EFFICACY AND SAFETY OF A FIRST-LINE COMBINED THERAPEUTIC APPROACH FOR YOUNG CLL PATIENTS STRATIFIED ACCORDING TO THE BIOLOGIC PROGNOSTIC FEATURES: ANALYSIS OF THE GIMEMA MULTICENTER STUDY (LLC0405)

Eighty-six previously untreated CLL patients ²60 years, with advanced or progressive disease, from 23 Italian centers, were included in a prospective GIMEMA study. Treatment approach was stratified according to the biologic features of the disease. High risk (HR) patients were defined by the presence of: 1) a 17p deletion (³20% of analyzed cells), or 2) a 11q deletion with ³1 additional unfavorable factor (IgVH germline; ZAP-70+, ³10%; CD38+, ³7%), or 3) a germline IgVH or mutated VH3-21 and ³2 unfavorable factors (ZAP+; CD38+ ; 6q deletion; trisomy 12). Low risk (LR) patients were defined by the absence of the above mentioned characteristics. For HR patients, treatment consisted of 4 monthly courses of Fludarabine and Campath-1H (FluCam; Flu 30 mg/m2 iv; Campath-1H 30 mg iv, days 1-3). Patients who achieved a response received a post-induction therapy (reduced intensity PBSCs allogeneic transplant or, in the absence of a sibling donor, an autologous PBSC transplant or, in the absence of a sufficient harvest, Campath-1H sc, 30 mg weekly for a maximum of 12 weeks). For LR patients, treatment included 6 monthly courses of Fludarabine and Cyclophosphamide (FC; Flu 30 mg/m2 iv and Cy 250 mg/m2, days 1-3). All patients received Bactrim prophylaxis. Patients treated with FluCam underwent weekly CMV antigenemia monitoring and valacyclovir prophylaxis (2g/8h). Forty-five HR patients (52%) and 41 LR (48%) have been included in the study. Thirty-five HR patients and 23 LR patients have completed the induction therapy. A response was observed in 31 HR patients: OR 89%, CR 34% (MRD negative CR: 23%) and in 23 LR patients: OR 96%, CR 61% (MRD negative CR: 22%). Grade III-IV granulocytopenia was the most common toxicity after FluCam and after FluCy. However, longlasting cytopenia was observed only in cases treated with FluCy. Asymptomatic CMV reactivation was detected in 3 cases treated with FluCam. Six patients, have died, 4 patients treated with FluCy (febrile granulocytopenia: 2 cases; cerebral hemorrhage: 1; cerebral abscesses of unknown origin: 1) and 2 patients treated with FluCam (disease progression: 2). Ten (32%) HR patients who achieved a response have undergone a PBSC transplantation (allogeneic 4, autologous 6). In conclusion, the results of this study, have shown a high CR rate with FluCy given to patients with a LR profile and a considerable response rate with a very few CMV reactivations with FluCam administered to patients with a HR profile.