Safety and outcomes of venetoclax initiation in patients with  AML and hyperleukocytosis

Abstract Introduction: Venetoclax in combination with hypomethylating agents has improved outcomes in acute myeloid leukemia. However, the FDA black box warning for tumor lysis syndrome, especially in patients with elevated white blood cell counts above 25,000/µL, raises concerns about its safe initiation. Hydroxyurea is often used to reduce WBC counts before starting venetoclax, but data on the true risk of TLS and patient outcomes remain limited. This study evaluates outcomes including TLS incidence in AML patients with hyperleukocytosis treated with venetoclax-containing regimens, with or without hydroxyurea pre-treatment. Methods: A retrospective cohort study using the TriNetX database included 107 centers and patients with AML and with WBC >25,000/µL from 2005 to 2025. Cohort A (n=145) received hydroxyurea for cytoreduction prior to treatment with hypomethylating agents (azacitidine or decitabine) plus venetoclax. Cohort B (n=73) started directly on hypomethylating agents plus venetoclax without prior hydroxyurea. Diagnoses, treatments, and labs were identified using ICD-10 codes. Outcomes included overall survival, remission, relapse, and incidence of TLS. Propensity score matching was applied to adjust for baseline differences. Results: Median overall survival was 168 days in Cohort A and 303 days in Cohort B (p=0.056; hazard ratio 1.56; 95% CI 0.99–2.46), indicating a non-significant trend favoring direct initiation without hydroxyurea. Death occurred in 48 and 31 patients in Cohorts A and B, respectively with a hazard ratio of 1.555 (95% CI 0.985-2.455), p value 0.821 indicating no statistically significant difference in mortality between the two groups. Rates of remission and relapse were similar between groups. TLS occurred in 19 patients in Cohort A and 12 patients in Cohort B. Median survival after TLS diagnosis was short, at 5 days for Cohort A and 13 days for Cohort B (hazard ratio 1.45; p=0.55), with no significant difference in TLS-related outcomes between the cohorts. Conclusion: Initiation of venetoclax combined with hypomethylating agents in AML patients with WBC counts over 25,000/µL does not appear to increase the risk of TLS whether or not hydroxyurea is used for cytoreduction. While TLS remains a serious complication with poor short-term survival, its incidence was low and comparable between cohorts. Our findings suggest that venetoclax can be safely initiated patients with AML and elevated WBC count without mandatory leukoreduction prior to use, although close monitoring for TLS is essential.