Immunochemotherapy with Fludarabine (F), Cyclophosphamide (C), and Rituximab (R) (FCR) Versus Fludarabine (F), Cyclophosphamide (C) and MabCampath (Cam) (FCCam) in Previously Untreated Patients (pts) with Advanced B-Chronic Lymphocytic Leukemia (B-CLL) : Experience On Safety and Efficacy within a Randomised Multicenter Phase III Trial of the french Cooperative Group On CLL and WM (FCGCLL/MW) and the “Groupe Ouest-Est d'Etudes Des Leucémies Aigües Et Autres Maladies Du sang” (GOELAMS) : CLL2007FMP (for fit medically patients).
Authors: Lepretre Stephane , Aurran Therese , Mahe Beatrice , Cazin Bruno , Tournihlac Olivier , Maisonneuve Hervé , Casasnovas Olivier , Delmer Alain , Leblond Veronique , Royer Bruno , Corront Brigitte , Chevret Sylvie , Delepine Roselyne , Vaudaux Sandrine , Van Den Neste Eric , Béné marie-Christine , Cymbalista Florence , Feugier Pierre 
Published: October 2019

Abstract
Abstract 538

Introduction:
Recent data suggest that FCR immunochemotherapy improves response rates and Progression-Free Survival (PFS) of previously untreated CLL pts. The monoclonal antibody alemtuzumab, a humanized anti-CD52 antibody (Campath), has shown activity alone and in combination in CLL pts. In order to validate the place of Campath in combination with the synergic association FC, the FCGCLL/MW and the GOELAMS conducted a multicenter French and Belgian phase III trial, CLL2007FMP, to evaluate the efficacy and toxicity of FCCam versus FCR in previously untreated patients with advanced CLL. PFS was the primary-end-point of this trial.

Methods and Patients:
A cohort of 178 fit medically pts (cumulative illness rating scale (CIRS) score of up to 6), less than 65 years old, without 17p deletion, were enrolled between November 2007 and January 2009. Pts were randomly assigned to receive 6 oral courses of FC (F 40mg/m2 d1-3 and C 250 mg/m2 d1–3; q 28 days) in combination with either R (n=83; 375 mg/m2 i.v. d 0 at first cycle and 500 mg/m2 d1 all subsequent cycles; q 28 days) or Cam (n=82; 30 mg s/cut d1-3; q 28 days). Patients were stratified according to IgVH mutational status and 11q deletion. Anti-infective prophylaxis included trimethoprim-sulfamethoxazole and valaciclovir during immunochemotherapy and until the CD4-positive lymphocyte count reached 0,2 109/l. In the FCCAm arm, CMV monitoring was monthly performed by either PCR or antigenemia. The use of GSCF was recommended. The trial's recruitment was stopped in January 2009 after 165 pts had been randomized (83 and 82 respectively in the FCR and FCCam arms) because of an excess of mortality in the FCCam arm, while 13 patients were enrolled but not randomized because of this decision.

Results:
We reported here a preliminary analysis including baseline characteristics and response rates in the first 100 included pts but safety analysis of the whole cohort ; among the first 100 pts, 81% were Binet B, 19 % Binet C ; median age was 56.8 years (range 52.8 to 60.6). Percentages of pts with 11q deletion, unmutated IgVH status, and elevated β2m, were 18.5%, 48.4%, and 77.6%, respectively. A number of 76.5% (FCR arm) and 71.4% (FCCam arm) of pts received 6 cycles. Reasons for discontinuation were mainly related to persistent grade 3-4 neutropenia. Safety analysis data were availabel for 165 pts. Number of patients reported with Common Toxicity Criteria (CTC) grade 3-4 adverse events were observed in 87.8% (FCCam arm) versus 90.2% (FCR arm) (p = 0.76). Grade 3-4 neutropenia was the most frequently reported adverse event (79.6% with FCCam and 74.6% with FCR arm). Interestingly, percentage of observed grade 4 neutropenia was stable during FCR treatment (17.6% for cycle 1 and 17.9% for cycle 6) but increased during FCCam treatment (28.4% for cycle 1 and 45.5% for cycle 6). A total of 63 Serious Adverse events (SAE) were declared (19 with 18 pts in FCR arm, and 44 with 35 pts in FCCam arm) consisting mostly of the cases in febrile neutropenia (13 with FCR arm, 27 with FCCam arm); 7 patients died, all in the FCCam arm : 3 of B diffuse large B-cell lymphoma (one of them EBV positive), 1 of mucormycosis, 1 of septic shock due to P.aeruginosae and 2 of heart failure during neutropenia. The Overall Response Rate ( ORR) in the first 100 patients was 96% in the FCR arm compared to 85% in the FCCam arm (p=0.086). The Complete Response rate was 78% (FCR arm) versus 58% (FCCam arm) (p=0.072). PFS and OS are not yet evaluable.

Conclusion:
the FCCam regimen for the treatment of advanced CLL appeared to be associated with an unfavourable safety profile representing a significant limitation of its use in this indication. Other combinations with Alemtuzumab may be studied.

Disclosures:
No relevant conflicts of interest to declare.