Clofarabine

Clofarabine is a purine nucleoside antimetabolite. Its antitumour activity is believed to rest on three mechanisms, all carried out by its active intracellular form, clofarabine 5’-triphosphate. In laboratory studies it inhibited the growth of many rapidly proliferating blood-cancer and solid-tumour cell lines and was cytotoxic to them, and it was also active against resting (quiescent) lymphocytes and macrophages.

Mechanism of Action

• Activation inside the cell: clofarabine enters target cells by diffusion or transport and is phosphorylated step by step to the mono- and diphosphate and finally to the active 5’-triphosphate. It binds the activating enzyme deoxycytidine kinase with an affinity higher than that of the natural substrate, deoxycytidine.
• DNA polymerase α inhibition: terminates DNA chain elongation and blocks DNA synthesis and repair.
• Ribonucleotide reductase inhibition: reduces the cell’s pools of deoxynucleotide triphosphates, the building blocks of DNA.
• Mitochondrial effect: the triphosphate disrupts the integrity of the mitochondrial membrane, releasing cytochrome C and other pro-apoptotic factors and leading to programmed cell death, even in non-dividing lymphocytes.
• Resistance to breakdown: compared with other medicines of its class, clofarabine is more resistant to degradation by adenosine deaminase and less susceptible to phosphorolytic cleavage, and its triphosphate binds DNA polymerase α and ribonucleotide reductase as strongly as, or more strongly than, deoxyadenosine triphosphate.

Pharmacokinetics

• Studied in: 40 patients aged 2 to 19 years with relapsed or refractory ALL or acute myeloid leukaemia (AML) who received repeated intravenous infusions.
• Distribution: steady-state volume of distribution 172 L/m²; about 47% bound to plasma proteins.
• Metabolism: clofarabine is not detectably metabolised by the cytochrome P450 system. Inside cells it is phosphorylated to the active triphosphate, whose half-life is more than 24 hours.
• Elimination: plasma elimination (β) half-life of clofarabine 5.2 hours; systemic clearance 28.8 L/h/m² and renal clearance 10.8 L/h/m². About 57–60% of the dose is excreted unchanged in the urine. Clearance is much higher than glomerular filtration, which suggests filtration plus tubular secretion; the routes of non-renal elimination are unknown.
• Body weight: exposure at 52 mg/m² is equivalent across a wide range of weights, but peak concentration (Cmax) is inversely related to weight, so small children can reach a higher peak at the end of the infusion than a typical 40 kg child. For this reason a longer infusion is considered below 20 kg.
• Special populations: no apparent difference between patients with ALL and AML, or between males and females. Clofarabine may accumulate when creatinine clearance is reduced (see Administration and Dosage). Data in adults are insufficient.

• Relapsed or refractory acute lymphoblastic leukaemia (ALL) in paediatric patients: treatment of paediatric patients who have relapsed or are refractory after receiving at least two prior regimens and where there is no other treatment option anticipated to result in a durable response.
• Safety and efficacy have been assessed in studies of patients aged 21 years or younger at initial diagnosis.

• Hypersensitivity to clofarabine or to any of the excipients.
• Severe renal insufficiency.
• Severe hepatic impairment.
• Breastfeeding.

The figures come from 115 patients aged over 1 year and up to 21 years with ALL or AML who received 52 mg/m² daily for 5 days. Nearly all (98%) had at least one reaction considered related to clofarabine, and 59% (68 patients) had at least one serious related reaction. The most frequent were nausea (61%), vomiting (59%), febrile neutropenia (35%), headache (24%), rash (21%), diarrhoea (20%), pruritus (20%), pyrexia (19%), palmar-plantar erythrodysaesthesia syndrome (15%), fatigue (14%), anxiety (12%), mucosal inflammation (11%) and flushing (11%). Because patients with advanced leukaemia have many confounding conditions and take many medicines, causality is often hard to assess.

Very common (≥1/10): febrile neutropenia, anxiety, headache, flushing, vomiting, nausea, diarrhoea, fatigue, pyrexia, mucosal inflammation, palmar-plantar erythrodysaesthesia syndrome, pruritus.

Common (≥1/100 to <1/10): septic shock, sepsis, bacteraemia, pneumonia, herpes zoster, herpes simplex, oral candidiasis; tumour lysis syndrome; neutropenia; hypersensitivity; anorexia, decreased appetite, dehydration; agitation, restlessness, mental status change; somnolence, peripheral neuropathy, paraesthesia, dizziness, tremor; hypoacusis; pericardial effusion, tachycardia; hypotension, capillary leak syndrome, haematoma; respiratory distress, epistaxis, dyspnoea, tachypnoea, cough; mouth haemorrhage, gingival bleeding, haematemesis, abdominal pain (including upper abdominal pain), stomatitis, proctalgia, mouth ulceration; hyperbilirubinaemia, jaundice, veno-occlusive disease, raised alanine and aspartate aminotransferases, hepatic failure; multi-organ failure, systemic inflammatory response syndrome, pain, chills, irritability, oedema, peripheral oedema, feeling hot, feeling abnormal; maculo-papular, pruritic, generalised and erythematous rash, petechiae, erythema, skin exfoliation, alopecia, skin hyperpigmentation, dry skin, hyperhidrosis; pain in the limbs, bones, chest wall, neck and back, myalgia, arthralgia; haematuria; renal failure, acute renal failure; weight decreased; contusion.

Uncommon (≥1/1,000 to <1/100): hepatitis.

Not known: C. difficile colitis, hyponatraemia, pancreatitis, raised serum amylase and lipase, enterocolitis, neutropenic colitis, caecitis, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Serious and sometimes fatal reactions include severe bone marrow suppression with bleeding (cerebral, gastrointestinal and pulmonary haemorrhage), severe infections and sepsis, enterocolitis, Stevens-Johnson syndrome and toxic epidermal necrolysis, tumour lysis syndrome, systemic inflammatory response syndrome and capillary leak syndrome (reported in 5% of the paediatric patients), hepatotoxicity including veno-occlusive disease, and renal failure. In the trials three patients died of events judged related to treatment (respiratory distress with liver damage and capillary leak syndrome; sepsis with multi-organ failure; septic shock with multi-organ failure). Laboratory abnormalities were frequent: anaemia (83.3%), leukopenia (87.7%), lymphopenia (82.3%), neutropenia (63.7%) and thrombocytopenia (80.7%), mostly grade 3 or higher.

No interaction studies have been performed, and no clinically significant interactions with other medicines or laboratory tests are known. Clofarabine is not detectably metabolised by cytochrome P450 enzymes and is unlikely to inhibit the five major isoforms (CYP1A2, 2C9, 2C19, 2D6, 3A4) or to induce CYP1A2 and CYP3A4 at the concentrations reached, so it is not expected to affect the metabolism of their substrates.

• Kidney-toxic medicines and medicines cleared by tubular secretion (NSAIDs, amphotericin B, methotrexate, aminoglycosides, organoplatinum compounds, foscarnet, pentamidine, ciclosporin, tacrolimus, aciclovir, valganciclovir): clofarabine is excreted mainly by the kidneys, so these should be avoided, particularly during the 5-day infusion period. Medicines not known to be nephrotoxic are preferred.
• Liver-toxic medicines: the liver is a potential target organ, so medicines associated with hepatic toxicity should be avoided wherever possible.
• Medicines affecting blood pressure or cardiac function: patients should be monitored closely.
• Other medicines in the same infusion line: Evoltra must not be mixed with, or given through the same intravenous line as, other medicinal products.
• Herbal products: DrugBank advises avoiding echinacea, which should be used with caution, if at all, in patients receiving immunosuppressive therapy.

Clofarabine must be started and supervised by a physician experienced in the management of patients with acute leukaemias. It is given by intravenous infusion (in clinical trials it was also given through a central venous catheter). Section 6.6 of the SmPC gives instructions for filtration and dilution before administration.

Recommended Dose

• Children and adolescents (1 year and older): 52 mg/m² of body surface area (BSA) by intravenous infusion over 2 hours daily for 5 consecutive days, as monotherapy. BSA is calculated from the actual height and weight before each cycle.
• Cycles: repeated every 2 to 6 weeks (counted from the first day of the previous cycle) once normal haematopoiesis has recovered (absolute neutrophil count, ANC, at least 0.75 × 10⁹/L) and organ function is back to baseline.
• Duration: most responders respond after 1 or 2 cycles. If there is no haematological or clinical improvement after 2 cycles, the treating physician should weigh the benefit and risk of continuing. Experience with more than 3 cycles is limited.
• Children weighing below 20 kg: an infusion time longer than 2 hours should be considered, to help reduce symptoms of anxiety and irritability and to avoid unduly high peak concentrations.

Dose Adjustments

• Haematological toxicity: if ANC has not recovered 6 weeks after the start of a cycle, a bone marrow aspirate or biopsy is done to look for refractory disease. If persistent leukaemia is not evident, the next cycle is given at a dose reduced by 25% once ANC is back to at least 0.75 × 10⁹/L. The same 25% reduction applies if ANC stays below 0.5 × 10⁹/L for more than 4 weeks from the start of the last cycle.
• Infections: after a clinically significant infection, treatment may be withheld until it is clinically controlled and then restarted at the full dose. After a second clinically significant infection, withhold until controlled and restart with a 25% reduction.
• Severe non-infectious toxicity (grade 3, excluding nausea and vomiting): delay treatment until the toxicity returns to baseline or is no longer severe and the benefit of continuing outweighs the risk, then give a 25% lower dose. If the same toxicity recurs, delay again and reduce by a further 25%. Withdraw the patient after a third severe toxicity, a severe toxicity that does not recover within 14 days, or a life-threatening or disabling (grade 4) toxicity.

Special Populations

• Adults, including elderly patients: data are insufficient to establish safety and efficacy.
• Children below 1 year: there are no pharmacokinetic, safety or efficacy data, so no dose can be recommended.
• Renal impairment: clofarabine may accumulate when creatinine clearance is reduced. It is contraindicated in severe renal insufficiency and used with caution in mild to moderate impairment; moderate impairment (creatinine clearance 30 to under 60 mL/min) requires a 50% dose reduction.
• Hepatic impairment: there is no experience in patients with serum bilirubin above 1.5 × the upper limit of normal (ULN) together with AST and ALT above 5 × ULN, and the liver is a potential target organ. It is contraindicated in severe hepatic impairment and used with caution in mild to moderate impairment.

Monitoring

• Complete blood and platelet counts at regular intervals, more often in patients who develop cytopenias.
• Renal and hepatic function before, during and after treatment. Clofarabine is stopped immediately if creatinine, liver enzymes or bilirubin rise substantially.
• Respiratory status, blood pressure, fluid balance and body weight throughout, and immediately after, the 5-day infusion period.

Bone Marrow Suppression, Bleeding and Infection

Bone marrow suppression should be anticipated; it is usually reversible and appears to be dose-dependent. Severe neutropenia, anaemia and thrombocytopenia have been seen. Haemorrhage, including cerebral, gastrointestinal and pulmonary haemorrhage, has been reported and may be fatal; most cases were associated with thrombocytopenia. Because many patients are already immunocompromised and neutropenia can be prolonged, there is an increased risk of severe opportunistic infections, including severe sepsis with potentially fatal outcome. Patients should be watched for signs of infection and treated promptly.

Enterocolitis

Enterocolitis, including neutropenic colitis, caecitis and C. difficile colitis, has been reported, more often within 30 days of treatment and during combination chemotherapy. It may lead to necrosis, perforation or sepsis and can be fatal, so patients should be monitored for signs and symptoms.

Severe Skin Reactions

Stevens-Johnson syndrome and toxic epidermal necrolysis, including fatal cases, have been reported. Clofarabine must be discontinued for an exfoliative or bullous rash, or if either condition is suspected.

Tumour Lysis Syndrome, Cytokine Release and Capillary Leak

Clofarabine rapidly reduces circulating leukaemia cells. Patients must be evaluated and monitored for tumour lysis syndrome and for cytokine release (for example rapid breathing, fast heart rate, low blood pressure, pulmonary oedema), which can progress to systemic inflammatory response syndrome (SIRS), capillary leak syndrome and organ dysfunction.

• Prophylactic allopurinol should be considered if hyperuricaemia from tumour lysis is expected.
• Intravenous fluids are given throughout the 5-day infusion period.
• Prophylactic steroids (for example hydrocortisone 100 mg/m² on days 1 to 3) may help prevent signs of SIRS or capillary leak.
• Clofarabine is stopped immediately at the first signs of SIRS, capillary leak or substantial organ dysfunction, and if hypotension develops for any reason during the 5 days. Further treatment, generally at a lower dose, can be considered once the patient is stable and organ function is back to baseline.

Heart, Kidney and Liver

• Heart: patients with cardiac disease, or taking medicines that affect blood pressure or cardiac function, need close monitoring.
• Kidney: clofarabine is excreted mainly by the kidneys and may accumulate when creatinine clearance is reduced. There is no clinical study experience in paediatric patients with renal insufficiency (serum creatinine at least 2 × ULN for age), and safety has not been established in severe renal impairment or renal replacement therapy. Renal failure has been seen as a consequence of infection, sepsis and tumour lysis syndrome. Kidney function is monitored and clofarabine stopped as necessary.
• Liver: patients who previously had a haematopoietic stem cell transplant may be at higher risk of hepatotoxicity suggestive of veno-occlusive disease (VOD) when clofarabine is combined with etoposide and cyclophosphamide. After marketing, serious VOD with fatal outcome has been reported in paediatric and adult patients, as have cases of hepatitis and hepatic failure, some fatal.
• Combination use: infections, myelosuppression (neutropenia) and hepatotoxicity are more frequent and more severe when clofarabine is used in combination regimens, which need close monitoring.

Dehydration

Vomiting and diarrhoea can occur. Patients should be advised on measures to avoid dehydration and to seek medical advice for dizziness, fainting spells or reduced urine output. Prophylactic antiemetic medicines should be considered.

Pregnancy, Breastfeeding and Fertility

• Contraception: because of the genotoxic risk, women of childbearing potential must use effective contraception during treatment and for 6 months after it ends. Men should use effective contraception, should not father a child during treatment, and should continue for 3 months after it ends.
• Pregnancy: there are no data in pregnant women. Animal studies showed reproductive toxicity including teratogenicity, and clofarabine may cause serious birth defects. It should not be used during pregnancy, especially the first trimester, unless clearly necessary, that is, only if the benefit to the mother outweighs the risk to the foetus. A patient who becomes pregnant during treatment should be told of the possible hazard to the foetus.
• Breastfeeding: it is unknown whether clofarabine is excreted in human milk. Because of the potential for serious reactions in nursing infants, breastfeeding must be discontinued before, during and for 2 weeks after treatment (breastfeeding is a contraindication).
• Fertility: dose-related toxicity on male reproductive organs was seen in mice, rats and dogs, and on female reproductive organs in mice. The effect on human fertility is unknown, so reproductive planning should be discussed with patients.

Sodium Content

Each 20 mL vial contains 72 mg sodium, equivalent to 3.6% of the WHO recommended maximum daily intake for sodium; the maximum daily dose equals 23.4%. Evoltra is considered high in sodium, which matters for patients on a low-salt diet.

Effect on Driving

No studies have been done. Patients may experience dizziness, light-headedness or fainting spells during treatment and should not drive or operate machines in such circumstances.

Evoltra vials must not be frozen. Section 6.4 of the SmPC names no other storage condition or temperature range for the unopened vial, so no refrigeration requirement is stated; supply and transport should simply avoid freezing. Storage after dilution is described under Shelf Life. The concentrate is a clear, practically colourless solution supplied in 20 mL Type I glass vials with a bromobutyl rubber stopper and aluminium overseal, in boxes of 1, 3, 4, 10 or 20 vials (not all pack sizes may be marketed).

3 years. The diluted concentrate is chemically and physically stable for 3 days at 2–8 °C and at room temperature (up to 25 °C). From a microbiological point of view it should be used immediately; if it is not, in-use times and conditions are the user’s responsibility and would normally not exceed 24 hours at 2–8 °C, unless dilution took place under controlled and validated aseptic conditions.

Prescription only (Rx): a medicinal product subject to restricted medical prescription (Annex II B), started and supervised by a physician experienced in the management of acute leukaemias. Evoltra is given by intravenous infusion in hospital, so it is supplied to the hospital or clinic that administers it.