Pentostatin

Pentostatin is a potent transition-state inhibitor of the enzyme adenosine deaminase (ADA). ADA activity is highest in cells of the lymphoid system, higher in T cells than in B cells, and higher in T-cell than in B-cell malignancies. Pentostatin is active against several lymphoid neoplasms, but most active against indolent ones with low ADA concentrations, such as hairy cell leukaemia.

Mechanism of Action

• ADA inhibition: by blocking ADA, pentostatin prevents the breakdown of adenosine and deoxyadenosine. The resulting rise in intracellular deoxyadenosine triphosphate (dATP) is thought to block DNA synthesis by inhibiting ribonucleotide reductase.
• Other cytotoxic effects: direct inhibition of RNA synthesis and increased DNA damage may also contribute to the cytotoxic effect, which is cell-cycle specific (S phase).
• Hairy cell leukaemia: the precise antitumour mechanism of pentostatin in this disease is not known.
• Immune effects: pentostatin is lymphotoxic and immunosuppressive, particularly through suppression of the CD4+ lymphocyte subset (see Side Effects).

Pharmacokinetics

• Absorption: not absorbed orally, so it is given intravenously. Pharmacokinetics are linear: plasma concentrations rise in proportion to the dose.
• Distribution: after a single 4 mg/m² dose infused over 5 minutes, the distribution half-life was 11 minutes. Plasma protein binding is low (about 4 %). Pentostatin crosses the blood-brain barrier and gives measurable concentrations in cerebrospinal fluid; in rats, radioactivity was highest in the kidneys with very little entering the central nervous system.
• Metabolism: mainly hepatic, but only small amounts are metabolised.
• Elimination: mean elimination half-life 5.7 hours (range 2.6 to 10 hours) and mean plasma clearance 68 mL/min/m². About 90 % of the dose was excreted in urine as unchanged pentostatin and/or metabolites, measured as ADA-inhibitory activity.
• Renal function: clearance correlates directly with creatinine clearance (between 60 and 130 mL/min). In two patients with creatinine clearance below 50 mL/min the half-life was about 18 hours, compared with about 6 hours in patients with creatinine clearance above 60 mL/min.

• Hairy cell leukaemia: pentostatin is indicated as monotherapy for the treatment of adult patients with hairy cell leukaemia. The disease occurs in adults, most often in the sixth decade of life.

• Hypersensitivity to pentostatin or to any of the excipients.
• Impaired renal function (creatinine clearance below 60 mL/min).
• Active infection.

Pentostatin is lymphotoxic. As well as suppressing the bone marrow, it is immunosuppressive, especially through the CD4+ lymphocyte subset: CD4+ counts below 200 per µL are usual during treatment and may persist for more than 6 months afterwards. Apart from frequent herpes zoster infections, the clinical consequences of this are not well understood, and there is currently no evidence of more secondary cancers. In hairy cell leukaemia studies, most patients had at least one adverse event. Nausea and/or vomiting or leukopenia affected about 60 % of patients, and fever, rash and fatigue about 40 %. Most events were mild or moderate and became less frequent as treatment continued; 12 % of patients stopped because of an adverse event. No extravasation injuries were recorded. It can be hard to separate drug-related events from those due to the disease.

The reactions below were recorded in hairy cell leukaemia studies and in post-authorisation use, alone or combined with other medicines for non-approved indications. The common group lists reactions seen in at least 3 % of patients in the initial phase of the SWOG study; the uncommon and rare groups are based on 1,549 patients in post-marketing studies up to October 2005. The SmPC table holds further terms.

Very common (≥1/10): Infections: upper respiratory tract infection, rhinitis, pharyngitis, viral infection. Blood: leukopenia, thrombocytopenia, anaemia, eosinophilia, hypochromic anaemia, pancytopenia, blood abnormalities. Immune: allergic reaction. Nervous system: headache, neurotoxicity. Respiratory: cough, lung disorders. Gastrointestinal: nausea and/or vomiting, diarrhoea, abdominal pain, anorexia, rectal disorder, rectal haemorrhage. Liver: raised liver function tests, jaundice, hyperbilirubinaemia, raised ALT and AST. Skin: rash, pruritus, sweating, maculopapular rash, skin disorders. Musculoskeletal: myalgia, bone disorder, arthropathy. Renal and urinary: genitourinary disorder, raised blood urea nitrogen. General: fever, fatigue, chills, asthenia, pain.

Common (≥1/100 to <1/10): Infections: herpes zoster, unspecified infection, sinusitis, cellulitis, bacterial infection, pneumonia, conjunctivitis, furunculosis, herpes simplex, bronchitis, sepsis, urinary tract infection, skin abscess, oral candidiasis, fungal skin infection, perianal abscess, E. coli pneumonia, fungal pneumonia, septic shock, staphylococcal infection, urosepsis, osteomyelitis. Neoplasms: neoplasm, skin cancer. Blood: agranulocytosis, acute leukaemia, febrile neutropenia, ecchymosis, lymphadenopathy, splenomegaly. Immune: graft-versus-host disease (reported only in studies of that condition). Metabolism: dehydration, gout, electrolyte imbalance, hypercalcaemia, hyponatraemia, hyperglycaemia, weight gain, weight loss, raised LDH. Psychiatric: anxiety, depression, nervousness, abnormal dreams, decreased or lost libido, emotional instability, hallucinations, hostility, neurosis, abnormal thinking, depersonalisation. Nervous system: confusion, dizziness, insomnia, paraesthesia, somnolence, amnesia, ataxia, convulsions, dysarthria, dysgeusia, encephalitis, hyperkinesia, meningism, neuralgia, neuritis, neuropathy, paralysis, syncope, tremor, vertigo, hypoaesthesia. Eye: dry eye, lacrimal duct obstruction, photophobia, retinopathy, abnormal vision, fixed pupil, increased lacrimation, eye pain. Ear: deafness, ear pain, labyrinthitis, tinnitus. Cardiac: angina pectoris, arrhythmia, atrioventricular block, bradycardia, ventricular extrasystoles, cardiac arrest, heart failure, pericardial effusion, sinus arrest, tachycardia, atrial fibrillation, congestive heart failure, flushing, abnormal ECG. Vascular: haemorrhage, hypotension, hypertension, deep thrombophlebitis, phlebitis, vasculitis. Respiratory: asthma, dyspnoea, laryngeal oedema, pulmonary oedema, pulmonary embolism, epistaxis. Gastrointestinal: dental disorder, dyspepsia, gingivitis, stomatitis, constipation, dysphagia, flatulence, glossitis, ileitis, dry mouth. Skin: dry skin, urticaria, acne, alopecia, eczema, petechial rash, photosensitivity reaction, exfoliative dermatitis, skin discolouration, bullous dermatitis, seborrhoea. Musculoskeletal: arthralgia, arthritis. Renal and urinary: raised creatinine, renal insufficiency, nephropathy, renal failure, nephrolithiasis, acute renal failure, dysuria, urinary retention. Reproductive: amenorrhoea, breast lump, erectile dysfunction. General: chest pain, death, facial oedema, peripheral oedema, influenza-like symptoms, back pain, dizziness.

Uncommon (≥1/1,000 to <1/100): acute gastroenteritis, pulmonary aspergillosis, Clostridium difficile colitis, cystitis, cytomegalovirus infection; tumour lysis syndrome; pure red cell aplasia, autoimmune haemolytic anaemia, haemolytic anaemia, aplastic anaemia, haemolytic uraemic syndrome, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura; graft failure; hyperkalaemia, hypokalaemia, decreased oxygen saturation; cardiomyopathy, myocardial infarction; capillary leak syndrome; adult respiratory distress syndrome, acute respiratory failure, bronchospasm, pleural effusion, pneumothorax, respiratory tract haemorrhage, wheezing; acute enteritis; angioneurotic oedema; pain in extremity; haemorrhagic cystitis; mucositis, multiorgan failure.

Rare (≥1/10,000 to <1/1,000): oesophageal candidiasis; autoimmune thrombocytopenia; anaphylaxis; fluid overload, hypocalcaemia; suspected Alzheimer-type dementia, grand mal convulsions, migraine, aggravated Parkinson’s disease, petit mal epilepsy; blepharitis; pericarditis, decreased ejection fraction; shock; alveolitis, fibrosing alveolitis, cryptogenic organising pneumonia, diffuse alveolar damage, obstructive airway disease, alveolar pulmonary haemorrhage; pemphigus, Stevens-Johnson syndrome; systemic inflammatory response syndrome, lower limb weakness.

Very rare (<1/10,000): unilateral uveitis with loss of vision.

Serious reactions to watch for include severe myelosuppression and infection, neurotoxicity, renal and liver toxicity, severe rash, and fatal pulmonary toxicity when combined with fludarabine.

• Fludarabine phosphate: not recommended. In a study in refractory chronic lymphocytic leukaemia, 4 of 6 patients given pentostatin at the recommended dose with fludarabine phosphate had severe or fatal pulmonary toxicity.
• High-dose cyclophosphamide: not recommended. Fatal acute pulmonary oedema and hypotension have been reported in the literature when pentostatin was combined with carmustine, etoposide and high-dose cyclophosphamide in an ablative bone marrow transplant regimen.
• Vidarabine: biochemical studies show that pentostatin increases the effects of vidarabine, a purine nucleoside with antiviral activity. Using the two together may increase the adverse reactions of each, and a therapeutic benefit has not been established.
• Allopurinol: both medicines are associated with skin rash. In 25 refractory patients given both, the combination did not appear to cause more rash than pentostatin alone, but one patient had a fatal hypersensitivity vasculitis and it could not be established whether the combination was responsible.

Pentostatin must be given under the supervision of a qualified physician experienced in anticancer chemotherapy, and is intended for adults. The reconstituted solution contains 2 mg/mL; the SmPC (section 6.6) gives the reconstitution and dilution steps. Before each dose, patients should be hydrated with 500 to 1,000 mL of 5 % glucose solution, alone or in 0.18 % or 0.9 % saline, or an equivalent glucose/saline solution named in the SmPC, and a further 500 mL should be given afterwards.

Recommended Dose

• 4 mg/m² as a single dose every other week, by intravenous bolus injection or diluted in a larger volume and infused over 20–30 minutes.
• Higher doses are not recommended. No extravasation injuries were reported in clinical studies.

Duration of Treatment

• The optimal duration has not been determined. If there is no severe toxicity and the patient keeps improving, treatment continues until complete remission; two further doses after complete remission are recommended, although this is not fully established.
• Response is assessed at 6 months. Treatment is stopped if neither complete nor partial remission has been reached. With a partial remission, treatment continues to try to reach a complete one. If the best response after 12 months is only a partial remission, stopping is recommended.

Dose Adjustments

• Individual doses may need to be withheld or stopped for severe adverse reactions. Treatment should be stopped in patients with a severe skin rash, and withheld or stopped if there is evidence of nervous system toxicity.
• In patients with an active infection, treatment is withheld and may restart once the infection is controlled.
• Cytopenias: no dose reduction is recommended at the start of treatment for anaemia, neutropenia or thrombocytopenia, nor during treatment for anaemia or thrombocytopenia. Pentostatin should be withheld if, in a patient with a starting neutrophil count above 500 cells/mm³, the count falls below 200 cells/mm³, and can resume when the count returns to the pre-treatment value.

Special Populations

• Renal impairment: creatinine clearance should be determined before each administration. Experience in patients with creatinine clearance below 60 mL/min is limited (see Contraindications).
• Hepatic impairment: experience is limited, so treat with caution.
• Elderly: the dose is the same (4 mg/m² every other week). Studies that included patients over 65 years reported no age-specific adverse effects.
• Children: hairy cell leukaemia is an adult disease; safety and efficacy in children have not been established.

Supervision and Monitoring

• Doses above those recommended are not advised: in phase I studies at 20–50 mg/m² per cycle, severe dose-limiting toxicity affected the kidneys, liver, lungs and central nervous system.
• Renal function (serum creatinine and/or creatinine clearance) is assessed before starting. A full blood count, serum creatinine and blood urea nitrogen are checked before every dose and at intervals during treatment. Hairy cells in peripheral blood are checked periodically, and bone marrow aspirates and biopsies every 2–3 months may be needed to judge response.
• Take special care when starting treatment in patients in poor general condition.

Myelosuppression and Infection

• Myelosuppression can occur, especially in the first cycles, and neutropenia worsened in the first cycles in progressive disease, so blood counts are needed frequently. If severe neutropenia persists after the initial cycles, the disease, including the bone marrow, should be reassessed.
• Some patients with infections before treatment worsened and died, while others reached complete remission. Patients with infections should be treated only when the potential benefit justifies the risk, and the infection should be controlled before treatment starts or restarts.

Organ Effects

• Liver: raised liver function values occurred and were generally reversible.
• Kidney: toxicity occurred at high doses. At recommended doses creatinine rises were usually slight and reversible, but some patients with normal renal function at baseline had mild to moderate renal toxicity by the end of treatment.
• Skin: rashes are frequent, sometimes severe, and may worsen if treatment continues.

Pregnancy, Breastfeeding and Fertility

• Genotoxic potential: men should not father a child during treatment or for 3 months afterwards. Effective contraception is required in women of childbearing potential during treatment and for at least 6 months after the last dose, and in male patients with female partners of childbearing potential for at least 3 months after it. If pregnancy occurs, genetic counselling should be considered.
• Pregnancy: no data in pregnant women. Animal studies showed reproductive toxicity and pentostatin was teratogenic in rodents. It is not recommended in pregnancy or in women of childbearing potential not using effective contraception; a patient who becomes pregnant should be told of the potential risk to the foetus.
• Breastfeeding: it is unknown whether pentostatin passes into human milk. Because of the potential for serious adverse effects in infants, mothers should not breastfeed during treatment or for the week after the last dose.
• Fertility: no animal fertility studies have been carried out; see the SmPC for further information.

Sodium

Each vial contains less than 1 mmol (23 mg) of sodium, i.e. it is essentially sodium-free.

Effect on Driving

Pentostatin has a slight to moderate effect on the ability to drive and use machines. Patients should take care after the dose.

Store the vials in a refrigerator at 2–8 °C; the cold chain should be kept from supply to the hospital pharmacy. The medicine is supplied as 10 mg single-dose type I glass vials with silicone stoppers, one vial per carton. For the reconstituted solution, see Shelf Life.

3 years. After reconstitution, and after any further dilution for infusion, the solution should be used within 8 hours and not stored above 25 °C; immediate administration is recommended.

Prescription only (Rx). Pentostatin must be given under the supervision of a qualified physician experienced in anticancer chemotherapy, as an intravenous injection or infusion in hospital, so it is supplied to the hospital or clinic that administers it. As a refrigerated medicine it travels in the cold chain at 2–8 °C.