Hydroxycarbamide: Effects in Hematology and Oncology

Hydroxycarbamide, known as hydroxyurea in many countries (brand names Litalir, Siklos and generics), is an oral cytostatic agent with a history spanning more than six decades. Today, the substance is indispensable in various areas of hematology and oncology. In sickle cell disease, hydroxycarbamide is considered the most important disease-modifying therapy. In hematooncology, it is used for rapid reduction of elevated cell counts in chronic myeloid leukemia, polycythemia vera, essential thrombocythemia and in several other indications.

The advantages of the active substance lie in simple oral application, a manageable adverse effect profile and broad efficacy. At the same time, it is a cytostatic agent with potentially severe adverse effects that requires close monitoring in a hematooncology practice. The therapy is long-term and requires regular blood checks because bone marrow and blood counts change dynamically.

Mechanism of Action

Hydroxycarbamide inhibits the enzyme ribonucleotide reductase, which converts ribonucleotides to deoxyribonucleotides in DNA synthesis. Without this substrate, cells cannot replicate their DNA. The result is selective action on rapidly proliferating cells such as bone marrow cells and to a limited extent on tumor cells. Clinically, this manifests as a reduction in leukocytes, platelets and, secondarily, erythrocytes, with varying severity depending on the indication.

In sickle cell disease, hydroxycarbamide has another special mechanism of action: it induces the formation of fetal hemoglobin (HbF). HbF cannot polymerize like pathogenic HbS, so a higher HbF level reduces sickle cell formation, vasoocclusive crises and hemolysis. Studies such as the Multicenter Study of Hydroxyurea Program have shown that the frequency of painful crises, acute chest syndrome and blood transfusions decreases significantly under hydroxycarbamide.

Oral bioavailability is high (approximately 80 to 100 percent), with a half-life of around four hours. Hydroxycarbamide is partially metabolized hepatically and predominantly excreted renally. The effect occurs rapidly, with reduction in cell counts usually measurable within days to weeks.

Indications

• Sickle cell disease in adults and children from approximately two years of age, to reduce crises and complications
• Polycythemia vera, especially in older age or with additional thrombotic risk
• Essential thrombocythemia, often in patients over 60 years or with thromboembolic history
• Chronic myeloid leukemia, especially historically, today mostly replaced by tyrosine kinase inhibitors such as imatinib, nilotinib or dasatinib
• Acute hyperleukocytosis with leukostasis, short-term cell reduction until initiation of definitive therapy
• Other myeloproliferative disorders under specialized hematologic care

In case of desire for children or during pregnancy, hydroxycarbamide is generally contraindicated or indicated only under strict risk-benefit assessment. In acute leukemias or solid tumors, hydroxycarbamide is rarely first choice today.

Dosage and Administration

Sickle cell disease: Begin with 15 to 20 mg per kg body weight daily orally. Increase in steps of 5 mg per kg every eight to twelve weeks, depending on efficacy (HbF increase, crisis rate) and tolerability (blood count). Maximum 35 mg per kg per day.

Polycythemia vera and essential thrombocythemia: Begin with 500 to 1000 mg daily, titrate individually to normalization of hematocrit or platelet count.

Acute hyperleukocytosis: 50 to 100 mg per kg per day divided into two to three doses for a few days.

Administration: Swallow capsules and tablets whole without chewing. For swallowing difficulties, oral solution (for example Siklos in some strengths) is an alternative. With or without food, adequate water. Wash hands after use.

Renal impairment: dose reduction required at eGFR below 60 ml per minute, at eGFR below 30 very cautious use with close level monitoring. Hepatic impairment: individualized dose adjustment if function is compromised.

Pregnancy and breastfeeding: Substance is teratogenic, contraception mandatory during therapy and for several months thereafter.

Adverse Effects

Very common: Bone marrow suppression with leukopenia, thrombocytopenia and anemia, nausea, vomiting, diarrhea, mucositis, hyperpigmentation of skin, nail changes, alopecia.

Common: Fatigue, headaches, fever, rash, elevation of liver transaminases, dermatological changes such as atrophic skin or skin ulcerations, especially on lower legs.

Occasional to rare: Acute pneumonitis, acute interstitial nephritis, secondary malignant diseases such as myelodysplastic syndrome or acute leukemias with long-term use, skin cancer especially with intense UV exposure, hyperuricemic crises.

Skin ulcers: Typical are painful sores on the lower legs, often refractory to treatment. If they occur, consider therapy interruption or discontinuation. Alternative therapies are anagrelide or pegylated interferon alpha in myeloproliferative diseases.

Reproductive: Reversible spermatogenesis disorder possible, with desire for children ideally cryopreservation before therapy initiation.

Drug Interactions

• Other myelotoxic agents (for example methotrexate, azathioprine, other cytostatics): additive bone marrow suppression.
• Antiretroviral therapy with didanosine and stavudine: increased risk of pancreatitis and hepatotoxicity.
• Live vaccines: contraindicated due to relative immunosuppression.
• Selected antibiotics and antifungals: potential additive toxicity, especially with long-acting substances.
• Allopurinol: useful in hyperuricemia because hydroxycarbamide increases cell turnover.
• Vitamins and folic acid: in sickle cell disease folic acid substitution often useful because erythropoiesis is increased.

Special Notes

Pregnancy: Hydroxycarbamide is teratogenic and contraindicated in pregnancy, except for life-threatening indications and after individual counseling in a center. Women of childbearing age require reliable contraception during therapy and at least six months thereafter. Men with desire for children should also consider counseling and sperm cryopreservation before therapy initiation. Breastfeeding: Breastfeeding is not recommended during therapy.

Children: In sickle cell disease, children from two years of age are treatable and established in pediatric hematology. Indication is determined in specialized centers.

Before therapy initiation: Complete blood count, differential blood count, eGFR, liver values, uric acid, pregnancy test, HBV and HCV status. In sickle cell disease additionally HbF determination and reticulocyte-specific markers.

Monitoring: During titration phase blood count every one to two weeks, later every four to eight weeks. In polycythemia vera regular hematocrit, in essential thrombocythemia platelet count, in sickle cell disease HbF proportion.

UV protection: Due to increased skin cancer risk, regular sun protection, annual dermatological check-up.

Patient education: Patients must be informed about contraception requirements, skin ulcers, dermatological inspection, regular laboratory checks and possible late complications such as secondary malignancies.

Fitness to drive: Generally maintained, with marked fatigue or dizziness individual assessment.

You May Also Be Interested In

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• Oxaliplatin, platinum compound in gastrointestinal oncology
• Fluorouracil, pyrimidine analog cytostatic

Frequently Asked Questions

Sources

• Gelbe Liste, Hydroxycarbamide Active Substance Profile
• BfArM, Federal Institute for Drugs and Medical Devices
• AWMF, Guidelines Sickle Cell Disease, Polycythemia Vera, ET
• ESMO, European Society for Medical Oncology