed, particularly in patients with initial neutropenia in the first year of HMA treatment,” the authors concluded. “Thus, the administration of G-CSF prior to AZA represents an improvement to the standard AZA regimen in patients with high-risk MDS and oligoblastic AML.”


Stopka T, Minařík L, Dusilková N, et al. G-CSF plus azacitidine versus azacitidine alone for patients with high-risk myelodysplastic syndrome: academic, open label, randomized trial. Blood Cancer J. Published online July 7, 2022. doi:10.1038/s41408-022-00698-2

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