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S.E. Sylvan et al.
Table 2. First-line treatment by time period and response/infection rates. Time period (%)
ORR# (%)
127 (75)
240 (84)
32 (67)
174 (43)
47 (75)
22 (82)
22 (67)
9 (50)
673 (64)
Infection# >Grade III (%)
48 (29)
84 (30)
17 (35)
77 (19)
20 (32)
9 (33)
8 (25)
2 (11)
265 (25)
Treatment
F/FC
FCR Alemtuzumab CLB±R
B/BR CHOP/CVP±R Other Rituximab alone
Total
2007-2009
95 (29)
32 (10) 17 (5) 159 (48) 1 (0) 16 (5) 6 (2) 4 (1)
330 (100)
2010-2013
74 (10)
253 (35) 31 (4) 245 (34) 61 (9) 11(2) 26(4) 14 (2)
715 (100)
2007-2013
169 (16)
285 (27)
48 (5)
404 (39)
62 (6)
27 (3)
32 (3)
18 (2)
1045
#For the whole time period 2007-2013. ORR: overall response rate; F: fludarabine; FC: fludarabine in combination with cyclophosphamide; FCR: fludarabine in combination with cyclophosphamide and rituximab; CLB±R: chlorambucil and rituximab; B/BR: bendamustine/bendamustin and rituximab; CHOP/CVP±R: cyclophosphamide+hydroxydaunoru- bicin+vincristine+prednisone / cyclophosphamide+ vincristine+prednisone+rituximab.
hospitals (43%). The use of CLB declined significantly over the years, with 58% usage in 2007 to 31% in 2013 (P<0.0001). However, by the end of 2013, the CLB first- line usage was still high, varying between regions from 27% to 49%.
Response to first-line therapy
The ORR for the study group was 64% (15% CR): CLB 43%, FCR 84%, FC 75% and B/BR 75%. ORR was signif- icantly associated with type of treatment (P<0.001), per- formance status (P<0.001), del(17p) (P=0.007), age (P<0.001), and compliance to national guidelines (P=0.003), but not with gender, Rai stage or type of hos- pital (univariate analysis). Patients included in clinical tri- als showed a numerically better response rate (82%) than those treated according to national guidelines (65%) and compared to patients treated neither according to guide- lines nor to a clinical study protocol (54%).
Progression-free and overall survival
Median PFS was 24 months (range 20-26 months) and median OS was 58 months (range 40-76 months). At 5-y follow up, 51% of all patients were deceased, and nearly two-thirds had died from CLL or CLL-related infections.
Progression-free survival in relation to type of first-line therapy is shown in Figure 1A. As expected, the longest PFS was observed with FCR, whereas the median PFS in patients who received CLB was only nine months. PFS in relation to FISH results are shown in Figure 1B. Shortest PFS was observed for del(17p). Similar results were observed for type of treatment and FISH data in relation to OS (Figure 2A and B). Notably, CLB-treated patients had a median OS of only 33 months. Survival in relation to type of hospital is shown in Figure 2C and in relation to age in Figure 2D.
In a multivariate analysis, both PFS and OS were signif- icantly associated with type of treatment, cytogenetic sta- tus, performance status, gender and age (Table 3). OS was also significantly associated with geographical region (P=0.003). There was a tendency but no significant differ- ence (P=0.07) in OS between the two time periods (2007- 2009 vs. 2010-2013). IGHV analysis was only performed in a small fraction of patients and did not provide suffi- cient power when included in the model (both PFS and OS were non-significant). Thus, this analysis was exclud- ed from multivariate analysis regarding this time period. However, we also analyzed the prognostic impact of IGHV on the whole study population. The results from
AB
Figure 1. Progression-free survival (PFS) after first-line therapy. PFS according to (A) treatment and (B) fluorescence in situ hybridization (FISH) cytogenetic status. F/FC: fludarabine/fludarabine in combination with cyclophosphamide; CLB+/-R: chlorambucil and rituximab; FCR: fludarabine in combination with cyclophos- phamide and rituximab; B/BR: bendamustine/bendamustin and rituximab; ALEM: alemtuzumab; CHOP/CVP+/-R: cyclophosphamide+hydroxydaunorubicin+vin- cristine+prednisone/cyclophosphamid+vincristine+prednisone+rituximab.
800
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