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Fludarabine Plus Cyclophosphamide Combination: a New Standard for First-Line Therapy in Chronic Lymphocytic Leukaemia

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Fludarabine Plus Cyclophosphamide Combination: a New Standard for First-Line Therapy in Chronic Lymphocytic Leukaemia Hematology Meeting Reports 2007; 1(5):12–17 Fludarabine plus cyclophosphamide combination: a new standard for first-line therapy in chronic lymphocytic leukaemia Peter Hillmen ABSTRACT Leeds Teaching Hospitals NHS Trust, Leeds, West Yorkshire, Phase III studies have demonstrated that the purine analogue fludarabine United Kingdom is an effective first-line agent in the primary treatment of B-cell chronic lymphocytic leukaemia (CLL) with superior efficacy to chlorambucil. Corresponding author: However, although fludarabine improves responses, including an Peter Hillmen improvement in progression-free survival (PFS) in some studies, this Email: [email protected] remains sub-optimal. Thus, combination treatment with fludarabine has been considered. Both fludarabine and the alkylating agent cyclophos- phamide are dose-dependently cytotoxic, and the extent of apoptosis when they are combined is more than the additive effect for each indi- vidual agent. Such increased apoptosis may be due to a synergistic effect between alkylation by cyclophosphamide and inhibition of DNA repair by fludarabine. Phase II studies in first-line CLL have shown that the efficacy of fludarabine plus cyclophosphamide (FC) is promising, with response rates often exceeding 90%. Data from Phase III studies have demonstrated that FC induces significantly higher response rates than fludarabine monotherapy across all patient age groups, including rela- tively young patients. PFS was also significantly longer with FC than with fludarabine monotherapy. Fludarabine is available in either intra- venous or oral formulations and both appear to be similarly effective. The rationale for fludarabine plus cyclophos- easy to administer, facilitates outpatient treatment phamide in chronic lymphocytic leukaemia and is more convenient for both healthcare practi- tioners and patients. In addition, similar efficacy 1,2 to the IV form has been demonstrated. It is well The purine analogue fludarabine is one of the tolerated in patients with previously untreated B- most potent cytotoxic drugs currently available for cell CLL, and its safety profile is similar to that of the treatment of B-cell chronic lymphocytic the IV formulation, with the exception of leukaemia (CLL). Its cytotoxicity is due to its abil- increased gastrointestinal toxicity, which is gener- ity to induce apoptosis, and it is available in both 1,2 ally mild-to-moderate and usually does not require intravenous and oral formulations. The bioavail- a modification of treatment. Quality of life (QOL) ability of oral fludarabine is approximately 55% scores are not adversely affected by use of the oral 3 of a dose via the intravenous route; systemic formulation, and it may even be associated with 2 1 exposure following an oral dose of 40 mg/m has improved emotional and insomnia scores. been found to be equivalent to an IV dose of 25 However, these findings need to be interpreted 2 mg/m . The oral formulation of fludarabine offers with caution, as such improvements could also be potential benefits over the IV form because it is due to the response shift phenomenon. For exam- | 12 | Changing the Paradigm: New Perspectives in the Treatment of Haematological Malignancies ple, a patient’s impression that treatment is received other chemotherapeutic agents during improving their condition may reduce anxiety, the course of their disease confounding the which could in turn reduce insomnia. The oral interpretation of the survival time data. In formation is recommended by the UK National addition, many patients randomized to alkylat- Institute of Clinical Excellence (NICE) over ing agent therapy receive a purine analogue the intravenous form on the basis of better cost when they relapse further confounding the effectiveness (cost per course: UK£3000 vs. interpretation of the effect of fludarabine on 5,7 UK£5300); use of the intravenous form should overall survival. be reserved for when the oral form is con- Both fludarabine and mafosfamide (the 4 traindicated. active form of cyclophosphamide in vitro) are Superiority of fludarabine over chlorambucil dose-dependently cytotoxic to cells from B- for the primary treatment of CLL has been cell CLL. In vitro studies have demonstrated demonstrated in a phase III clinical trial.5 In that the exposure of CLL cells to the combina- this study, eligible patients with previously tion of fludarabine plus mafosfamide results in untreated CLL received 10- to 30-minute IV an increased, synergistic cytotoxicity com- 2 8,9 infusions of fludarabine 25 mg/m on days 1–5 pared with either agent alone. When B-cell 2 (n=179), oral chlorambucil 40 mg/m on day 1 CLL cells were incubated for 48 hours with (193) or combination therapy with IV fludara- fludarabine and mafosfamide alone and in 2 bine 20 mg/m on days 1–5 plus oral chloram- combination, the degree of cytotoxicity seen 2 bucil 20 mg/m on day 1 (137), with all regi- with the combination was significantly greater mens repeated every 28 days. Patients with an than the additive cytotoxicity of the two additional response at each monthly evaluation agents, indicating the presence of synergy. continued to receive the assigned treatment for Notably, the addition of mafosfamide signifi- a maximum of 12 cycles. Fludarabine was cantly increased fludarabine-induced apopto- + + associated with higher complete remission sis of CD19 (p=0.007), but not CD3 , cells. A (CR) rates and longer duration of remission similar synergistic effect has been seen in and progression-free survival (PFS) than chlo- another study in which fludarabine plus mafos- rambucil. However, the improved PFS with famide was associated with greater apoptosis 9 first-line fludarabine at 25–32 months was still than with the individual agents. The mecha- deemed suboptimal, particularly in younger nism underlying this synergy appears to be that patients. DNA repair mechanisms in CLL cells, initiat- Other phase III trials have demonstrated that ed in response to cyclophosphamide exposure, 10 fludarabine is superior to a combination of appear to be inhibited by fludarabine. cyclophosphamide, adriamycin and pred- 6,7 nisone for the treatment of CLL. When used Efficacy and safety of fludarabine plus as first-line therapy, fludarabine significantly cyclophosphamide in chronic lymphocytic increased the duration of remission, compared leukaemia with the three-drug regimen, and was associat- ed with significantly greater rates of CR and partial remission (PR) when used as second- Data from clinical studies to date have gen- line therapy. However, median overall survival erally found fludarabine combined with was not increased by fludarabine in any of cyclophosphamide (FC) to be an effective and these phase III studies, but many patients who relatively well-tolerated regimen for the treat- received fludarabine subsequently also ment of CLL. Data from phase II studies inves- Hematology Meeting Reports 2007: 5 | 13 | P. Hillmen tigating the use of FC in CLL have indicated severe neutropenia (polymorphonuclear neu- 9 promising efficacy, with response rates rang- trophil count <0.5×10 /L). Bacterial infections ing from 63.9 to 100%, and >90% in most were also common, being reported in 28% of studies for both previously untreated and pre- patients, with 70% of these occurring in previ- 11-17 treated patients. ously treated patients. After a median follow- For example, in one such study, 36 CLL up of 24 months (range 8–48), 20/32 (62%) patients (median age 59 years) received a reg- patients remained alive and 14/32 (44%) were 2 imen of fludarabine 30 mg/m plus cyclophos- free from progression. Median overall survival 2 phamide 250 mg/m , both as a 30-minute IV and median time to progression were 35 and infusion on days 1–3, with treatment cycles 25 months, respectively. repeated every 28 days.13 Twenty-one patients had previously received 1–3 different treat- Front-line therapy with fludarabine plus ments and 15 patients had received no prior cyclophosphamide therapy. Treatment responses according to the National Cancer Institute criteria were achieved in 29/32 (91%) evaluable patients, Data to date on the efficacy and safety of FC with CR in 5 patients and PR in 24. Grade 3 for front-line treatment of CLL indicate that and 4 neutropenia and leucocytopenia were the this combination provides better overall most commonly reported adverse events (69% response rates, PFS and treatment-free sur- and 55% of patients, respectively). Anaemia vival than fludarabine monotherapy. FC is and thrombocytopenia each occurred in only associated with acceptable adverse events in 17% of patients and other grade 3 and 4 these studies. One phase II study has evaluated adverse events, including allergy, disorienta- the clinical and molecular response, toxicity tion, dysrhythmia, incontinence, phlebitis, and and complications associated with the FC for elevated bilirubin levels, occurred in <3% of front-line treatment of CLL.17 Patients, aged patients; all low-grade adverse events were 43–74 years (mean: 60 years), with untreated uncommon. No treatment-related deaths or CLL (n=26) received 3 days’ treatment with IV 2 grade 3 or 4 infections were reported. fludarabine 25 mg/m plus cyclophosphamide 2 In another study, 32 patients with newly 300 mg/m repeated every 28 days. Initially six diagnosed (47%) or relapsed/refractory (53%) cycles were planned, but this was decreased to CLL received six courses of fludarabine 30 four due to the high rate of haematological tox- 2 2 mg/m IV plus cyclophosphamide 300 mg/m icity seen in the first patients to receive treat- on days 1–3; relapsed/refractory patients had ment. Among 20 evaluable patients, 15 (75%) previously received ≤5 different chemotherapy achieved a CR and 3 (15%) achieved a PR regimens.16 CR was achieved in 32 (44%) (overall response rate of 90%). Disease pro- patients and 16 (50%) achieved a PR. As gression after 21 months of follow-up was expected, the CR rate was higher in previously reported in only one patient, who had an initial untreated patients at 9/15 (60%), compared PR.
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