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Efficacy of BR as first salvage treatment in CLL
comorbidities (27.2 months vs. 39.1) were of borderline significance, whereas age and the creatinine clearance had no impact on TTNT. First-line treatment with a CIT regi- men was the only predictive factor for a shorter TTNT at multivariate analysis.
Seventy-three patients died due to CLL (n=14), infection with or without active CLL (n=27), second primary tumors (n=7), Richter’s syndrome (n=4). In 12 patients, the cause of death was not reported. Other causes of death in single patients (n=9) are listed in Online Supplementary Table S3.
Overall survival at 12, 36 and 60 months was 92.7%, 72.2% and 54%, respectively, with a median OS of 74.5 months (Figure 2). Fifty-eight percent of patients in advanced stage were alive at 36 months compared to 75.8% in stage 0-II; 42.4% of patients who did not respond to BR were alive at 36 months compared to 78.2% of those who responded. An advanced stage (i.e. Rai stage III-IV or Binet stage C) and resistant disease were the only parameters significantly associated with a shorter OS at univariate and multivariate analysis (Table 4 and Figure 2).
Safety
A detailed report of grade 3-5 adverse events (AE) is shown in Online Supplementary Table S4. Thirty-three per- cent of patients (n=79) reported at least one grade 3-4 AE. Overall, cytopenia was recorded in 24.9% of patients. Grade 3-4 neutropenia (including febrile neutropenia) occurred in 20.7% of cases, thrombocytopenia in 6 patients (2.5%), anemia in 3 patients (1.2%), 2 of whom had autoimmune hemolytic anemia. Grade 3-5 infections were recorded in 16 patients including 4 with febrile neu- tropenia (6.7%), 8 of whom (3.4%) had a lung infection. One case of fatal infection was reported (encephalitis). Rash and/or dermatitis were reported in 2 patients (0.8%).
Efficacy of ibrutinib in the UK CLL forum and in the Italian Named Patient Program
Ninety-five patients were treated in 2014-2015 with sin- gle agent ibrutinib in second-line within the NPP (73 in the UK and 22 in Italy). Median follow up in the UK cohort was 3.1 years. These 95 patients were heterogeneous in baseline risk factors (Table 1), with an Eastern Cooperative Oncology Group (ECOG) PS≥2 being the
Table 2. Progression-free survival (PFS) with bendamustine and rituximab (BR) in second-line: univariate and multivariate analysis.
Univariate HR (95% CI)
Age, years ≤65 vs. >65
Sex,Fvs.M
Stage others vs. Rai III/IV or Binet C
Bulky lymph nodes (>5cm) yes vs. no
Comorbidities 0-1 vs. ≥2
Creatinine clearance (mL/min) ≤70 vs. > 70
CD38 (>20%) neg vs. pos
FISH 17p- vs. others
IGHV mutated vs. unmutated
Months between 1st and 2nd treatment < 36 vs. ≥36
First-line chemo vs. CIT
<6 cycles and/or dose reductions no vs. yes
HR: Hazard Ratio; CI: Confidence Interval; Chemo: chemotherapy; CIT: chemoimmunotherapy; F: female; M: male.
Multivariate
HR (95% CI) P
- - - -
0.0192
0.0004 0.0299 - - -
Variable
P
0.899 (0.636-1.271) 1.110 (0.787-1.566) 0.676 (0.454-1.005) 1.643 (0.959-2.815) 1.159 (0.844-1.592) 1.179 (0.846-1.643) 0.841 (0.531-1.330) 1.965 (1.214-3.180) 0.484 (0.297-0.787) 1.398 (1.018-1.921) 0.846 (0.612-1.168) 0.752 (0.547-1.034)
0.5467 0.5519 0.0529 0.0705 0.3625 0.3312 0.4587 0.0060 0.0035 0.0387 0.3088 0.0794
0.536 (0.319-0.903)
- - - - - - - -
2.92 (1.61-5.296) 0.53 (0.299-)0.94 -
-
-
Table 3. Time to next anti-leukemic treatment with bendamustine and rituximab second-line: univariate and multivariate analysis.
Univariate HR (95% CI)
Age (years) ≤65 vs. >65
Sex,Fvs.M
Stage others vs. Rai III/IV or Binet C
Bulky lymph nodes (>5 cm) yes vs. no
Comorbidities 0-1 vs. ≥2
Creatinine clearance (mL/min) ≤ 70 vs. > 70
CD38 (>20%) neg vs. pos
FISH 17p- vs. others
IGHV mutated vs. unmutated
Months between 1st and 2nd treatment < 36 vs. ≥36
First-line chemo vs. CIT
<6 cycles and/or dose reductions no vs. yes
HR: Hazard Ratio; CI: Confidence Interval; Chemo: chemotherapy; CIT: chemoimmunotherapy; F: female; M: male.
Multivariate HR (95% CI)
-
-
-
-
-
-
-
-
-
-
0.59 (0.41-0.84) -
Variable
P
P
- - - - -
-
- - - - 0.0040 -
1.299 (0.918-1.838) 1.040 (0.716-1.511) 0.881 (0.557-1.393) 1.598 (0.877-2.912) 1.372 (0.978-1.923) 0.833 (0.579-1.199) 1.079 (0.650-1.793) 1.863 (1.096-3.166) 0.597 (0.345-1.033) 1.044 (0.741-1.469) 0.586 (0.407-0.843) 0.776 (0.546-1.104)
0.1400 0.8349 0.5873 0.1256 0.0671 0.3261 0.7678 0.0215 0.0653 0.8062 0.0040 0.1593
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