Safety and Efficacy of Abbreviated Induction with Oral Fludarabine (F) and Cyclophosphamide (C) Combined with Dose-Dense IV Rituximab (R) in Previously Untreated Patients with Chronic Lymphocytic Leukemia (CLL) Aged > 65 years : Results of a Multicenter Trial (LLC 2007 SA) On Behalf of the French Goelams/Fcgcll-WM Intergroup

The German CLL8 trial has demonstrated that addition of R to FC improves quality and durability of response in CLL (Hallek et al, 2010), which has led to the recommendation of FCR as first line therapy for fit patients. Although elderly patients were included in the CLL8 trial (up to 81 y-old), the median age of the cohort was 61 y, thus at least 10 y younger than median age at CLL diagnosis. The elderly population is underrepresented in clinical trials and it is still not clear how FCR should be applied in this subgroup. In December 2007, the French intergroup launched the LLC 2007 SA trial (NCT00645606) in which CLL patients aged > 65 y receive an induction with abbreviated FCR followed by randomization between observation or maintenance with rituximab. We now report the safety and efficacy of the induction part in the first 200 patients enrolled in this study.

Stage B or C previously untreated fit (CIRS ≤ 6, CCR ≥ 60 ml/min, PS ≤ 1) CLL patients aged > 65 y needing treatment (NCI criteria) were included. Patients with del17p and/or Matutes scoring < 4 were excluded. From these 200 first patients included, 6 were removed because of incorrect inclusion (n=4) or consent withdrawal (n=2). In total, 194 patients (included between Dec/07 and Feb/10) were analyzed. FCR consisted of four monthly cycles of oral FC (F 40 mg/msq/d and C 250 mg/msq/d, × 3d) and iv R (375 mg/msq d1 cycle 1, 500 mg/msq d14 cycle 1, d1 and 14 of cycle 2, and d1 of cycles 3 and 4). Response was assessed by NCI criteria. MRD analysis was done using 6-color FCM in PB and BM. No later than 90 d after the last FCR, patients were further randomized as per protocol. Disease outcome after randomization remains completely blinded to date.

The median age was 71 y (range 65–85) and 65% were males. 83% had CIRS between 0 and 3. Binet stage was B in 127 (65.5%) and C in 67 (34.5%). Median (n=143) Beta-2-microglobulin was 4 mg/L (range 2–8). Fifty-six % had unmutated IgVH and FISH revealed 18% with del11q, 15% with trisomy 12, and 57% with del13q. Karyotype (ODN+IL2-stimulated) was abnormal in 67%. Balanced and unbalanced translocations were seen in 16% and 17%, respectively. Complex (>2 abn) karyotype occurred in 14% of the patients.

167 (86%) received all four cycles of FCR. Only 4.6% and 3.2% of patients did not receive d14 rituximab at cycle 1 and 2, respectively. 158 patients (81%) could proceed to the randomization (the main reason for failure was insufficient marrow recovery). Dose delay (by ≥ 1 w) and dose reduction (by ≥ 25% of F and C) for cycles 2, 3, and 4 were 12% and 7%, 14% and 8%, 15% and 11%, respectively. Neutropenia g3/4 occurred after cycle 1, 2, 3 and 4, in 46% (19% g4), 50% (21% g4), 53% (29% g4), and 46% (26% g4) of the patients. G-CSF was given in 32%, 46%, 48%, and 52% of them after cycles 1, 2, 3, and 4. G4 thrombocytopenia occurred in less than 2% of the cycles. G3/4 anemia was seen in 11%, 7%, 6%, and 3% of the patients after cycle 1, 2, 3, and 4, respectively. G 3/4 infectious events occurred in 6.2%, 4.8%, 7.6%, and 6.2% of the patients after each of the 4 cycles. Seventy SAE (including 46 febrile neutropenia and/or documented infection) were declared in 53 patients during the induction and the period of recovery prior to randomization. In total, 6.3% of the 732 cycles were followed by febrile neutropenia or infection qualified as SAE. Six deaths (all infections) occurred during induction, corresponding to a 3.1% (6/194) death rate from immediate toxicity.

Among 188 evaluable patients, complete responses (CR) were observed in 19.7%, nodular partial response (PR) in 2.7%, and PR in 73.9%, for an ORR of 96.3%, using stringent criteria. According to the updated guidelines of 2008 (Hallek), CR, CRi, and PR rates were 19.7%, 13.3%, and 63.3%, respectively.

Four cycles of oral FC combined with 6 doses of R appear feasible in elderly patients with CLL; only 14% cannot receive the 4 courses and only 19% cannot proceed to randomization planned at day 90 post FCR4. Dose reduction and treatment interruption are unusual despite strict stopping criteria. Grade 3/4 neutropenia is frequent but rarely translates into serious infection. The response rate is high, and further analysis of MRD eradication is ongoing and will be presented. In conclusion, this approach could enable the safe administration of FCR to elderly fit CLL patients in first line. Long-term toxicity, occurring after randomization, will be scrutinized.

Dartigeas:Roche: Consultancy. Van Den Neste:Roche: Consultancy. Leblond:Mundipharma: Honoraria; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria.