Hydroxyurea

Malignancy (FDA Approved)
1. Chronic Myelogenous Leukemia (CML, resistant)
2. Head and Neck Squamous Cell Cancer (combined with radiation)
Malignancy (Off-Label Use)
1. Polycythemia Vera
  1. First-line agent indicated in high risk disease (history of thrombosis or age over 60 years old)
2. Essential Thrombocythemia
3. Melanoma
Sickle Cell Anemia (FDA Approved)
1. Indications in adults
  1. Sickle Cell Crisis 3 or more times in 12 months
  2. Severe or recurrent Acute Chest Syndrome
  3. Severe symptomatic chronic Anemia affecting functional status
  4. Sickle cell associated pain significantly impacting function or quality of life
2. Indications in children over age 9 months
  1. All children over age 9 months should be offered Hydroxyurea to reduce complications

General
1. Hydroxycarbamate antimetabolite agent used as a Antineoplastic Agent as well as in Sickle Cell Anemia
2. Inhibits ribonucleoside diphosphate reductase, a key enzyme in the DNA synthesis pathway
  1. Specifically blocks ribonucleoside diphosphate conversion to deoxyribonucleoside diphosphate
  2. Lowers intracellular dNTP pools
  3. Inhibits DNA Replication and repair
  4. Limits Cell Cycle to G1/S phase (cancer cells are sensitive to Radiation Therapy in G1 phase)
Sickle Cell Anemia
1. Increases production of fetal Hemoglobin (HbF) which does not sickle

Hydroxyurea Capsules (Hydrea): 500 mg (generic); also available as 200, 300 and 400 mg (Droxia)
Hydroxyurea Tablets: 100, 1000 mg

General
1. Wear gloves while handling medication
2. Often managed in conjunction with Sickle Cell Disease specialist
3. Trial for minimum of 6 months before assessing efficacy
4. Encourage compliance for maximal effect
Starting Doses of Hydroxyurea (Droxia)
1. Obtain baseline labs as above prior to initiating Hydroxyurea
2. Arrange reliable Contraception for while on Hydroxyurea
3. Dosing: Infants and Children
  1. Hydroxyurea 20 mg/kg daily
4. Dosing: Adults with normal Renal Function
  1. Hydroxyurea 15 mg/kg (round up to nearest 500 mg) daily
5. Dosing: Adults with Chronic Kidney Disease
  1. Hydroxyurea 5-10 mg/kg daily
Adjusting dose
1. See lab monitoring as above
2. Maximum daily dose: 35 mg/kg/day
3. Decreasing dose
  1. Indications
    1. Neutropenia (ANC <2000/mm3)
    2. Thrombocytopenia (Platelet Count <80,000/mm3)
  2. Approach
    1. Consult with specialist
    2. In some infants and children, ANC >1250/mm3 (instead of 2000/mm3) may be acceptable
    3. Increase lab monitoring to weekly as above
    4. Reduce Hydroxyurea dose by 5 mg/kg/day
4. Increasing dose
  1. Target ANC 2000 to 4000/mm3
  2. Contraindications to dose increase
    1. White Blood Cell Count <2500/mm3
    2. Platelet Count <95,000/mm3
    3. Hemoglobin <5.3 g/dl
  3. Increase by 5 mg/kg/day increments every 8 weeks in children and every 12 weeks in adults
  4. Maximum 35 mg/kg/day

General
1. Wear gloves while handling medication
2. Decrease dosing in elderly and Creatinine Clearance <60 ml/min
Head and Neck Squamous Cell Cancer (combined with radiation)
1. Adult: Hydrea 15 mg/kg orally daily
Chronic Myelogenous Leukemia (resistant)
1. Adult: Hydrea 15 mg/kg orally daily
2. Taken with Folic Acid
Essential Thrombocythemia or Polycythemia Vera
1. Indicated in high risk disease (history of thrombosis or age over 60 years old)
2. Start: 500 mg orally daily
3. Range: 100 to 1000 mg orally daily
4. Titrate to Platelet Count <400,000

Oral Ulcers
Skin Ulcers
Hyperpigmentation
Myelosuppression
1. Anemia
2. Neutropenia
Leukemogenicity risk in Polycythemia Vera (Exercise caution in age under 40 years old)
1. Leukemic transformation 0.4% persons per year
2. Myelofibrosis 5% at five years, 33.7% at 10 years
3. Ferrari (2019) Hematologica 104(12): 2391-9 [PubMed]
Cutaneous Vasculitis (case reports, concurrent Interferon use)
1. Ulcerative lesions
2. Gangrene

Avoid in Lactation
Avoid in pregnancy (all trimesters)
1. Use reliable Contraception
Monitoring
1. See specific monitoring in Sickle Cell Anemia below
2. Complete Blood Count
3. Renal Function tests

Baseline
1. Complete Blood Count with differential
2. Reticulocyte Count
3. Hemoglobin F quantitative measurement
4. Comprehensive metabolic panel (Renal Function tests, Liver Function Tests)
5. Pregnancy Test
Labs while adjusting dose (every 4 weeks or more)
1. Reticulocyte Count
2. Complete Blood Count with differential and Platelets
  1. Maintain Absolute Neutrophil Count (ANC) > 2,000/mm3
  2. Maintain Platelet Count >80,000/mm3
Labs when cytopenia occurs (every 1 week)
1. Reticulocyte Count
2. Complete Blood Count with differential and Platelets
Periodic labs when on stable dose (every 2-3 months)
1. Reticulocyte Count
2. Complete Blood Count with differential and Platelets
3. Hemoglobin F quantitative measurement may be obtained to evaluate for response

Full benefits may not be seen for the first 6 months after starting Hydroxyurea
Reduces Sickle Cell Anemia mortality and hospitalizations (fewer episodes of crisis and Acute Chest Syndrome)
Reduces Sickle Cell Crisis by 50%
Steinberg (2003) JAMA 289:1645-51 [PubMed]