Evoltra (Clofarabine)
Antineoplastic Agent for Relapsed or Refractory Acute Lymphoblastic Leukemia
Quick Facts About Evoltra
Key Takeaways About Evoltra
- Specialized leukemia treatment: Evoltra is used for relapsed or refractory acute lymphoblastic leukemia (ALL) in patients aged 1–21 years when other treatments have failed
- Hospital-only medication: Clofarabine is administered as an intravenous infusion over 2 hours, once daily for 5 days, under strict medical supervision in specialized oncology units
- Severe bone marrow suppression: The most significant risk is myelosuppression, which dramatically reduces blood cell counts and increases vulnerability to life-threatening infections
- Organ monitoring essential: Liver and kidney function must be closely monitored throughout treatment, as clofarabine can cause hepatotoxicity and nephrotoxicity
- Contraception required: Both male and female patients of reproductive age must use effective contraception during and for at least 6 months (women) or 3 months (men) after treatment due to potential harm to unborn children
What Is Evoltra and What Is It Used For?
Evoltra contains the active substance clofarabine, a purine nucleoside analogue that belongs to the group of cytotoxic/antineoplastic agents (cancer medicines). It is specifically approved for the treatment of acute lymphoblastic leukemia (ALL) in children, adolescents, and young adults aged 1 to 21 years when prior treatments have failed or when the disease has relapsed.
Acute lymphoblastic leukemia (ALL) is a type of blood cancer that originates in the bone marrow, where blood cells are produced. In ALL, the bone marrow produces an excessive number of immature, abnormal white blood cells called lymphoblasts. These abnormal cells crowd out normal blood cells, leading to anaemia (low red blood cells), thrombocytopenia (low platelets), and neutropenia (low infection-fighting white blood cells). ALL is the most common cancer in children, accounting for approximately 25% of all childhood cancers worldwide according to the World Health Organization.
Clofarabine works by targeting rapidly dividing cells, which is a hallmark characteristic of cancer cells. Once inside the cell, clofarabine is converted into its active form (clofarabine triphosphate), which inhibits two critical enzymes involved in DNA production: ribonucleotide reductase and DNA polymerase alpha. By blocking these enzymes, clofarabine disrupts the cancer cell's ability to replicate its DNA and repair any existing DNA damage. This dual mechanism of action ultimately triggers programmed cell death (apoptosis) in the leukemia cells.
Evoltra is approved under exceptional circumstances by the European Medicines Agency (EMA), meaning that because ALL is a rare disease, it has not been possible to obtain complete clinical information. The EMA reviews all new data that becomes available each year and updates the prescribing information as needed. Despite this classification, clofarabine has demonstrated meaningful clinical activity in heavily pre-treated patients with relapsed or refractory ALL, providing an important treatment option where few alternatives exist.
In clinical trials, clofarabine achieved complete remission in approximately 20–30% of paediatric patients with relapsed or refractory ALL. While these response rates may seem modest, they are clinically significant given that these patients have already failed multiple prior treatment regimens. Achieving remission with clofarabine can serve as a bridge to potentially curative haematopoietic stem cell transplantation (bone marrow transplant), which remains the definitive treatment goal for many of these patients.
Evoltra was first authorised in the European Union in 2006. It is manufactured by Sanofi and is available in 20 ml glass vials, each containing 20 mg of clofarabine. The medicine has been approved under exceptional circumstances because the disease it treats is rare, and full clinical data collection has been challenging. The EMA reviews all new available information annually.
What Should You Know Before Receiving Evoltra?
Before receiving Evoltra, your doctor must assess your kidney function, liver function, and heart health. Clofarabine is contraindicated in patients with severe kidney or liver impairment and should not be used during breastfeeding. A thorough assessment of risks versus benefits must be performed for every patient.
Contraindications
You should not receive Evoltra if any of the following apply:
- Allergy to clofarabine or any of the other ingredients in Evoltra (sodium chloride, water for injections) – symptoms may include rash, itching, swelling, or difficulty breathing
- Severe kidney disease – clofarabine is eliminated partly through the kidneys, and impaired renal function can lead to dangerous drug accumulation
- Severe liver disease – clofarabine can cause additional hepatotoxicity, and pre-existing severe liver impairment significantly increases the risk of liver failure
- Breastfeeding – it is not known whether clofarabine passes into breast milk, and because of its cytotoxic nature, breastfeeding must be stopped before treatment begins and must not be resumed until at least 2 weeks after treatment ends
If you are a parent or carer of a child being treated with Evoltra, you should inform the treating doctor if any of these conditions apply to the patient.
Warnings and Precautions
Tell your doctor before receiving Evoltra if you have or have ever had any of the following conditions, as extra care and monitoring may be needed:
- Previous severe reaction to chemotherapy – patients who have experienced severe toxicity from prior treatment may be at higher risk of complications
- Kidney disease or history of kidney problems – clofarabine may further impair kidney function, and dose adjustments may be necessary
- Liver disease or history of liver problems – hepatotoxicity, including hepatic veno-occlusive disease, has been reported and can be fatal
- Heart disease or history of heart problems – cardiac toxicity, including pericardial effusion and changes in heart rhythm, has been observed in some patients
Contact your doctor or medical team immediately if you experience any of the following during treatment with Evoltra: fever or high temperature (increased infection risk due to low white blood cells), difficulty breathing or shortness of breath, changes in heart rhythm or palpitations, dizziness or fainting (possible low blood pressure), severe nausea or diarrhoea, dark-coloured urine (dehydration), blistering skin rash or mouth sores, yellowing of the skin or eyes (liver damage), or very low or no urine output (kidney failure).
During treatment with Evoltra, your doctor will perform regular blood tests and other investigations to monitor your health. Because of how the medicine works, it affects the blood and other organs. Your doctor will pay particular attention to your complete blood count, liver function tests, kidney function tests, and electrolyte levels. Adequate hydration with intravenous fluids is essential throughout treatment to help protect the kidneys and prevent tumour lysis syndrome.
Pregnancy and Breastfeeding
Clofarabine should not be used during pregnancy unless absolutely necessary and the potential benefit justifies the potential risk to the foetus. Animal studies have shown that clofarabine can cause birth defects and developmental abnormalities. If you are pregnant or become pregnant during treatment with clofarabine, seek immediate medical advice.
Women of childbearing potential must use effective contraception during treatment with clofarabine and for at least 6 months after the last dose. Male patients must also use effective contraception and are advised not to father a child while receiving clofarabine and for at least 3 months after the last dose. Clofarabine may damage both male and female reproductive organs, and patients who wish to have children in the future should discuss fertility preservation options with their doctor before starting treatment.
Breastfeeding must be discontinued before treatment with Evoltra begins. You must not breastfeed during treatment or for at least 2 weeks after the last dose, as it is unknown whether clofarabine is excreted in human breast milk, and the potential for serious adverse reactions in nursing infants cannot be excluded.
Driving and Operating Machinery
Clofarabine can cause dizziness, light-headedness, and fainting. If you experience any of these symptoms, you should not drive or operate machinery. Given the nature of the treatment and its side effects, most patients receiving Evoltra will be in a hospital setting and will not be driving during the treatment period. However, these precautions also apply during the recovery period between treatment cycles.
Sodium Content
Evoltra contains 72 mg of sodium per vial, equivalent to 3.6% of the WHO-recommended maximum daily sodium intake for an adult. If you require 5 or more vials daily during a treatment cycle over an extended period, this should be discussed with your doctor or pharmacist, particularly if you have been advised to follow a low-sodium diet.
How Does Evoltra Interact with Other Drugs?
Clofarabine can interact with medications that affect the kidneys, liver, or heart. Because Evoltra is administered in a hospital under specialist supervision, all concurrent medications are carefully reviewed by the medical team. You must inform your doctor about all medicines you are taking, including over-the-counter and herbal products.
Although specific drug interaction studies with clofarabine are limited (because the drug is used in a controlled hospital setting), potential interactions exist based on the pharmacological properties of the medicine. Clofarabine is primarily eliminated through the kidneys (approximately 49–60% excreted unchanged in urine), and it undergoes limited hepatic metabolism. Any drug that affects kidney function can therefore influence clofarabine levels in the body.
Major Interactions
| Drug / Class | Category | Effect | Recommendation |
|---|---|---|---|
| Nephrotoxic drugs (e.g., aminoglycosides, amphotericin B, cisplatin, NSAIDs) | Various | Increased risk of kidney damage when used with clofarabine; clofarabine itself is nephrotoxic | Avoid concurrent use; if unavoidable, monitor renal function closely |
| Hepatotoxic drugs (e.g., methotrexate, azathioprine, valproic acid) | Various | Increased risk of liver damage; clofarabine can cause hepatotoxicity including veno-occlusive disease | Monitor liver function tests frequently; consider dose adjustments |
| Cardiac medications (e.g., beta-blockers, calcium channel blockers, digoxin) | Cardiovascular | Clofarabine may cause hypotension, tachycardia, and pericardial effusion, potentially compounding cardiac effects | Monitor heart function and blood pressure closely; adjust cardiac medications as needed |
| Antihypertensive drugs | Blood pressure medications | Clofarabine frequently causes hypotension, which may be exacerbated by blood pressure-lowering drugs | Monitor blood pressure closely; may need to withhold antihypertensives during treatment |
Additional Precautions
| Drug / Class | Category | Effect | Recommendation |
|---|---|---|---|
| Live vaccines (e.g., MMR, varicella, BCG) | Immunisation | Clofarabine causes severe immunosuppression; live vaccines may cause uncontrolled infection | Contraindicated during treatment and for a prolonged period after; consult oncologist for timing |
| Other myelosuppressive agents | Chemotherapy | Additive bone marrow suppression, increasing risk of severe cytopenias | Careful timing of sequential chemotherapy; monitor blood counts closely |
| Probenecid, indomethacin | Various | May inhibit renal tubular secretion of clofarabine, increasing drug exposure | Avoid during clofarabine treatment cycles |
| Anticoagulants (e.g., warfarin, heparin) | Blood thinners | Increased bleeding risk due to clofarabine-induced thrombocytopenia | Monitor platelet counts and coagulation parameters closely |
Because Evoltra is administered in a specialist hospital setting, the medical team will review all of your current medications (including vitamins, supplements, and herbal products) before starting treatment. This comprehensive medication review helps minimise the risk of harmful drug interactions throughout the treatment course.
What Is the Correct Dosage of Evoltra?
The recommended dose of Evoltra is 52 mg/m² of body surface area per day, given as an intravenous infusion over 2 hours, once daily for 5 consecutive days. Treatment cycles may be repeated after the patient has recovered, typically every 2 to 6 weeks. The dose is calculated based on the patient's height and weight.
Evoltra treatment is prescribed and supervised by a qualified physician experienced in treating leukemia. The medicine must be administered in a hospital setting with appropriate monitoring facilities. Before administration, the concentrated solution is diluted with 0.9% sodium chloride (saline) solution and filtered through a sterile 0.2 micrometre filter.
Standard Dosing
Children, Adolescents, and Young Adults (1–21 years)
Dose: 52 mg/m² body surface area per day
Route: Intravenous infusion over 2 hours
Schedule: Once daily for 5 consecutive days
Cycle: Treatment cycles may be repeated every 2–6 weeks depending on recovery
Note: For patients weighing less than 20 kg, the infusion time may be extended beyond 2 hours to ensure appropriate drug delivery.
Dilution Guidelines
| Body Surface Area (m²) | Concentrate Volume (ml) | Total Dilution Volume |
|---|---|---|
| ≤ 1.44 m² | ≤ 74.9 ml | 100 ml |
| 1.45 – 2.40 m² | 75.4 – 124.8 ml | 150 ml |
| 2.41 – 2.50 m² | 125.3 – 130.0 ml | 200 ml |
Each ml of concentrate contains 1 mg of clofarabine, and each 20 ml vial contains 20 mg. For patients with a body surface area of 0.38 m² or less, only part of a single vial is needed. For larger patients, 1 to 7 vials may be required per daily dose.
Dose Adjustments
Your doctor may adjust or delay your dose depending on how you respond to treatment. Dose modifications are typically made in response to:
- Haematological toxicity: If blood counts do not recover sufficiently between cycles, the dose may be reduced by 25% or the next cycle may be delayed
- Non-haematological toxicity: For significant organ toxicity (liver, kidney), treatment may be interrupted until the organ function recovers, and the dose may be reduced for subsequent cycles
- Infections: If serious infections develop, treatment is typically withheld until the infection is controlled
Missed Dose
Because Evoltra is administered in a hospital setting by healthcare professionals, missed doses are uncommon. However, if a dose is missed for any reason (such as a medical complication), your doctor will advise when the next dose should be given. Do not attempt to make up for a missed dose by receiving a double dose.
Overdose
There is no specific antidote for clofarabine overdose. If an overdose is suspected, treatment is supportive and symptomatic. The medical team will closely monitor blood counts, organ function, and vital signs. In clinical experience, overdose symptoms are expected to include severe myelosuppression (dangerously low blood counts), gastrointestinal toxicity (severe nausea, vomiting, diarrhoea), and multi-organ dysfunction. Immediate intensive care support may be required.
It is critical to drink plenty of water and maintain adequate hydration throughout treatment with Evoltra. Your medical team will also administer intravenous fluids to help protect the kidneys and reduce the risk of tumour lysis syndrome, a potentially life-threatening condition that can occur when large numbers of cancer cells are destroyed rapidly.
What Are the Side Effects of Evoltra?
Like all chemotherapy medicines, Evoltra can cause significant side effects. The most common include nausea, vomiting, diarrhoea, fever, fatigue, skin rash, and increased susceptibility to infections due to bone marrow suppression. Not everyone will experience all side effects, and your medical team will monitor you closely throughout treatment.
Side effects from clofarabine are often related to its mechanism of action – because it targets rapidly dividing cells, it also affects normal cells that divide quickly, such as those in the bone marrow, digestive tract, and skin. The severity of side effects depends on the dose, the patient's overall health, and the cumulative exposure to prior chemotherapy regimens.
Very Common Side Effects
May affect more than 1 in 10 patients
- Anxiety, headache, fever, fatigue
- Nausea and vomiting, diarrhoea
- Flushing, itchy and inflamed skin
- Inflammation of mucous membranes (mouth and other areas)
- Increased susceptibility to infections (due to reduced blood cell counts)
- Skin rash (including redness, pain, peeling skin on palms and soles – hand-foot syndrome)
- Small red or purple spots under the skin (petechiae)
Common Side Effects
May affect up to 1 in 10 patients
- Blood infections (sepsis), pneumonia, herpes zoster (shingles), oral thrush, cold sores
- Changes in blood composition, white blood cell count changes
- Allergic reactions
- Thirst, dark-coloured urine, decreased appetite, weight loss
- Agitation, irritability, restlessness
- Numbness or weakness in arms and legs, drowsiness, dizziness, tremor
- Hearing problems
- Fluid accumulation around the heart (pericardial effusion), rapid heart rate
- Low blood pressure, bruising
- Capillary leak, rapid breathing, nosebleeds, breathing difficulties, shortness of breath, cough
- Vomiting blood, abdominal pain, rectal pain
- Bleeding within the head, stomach, intestines, lungs, mouth, or gums; mouth ulcers
- Yellowing of skin and eyes (jaundice), liver disease, liver failure
- Hair loss, skin colour changes, increased sweating, dry skin
- Chest or breastbone pain, neck or back pain, limb pain, muscle or joint pain
- Blood in urine
- Organ failure, pain, increased muscle tension, fluid retention and swelling (including in arms and legs)
- Changes in mood, feeling unusually warm, cold, or abnormal
Uncommon Side Effects
May affect up to 1 in 100 patients
- Hepatitis (inflammation of the liver)
- Acute kidney failure (little or no urine output, drowsiness, nausea, vomiting, breathlessness, loss of appetite, weakness)
Clofarabine can trigger a serious condition known as SIRS or capillary leak syndrome, characterised by rapid breathing, rapid heart rate, low blood pressure, and fluid accumulation in tissues. This occurs because clofarabine causes the release of inflammatory cytokines from dying cancer cells. Prophylactic corticosteroids (such as hydrocortisone) may be given to help prevent this complication. If symptoms of SIRS develop, treatment with clofarabine should be interrupted immediately, and supportive care should be initiated.
Your doctor will perform regular blood tests to monitor the effects of clofarabine on your blood cells and organ function. Clofarabine can affect the levels of various substances in your blood, including electrolytes, liver enzymes, and kidney markers. These laboratory values are an essential part of monitoring your safety throughout treatment.
It is important to report suspected side effects after the medicine has been authorised. This allows ongoing monitoring of the medicine's benefit-risk balance. Healthcare professionals and patients can report side effects to their national medicines regulatory authority (e.g., FDA MedWatch in the US, Yellow Card scheme in the UK, or EMA EudraVigilance in Europe).
How Should You Store Evoltra?
Evoltra should be stored out of the sight and reach of children. Do not use after the expiry date on the label. Do not freeze. Once diluted, use immediately or within 24 hours if refrigerated at 2°C–8°C.
As Evoltra is a hospital medication, storage is managed by pharmacy and nursing staff. However, the following storage information is important for understanding how the medicine is handled:
- Unopened vials: Store below 25°C. Do not freeze. Keep the vial in the outer carton to protect from light.
- After dilution: The diluted solution should be used immediately. If not used straight away, it may be stored for up to 24 hours in a refrigerator (2°C–8°C), provided that dilution was performed under controlled aseptic conditions.
- Chemical stability: The diluted concentrate is chemically and physically stable for 3 days at 2°C–8°C and at room temperature (up to 25°C).
- Visual inspection: The diluted solution should be a clear, colourless liquid. It must be visually inspected for particulate matter and discolouration before administration.
- Disposal: Any unused medicine or waste material should be disposed of in accordance with local requirements for cytotoxic waste. Do not dispose of through household waste or wastewater.
What Does Evoltra Contain?
Each ml of Evoltra contains 1 mg of clofarabine as the active substance. Each 20 ml vial contains 20 mg of clofarabine. The other ingredients are sodium chloride and water for injections.
Evoltra is a concentrate for solution for infusion. It is a clear, practically colourless solution that must be prepared (diluted) before use. The medicine is supplied in 20 ml glass vials. Vials are packed in cartons containing 1, 3, 4, 10, or 20 vials, although not all pack sizes may be marketed in every country.
The marketing authorisation holder is Sanofi B.V., based in Amsterdam, Netherlands. The medicine is manufactured by Sanofi Winthrop Industrie in Tours, France. For further information about Evoltra, contact your local Sanofi representative or visit the European Medicines Agency website for the full European Public Assessment Report (EPAR).
Handling Precautions for Healthcare Professionals
Evoltra is a cytotoxic medicine and must be handled with appropriate precautions. Healthcare professionals should follow standard procedures for the safe handling of cytotoxic drugs:
- Use disposable gloves and protective clothing during preparation and administration
- If the medicine contacts eyes, skin, or mucous membranes, rinse immediately with copious amounts of water
- Pregnant women should not handle Evoltra
- The concentrate should be filtered through a sterile 0.2 micrometre syringe filter before dilution with 0.9% sodium chloride solution
- The medicine is for single use only; any unused portion must be disposed of as cytotoxic waste
Frequently Asked Questions About Evoltra
Evoltra (clofarabine) is used to treat acute lymphoblastic leukemia (ALL) in children aged 1 year and older, adolescents, and young adults up to 21 years of age. It is specifically indicated for patients whose leukemia has relapsed (returned) or is refractory (has not responded) to at least two prior treatment regimens. Clofarabine works by inhibiting the growth of abnormal white blood cells and ultimately destroying them, and it is most effective against rapidly dividing cancer cells.
Evoltra is given as an intravenous (IV) infusion over 2 hours, once daily for 5 consecutive days. The concentrated solution is diluted with saline before administration and infused through a vein or a port-a-cath (an implanted medical device). The dose is calculated based on the patient's body surface area (height and weight). For patients weighing less than 20 kg, the infusion time may be longer. Treatment cycles can be repeated every 2 to 6 weeks, depending on recovery of blood counts and overall condition.
The most serious risks include severe bone marrow suppression (myelosuppression), which dramatically lowers blood cell counts and increases the risk of life-threatening infections and bleeding. Other serious risks include hepatotoxicity (liver damage, including potentially fatal veno-occlusive disease), nephrotoxicity (kidney damage), systemic inflammatory response syndrome (SIRS) or capillary leak syndrome, and cardiac complications including pericardial effusion and hypotension. All patients require close monitoring with regular blood tests throughout treatment.
Evoltra is approved for patients aged 1 to 21 years in most regulatory jurisdictions. It is not routinely approved for adults over 21. However, clofarabine has been studied in clinical trials in older adult patients with acute leukemias, and some oncologists may use it off-label in combination with other agents for adult patients with relapsed or refractory acute leukemia. Any use in adults should be under specialist supervision at an experienced haematology-oncology centre and should follow institutional protocols.
Yes, clofarabine can potentially damage both male and female reproductive organs. Patients of childbearing potential should discuss fertility preservation options with their doctor before starting treatment. Women must use effective contraception during treatment and for 6 months after the last dose. Men must use effective contraception during treatment and for 3 months after the last dose. If you wish to have children in the future, ask your oncologist about options such as sperm banking or oocyte (egg) freezing before beginning chemotherapy.
All information is based on the European Medicines Agency (EMA) Summary of Product Characteristics for Evoltra, FDA prescribing information for clofarabine, World Health Organization (WHO) guidance on essential medicines, and peer-reviewed clinical trial publications including the pivotal Phase II studies in paediatric ALL. Evidence is graded according to the GRADE framework and aligned with international guidelines from the National Comprehensive Cancer Network (NCCN) and the Children's Oncology Group (COG).
References
- European Medicines Agency (EMA). Evoltra (clofarabine) – Summary of Product Characteristics. Last updated 2023. Available at: EMA EPAR – Evoltra
- Jeha S, Gaynon PS, Razzouk BI, et al. Phase II study of clofarabine in pediatric patients with refractory or relapsed acute lymphoblastic leukemia. Journal of Clinical Oncology. 2006;24(12):1917–1923. doi:10.1200/JCO.2005.03.8554
- Kantarjian HM, Gandhi V, Kozuch P, et al. Phase I clinical and pharmacology study of clofarabine in patients with solid and hematologic cancers. Journal of Clinical Oncology. 2003;21(6):1167–1173.
- National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology: Pediatric Acute Lymphoblastic Leukemia. Version 1.2025.
- World Health Organization (WHO). WHO Model List of Essential Medicines for Children. 9th List, 2023.
- Faderl S, Gandhi V, O'Brien S, et al. Results of a phase 1-2 study of clofarabine in combination with cytarabine (ara-C) in relapsed and refractory acute leukemias. Blood. 2005;105(3):940–947.
- FDA. Clolar (clofarabine) – Prescribing Information. Reference ID: 4760012. U.S. Food and Drug Administration.
- Locatelli F, Testi AM, Bernardo ME, et al. Clofarabine, cyclophosphamide and etoposide as single-course re-induction therapy for children with refractory/multiple relapsed acute lymphoblastic leukemia. British Journal of Haematology. 2009;147(3):371–378.
Editorial Team
This article has been written and reviewed by the iMedic Medical Editorial Team, consisting of licensed specialist physicians, pharmacologists, and medical researchers with expertise in oncology, haematology, and clinical pharmacology.
Medical Writing
Licensed physicians with specialisation in oncology and clinical pharmacology. Evidence-based content following GRADE framework and international guidelines (EMA, FDA, NCCN, WHO).
Medical Review
Independent review by board-certified haematologist-oncologists and paediatric oncology specialists. All clinical claims verified against peer-reviewed sources and current prescribing information.
Conflict of interest statement: The iMedic editorial team has no financial relationships with pharmaceutical companies. All content is independently produced without commercial funding or sponsorship.