Efficacy and Safety of a First-Line Combined Therapeutic Approach for Young CLL Patients Stratified According to the Biological Prognostic Features: First Analysis of the GIMEMA Multicenter LLC0405 Study
Authors: Mauro Francesca Romana , Cortelezzi Agostino , Molica Stefano , Laurenti Luca , Liso Vincenzo , Rizzi Rita , Carella Angelo Michele , Di Raimondo Francesco , Marasca Roberto , Fioritoni Giuseppe , Brugiatelli Maura , Musolino Caterina , Lauria Francesco , Buccisano Francesco , Zaja Francesco , Callea Vincenzo , Morabito Fortunato , Massaia Massimo , Gentile Giuseppe , Giudice Ilaria Del , De Propris Maria Stefania , Starza Irene Della , Marinelli Marilisa , Santangelo Simona , Nanni Mauro , Vignetti Marco , Graziosi Antonietta , Specchia Giorgina , Cuneo Antonio , Guarini Anna , Foà Robert 
Published: April 2020

Abstract
It is well known that cytogenetic abnormalities, the IgVH mutational status, ZAP-70 and CD38 have a significant prognostic role in chronic lymphocytic leukemia (CLL). We therefore designed a 1st line treatment approach for young CLL patients stratified according to the biological features of the disease. Between November 2005 and July 2008, previously untreated CLL patients ≤60 years, with advanced or progressive disease, from 21 Italian centers, were included in this study. High risk (HR) patients were defined by the presence of an adverse biologic profile: a 17p deletion in ≥20% of analyzed cells, or a 11q deletion associated with at least one additional poor prognostic factor (IgVH germline, ZAP-70+ ≥10% or CD38+ ≥7%), or a germline IgVH or mutated VH3-21 status and at least 2 additional unfavorable prognostic factors (ZAP+ ≥10%, CD38+ ≥7%, 6q deletion or 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 with evidence of residual disease - by CT scan, flow cytometry and/or PCR - received a post-induction therapy including a 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 (FluCy; Flu 30 mg/m2 iv and Cy 250 mg/m2, days 1–3). Patients with no response after 4 courses, were treated with Campath-1H sc (30 mg weekly for a maximum of 12 weeks). All patients received Darbepoietin alpha in case of anemia, G-CSF and Ciprofloxacin in case of severe granulocytopenia and PC prophylaxis with Bactrim. In addition, patients treated with FluCam underwent weekly CMV antigenemia monitoring and valacyclovir prophylaxis (2g/8h). So far, 74 young patients with advanced or progressive disease fulfilling the above criteria have been included in the study, 41 (55%) with a HR profile and 33 (45%) with a LR profile. Forty-five patients have completed the induction therapy, 24 HR patients and 21 LR patients. A response was observed in 17 HR patients: OR 71%, CR 30%, with 17% of patients obtaining an MRD- status; and in 20 LR patients: OR 95%, CR 57%, with a 19% MRD negativity. The 7 FluCam refractory patients were characterized by the presence of a 17p deletion in 3 cases and by multiple enlarged nodes in 5 (bulky nodes: 3 cases). Grade III–IV granulocytopenia was the most common toxicity after FluCam and after FluCy. However, long-lasting cytopenia was observed only in cases treated with FluCy. Asymptomatic CMV reactivation was detected in 3 cases treated with FluCam. Four patients, all treated with FluCy, have died. The causes of deaths were: febrile granulocytopenia in 2 cases, cerebral hemorrhage in 1 and multiple cerebral abscesses of unknown origin in 1. At present, 9 HR patients who achieved a response to FluCam have undergone a PBSC transplantation (allogeneic 3, autologous 6). In conclusion, the first analysis of this study, focused on young CLL patients with progressive disease stratified according to the biologic profile of the disease, has shown a high CR rate after FluCy given to patients with a LR profile and a considerable response rate with a low number of CMV reactivations after FluCam administered to patients with a HR profile. Factors predicting FluCy-related myelotoxicity warrant further investigation.