Consolidation therapy with high-dose cyclophosphamide improves the qualityof response in patients with chronic lymphocytic leukemia treated with fludarabine as induction therapy

Fludarabine is the most active agent in the treatment of chronic lymphocyti c leukemia (CLL). Despite this activity only a minority of patients treated with fludarabine achieve a complete response. We evaluated a new treatment program of sequential therapy with fludarabine followed by high-dose cyclo phosphamide in previously untreated patients with CLL. This report details the results in 25 patients with previously untreated CLL. Patients received fludarabine (25 mg/m(2)/day x 5 days every 4 weeks for six cycles) as Indu ction followed by consolidation with high-dose cyclophosphamide at one of t hree dose levels 1.5 g/m(2), 2.25 g/m(2), or 3 g/m(2) administered every 2 weeks for three doses. High-dose cyclophosphamide was given with G-CSF supp ort (5 mu g/kg/day days 3-12). Complete response (CR) required a normal phy sical examination, normal CBC, a normal bone marrow evaluation including no residual lymphoid nodules on biopsy. A nodular response was defined as a c omplete response with the exception of an occasional residual nodule seen o n bone marrow biopsy. Flow cytometric analysis for CD5:CD19 dual staining a nd kappa/lambda clonal excess was performed in all patients as a sensitive measure of minimal residual disease (MRD). Selected patients had patient/tu mor-specific oligonucleotides generated that were subsequently used in a po lymerase chain reaction as an extremely sensitive measure of MRD. There wer e no treatment-related deaths and no patient encountered unacceptable toxic ity. After completion of this sequential regimen 76% (95% confidence interv al: 59-93%) of patients had a major response: eight (32%) achieved a CR, fo ur (16%) a nodular response, seven (28%) a PR, and six patients (24%) faile d. Four patients withdrew from study during induction with fludarabine and did not receive at least one cycle of cyclophosphamide. Of the 21 patients who received consolidation with cyclophosphamide 10 (48%) had an improved q uality of response when compared to that achieved with fludarabine. Two pat ients (8%) had no disease detectable by flow cytometry ('flow cytometric' C R) after six cycles of fludarabine. This improved to nine patients (36%) af ter high-dose cyclophosphamide. Following consolidation with high-dose cycl ophosphamide three patients (12%) tested negative by PCR. All of these pati ents had morphologic evidence of residual disease after six cycles of fluda rabine. Consolidation with high-dose cyclophosphamide increased the fractio n of patients achieving a nodular response or CR three-fold (16% to 48%). T his appears to be clinically relevant because with a median follow-up of 52 (range 34-78) months the projected 6-year survival for patients achieving a CR or NR is 91% compared to 41% for all others (P = 0.012). We conclude t hat sequential therapy with fludarabine followed by high-dose cyclophospham ide in previously untreated patients with CLL is safe and can Improve the q uality of response in a large proportion of patients compared to therapy wi th fludarabine alone.