What is the role of hydroxyurea in the management of Chronic Myeloid Leukemia (CML)?

Hydroxyurea for Chronic Myeloid Leukemia

Hydroxyurea is NOT recommended as definitive treatment for CML but serves only as a temporary cytoreductive agent before initiating tyrosine kinase inhibitor (TKI) therapy, which should be started immediately upon BCR-ABL1 confirmation. 1

Current Role in CML Management

Temporary Bridging Therapy Only

• Hydroxyurea should be used only for a short time before initiating a TKI, until the diagnosis of CML has been confirmed. 1
• The European LeukemiaNet explicitly states that busulfan is not recommended and hydroxyurea's role is limited to pre-TKI cytoreduction. 1
• Once BCR-ABL1 positivity is confirmed, TKI therapy should commence immediately, with hydroxyurea tapered before discontinuation. 1

Specific Indications for Short-Term Use

In adults:

• Hydroxyurea (40 mg/kg body weight/day) may be used as initial therapy before confirmation of BCR-ABL1 fusion when there is immediate need for therapy due to high leukocyte counts or clinical symptoms. 1
• The FDA has approved hydroxyurea for "resistant chronic myeloid leukemia," indicating its use only when patients have failed or cannot tolerate standard therapies. 2

In pediatric patients:

• Children with hyperleukocytosis (WBC >100 × 10⁹/L) and/or signs of leukostasis should receive hydroxyurea (25-50 mg/kg/day in 2-3 divided doses) in conjunction with intravenous hyperhydration. 1
• Hydroxyurea achieves 50% WBC reduction in 1-2 weeks, which is comparable to TKIs but slower than intensive chemotherapy or leukapheresis. 1
• In emergency organ-threatening conditions (cerebral/pulmonary leukostasis, priapism), hydroxyurea must be reinforced with faster-acting cytoreductive measures like leukapheresis or exchange transfusion. 1

Why TKIs Have Replaced Hydroxyurea

Superior Outcomes with TKI Therapy

• First-line treatment of chronic phase CML should be any of the three approved TKIs: imatinib (400 mg once daily), nilotinib (300 mg twice daily), or dasatinib (100 mg once daily). 1
• These TKIs target the molecular pathophysiology of CML and achieve deep molecular responses that translate to near-normal survival, which hydroxyurea cannot accomplish. 1
• Historical data showed hydroxyurea had similar median survival to busulfan (51 vs 45 months), but this is vastly inferior to modern TKI therapy where patients achieve near-normal life expectancy. 3

Hydroxyurea's Limitations

• Hydroxyurea provides only cytoreduction without addressing the underlying BCR-ABL1 fusion protein that drives CML pathogenesis. 1
• While hydroxyurea can control white blood cell counts, it does not prevent disease progression to accelerated or blast phase. 4
• In a study of 176 CML patients treated primarily with hydroxyurea, 43.2% showed disease advancement and 20% transformed to acute leukemia, demonstrating its inadequacy as definitive therapy. 4

Critical Pitfalls to Avoid

Do Not Delay TKI Initiation

• The most critical error is continuing hydroxyurea beyond the brief period needed for diagnosis confirmation and initial cytoreduction. 1
• Every day without TKI therapy represents lost opportunity for achieving optimal molecular responses that predict long-term survival. 1
• Hydroxyurea should be tapered before discontinuation to avoid rebound leukocytosis, but this tapering should not delay TKI initiation. 1

Recognize Hydroxyurea's Toxicity Profile

• Myelosuppression is the primary concern; bone marrow function must be monitored, and treatment interrupted if marked depression occurs. 2
• Hemolytic anemia can occur and requires discontinuation if it persists. 2
• Secondary malignancies are a risk with prolonged use, reinforcing that hydroxyurea should never be used long-term in CML. 2
• Vasculitic toxicities require immediate discontinuation. 2

Practical Management Algorithm

Step 1: At CML Presentation

• If WBC >100 × 10⁹/L or symptomatic hyperleukocytosis: Start hydroxyurea 40 mg/kg/day (adults) or 25-50 mg/kg/day (pediatrics) with aggressive hydration (2.5-3 L/m²/day). 1
• If WBC <100 × 10⁹/L and asymptomatic: Proceed directly to confirmatory testing without hydroxyurea. 1

Step 2: During Diagnostic Confirmation (Days 1-7)

• Continue hydroxyurea only while awaiting BCR-ABL1 confirmation by cytogenetics or molecular testing. 1
• Monitor CBC every 2-3 days to avoid excessive myelosuppression. 2
• Maintain hydration and consider allopurinol only if uric acid is elevated or tumor lysis parameters are abnormal. 1

Step 3: Upon BCR-ABL1 Confirmation

• Immediately initiate TKI therapy (imatinib, nilotinib, or dasatinib). 1
• Begin tapering hydroxyurea over 3-5 days while TKI is started. 1
• Do not wait for complete WBC normalization before starting TKI. 1

Step 4: Emergency Situations

• If leukostasis with organ dysfunction (cerebral, pulmonary) or priapism: Add leukapheresis or exchange transfusion to hydroxyurea, as hydroxyurea alone is too slow. 1
• These emergencies require multidisciplinary involvement (urology for priapism, apheresis service for leukapheresis). 1

Special Populations

Pediatric Considerations

• The ELTS risk score should guide whether to use second-generation TKIs (nilotinib/dasatinib) upfront in high-risk pediatric patients. 1
• Leukostasis is less common in children (16.5% incidence) despite higher median WBC counts (240,000/µL), but when present requires aggressive management. 1

Contrast with CMML

• Hydroxyurea has a legitimate ongoing role in myeloproliferative CMML (MP-CMML) for cytoreduction and organomegaly control, which is fundamentally different from its temporary role in CML. 1, 5
• This distinction is critical: CMML lacks the BCR-ABL1 target that makes TKIs curative in CML. 1, 5