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.
Authors: Mauro Francesca R. , Giammartini Elena , De Propris Maria S. , Gentile Giuseppe , Nanni Mauro , Ghia Emanuela M. , Della Starza Irene , Del Giudice Ilaria , Santangelo Simona , Marinelli Marilisa , Brugnoletti Fulvia , Minotti Clara , Capria Vera , Guarini Anna , Foa Robert 
Published: October 2019

Abstract
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.