What is the role of hydroxyurea in acute myeloid leukemia?

Role of Hydroxyurea in Acute Myeloid Leukemia

Hydroxyurea serves as a rapid cytoreductive agent for emergency management of hyperleukocytosis (WBC >100 × 10⁹/L) and leukostasis in AML, and as best supportive care in patients unfit for intensive therapy, but it is not a definitive treatment modality. 1

Emergency Cytoreduction in Hyperleukocytosis

Hydroxyurea at 50–60 mg/kg/day (up to 2–3 g/day in divided doses) is the preferred first-line agent to rapidly reduce white blood cell counts in patients with blast counts >50,000–100,000/mcL who are at risk for tumor lysis syndrome and organ dysfunction from leukostasis. 1, 2

• The drug achieves 50% WBC reduction within 1–2 weeks, making it essential for stabilizing patients before definitive chemotherapy can be initiated 1, 2
• Hydroxyurea is superior to leukapheresis, which has not demonstrated long-term survival benefit and may worsen coagulopathy 2
• Pre-treatment with hydroxyurea prior to intensive chemotherapy reduces hospital mortality (19% vs 34% without hydroxyurea, p=0.047) in hyperleukocytic AML 3
• Prompt institution of definitive therapy remains essential even when hydroxyurea is used 1

Critical Timing Consideration

Hydroxyurea should be discontinued and definitive therapy started once WBC is controlled, as prolonged use (>4 days) is associated with higher relapse risk. 4

• Emergency cytoreduction with hydroxyurea does not compromise enrollment on clinical trials or acquisition of complete genomic data 5
• The approach allows a bridge period of 1–2 weeks for cytogenetic and molecular results to guide optimal therapy selection 5

Best Supportive Care in Unfit Patients

For patients ≥60 years with poor performance status (PS >2) or significant comorbidities who are not candidates for intensive chemotherapy, hydroxyurea represents a component of best supportive care alongside transfusion support. 1

• This indication applies specifically to patients who decline or cannot tolerate intensive therapy, low-intensity therapy (azacitidine/decitabine), or intermediate-intensity regimens 1
• Hydroxyurea in this setting provides cytoreduction to control symptoms from myeloproliferation but does not offer curative potential 1
• The 2017 NCCN guidelines position hydroxyurea as the least preferred option, after clinical trials and hypomethylating agents, for older unfit patients 1

Dosing and Toxicity Profile

Standard dosing ranges from 50–60 mg/kg/day for emergency cytoreduction, with lower maintenance doses of 1500 mg twice daily for ongoing disease control. 1, 6

• High-dose hydroxyurea (≥75 mg/kg/day) is associated with significantly more grade 3–4 mucositis (28.6% vs 0%, p=0.002) and higher cumulative narcotic requirements compared to lower doses 7
• Dose-related mucositis represents a significant toxicity that should prompt dose reduction or formulation changes 7
• The FDA-approved indication for hydroxyurea is resistant chronic myeloid leukemia, not AML, though off-label use in AML is guideline-supported 8

Combination Regimens (Limited Role)

Hydroxyurea has been studied in combination with azacitidine and gemtuzumab ozogamicin in elderly AML patients, achieving 70% complete remission rates, but this is not standard practice. 6

• A pilot study using hydroxyurea followed by azacitidine 75 mg/m² × 7 days plus gemtuzumab ozogamicin 3 mg/m² showed promising results (median survival 10 months) 6
• However, modern venetoclax-based combinations have superseded such regimens, with venetoclax plus azacitidine achieving 66.4% composite CR rates and 14.7-month median overall survival 2, 9, 10

Common Pitfalls to Avoid

• Do not use leukapheresis as primary cytoreduction – it lacks mortality benefit and may worsen outcomes compared to hydroxyurea 2
• Do not delay hydroxyurea initiation while awaiting azacitidine's delayed therapeutic effect, which unfolds over weeks to months 2
• Do not continue hydroxyurea beyond 4 days once WBC is controlled, as prolonged use increases relapse risk 4
• Do not transfuse red blood cells until leukocyte count is reduced, as transfusions increase blood viscosity and worsen leukostasis 2
• Do not use hydroxyurea as monotherapy when venetoclax-based regimens are feasible in unfit patients, as the latter provide superior outcomes 9, 10

Current Standard of Care Context

The role of hydroxyurea has diminished with the advent of venetoclax-based regimens, which are now preferred for older/unfit AML patients over hydroxyurea-based best supportive care. 1, 9, 10

• The 2025 ASH guidelines recommend treatment over best supportive care and venetoclax-based regimens over monotherapies in appropriate patients 9
• Hydroxyurea remains relevant only for emergency cytoreduction and for the rare patient who refuses or cannot receive any form of antileukemic therapy 1, 9