Combination of Low White Blood Cell Count and Impaired Renal Function Is a Risk Factor for Higher Concentrations of Venetoclax and Prolonged Neutropenia in AML Patients with Venetoclax Combined Regimen: Real World Experience in the Japanese Cohort

Aim: Severe and prolonged neutropenia is one of the most critical adverse events associated with venetoclax (VEN) in combination with azacitidine (Aza). The pharmacokinetics (PK) of VEN could be a key factor in predicting neutropenia. A comprehensive analysis of VEN PK in patients with AML (Brackman D et al. Hematol Oncol. 2022) demonstrated a relationship between VEN exposure and neutropenia. Previous studies demonstrated that Asian patients tended to have higher VEN concentrations, and were more likely to experience treatment related neutropenia. Therefore, we hypothesized that PK-guided dose adjustment is necessary to manage neutropenia during VEN treatment for Asian AML populations. Additionally, the target VEN concentration should be adjusted according to the duration of VEN administration, as shortening the VEN duration to avoid severe neutropenia is becoming common in real-world settings. Method: We conducted a prospective observational study at three Japanese institutions to monitor PK factors, including trough concentration (Cmin), maximum concentration (Cmax), and area under the time-concentration curve (AUC) 0-12 at steady state. On the after day 7 of treatment, blood samples were collected via venipuncture into potassium EDTA-containing tubes immediately before VEN dosing (0 hours) and at 6, and 12 hours post-dosing. Plasma concentrations of VEN were determined using a validated liquid chromatography-tandem mass spectrometry method. AML patients (newly diagnosed or refractory/relapse) aged over 18 years old, treated with VEN plus Aza or LDAC were enrolled. The dose of VEN was adjusted based on an azole anti-fungal agent, according to previous literature. The correlation between VEN PK and the duration of neutropenia was assessed using Pearson's product-moment correlation coefficient, and a comparison between 2 groups was performed using the t-test. This study conformed to the principles of the Declaration of Helsinki and was approved by the ethics committee at the Aiiku Hospital (UMIN000047371). Results: Thirty-six patients (23 newly diagnosed and 13 refractory/relapse AML) were registered, and 44 samples were submitted to analyze PK factors. One sample was obtained from a patient who had received a VEN + LDAC regimen, while the remaining samples were from patients who had been treated with VEN + Aza. Among the 44 samples, 4 had favorable disease risk in ELN2017, 14 had intermediate risk, 20 had adverse risk, and 6 were not determined. The median VEN dose was 400 mg (range, 50-400) and the median duration was 21 days (range, 8-28). The mean Cmin of VEN was 1745 ng/ml [range 259 - 4510]. Cmax was 3009 ng/ml [range 896 - 5870], and the mean AUC0-12 was 29636 h・ug/l [range 9443-60840], which were higher than previous literature. Nine of 44 samples were administered an azole anti-fungal agent and 8 received an echinocandin anti-fungal agent. The Cmin, Cmax, and AUC were almost similar across anti-fungal drug groups. The duration of grade 3 neutropenia (less than 1000/ul) was positively correlated with VEN Cmax and AUC (r = 0.398, p = 0.027 for Cmax and r = 0.398, p = 0.029 for AUC) in patients who achieved composite CR (CRc: CR+CRi, n = 39). Next, we calculated VEN intensity by multiplying each PK factor by administration duration. Cmax x duration (days) and AUC0-12 x duration had a significant association with grade 3 neutropenia (r = 0.351, p = 0.049 for Cmax and r = 0.358, p = 0.044 for AUC). Patients with WBC < 3000/ul and estimated GFR (eGFR) <60ml/min showed higher VEN AUC values compared to others (Low WBC and low eGFR: mean 38935 h・ug/l vs others: mean 26901 h・ug/l, p = 0.020). Importantly, this population also demonstrated a significantly longer period of grade 3 neutropenia (Low WBC and low eGFR: mean 31.9 days vs others: mean 18.3 days, p =0.011). Conclusion: The current study demonstrated monitoring VEN concentrations could be useful in estimating neutrophil recovery after VEN-Aza treatment for AML patients who achieved CRc. VEN intensity, corrected by concentration and duration, was correlated with the incidence of severe neutropenia as well. And importantly, we discovered patients with low WBC count and low renal function could be risk factors for higher concentrations of VEN and, eventually, prolonged neutropenia. VEN intensity-guided adjustment might be worth considering to manage neutropenia for Asian AML populations, especially patients with low WBC and impaired renal function.