Purine Analog Based Combination Chemotherapy

Fludarabine has produced high overall response rates when used as initial therapy of CLL and has shown greater activity than chlorambucil. However, most responses are partial, with only a minority of patients achieving a complete response. This has led to the use of fludarabine in combination with other agents to improve efficacy.

3.4.1. Fludarabine and Doxorubicin or Mitoxantrone

The combination of fludarabine and doxorubicin with or without prednisone was investigated in 30 patients with previously treated CLL, most of whom had received prior fludarabine. This combination was active, with an overall response rate of 55%, but complete remissions were seen in only 3% of patients (59).

The combination of fludarabine and mitoxantrone was given to 53 previously treated patients with CLL. Complete and partial responses were observed, but, despite its significant activity in low grade lymphoma, this combination did not appear to be more effective than fludarabine alone in the treatment of CLL (60,61).

3.4.2. Fludarabine and Alkylating Agents

The combination of fludarabine with alkylating agents is under investigation, based on promising in vitro findings. The incubation of lymphocytes from patients with CLL with activated cyclophosphamide produced DNA interstrand crosslinks that were efficiently repaired in 6-8 h; in the presence of fludarabine, this repair mechanism was inhibited, and 80% of the DNA interstrand crosslinks were still detected 24 h later (61,62).

Two small phase I studies of the combination of fludarabine and chlorambucil were conducted by Elias et al. (63) and Weiss et al. (64). Both demonstrated clinical activity, but the treatment was limited by significant myelosuppression, especially thrombocytopenia. Another study reported on continuous-infusion cisplatin (although not a classical alkylating agent, this drug also produces DNA crosslinks) and fludarabine plus cytarabine in 26 patients. Patients had received extensive prior treatment for CLL, and most of them were refractory to fludarabine. Responses were seen in 19% of the patients, myelosuppression was reported in more than half of the patients treated, and a high incidence of infectious complications was noted (65).

3.4.2.1. Fludarabine and Cyclophosphamide. The combination of fludarabine, at a dose of 30 mg/m2 given daily for 3 d, and cyclophosphamide at doses between 300 and 500 mg/m2 daily for 3 d was investigated in 128 patients by O'Brien et al. (66). The initial dose of cyclophosphamide was 500 mg/m2, but this was reduced to 300 mg/m2 because of excessive myelosuppression. Remission rates differed according to disease status at the beginning of treatment. The overall response rates were 88% for patients who had not received prior treatment, 85 and 80% for patients who had received prior treatment with alkylating agents and fludarabine, respectively, and 39% for patients who were refractory to fludarabine; complete response rates were 34, 15, 12, and 3%, respectively. The most significant side effects were myelosuppression and infections. Remission durations appeared to be longer than those seen in comparable patients treated with single agent fludarabine.

Flinn et al. (67) gave cyclophosphamide, 600 mg/m2, on the first day and fludarabine, 20 mg/ m2 daily for 5 d, followed by filgastrin, 5 ^g/kg/sc daily, to 60 patients with previously untreated lymphoid malignancies. This study included 17 patients with CLL; all 17 responded, with 47% of them achieving a complete remission and 53% achieving a partial response. Hematological toxicity was mild with the filgastrin support (67).

A multicenter study using fludarabine, 30 mg/m2 daily for 3 d, and cyclophosphamide, 250 mg/ m2 daily for 3 d, in 32 patients with CLL was conducted by Hallek et al. (68). The overall response rates were 86% in the previously untreated patients and 94% in the previously treated patients, and the complete response rates were 21 and 11%, respectively. Myelosuppression and infections were again reported with this combination treatment.

3.4.3.2. Fludarabine, Cyclophosphamide, and Rituximab. Rituximab is a chimeric antibody targeting CD20 that has significant activity in the treatment of non-Hodgkin's lymphoma (69). Rituximab has been studied as a single agent in CLL in both previously treated and untreated patients. Nguyen et al. (70) treated 15 patients with resistant/relapsed CLL with rituximab at 375 mg/m2 weekly for 4 wk; a marked decrease in the number of circulating leukemia cells was observed, but none of the patients achieved a response. In a recently reported study by the German Chronic Lymphocytic Leukemia Study Group (71), rituximab at the standard dose of 375 mg/m2 weekly for 4 consecutive wk was given to patients with CLL who had received prior treatment. No complete responses and a partial response of 25% were seen in the 28 evaluable patients. Rituximab was given at higher doses (500 mg/m2 to 2250 mg/ m2) to 40 previously treated patients with CLL; a response rate of 36% was observed, with a higher response rate at the higher doses, and no complete remissions were observed (72). Similar results were obtained by Byrd et al. (73) when rituximab was given at the standard dose (375 mg/m2) but three times a week for 4 wk. The overall response rate in 26 previously treated patients with CLL was 46%, none of the patients achieved a complete response.

Rituximab has shown greater activity when it was investigated in chemotherapy-naive patients. Rituximab at 375 mg/m2 weekly for 4 wk produced partial responses in 8 of 14 (57%) patients with CLL who had not received prior treatment (74). Thomas et al. (75) reported an overall response rate of 83% and a complete response rate of17% in patients with early-stage CLL treated with 8 wk of standard dose rituximab.

The first infusion of rituximab in patients with CLL has been associated with fever and chills and less commonly, nausa, vomiting, hypotension, and dyspnea. In some patients a cytokine-release syndrome has been observed and is associated with an increase in plasma levels of tumor necrosis factor-a, interleukin-6, and interleukin-8. Fractionating the first dose of rituximab may attenuate its severity (73,76). Tumor lysis syndrome has rarely been reported following rituximab administration (77).

Despite rituximab's modest single-agent activity in CLL, the combination of this antibody with chemotherapy appears to be a promising strategy. A combination of fludarabine, cyclophosphamide, and rituximab is being studied in patients with CLL. Fludarabine is given at a dose of 25 mg/m2 and cyclophosphamide at a dose of 250 mg/m2 for three consecutive days; rituximab is given on the first day of each cycle. The rituximab dose is 375 mg/m2 in the first cycle and 500 mg/m2 in the subsequent cycles. Patients receive up to six cycles of treatment. The results of this ongoing study were recently updated: among 136 previously treated patients, the overall response rate was 71%, the complete response rate was 21%, and documentation of molecular remission by undetectable Ig rearrangements on polymerase chain reaction analysis was obtained in 5 of 13 patients who achieved a complete response (78). The treatment was well tolerated; first-infusion side effects were noted and were rare in subsequent cycles. Mild gastrointestinal toxicity and moderate myelosuppression and immunosuppression were also seen.

The same three-agent regimen is under investigation in chemotherapy-naive patients. Wierda et al. (79) reported results in 135 patients; the overall response rate was 95%, complete responses were seen in 63%, and molecular remissions were demonstrated in 31 of 55 patients who had bone marrow examined for the presence of Ig rearrangements by polymerase chain reaction analysis. Grade 3-4 neutropenia, but not thrombocytopenia, appeared to be more frequent with the three-drug regimen compared with the use of the same chemotherapy without rituximab. Median follow-up is less than 2 yr; most patients have not relapsed, and median time to progression is not yet known. These preliminary results suggest that this combination is the most active regimen reported so far in the treatment of CLL 79.

3.4.3.3. Fludarabine and Rituximab. The Cancer and Leukemia Group B (CALGB) conducted a randomized trial of fludarabine (25 mg/m2, d 1-5) given monthly for 6 mo followed 2 mo later by rituximab (375 mg/m2) given weekly for 4 wk compared to concomitant fludarabine and rituximab (fludarabine 25 mg/m2, d 1-5 monthly for 6 mo and rituximab 375 mg/m2 given on d 1 and 4 of the first cycle, than monthly on d 1 of fludarabine). Byrd et al. (80) recently reported results in 104 patients; the overall response rate was 90% in the arm with concomitant treatment and 77% in the arm with sequential treatment; complete responses were 47 and 28%, respectively. Neutropenia was more common in patients treated with concomitant fludarabine and rituximab. First infusion reactions were more severe in the concomitant fludarabine and rituximab arm of the study and could be overcome by using a stepped-up dosing of rituximab (50 mg/m2 on d 1, 325 mg/m2 on d 3, and 375 mg/m2 on d 5).

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