The addition of rituximab to fludarabine-cyclophosphamide (R-FC) significantly improves outcome in CLL patients (pts). Myelotoxicity and immunosuppression represent an important limitation limitation for the use of R-FC in elderly patients who frequently show impaired performance status and multiple comorbidities. Aims. This study was designed to determine whether the CLB-R combination is a feasible and beneficial first-line treatment for elderly CLL patients and to define the role of maintenance with R. Methods. Between October 2008 and January 2010, 97 elderly patients with untreated CLL requiring therapy according to the IWCLL criteria were enrolled. Written informed consent was obtained from all patients. CLB was administered every 28 days up to 8 courses at a dose of 8 mg/m²/day on days 1-7 combined with 375 mg/m² R for cycle 3 and 500 mg/m² for cycles 4-8. Responsive patients were subsequently randomized to receive R maintenance every 2 months for 2 years or clinical observation. At baseline, blood samples were analyzed for FISH, IGHV mutational status, p53 mutation, and Zap-70 and CD38 expression. Minimal residual disease (MRD) was evaluated by flow cytometry and PCR on CR patients. The primary endpoint was the overall response rate (ORR) at the end of the induction phase on an intention-to-treat (ITT) population (all enrolled patients who received at least 1 R dose). Results. Eighty-five patients from 19 Italian centers were evaluable on an ITT basis. Median age was 70.0 years (range 61-84). Overall, 52.9% of patients were ≥70 years. One or more comorbidities were recorded at baseline in 47.1% of cases. Binet’s stage was A in 25.9% of cases, B in 57.6% and C in 16.5%. Trisomy 12, deletion 13q, deletion 11q and deletion 17 were found in 26.5%, 48.2%, 19.3% and 4.8% of cases, respectively. p53 mutations were recorded in 4.8% of patients. Fiftyeight percent were IGHV unmutated, 41% CD38+ and 75.9% Zap- 70+. The ORR was 81.2% (69 pts). CR, confirmed by CT scan, was found in 16.5% of pts (14 pts), CRi in 2.4% (2 pts), nPR 2.4% (2 pts) and PR in 60% (51 pts). In the 14 CR cases, MRD evaluated by flow cytometry in blood and marrow was negative in 2; no patient was PCR negative. A treatment failure was recorded in 18.8% of cases (16 pts): PD 3.5% (3 pts), SD 4.7% (4 pts) and lack of response assessment 10.6% due to early treatment withdrawal (9 pts: investigator’s decision, 2; treatment-related AEs, 4; treatment-unrelated AEs, 3). Twenty SAEs were recorded in 17 patients: 5 (4 pts) related to CLB only, 3 (3 pts: pleural effusion, 1; anemia, 1; neutropenia, 1) related to CLB-R and 12 (12 pts) treatment-unrelated. The most common hematologic toxicity was neutropenia (grade III-IV: 13.5% of patients, 7.4% of episodes and 2.9% of cycles). The median number of administered CLB-R cycles in patients <80 years was 6. A dose reduction of CLB was required in 7.8% of cycles, mainly for myelotoxicity. Conclusions. This study shows that R-CLB is an active and well tolerated front-line regimen for elderly CLL patients.
A PHASE II STUDY OF CHLORAMBUCIL+RITUXIMAB (CLB-R) FOLLOWED BY R MAINTENANCE VS OBSERVATION IN ELDERLY PATIENTS WITH PREVIOUSLY UNTREATED CHRONIC LYMPHOCYTIC LEUKEMIA (CLL): INDUCTION PHASE RESULTS
CUNEO, Antonio;M. Mura;
2011
Abstract
The addition of rituximab to fludarabine-cyclophosphamide (R-FC) significantly improves outcome in CLL patients (pts). Myelotoxicity and immunosuppression represent an important limitation limitation for the use of R-FC in elderly patients who frequently show impaired performance status and multiple comorbidities. Aims. This study was designed to determine whether the CLB-R combination is a feasible and beneficial first-line treatment for elderly CLL patients and to define the role of maintenance with R. Methods. Between October 2008 and January 2010, 97 elderly patients with untreated CLL requiring therapy according to the IWCLL criteria were enrolled. Written informed consent was obtained from all patients. CLB was administered every 28 days up to 8 courses at a dose of 8 mg/m²/day on days 1-7 combined with 375 mg/m² R for cycle 3 and 500 mg/m² for cycles 4-8. Responsive patients were subsequently randomized to receive R maintenance every 2 months for 2 years or clinical observation. At baseline, blood samples were analyzed for FISH, IGHV mutational status, p53 mutation, and Zap-70 and CD38 expression. Minimal residual disease (MRD) was evaluated by flow cytometry and PCR on CR patients. The primary endpoint was the overall response rate (ORR) at the end of the induction phase on an intention-to-treat (ITT) population (all enrolled patients who received at least 1 R dose). Results. Eighty-five patients from 19 Italian centers were evaluable on an ITT basis. Median age was 70.0 years (range 61-84). Overall, 52.9% of patients were ≥70 years. One or more comorbidities were recorded at baseline in 47.1% of cases. Binet’s stage was A in 25.9% of cases, B in 57.6% and C in 16.5%. Trisomy 12, deletion 13q, deletion 11q and deletion 17 were found in 26.5%, 48.2%, 19.3% and 4.8% of cases, respectively. p53 mutations were recorded in 4.8% of patients. Fiftyeight percent were IGHV unmutated, 41% CD38+ and 75.9% Zap- 70+. The ORR was 81.2% (69 pts). CR, confirmed by CT scan, was found in 16.5% of pts (14 pts), CRi in 2.4% (2 pts), nPR 2.4% (2 pts) and PR in 60% (51 pts). In the 14 CR cases, MRD evaluated by flow cytometry in blood and marrow was negative in 2; no patient was PCR negative. A treatment failure was recorded in 18.8% of cases (16 pts): PD 3.5% (3 pts), SD 4.7% (4 pts) and lack of response assessment 10.6% due to early treatment withdrawal (9 pts: investigator’s decision, 2; treatment-related AEs, 4; treatment-unrelated AEs, 3). Twenty SAEs were recorded in 17 patients: 5 (4 pts) related to CLB only, 3 (3 pts: pleural effusion, 1; anemia, 1; neutropenia, 1) related to CLB-R and 12 (12 pts) treatment-unrelated. The most common hematologic toxicity was neutropenia (grade III-IV: 13.5% of patients, 7.4% of episodes and 2.9% of cycles). The median number of administered CLB-R cycles in patients <80 years was 6. A dose reduction of CLB was required in 7.8% of cycles, mainly for myelotoxicity. Conclusions. This study shows that R-CLB is an active and well tolerated front-line regimen for elderly CLL patients.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
