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A. Cuneo et al.
First-line treatment included CIT regimens combining rituximab with fludarabine (with or without cyclophos- phamide), bendamustine or chlorambucil in 59% of patients; 41% of patients received chemotherapy or, in 2 cases, single agent treatment with rituximab or alem- tuzumab. No patient received ibrutinib or other novel oral agents front line. The use of chemotherapy alone front line was more frequent before 2010 (52.8% of patients) than from 2011 onwards (27.9% of patients). Eighteen patients (9.4%) were refractory to first-line treatment.
Treatment with BR
One hundred and sixty-five of the 237 patients (69.6%) received the planned number of cycles; treatment was dis- continued early in 72 patients as a result of toxicity (n=39), withdrawal of consent (n=7), progressive disease (n=6), or for other reasons (n=20). The number of cycles actually administered to patients who discontinued treatment was ≥4 in 52.8% (n=38) of cases.
Dose reduction of over 10% of the planned dose of ben- damustine (i.e. <70 mg/m2) was recorded in 28.9% of cases; a treatment delay occurred in 22.5% of patients. Overall, 95 patients (40.1%) received 6 cycles without dose reduction. The median dose administered to the patients who discontinued treatment or received a reduced dose was 350 mg/m2.
Efficacy
The 12-month PFS rate was 78.6% (95%CI: 73.5- 84.1%). The estimated PFS at 30 and 60 months was 30.9% (95%CI: 24.8-38.5%) and 16.2% (95%CI: 10.6- 24.6%), respectively, with a median overall PFS of 25
months (Figure 1) (median follow up 37.1 months, range 0.4-98.5).
Factors predicting for a shorter PFS at univariate analysis (Table 2) were 17p deletion (median 14.5 months vs. 25.5 months), U-IGHV (median 20.7 months vs. 32.1) and a less than 36-month interval between first- and second-line treatment (median 21.1 months vs. 26.8), whereas an advanced stage was of borderline significance (median 20.6 vs. 25.8 months). Age (cutoff 65 years), creatinine clearance [cutoff 70 mL/minute (min)] and the presence or absence of 2 or more comorbidities had no impact on PFS. The presence of 17p-, U-IGHV and Binet/Rai stage C/III- IV were associated with a shorter PFS at multivariate analysis (Table 2). Patients with a low-risk profile, i.e. without del(17p), with M-IGHV and Rai stage 0-2 (12.2% of the total patient population), had a median PFS of 40.4 months compared to 20.7 months in the remaining patients (P=0.003) (Online Supplementary Figure S1).
The ORR was 82.3% and the probability of attaining a response was significantly lower in patients with del(17p) (69.6%) compared to patients with del(11q) (73.7%), del(13q) (82.2%), no aberrations (86.7%) or +12 (96.9%) (P=0.04). The other clinico-biological variables had no sig- nificant impact on the ORR (Online Supplementary Table S2).
The TTNT at 12 months was 18.1% (95%CI: 12.6-22.2) (median 31.3 months) (Online Supplementary Figure S2). A shorter TTNT was associated with del(17p) (median 20.2 months vs. 34.6) and with the group of patients who received previous CIT vs. chemotherapy as front-line reg- imen (27.2 months vs. 40.4) (Table 3). An U-IGHV status (29.3 months vs. 45.7) and the presence of 2 or more
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B
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Figure 1. Progression-free survival (PFS) of patients treated with bendamustine and rituximab (BR) second-line. PFS of all 237 patients (A), by fluorescence in situ hybridization (B), IGHV status (C), and interval between first-line and second-line treatments (D).
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