Comparison of Oral and Intravenous Fludarabine in the LRF CLL4 Trial.
Authors: Hillmen Peter , Richards Sue , Catovsky Daniel ,   UK NCRI CLL Trials Group
Published: April 2020

Abstract
The LRF CLL4 trial opened in 2/99 and closed in 10/04. 783 previously untreated patients with CLL requiring therapy by conventional criteria were entered and 6 were excluded. Patients were randomized between chlorambucil (10mg/m2 x 7 days; n=387) and fludarabine alone (FDR; n=194) or combined with cyclophosphamide (FC; n=196). A full report of the responses and outcomes of the trial will be presented elsewhere in the Meeting (Catovsky et al.). FDR and FC were initially given intravenously (IV; FDR 25mg/m2 x 5 days or FDR 25mg/m2 plus cyclophosphamide 250mg/m2 for 3 days) until 2001 when oral FDR became available and the protocol was modified to allow it’s use. The oral dose of fludarabine (FDR 40mg/m2 x 5 days or FDR 24mg/m2 plus cyclophosphamide 150mg/m2 for 5 days) was considered equivalent to the IV dose as previous studies indicated that the bioavailability of oral fludarabine was approximately 55% of the IV route. Dosing in the chlorambucil arm of the trial remained unchanged. The chemotherapy dose was reduced if there was a 2 week delay in therapy due to neutropenia or thrombocytopenia and the fludarabine dose was reduced if the creatinine clearance was between 30 to 60ml/min. 223 patients received oral FDR (107 FDR alone and 116 FC) and 106 patients received IV FDR (51 FDR alone and 55 FC). 6 FDR and 15 FC patients were not assessable for response. Among the remainder, responses were better with IV fludarabine compared to oral therapy (FDR: CR/NPR = 54% v 41%, NR = 8% v 26%, p=0.02; FC: CR/NR = 73% v 59%, NR = 2% v 10%, p=0.04). There was no difference between the oral and IV patients in age, gender or stage, but as expected the proportion receiving oral therapy increased over the years (2001 75%, 2002 85%, 2003 89%, 2004 91%; p for trend=0.008) and patients entered after 2001 were older (mean 64.4 versus 62.5; p=0.02). However the response rate also decreased by year of entry in the chlorambucil arm (1999/2000 vs 2001/02 vs 2003/04: CR/NPR = 33% vs 30% vs 20%; NR/PD = 17% vs 28% vs 38%, p=0.004) with no significant difference over time when the responses for the two fludarabine-containing regimes, including oral and IV, were combined (1999/2000 vs 2001/02 vs 2003/04: CR/NPR = 57% vs 51% vs 51%; NR/PD = 6% vs 13% vs 16%, p=0.16). In multivariate Cox regression analysis of progression free survival (PFS) for patients entered from 2001, including treatment (FDR or FC), age, gender, stage, year of entry and IV or oral FDR as possible variables in the model, treatment (p=0.0003) and IV/oral (Hazard ratio (HR) = 1.9; p=0.05) were significant. Age was the only significant variable in analysis of survival (HR = 1.05; p=0.0003). There was no significant difference in the main toxicities (neutropenia, thrombocytopenia, anaemia, nausea and vomiting, alopecia, diarrhoea) for oral or IV fludarabine. In summary, analysis of the data suggests that the observed difference in response rates between intravenous and oral fludarabine in the LRF CLL4 trial is probably not due to the route of administration of fludarabine but is more likely to be explained because older patients with a poorer prognosis were entered later in the study when all patients were guaranteed to receive oral therapy. Although a randomised controlled trial would be required to formally prove that oral fludarabine is not inferior to intravenous fludarabine our data are suggestive that there are unlikely to be significant differences in response rates between routes of administration of fludarabine.