Germline IgVH, del(17p13.1) and del(11q22.3) Predict Duration of Response in Patients Affected by Chronic Lymphocytic Leukaemia Treated with Oral Fludarabine and Cyclophosphamide as First-Line Therapy.
Authors: Laurenti Luca , Efremov Dimitar , Tarnani Michela , de Padua Laura , Piccirillo Nicola , Chiusolo Patrizia , Sora’ Federica , Sica Simona , Zini Gina , Garzia Mariagrazia , Leone Giuseppe 
Published: November 2019

Abstract
We test the efficacy and safety of the oral formulation of fludarabine combined with cyclophosphamide as front-line therapy of CLL. We studied the influence of IgVH gene mutation status, interphase cytogenetic abnormalities, and expression of ZAP-70 and CD38 on the overall response rate (OR), progression free survival (PFS), time to re-treatment (TTR) and overall survival (OS). Twenty seven patients were male and 10 were female, with a median age of 68 years (range, 52 to 75 years). Thirty patients were in stage B/II, 1 in stage C/III, and 6 in stage C/IV. The treatment schedule consisted of oral fludarabine (30 mg/m2) and oral cyclophosphamide (250 mg/m2) for 3 consecutive days every 4 weeks, for a maximum of 6 cycles. Eighteen patients had unmutated and 15 had mutated IgVH genes; in 4 patients the mutation status was not determined. Nine patients (24%) had the ‘high risk’ cytogenetic abnormality del(11q22.3) or del(17p13.1). Fifteen patients had more than 20% ZAP-70-positive and 8 patients had more than 30% CD38-positive CLL B-cells, respectively. Thirty-five patients were evaluable for response to treatment. Two patients discontinued the treatment protocol because of the development of immune thrombocytopenia after 2 and 4 cycles, respectively. Both of them belonged to the ‘high risk’ cytogenetic category. Fourteen patients (40%) obtained a complete response and 13 (37%) a partial response with an ORR of 77%. Four patients showed stable disease and four patients experienced progressive disease after 2, 3, 4 and 6 cycles, respectively. The median PFS was 23 months (range 2–42) and the median TTR was 38 months (range 2–42). The ‘high risk’ cytogenetic abnormalities del (17p13.1) and del (11q22.3) were predictive of a lower OR rate (43% vs 85%, p=0.011) as well as a shorter PFS (22 vs 27 months, p= 0.015) and shorter TTR (22 vs 40 months, p=0.031). In addition, unmutated IgVH genes were significantly associated with a reduced TTR (26 vs 41 months, p=0.035), whereas no significant impact was noticed in terms of OR, PFS and OS, even though all four deaths occurred in patients with unmutated IgVH genes. Expression of CD38 and ZAP-70 had no significant impact on clinical outcome. At present, median follow-up is 30 months, with an OS rate of 89%. The median time of OS has not been reached for any of the prognostic categories. In terms of haematological toxicity, ten patients developed grade IV neutropenia during treatment and received G-CSF. Three patients developed grade III and IV anemia that required red blood cell transfusions. Extra-hematological toxicity consisting of nausea was detected in 14 patients (40%) of whom 12 with grade I–II and 2 (6%) with grade III; half of these patients also experienced vomiting (6 patients grade I–II and one patient grade III). One patient developed fever of unknown origin after the first cycle of chemotherapy, which spontaneously resolved without hospitalization. The oral combination of fludarabine and cyclophosphamide is an effective, safe and well tolerated regimen that appears especially appropriate for a subset of previously untreated CLL patients characterized by mutated IgVH genes and the absence of “high risk” cytogenetic abnormalities.