A Retrospective Population-Based Study of a Series of 307 Treatment-naïve Patients with Chronic Lymphocytic Leukemia (CLL): Study of the Clinical Features and Efficacy of First-Line Therapy

Clinical trials have shown an improved response rate and progression free survival (PFS) among the different treatment options used in the last two decades, specially with rituximab in combination with fludarabine and cyclophosphamide. We wished to analyze, in an unselected community based population, the clinical characteristics and efficacy of first line therapy with several treatment options used throughout a ten-year period.

We included 307 patients diagnosed of CLL and requiring first-line treatment between January 2000 and September 2009. Patients were treated at 20 hospitals placed in the Community of Valencia and Murcia and received first-line therapy according to the clinical guidelines of each hospital. PFS was calculated from date of first treatment to date of progression/relapse. We performed a descriptive analysis of clinical and biological features. The survival curves were built with Kaplan-Meier method and compared with the log rank test. Multivariate analysis for response and PFS were performed by logistic and Cox regression methods respectively, using the statistical package SPSS (v15).

Median age at treatment was 67 years (range 28–94) with 58% (n=179) men. 39% (120/305) were in Binet A, 38% (117) in Binet B and 22% (68) in Binet C. 27% (84) were Rai III-IV. B symptoms were present in 25% (77) and fever was a rare symptom 3%. Patients were asymptomatic in 59% (181) of the cases with ECOG performance status 0–1 in 83% (256). Splenomegaly was present in 41% (127) and hepatomegaly only in 8% (24). 42% of the patients (129) had at least three lymph-node areas affected with bulky disease (diameter higher than >5cm) in 10% (32). Median haemoglobin level was 126gr/L (46–169), lymphocyte count 49 x109/L (0,5–613) with lymphocyte doubling time (LDT) <12 months in 43%. LDH was elevated in 34% (95/284) and b2-microglobulin levels in 61% (154/251). CD38 expression was positive in 42% (107/255) and ZAP-70 in 75% (91/122). The overall incidence of trysomy 12, 13q, 11q23 and 17p deletions detected by FISH were 17%, 15%, 12% and 5% respectively. Median follow-up was 33.5 months (0.6–156). First line treatment schedules and treatment response in every group are detailed in table 1.

Patients receiving rituximab (group 3–4, n=73) achieved a significant higher response rate (CR or PR) than patients without rituximab (93% vs 61%). The main clinical variables with prognosis significance in the univariate analysis for PFS were: lymphocyte count (p=0,026, HR 1.002, CI95% (1.000–1.004)); haemoglobin level (p=0,02, HR 0.890, CI95% (0.826–0.958); b2-microglobulin (p=0,002, HR 1.372, CI95% (1.125–1.672)); bulky mass (p=0,055, HR 1.656, CI95% (0.989–2.775)); CD38 expression (p=0,045, HR 1.005, CI95% (1.000–1.011)); p53 deletion (p=0,014, HR 2,231, CI95% (1,180–4,217)) and 11q23 deletion (p=0,03, HR 2,138, CI95% (1,290–3,542)). The median PFS for patients in the different groups were: G1:26.9 months (22.4–31.3), G2 45.5 months (32.7–58.4), G3: not reached, G4: 20.5 months (29.6–47.3), p < 0.0001.

In the multivariate analysis the variables with independent prognostic significance for PFS were: lymphocyte count (p=0.003, HR 1.004, CI 95% (1.001 −1.007)), 17deletion (p=0.01, HR 2.7 CI95% (1.273–5.73)), 11q deletion (p=0.006, HR 2.193 CI95% (1.248–3.852)) and treatment received (G1 as reference): G2 (p=0.005, HR 0.464, CI95% (0.271–0.794)), G3 (p < 0.001, HR 0.179, CI95% (0.083–0.386)), G4 (p=0.223, HR 0.289, CI95% (0.039–2.130)).

In this community based population, treatment with rituximab containing regimens results in a higher global and complete response rate and a longer PFS compared with alquilating agents and purine analogs. Fludarabine containing-schedules also achieved a significant higher response rate than alquilating agents. Rituximab in combination with purine analogs provide the better quality of response. These results confirm the data provided by clinical trials and support their use as front-line treatment.

Terol: ROCHE: Consultancy.