Several recent studies have investigated the combination of fludarabine with cyclophosphamide (Bristol-Myers Squibb’s Cytoxan, Baxter’s Endoxan/Endoxana, Pfizer’s Neosar/Cyclostin, generics), and this regimen is used in both first and subsequent lines of treatment.
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.
In one such 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.