Note. The name FluCam has been used for a regimen of fludarabine with alemtuzumab. Distinguish from Flucam, which is ampiroxicam.
Pharmacopoeias. In Europe and US.
European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 and 6.2 (Fludarabine Phosphate). A white or almost white, hygroscopic, crystalline powder. Slightly soluble in water; very slightly soluble in dehydrated alcohol; freely soluble in dimethylformamide. Store in airtight containers at a temperature of 2° to 8°. Protect from light.
The United States Pharmacopeia 31, 2008 (Fludarabine Phosphate). A white to off-white, hygroscopic, crystalline powder. Slightly soluble in water and in 0.1M hydrochloric acid; practically insoluble in dehydrated alcohol; freely soluble in dimethylformamide. Store at 2° to 8°. Protect from light.
Mechanism of Action
Fludarabine is a purine analogue and is metabolized rapidly to F-Ara-ATP, which inhibits DNA synthesis by inhibition of DNA polymerases and prevents elongation of DNA strands through direct incorporation into the DNA molecule.
Cyclophosphamide is an alkylating agent. These agents alkylate DNA bases, thereby producing “cross-links” that covalently link the two DNA strands and prevent cell replication.
A trial published in 2003 investigated this combination in both treated and untreated patients of performance status 0,1, or 2. The untreated patient cohort contained 15 patients with Rai stage III-IV chronic lymphocytic leukemia or stage II with bulky disease. Within this group, 60% of patients achieved CR and 40% achieved PR status. Seventeen patients had received previous therapy, 6 of whom received fludarabine or fludarabine combinations. Response rates were lower in the previously treated group: 29% achieved CR and 59% achieved PR.
The median time to progression (TTP) (median follow-up = 24 months) for the entire population was 25 months (median TTP in untreated patients had not yet been reached versus 18 months in treated patients). The median survival was 35 months (median survival in the untreated group had not yet been reached versus 20 months in treated patients). The program of six courses of fludarabine/cyclophosphamide was administered in 75% of patients and reduced in 19% of patients because of severe myelosuppression and/or sepsis, which was fatal in one patient. Two patients discontinued therapy after two courses because of primary resistance; both patients had been heavily pretreated and had been refractory to previous chemotherapy.
Toxicities included severe neutropenia in 31% of patients, which delayed subsequent courses of therapy and required the use of prophylactic granulocyte colony-stimulating factor (G-CSF). Red cell transfusions were required in 22% of cases because of decreased hemoglobin. No cases of grade 3/4 thrombocytopenia were observed. Infections, including seven cases of pneumonia and two of sepsis — one of which was fatal — occurred in 28% of patients.
In another study, the efficacy of fludarabine/cyclophosphamide in a population of chronic lymphocytic leukemia patients was accurately determined by analyzing response rates according to the patients’ treatment history. Patients were divided into four cohorts:
- No prior treatment.
- Prior therapy with alkylating agents either alone or in combination.
- Prior therapy with alkylating agents and fludarabine. Initial response to fludarabine therapy followed by relapse.
- Prior therapy with alkylating agents and fludarabine. Patients relapsed after or were refractory to alkylating agents and failed to achieve a PR with their last fludarabine-based therapy.
Patients who had not received prior therapy (n = 34) had an overall response rate of 88%, which comprised 35% CR, 29% nPR, and 24% PR. Their median TTP and overall survival had not yet been reached after a follow-up of 41 months. Previously untreated patients receiving fludarabine monotherapy reportedly achieved an overall response rate of 60-80%, similar to the data presented in this trial. The CR rate was also not significantly different from that reported for fludarabine alone. However, these authors suggested that CRs achieved with fludarabine/cyclophosphamide may be more durable because the percentage of patients with CD5+ B cells still present in their bone marrow at the time of CR was less than that found in patients receiving fludarabine with or without prednisone (8% versus 33%).
The combination of fludarabine/cyclophosphamide was significantly more efficacious as salvage therapy for previously treated patients than was single-agent fludarabine. Previous Phase II studies have reported response rates of 45-65% in patients receiving fludarabine following failure of therapy with alkylating agents.
The Results of One Study
In this study, patients (n = 20) achieved an overall response rate of 85% (15% CR, 25% nPR, 45% PR) and estimated median overall survival of 38 months. In the group of patients who had previously received both drug therapies, those who were fludarabine-sensitive (n = 46) showed an overall response rate of 80% (12% CR, 17% nPR, 51% PR) and a median overall survival of 21 months. Fludarabine-resistant patients have an extremely poor prognosis and a median survival of less than one year, with most combination regimens providing less than or equal to 15% response. In this trial, patients achieved a response rate of 38% and a median overall survival of 12 months. However, the majority of these remissions were partial (3% CR, 13% nPR, 26% PR), and median TTP was less than a year.
Significant toxicities were observed with this regimen, resulting in dose reductions of cyclophosphamide and 25% of patients unable to complete the planned number of six courses of therapy. Both alkylating agents and purine analogues are known to cause myelosuppression, which can result in a high infection rate. The dose of cyclophosphamide was reduced from 500 mg/m2 to 300 mg/m2 daily for three days because of the occurrence of grade 3/4 neutropenia occurring in 88% of patients and grade 3/4 thrombocytopenia in 30% of patients at the highest dose. Even at 300 mg/m2 of cyclophosphamide combined with fludarabine, 75% of patients had grade 3 and 48% grade 4 neutropenia. Infections were common, and serious infections including bacteremia and/or pneumonia occurred in 25% of patients.
Adverse Effects, Treatment, and Precautions
For general discussions see Antineoplastics.
Bone-marrow suppression from fludarabine is dose-limiting, manifesting as neutropenia, thrombocytopenia, and anaemia; the nadir of the white cell and platelet counts usually occurs after about 13 to 16 days. Myelosuppression can be severe and cumulative; prolonged lymphopenia with concomitant risk of opportunistic infections may occur. Bone marrow hypoplasia or aplasia resulting in pancytopenia may sometimes be fatal.
Other common adverse effects include fever, fatigue, chills, cough, weakness, malaise, anorexia, gastrointestinal disturbances, mucositis, stomatitis, oedema, and skin rashes. Pulmonary toxicity, including pulmonary fibrosis, pneumonitis, and dyspnoea can occur. Other adverse effects include dysuria, haematuria, epistaxis, and abnormalities in hepatic or pancreatic enzymes. Tumour lysis syndrome has been reported, especially in patients with large tumour burdens. Autoimmune disorders, including auto-immune haemolytic anaemia, have been reported, and may be life-threatening or fatal.
Patients should be monitored for signs of haemolysis and therapy stopped if it occurs. Rarely reported effects include heart failure, arrhythmias, anaphylaxis, and haemorrhagic cystitis. Neurological disturbances include peripheral neuropathy, agitation, confusion, visual disturbances, hearing loss, headache, sleep disorders, and seizures; high doses have been associated with progressive encephalopathy, blindness, coma, and death.
Exacerbation of existing skin cancer lesions as well as new onset of skin cancer has been reported in some patients. Transfusion-associated graft-versus-host disease has been seen after transfusion of non-irradiated blood in patients treated with fludarabine, and fatalities have occurred; patients should only receive irradiated blood.
Dosage should be reduced in renal impairment (see below). It should also be avoided in patients with decom-pensated haemolytic anaemia.
A study in patients with chronic lymphocytic leukaemia who were treated with fludarabine found that there was no significantly increased risk of secondary malignancy following therapy, despite the immunosuppressive properties of this drug. A review of this and other studies concluded that no significant increase in the risk of secondary malignancy had been shown, but also that long-term follow-up of patients treated with fludarabine was needed.
Effects on the eyes
See under Effects on the Nervous System, below.
Effects on the lungs
Pulmonary toxicity manifest as dyspnoea, fever, hypoxaemia, and radiographic evidence of interstitial and alveolar infiltrates was diagnosed in 9 patients of a cohort of 105 treated with fludarabine. Lung biopsies were performed in 6 patients and showed diffuse chronic interstitial inflammation and fibrosis. Patients with chronic lymphocytic leukaemia appeared to be at greater risk of developing this complication than those with non-Hodgkin’s lymphoma.
Effects on the nervous system
High doses (of the order of 100mg/m daily intravenously) of fludarabine are associated with severe, life-threatening neurotoxicity. However, a few cases of progressive multifocal leukoencephalopathy have also been reported in patients given fludarabine in usual doses. The prolonged immunosuppression caused by fludarabine might increase the risk of developing this fatal demyelinating disease, which is caused by opportunistic JC virus infection. Ocular toxicity, including irreversible loss of vision, has also been reported occasionally, including with low-dose regimens.
Transfusion-associated graft-versus-host disease has been reported when blood products were used in patients treated with fludarabine. Fludarabine-treated patients should receive irradiated red cells and platelets (to inactivate any viable T-cells) if they require a transfusion
A review of patients treated with fludarabine-containing regimens showed that therapy was associated with serious infections including listeriosis, pneumocystis pneumonia, mycobacterial infections, and opportunistic fungal and viral infections. The risk was exacerbated by previous or current corticosteroid therapy. Prophylactic therapy with co-trimoxazole, triazole antifungals, aciclovir, and colony-stimulating factors was recommended in at-risk patients. A high incidence of herpesvirus infections was also found in another review of patients treated with fludarabine.
Combination therapy using chlorambucil and fludarabine resulted in more infections than when either was used alone, but single-agent fludarabine was associated with more major infections and herpesvirus infections than chlorambucil alone. The frequency of serious infection has also been reported to be increased in patients after their conditions became refractory to fludarabine and they were being treated with conventional chemotherapy.
For reports of progressive multifocal leukoencephalopathy caused by opportunistic JC virus infection in patients receiving fludarabine, see Effects on the Nervous System, above.
Increased pulmonary toxicity, sometimes fatal, has been reported in patients given fludarabine with pentostatin. Pretreatment with cytarabine may reduce the metabolic activation of fludarabine, but pretreatment with fludarabine results in increased intracellular concentrations of cytarabine. The therapeutic efficacy of fludarabine may also be reduced by dipyridamole and other inhibitors of adenosine uptake.
Severe ototoxicity occurred when a short course of gentamicin was given to a patient who had recently completed a course of fludarabine.
For a suggestion that use of fludarabine with corticosteroids may increase the risk of infection, see Infection, above.
Intravenous fludarabine phosphate is rapidly dephosphorylated to fludarabine which is taken up by lymphocytes and rephosphorylated to the active triphos-phate nucleotide. Peak intracellular concentrations of fludarabine triphosphate are seen about 4 hours after a dose. Fludarabine has a bioavailability of about 50 to 65% after oral doses of the phosphate. Clearance of fludarabine from the plasma is triphasic with a terminal half-life of about 20 hours. Elimination is mostly via renal excretion: 60% of a dose is excreted in the urine. The pharmacokinetics of fludarabine exhibit considerable interindividual variation.
Uses and Administration
Fludarabine is a fluorinated nucleotide analogue of the antiviral vidarabine; it acts as a purine antagonist antimetabolite. It is used for its antineoplastic properties in the treatment of chronic lymphocytic leukaemia. Fludarabine phosphate is given by bolus injection or by intravenous infusion over 30 minutes in a usual dose of 25 mg/m daily for 5 consecutive days. Alternatively it may be given orally in a dose of 40 mg/m daily for 5 consecutive days. Courses may be repeated every 28 days, usually for up to 6 cycles. Haematological function should be monitored regularly; the dosage may need to be reduced, or further courses delayed, if blood counts indicate severe or persistent myelosuppression (see also Bone-marrow Depression). Doses should be reduced in renal impairment (see below).
Administration in renal impairment
Doses of fludarabine phosphate should be reduced by up to 50% in patients with mild to moderate renal impairment (creatinine clearance between 30 and 70 mL/minute); the drug should not be given in more severe renal impairment.
Fludarabine is the preferred second-line therapy for chronic lymphocytic leukaemia once initial alkylating agent therapy fails, and may also be used for initial therapy. It has also been tried in other malignancies. Listed below are some references to the use of fludarabine phosphate for the treatment of chronic lymphocytic leukaemia, and its potential activity against a variety of other malignancies, including indolent low-grade non-Hodgkin’s lymphoma, mycosis fungoides, heavy chain disease, prolym-phocytic leukaemia, hairy cell leukaemia, and Walden-strom’s macroglobulinaemia.
The United States Pharmacopeia 31, 2008: Fludarabine Phosphate for Injection; Fludarabine Phosphate Injection.
Argentina: Fludakebir; Fludara; Fluradosa; Forclina;
Czech Republic: Fludara; Tazumara;
Hong Kong; Fludara;
Mexico: Beneflur; Fludara;
New Zealand: Fludara;
South Africa: Fludara;
United Kingdom (UK): Fludara;
United States of America (US and USA): Fludara;