Fludarabine, Ara-C, Novantrone and Dexamethasone Plus Campath-1H for the Treatment of Patients with Chronic Lymphocytic Leukemia (CLL) and Adverse Clinical and Biologic Prognostic Features.

This study was conducted to determine the feasibility, safety and efficacy of the FAND plus Campath-1H combination (FAND-Cam) given to 19 previously treated CLL patients with adverse prognostic features. The median age was 55 years (range 43–65), the median duration of CLL was 68 months; 89 % of patients were unmutated, 74% CD38+ and 75% ZAP-70+. A 17p− deletion was observed in 5/11 evaluable cases. The median number of prior treatments was 2 (range 1–6). Seventeen patients (89%) were refractory to prior therapy, which included fludarabine in 14 (fludarabine, n = 3; fludarabine-cyclophosphamide, n = 10; fludarabine-cyclophosphamide-rituximab, n = 1). The first 6 patients received 2 courses of FAND, for tumor debulking, followed by 2 FAND-Cam courses. However, a high infection rate was observed. In an attempt to reduce the risk of infection, the subsequent 13 patients received 2 courses of FAND-Cam without prior debulking with FAND. The treatment regimen of FAND was as follows: fludarabine, 25 mg/m² intravenously (IV) administered daily on days 1–3 (0, 24 and 48 hours); Ara-C, 700 mg/m² IV on days 1–3 (4, 28 and 52 hours); mitoxantrone, 10 mg/m² IV on day 1 at 6 hours; dexamethasone, 20 mg IV on days 1–3. Before the first FAND-Cam course, Campath-1H was dose escalated from 3 mg 10 mg and then to 30 mg IV. After the FAND regimen, patients received Campath-1H, 30 mg IV on 3 consecutive days. G-CSF was used in the event of severe neutropenia. Infection prophylaxis consisted of trimethoprim-sulfamethoxazole, fluconazole, acyclovir 200 mg 3 times a day, for the first 9 patients, valacyclovir 2g 3 times a day for the last 10 patients. CMV viremia was performed weekly. To date, the response is evaluable in 18 patients. All 6 patients who received 2 courses of FAND for tumor debulking, followed by 2 courses of FAND-Cam, responded to treatment (complete response [CR], n = 1; cytometric CR, n = 4; partial response [PR], n = 1). However, infections were recorded in all cases (Nocardia pneumonia + CMV reactivation, n = 1; pneumonia, n = 1; pneumonia + CMV reactivation, n = 1; sinus infection, n = 1; CMV reactivation, n = 2). In the second group of patients who, without prior debulking, received only 2 courses of FAND-Cam, a response was observed in 10/12 (83%) evaluable cases (CR, n = 3; cytometric CR, n = 3; PR, n = 4; no response [NR], n = 2). An infection was recorded in 8/12 cases (Pseudomonas sepsis, n = 1; Pseudomonas sepsis + CMV reactivation, n = 1; Aspergillus, n = 1; Pneumonia, n = 3; CMV reactivation, n = 2). Prophylactic treatment with valacyclovir reduced the rate of CMV reactivation from 67% (6/9 pts) to 11% (1/9pts). During treatment there were no deaths related to infection. Six patients who achieved a response after Fand-Cam underwent allogeneic peripheral stem cell transplantation. CLL refractory patients with adverse prognostic factors respond poorly to therapy and show a high infection rate due to the severe immunodeficiency related to both refractory disease and treatment. In this study, FAND-Cam combination proved to be a feasible and effective salvage therapy in most patients. Infections were common. Careful surveillance and extended prophylaxis for infection are therefore required.