Rituximab Maintenance Treatment After Combined Fludarabine, Cyclophosphamide and Rituximab In Previously Untreated Patients with Progressive B-Cell Chronic Lymphocytic Leukemia (CLL): Interim Analysis of An Ongoing Phase II Multicenter Trial On Behalf of the Spanish CLL Study Group (GELLC)

Combination of Rituximab (R) with fludarabine (F) and cyclophosphamide (C) as first line treatment of B-CLL, results in a high complete response rate, improved progression free and overall survival compared with FC in randomised trials (Hallek et al, Blood 2009). However, more than 30% of patients relapse or show disease progression at 3–4 years after FR or FCR treatment (Byrd et al., Blood 2005; Keating et al., J Clin Oncol 2005). We report on the efficacy and safety results of an interim analysis after one year of Rituximab maintenance (Rm) following FCR in previously untreated CLL patients (pts). Methods and Patients. Between October 2007 and June 2009, a cohort of 84 physically fit pts with CD20 positive CLL received treatment with 6 cycles of FCR (R:375mg/m² iv cycle-1 and 500mg/m² iv, cycles 2–6; F:25mg/m² iv, days 1–3; and C:250mg/m² iv days 1–3; every 28 days). After 3 months of clinical response evaluation, pts achieving a response were treated with R: 375mg/m² iv every 2 months for 3 years. Anti-infective prophylaxis included trimethoprim-sulfamethoxazole and acyclovir during treatment and until CD4 positive lymphocyte reached 0.3×10⁹/L. Pts achieving a complete response (CR) and negative minimal residual disease (MRD) in peripheral blood (PB) and bone marrow (BM) after 4 courses of FCR, were allowed to stop FC and complete 2 courses of R and continue with Rm. The median age was 59.5 (range 37–70), 32% were females, 6% were Rai low risk, 69% intermediate risk and 25% high risk stage. IGHV status was unmutated in 64.4%, CD38 positive (>30%) in 47.6% and ZAP-70 positive (>20%) in 57.3% of pts. The incidence of genetic abnormalities by FISH for del 6q, del 11q (ATM), trisomy 12, del 13q and del 17p (p53) was 3.5%, 26.1%,15,4%, 50% and 4.7% respectively. MRD was evaluated by multicolor flow cytometry (sensitivity: 1 CLL cell positive in 10000 leukocytes). The primary end point was to evaluate the response rates and adverse events (AEs) profile of FCR and Rm treatments. Secondary endpoints included progression free and overall survival, correlation of response with MRD after FCR and Rm treatments. The mean number of FCR cycles was 5.3, and the complete treatment was administered in 80% of pts.

We present the results of a planned interim analysis after 1 year (6 cycles) of Rm following FCR as induction treatment. Of 90 pts screened from 29 centres, 84 were assigned (6 failed eligible criteria) to FCR and were evaluable for response. On an intent to treat analysis, overall response, CR, partial response (PR), non response and progression rates were 95.2%, 73.8%, 21.4%, 3.6% and 1.2% respectively. Of 79 pts evaluable for BM-MRD status, MRD-negative CR, MRD-positive CR, MRD-negative PR and MRD-positive PR rates were 57%, 21.5%, 7.6% and 13.9% respectively. The most common AEs after FCR were rituximab infusion (65.1%), myelotoxicity (33.7%) in 29 pts and infections (34%) with 1 serious AEs (SAEs)(1 exitus by viral myocarditis). In addition, there were 12 non hematological SAEs. Seventy five out of 84 pts continued with Rm treatment, 9 were withdrawn by progression (1), toxicity (5) and investigator decision (3). As of June 2010, 70 out 75 eligible pts had initiated Rm and 37 (49.3%) had completed 1 year of Rm (6 cycles) and were evaluable for response. Of them, 24 (64.8%) pts were in MRD-negative CR and only 1 pts converted to MRD-positive CR; 8 (21, 6%) pts were in MRD-positive CR and 3 converted to MRD-Negative CR, while 5 (13.5%) continued in MRD-positive CR with a sustained decreasing number of CLL cells in BM. Five pts were in MRD-positive PR and of them, 4 were in sustained PR with BM-MRD response and one pts presented clinical progression. In summary, 70.2% reached MRD-negative CR and 97.3% were in sustained response. The most common AEs after Rm were grade 3/4 neutropenia between cycles in 6 (16.7%) pts, infections in 15 (41.7%) pts and there were 2 (5.6%) SAEs (2 pneumonia) reported in this population.

Based on these preliminary results, the addition of rituximab maintenance following FCR is feasible and effective in untreated CLL pts and increases the quality of clinical responses by obtaining a higher number of MRD-negative CR cases with an acceptable safety profile.

Garcia-Marco: ROCHE: Consultancy, Honoraria, Research Funding. Off Label Use: Rituximab is not approved as maintenance therapy. Leon: ROCHE: Employment.