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Efficacy of BR as first salvage treatment in CLL
without post-baseline assessments but known to be alive were censored at the time of first dose of study drug.
Secondary end points
The ORR was assessed in all the patients who started treatment (intention to treat). Time to next anti-leukemic treatment (TTNT) was calculated using the cumulative incidence method, from the date of the first dose of the study drugs until the date of retreat- ment. OS was calculated from the date of the first dose of the study drug until the date of death. Patients without follow-up assessment were censored at the day of the last treatment admin- istration. Evaluation of safety was reported according to NCI Common Terminology Criteria for Adverse Events version 4.0.
Indirect comparison with ibrutinib
Data from patients treated in second line with single agent ibru- tinib in the UK and Italy within the NPP were retrospectively retrieved. Patients with R/R CLL treated in the UK have been reported previously.20 Patients treated in Italy were extracted from the GIMEMA LLC1415 trial (clinicaltrials.gov identifier: 02582320). The end point for this analysis was OS.
Statistical analysis
Statistical analysis was performed following the intention-to- treat principle. Non-parametric tests were applied for comparisons between groups (χ2 and Fisher Exact test for categorical variables or response rate, Mann-Whitney and Kruskal-Wallis test for con- tinuous variables) and logistic regression were applied in multi- variate analysis. Survival distributions were estimated using the Kaplan-Meier Product Limit estimator.
Differences in terms of PFS, TTNT and OS were evaluated by Log-Rank test in univariate analysis and Cox regression model in multivariate analysis.
Cumulative Incidence curves were estimated using the proper non-parametric method. The Gray test was applied for signifi- cance tests on cumulative incidence curves.
All the analyses were performed using the SAS software (v.9.4 or later); all tests were two-sided. P=0.05 was considered statisti- cally significant. Confidence intervals were calculated at 95% (95%CI).
Results
Patients’ characteristics
A total of 237 patients treated at 37 centers (28 centers belonging to the GIMEMA group and 9 centers affiliated with the ERIC group) were enrolled (Online Supplementary Table S1). Baseline patients’ characteristics are outlined in Table 1: median age was 70.4 years, range 39.4-87.8; 70.9% of patients were over 65 years old; 58.3% had 2 or more comorbidities; 46.9% had a creatinine clearance ≤70 ml/min; and 21.4% had an advanced disease stage (i.e. Rai III-IV or Binet C). Seventy-three percent (data available in 61.6% of the patients) had an unmutated tumor immunoglobulin gene heavy chain variable region config- uration (U-IGHV) and 33.4% had 11q- and/or 17p13 dele- tion (data available in 79.3% of the patients). These patients were representative of the entire study popula- tion in terms of baseline characteristics and outcome (data not shown).
Frequency (%)
Table 1. Patients' characteristics. Variable
Benda + R n=237
P
0.344 0.427 0.215 0.147
33 (39.8)/ 50 (60.2) <0.001
Age, years [median, range]
Age, years ≤65/>65
Sex, M/F
ECOG PS (%) 0-1/≥2
Stage, Rai III/IV or Binet C no/yes Bulky lymph nodes (> 5cm) no/yes Comorbidities 0-1/≥2
70.4 [39.4-87.8]
69 (29.1)/168(70.9)
168 (70.9)/69 (29.1)
198 (90.0)/22 (10.0)
165 (78.6)/45 (21.4)
20 (8.9)/204 (91.1)
98 (41.7)/137 (58.3)
100 (46.9)/113 (53.1)
52 (47.3)/58 (52.7)
23 (12.6)/ 160 (87.4)
45 (24.6)/32 (17.5)/38 (20.8)/23 (12.6)/45 (24.6) 40 (27.4)/106 (72.6)
124 (52.3)/113 (47.7)
195 (82.3)/42 (17.7)
174 (90.6)/18 (9.4)
95 (41.0)/137 (59.0)
39 (41.1)/42 (44.2)/14 (14.7) 19 (13.9)/77 (56.2)/41 (29.9) 140 (59.6)/95 (40.4)
Ibrutinib n=95
69.3 [27.5-85.3] 32 (34.0)/62 (66.0) 60 (63.2)/35 (36.8) 75 (83.3)/15 (16.7)
Creatinine clearance (mL/min) ≤ 70/>70 CD38 (>20%) neg/pos
17p- yes/no
FISH 13q-/+12/11q-/17p-/no aberrations IGHV Mutated/unmutated
-- -- -- - - - -
--
Months between 1st and 2nd treatment <36/≥ 36 Previous treatment
ORR rate to 1st line treatment (%) yes/no Refractory no/yes
14 (38.9)/22 (61.1) 54 (75.0)/18 (25.0)
0.251 0.001 - 0.636
56 (78.9)/15 (21.1)
--
CIT no/yes
Chemo Chl/FL-based/bendamustine
CIT Chl/F-based/bendamustine
<6 cycles and/or dose reductions yes/no
22 (23.7)/71 (76.3) 0.005
--
- -
- -
n: number; ECOG: Eastern Cooperative Oncology Group; neg: negative; pos: positive; ORR: overall response rates; chemo: chemotherapy; Chl: chlorambucil; CIT: chemoim- munotherapy; M: male; F: female; FL: fludarabine.
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