Early and safe administration of G-CSF in AML patients treated with venetoclax-based therpy: Clinical and molecular insights from a single czech center

Abstract

Abstract Introduction: This analysis evaluates the impact of early administration of the growth factor G-CSF during the first therapy cycle in 117 patients with acute myeloid leukemia (AML) treated with venetoclax-based combination therapy. Not only were the clinical characteristics of patients across three groups (de novo AML, N=28; secondary AML [sAML], N=39; salvage treatment [previously treated with HMA for HR-MDS], N=50) taken into account, but also the influence of genetic mutations on hematological parameters, treatment response, and survival. Methods: We retrospectively analyzed AML patients receiving venetoclax-based therapy, stratified by treatment cohort. Associations between G-CSF use, infection rates, and clinical outcomes were assessed using chi-squared tests and Kaplan-Meier survival analysis. Multivariate Cox regression evaluated the impact of G-CSF, infections, and neutrophil recovery on OS. Separately, the influence of recurrent gene mutations on hematologic parameters, complete remission (CR), and OS was analyzed using linear regression, penalized logistic regression, and multivariate Cox models. Statistical significance was set at p < 0.05. Analyses were conducted in R (v4.4.3). Results: Use of G-CSF showed a statistically significant difference between the subgroups (χ² = 11.89; p = 0.0026). G-CSF was most frequently administered in patients in the sAML (89.7%) and salvage (78.0%) groups, while in de novo AML it was administered in only 53.6% of cases. The incidence of severe grade 4 neutropenia also differed significantly between groups (χ² = 8.56; p = 0.0138). The highest relative incidence was observed in patients with de novo AML (28.6%) and sAML (25.6%), while in the salvage group, Gr 4 neutropenia was present in only 6.0% of patients. The incidence of infections was higher in de novo and sAML patients and lower in the salvage group (p = 0.0099). The presence of infection during the first therapy cycle was associated with worse overall survival, although this did not reach statistical significance (p = 0.04). We did not observe statistically significant differences in response among subgroups (p = 0.2615), although the de novo group achieved the highest CR rate (64 %). Survival according to Kaplan-Meier analysis suggests a poorer prognosis for the salvage group. However, G-CSF administration was not associated with a decrease in overall survival (OS). Analysis of the effect of genetic mutations found in 97 patients showed that the presence of certain aberrations can significantly affect both the chance of achieving complete remission (CR) and selected hematological parameters. The most significant positive effect on achieving CR was observed for the IDH2 mutation, which was associated with a statistically significant higher probability of treatment response (OR 6.32; p = 0.0285). The NPM1 mutation also increased the chance of achieving CR (OR 4.62; p = 0.0500) and was associated with a trend toward improved overall survival (HR ~0.65). In contrast, EZH2 mutation indicated a negative impact on treatment response (OR 0.00), and although this effect was not statistically significant for survival. The mutations were further analyzed for their relationship to laboratory parameters such as baseline hemoglobin level (Hb), platelets (Plt), absolute neutrophil count (ANC), and percentage of blasts in peripheral blood. Mutations in EZH2 was associated with a significant decrease in hemoglobin levels (−30.13 g/L; p < 0.001), ASXL1 led to a significant reduction in ANC. Conclusions Based on the available data, we conclude that early administration of G-CSF during first-line treatment of AML is safe even in genetically at-risk patients. These results point to different patterns of toxicity and supportive care between clinical subgroups of AML, with the use of G-CSF not fully corresponding to the incidence of baseline severe neutropenia. The use of G-CSF may promote hematological regeneration in selected patients without fear of accelerating the progression of AML. Administration has no negative effect on survival. IDH2 and NPM1 mutations appear to be favorable in terms of treatment response, while EZH2 and ASXL1 mutations are associated with adverse changes in blood parameters. These results underscore the importance of the patient's genetic profile in predicting clinical course and response to therapy.