Final results on effectiveness and safety of Ibrutinib in patients with chronic lymphocytic leukemia from the non-interventional FIRE study

Final results on effectiveness and safety of Ibrutinib in patients with chronic lymphocytic leukemia from the non-interventional FIRE study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Final results on effectiveness and safety of Ibrutinib in patients with chronic lymphocytic leukemia from the non-interventional FIRE study Caroline DARTIGEAS, Anne QUINQUENEL, Loïc YSEBAERT, Marie-Sarah DILHUYDY, and 13 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3809070/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 06 Mar, 2024 Read the published version in Annals of Hematology → Version 1 posted 9 You are reading this latest preprint version Abstract We conducted an observational study (FIRE) to understand the effectiveness and safety outcomes of ibrutinib in patients with chronic lymphocytic leukemia (CLL) in France, after a maximum follow-up of five years. Patients were included according to the French marketing authorization in 2016 (i.e. patients with relapsed or refractoryCLL or to previously untreated CLL patients with deletion 17p and/or TP53 mutations unsuitable for chemoimmunotherapy) and could have initiated ibrutinib more than 30 days prior their enrolment in the study (i.e. retrospective patients) or between 30 days before and 14 days after their enrolment (i.e. prospective patients). The results showed that in the effectiveness population (N=388), the median progression-free survival (PFS) was 53.1 (95% CI: 44.5-60.5) months for retrospective patients and 52.9 (95% CI: 40.3-60.6) months for prospective patients and no difference was shown between the PFS of patients who had at least one dose reduction versus the PFS of patients without dose reduction (p=0.7971 for retrospective and p=0.3163 for prospective patients). For both retrospective and prospective patients, the median overall survival was not reached. The most frequent treatment-emergent adverse event of interest was infections (57.6% retrospective; 71.4% prospective). A total of 14.6% of the retrospective patients and 22.4% of the prospective patients had an adverse event leading to death. Our findings on effectiveness were consistent with other studies and the fact that patients with dose reductions had similar PFS than patients without dose reduction is reassuring. No additional safety concerns than those already mentioned in previous studies could be noticed. Trial registration ClinicalTrials.gov, NCT03425591. Registered 1 February 2018 – Retrospectively registered. Chronic Lymphocytic Leukemia Ibrutinib Real-World Evidence Effectiveness Safety Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults in Western countries [ 1 ]. In 2019, the global age-standardized incidence rate was 1.28 cases per 100,000 persons [ 2 ]. The median age at diagnosis is 70 years old [ 3 ] and the disease is more common in male patients (global sex ratio: 1.4 men/women) [ 2 ]. A decade ago, targeted therapies have been developed with ibrutinib, a first-in-class, oral, once daily Bruton’s Tyrosine Kinase inhibitor (BTKi). Such therapies started to progressively replace first chemoimmunotherapy for relapsed CLL patients and then in first line treatment. Ibrutinib has been authorized in Europe in October 2014 and commercialized in France since November 21st, 2014. Currently, it is indicated in Europe for the treatment of all CLL and Waldenström’s macroglobulinaemia adult patients, and for the treatment of relapsed or refractory (R/R) MCL in adult patients [ 4 , 5 ]. The efficacy of ibrutinib compared to chemoimmunotherapy-based treatment has been largely demonstrated in several clinical trials. Phase-3 studies (RESONATE-2 and RESONATE) showed that previously untreated patients with CLL and R/R CLL had better progression-free survival (PFS) and overall survival (OS) when treated with ibrutinib than with chlorambucil [ 6 ] or ofatumumab [ 7 , 8 ]. Other trials showed similar results in CLL (ALLIANCE: ibrutinib alone or in combination with rituximab versus bendamustine with rituximab; ILLUMINATE: ibrutinib in combination with obinutuzumab versus chlorambucil with obinutuzumab; HELIOS: ibrutinib in combination with bendamustine and rituximab versus bendamustine and rituximab; and GLOW: first-line fixed-duration ibrutinib in combination with venetoclax versus chlorambucil with obinutuzumab) [ 9 – 12 ]. To complement these clinical trials results, the FIRE study was set up to investigate, in France, in real-life conditions, the effectiveness and safety of ibrutinib treatment in patients with CLL (including small lymphocytic lymphoma (SLL)), along with those with high-risk features (e.g. deletion (del)17p or TP53 mutation; unmutated immunoglobulin heavy chain (IGHV) genes). Results of the second and third interim analyses were previously reported [ 13 , 14 ]. In the second interim analysis, with a median follow-up of 17.4 months, the findings confirmed effectiveness in R/R patients with high-risk features and did not highlight additional adverse events (AE) than those documented in clinical trials [ 13 , 15 ]. In the third interim analysis, with a median follow-up of 47.2 months, the results showed that ibrutinib was still an effective treatment for CLL patients and that patients who have received ibrutinib in earlier line of treatment had a better PFS [ 14 ]. Again, the effectiveness and safety profiles in this third interim analysis were consistent with the results of clinical trials. In this article, the objective was to report the final results of the FIRE study on effectiveness and safety outcomes for CLL patients, after a maximum follow-up of five years. Methods Study design FIRE was a retro-prospective, non-interventional, multicenter study, implemented in France through specialized onco-haematology centres. A total of 65 centres participated in the study. The first CLL patient was included on May 12th, 2016, and the last visit of the last CLL patient occurred on July 26th, 2022. Patients were recruited in the study for about one year and were followed for up to five years. Patients could have initiated ibrutinib more than 30 days prior their enrolment in the study and been enrolled regardless of whether or not they were still receiving ibrutinib at the time of inclusion (i.e. retrospective patients), or they could have started ibrutinib between 30 days before and 14 days after their inclusion (i.e. prospective patients). The overall design of the study has been provided in Online Resource 1. Study participants Adults with a confirmed diagnosis of CLL and who initiated ibrutinib therapy on or after November 21st, 2014, or who planned to initiate ibrutinib within the next 14 days could participate in the study. Patients were included according to the French marketing authorization in 2016, corresponding either to patients with R/R CLL or to previously untreated CLL patients with del17p and/or TP53 mutations unsuitable for chemoimmunotherapy. Patients who were part of the ibrutinib Temporary Authorization for Use, who participated at the same time in another research study and who did not sign the Informed Consent Form were not eligible. Outcomes The primary outcome was the progression-free survival (PFS). Secondary outcomes included overall survival (OS), treatment responses, duration of response (DOR), time to best response / first response / next treatment, treatment discontinuation (permanent), dose reductions, and safety. The definition of the different endpoints is provided in Online Resource 2. The safety analyses included treatment-emergent adverse events (TEAE), treatment-emergent bleeding events and AEs leading to death. Data collection All data were collected through the medical records of the patients. The data were collected at different time points between inclusion and the end of the study (Online Resource 1). For patients who initiated ibrutinib therapy at least 31 days before their enrolment, data were also collected retrospectively except for AEs not related to ibrutinib. All investigators were trained to fill in the Electronic Case Report Form and on the use of the Electronic Data Capture System. Sample size We used the following hypothesis to calculate our sample size: a 30-month PFS rate of 76% [ 15 ]. Therefore, the PFS at 24 months was estimated to be 80%. Considering this 24-month PFS rate, a rate of censored patients during the first 24 months of 10% and a Confidence Interval (CI) half-width of 4.1%, 400 CLL patients needed to be included to estimate a two-sided 95% CIs for a PFS rate. Data analysis and statistics The statistical analysis on effectiveness parameters (e.g. PFS, OS, DOR, etc.) was performed on all included patients who met the inclusion and non-inclusion criteria and who took at least one dose of ibrutinib (effectiveness population). The statistical analysis on safety parameters was performed on all included patients who took at least one dose of ibrutinib (safety population). Demographic information (i.e. age, gender), medical history and comorbidities, treatment history and subsequent treatment were obtained and summarized as frequency and percentage. All time-to-event variables (i.e. PFS, OS, DOR, time to first response / best response / next therapy) were analysed using standard survival analysis methods, including Kaplan-Meier product-limit survival curve. Responses were assessed by physicians. The median time to event with two-sided 95% CIs was estimated. In addition, the PFS was also analysed by mutation status (i.e. mutated (del17p and/or TP53) vs. not mutated) and by dose reduction (i.e. patients with at least one dose reduction vs. no dose reduction). For the PFS by dose reduction, an exploratory logrank test with a level of significance of p = 0.05 was used to determine the effectiveness of ibrutinib among those who had at least one dose reduction vs. those who did not. All data were analysed by inclusion type (i.e. retrospective / prospective) with SAS® version 9.4 (SAS Institute, North Carolina, USA). Results Patients’ characteristics at ibrutinib initiation A total of 388 patients was included in the effectiveness analysis (194 retrospective and 194 prospective) (Table 1 ). Most patients were male (66.5%), ≤ 75 years old (64.9%) and with an ECOG performance status of 0 or 1 (89.6%). Almost half of the patients (48.5%) had at least one medical history and comorbidity. Of those who underwent molecular and cytogenetic assessment, 58.2% (N = 156/268) had del17p and/or TP53 mutation and 30.0% (N = 81/270) del11q mutation. The median time between the initial diagnosis and the start of ibrutinib was 7.0 (range: 0.0–35.0) years. Most patients (85.3%, N = 331) were R/R patients. Among those who were previously treated, the median number of prior therapies was 2 (range: 1–7). All those who were previously untreated for CLL had del17p and/or TP53 mutations. Table 1 Patient and illness characteristics by type of inclusion (Effectiveness population, N = 388). RETRO (N = 194) PRO (N = 194) TOTAL (N = 388) Type of hematologic malignance, N (%) CLL 185 (95.4) 186 (95.9) 371 (95.6) SLL 9 (4.6) 8 (4.1) 17 (4.4) Demographic data Age at ibrutinib initiation, N (%) ≤ 75 years old 128 (66.0) 124 (63.9) 252 (64.9) > 75 years old 66 (34.0) 70 (36.1) 136 (35.1) Gender, N (%) Male 122 (62.9) 136 (70.1) 258 (66.5) Female 72 (37.1) 58 (29.9) 130 (33.5) Clinical assessment at ibrutinib initiation ECOG PS, N (%) a 0 79 (53.0) 76 (48.4) 155 (50.7) 1 56 (37.6) 63 (40.1) 119 (38.9) 2 11 (7.4) 15 (9.6) 26 (8.5) 3 3 (2.0) 3 (1.9) 6 (2.0) Medical history and comorbidity at ibrutinib initiation At least one medical history or comorbidity, N (%) 95 (49.0) 93 (47.9) 188 (48.5) Prior bleeding event, N (%) b 3 (1.6) 7 (3.7) 10 (2.6) History of significant cardiovascular disease, N (%) c 15 (7.7) 22 (11.5) 37 (9.6) Ongoing malignancy (other than CLL), N (%) d 5 (2.6) 4 (2.1) 9 (2.3) Ongoing active infection with hepatitis B or C, N (%) e 1 (0.5) 1 (0.5) 2 (0.5) Ongoing autoimmune haemolytic anaemia, N (%) f 3 (1.6) 8 (4.2) 11 (2.9) Ongoing atrial fibrillation, N (%) c 4 (2.1) 7 (3.6) 11 (2.8) Other ongoing cardiovascular disease, N (%) c 6 (3.1) 10 (5.2) 16 (4.1) Ongoing respiratory disease, N (%) c 14 (7.2) 16 (8.3) 30 (7.8) Ongoing uncontrolled active systemic infection or grade 3–4 infection, N (%) g - 2 (1.0) 2 (0.5) Creatinine clearance < 30 mL/min, N (%) h 1 (0.5) 3 (1.6) 4 (1.1) Creatinine clearance ≥ 30 mL/min and < 70 mL/min, N (%) h 39 (21.1) 43 (23.1) 82 (22.1) Molecular & cytogenetic at ibrutinib initiation Del(17p) present and/or mutated TP53, N (%) i 83 (59.3) 73 (57.0) 156 (58.2) Del(17p) present, N (%) j 70 (45.2) 52 (36.4) 122 (40.9) Del(13q) present, N (%) k 51 (41.1) 40 (37.7) 91 (39.6) Del(11q) present, N (%) l 44 (30.8) 37 (29.1) 81 (30.0) Trisomy 12 present, N (%) m 27 (22.1) 25 (27.2) 52 (24.3) TP53 mutated, N (%) n 59 (43.7) 50 (42.4) 109 (43.1) IGHV unmutated, N %) o 39 (81.3) 21 (72.4) 60 (77.9) Complex karyotype, N (%) p 60 (51.7) 62 (62.6) 122 (56.7) Treatment history at ibrutinib initiation Median time between initial diagnosis and ibrutinib initiation, median (range), years 6.48 (0.0–35.0) 7.24 (0.1–27.6) 6.98 (0.0–35.0) Median number of prior therapy among those previously treated (range) 2 (1–7) 2 (1–6) 2 (1–7) Number of prior line of therapies, N (%) 0 24 (12.4) 33 (17.0) 57 (14.7) 1 72 (37.1) 68 (35.1) 140 (36.1) 2 56 (28.9) 55 (28.4) 111 (28.6) ≥ 3 42 (21.6) 38 (19.6) 80 (20.6) Type of therapy previously received, N (%) Combination therapies 113 (66.5) 118 (73.3) 231 (69.8) Monotherapies 13 (7.6) 5 (3.1) 18 (5.4) Both 44 (25.9) 38 (23.6) 82 (24.8) Patients with prior stem cell transplant, N (%) q 4 (2.2) 8 (4.9) 12 (3.4) Treatment-free period between last therapy and < 36 months 118 (76.1) 97 (66.9) 215 (71.7) ibrutinib initiation, N (%) r ≥ 36 months 37 (23.9) 48 (33.1) 85 (28.3) Concomitant medications At least one concomitant systemic anti-cancer therapy 9 (4.6) 17 (8.8) 26 (6.7) At least one anti-thrombotic therapy 40 (20.6) 46 (23.7) 86 (22.2) Subsequent treatment N = 198 s N = 196 s N = 394 s Initiation of a subsequent treatment, N (%) 83 (41.9) 65 (33.2) 148 (37.6) Chemotherapy / Immunochemotherapy 21 (25.3) 18 (27.7) 39 (26.4) Venetoclax +/- Rituximab 45 (54.2) 32 (49.2) 77 (52.0) Ibrutinib t 12 (14.5) 12 (18.4) 24 (16.2) Idealisib – R 3 (3.6) 3 (4.6) 6 (4.1) Allotransplantation 2 (2.4) - 2 (1.4) Abbreviations: CLL, Chronic Lymphocytic Leukaemia; Del, Deletion; ECOG PS, Eastern Cooperative Oncology Group Performance Status; IGHV, Immunoglobulin Heavy Chain Variable Region; PRO, Prospective; RETRO, Retrospective; SLL, Small Lymphocytic Lymphoma; TP53, Tumour Protein P53. Note: The percentages were presented on non-missing values. They are rounded and sometimes do not add to 100%. a Missing data: 45 retrospective, 37 prospective, 82 total. b Missing data: 1 retrospective, 5 prospective, 6 total. c Missing data: 2 prospective, 2 total. d Missing data: 1 retrospective, 3 prospective, 4 total. e Missing data: 9 retrospective, 7 prospective, 16 total. f Missing data: 2 retrospective, 5 prospective, 7 total. g Missing data: 2 retrospective, 3 prospective, 5 total. h Missing data: 9 retrospective, 8 prospective, 17 total. I Missing data: 54 retrospective, 66 prospective, 120 total. j Missing data: 39 retrospective, 51 prospective, 90 total. k Missing data: 70 retrospective, 88 prospective, 158 total. l Missing data: 51 retrospective, 67 prospective, 118 total. m Missing data: 72 retrospective, 102 prospective, 174 total. n Missing data: 59 retrospective, 76 prospective, 135 total. o Missing data: 146 retrospective, 165 prospective, 311 total. p Missing data: 78 retrospective, 95 prospective, 173 total. q Missing data: 9 retrospective, 31 prospective, 40 total. r Missing data: 15 retrospective, 16 prospective, 31 total. s Safety analysis: 4 retrospective and 2 prospective patients were included although they met ≥ 1 exclusion criteria and/or not all inclusion criteria. t Including restart of ibrutinib therapy after permanent discontinuation of ibrutinib (i.e. for more than three months). Effectiveness For retrospective patients, the median follow-up duration was 59.2 (range: 3.7–72.0) months with a median PFS of 53.1 (95% CI: 44.5–60.5) months (Table 2 ). PFS rates were 93.2%, 68.1% and 45.5% at month 12, 36 and 60 respectively (Fig. 1). The median OS was not reached (Table 2 and Fig. 2). The OS rates were 97.9%, 79.7% and 64.5% at month 12, 36 and 60 respectively. The median DOR was 59.5 (95% CI: 56.6 – NA) months (Table 2 and Online Resource 3). The median time to first response, best response and next therapy were 2.8 (95% CI: 2.4–3.0), 8.4 (95% CI: 6.7–9.4) and 50.1 (95% CI: 41.9–60.1) months (Table 2 , Online Resources 4 and 5, and Fig. 3). At 60 months, 96.8% of the retrospective patients had a response to ibrutinib treatment: 40.7% had a complete response and 56.1% a partial response (Table 2 ). The disease progressed in 34.0% of the cases (until month 60). Table 2 Survival, best response and treatment modifications by type of inclusion. Effectiveness population RETRO (N = 194) PRO (N = 194) Survival Median follow-up duration (range), months a 59.24 (3.7–72.0) 58.53 (0.1–68.7) Median PFS (95% CI), months 53.06 (44.52–60.45) 52.93 (40.34–60.58) Median OS (95% CI) b , months Not reached Not reached Median DOR (95% CI), months 59.50 (56.61-NA) Not reached Median TTBR (95% CI), months 8.44 (6.74–9.43) 8.21 (5.03–10.55) Median TTFR (95% CI), months 2.76 (2.43–2.99) 2.76 (2.60–2.92) Median TTNT (95% CI), months 50.14 (41.86–60.06) 50.63 (41.89–58.28) Best response at 60 months, N (%) c 189 178 Overall response 183 (96.8) 172 (96.6) CR 77 (40.7%) 68 (38.2%) PR d 106 (56.1) 104 (58.4) Stable disease 4 (2.1%) 2 (1.1%) Disease progression 2 (1.1%) 4 (2.2%) Dose reduction Patients with no ibrutinib dose reduction N = 124 N = 122 Median PFS (95% CI), months 49.35 (44.45–61.54) 52.93 (30.85-NA) Patients with at least one ibrutinib dose reduction e N = 70 N = 72 Median PFS (95% CI), months 55.23 (39.66-NA) 49.08 (40.34-NA) Safety population RETRO (N = 198) PRO (N = 196) Dose reduction Time to dose reduction as first dose modification f N = 43 N = 51 Median time (range), months 7.39 (0.39–60.88) 9.30 (0.39–57.43) Permanent discontinuation Time to permanent discontinuation g N = 119 N = 127 Median time (range), months 28.65 (0.7–62.8) 18.00 (0.1–61.1) Abbreviations: CI, Confidence Interval; CLL, Chronic Lymphocytic Leukaemia; CR, Complete Response; DOR, Duration of Response; NA, Not Available; OS, Overall Survival; PFS, Progression-Free Survival; PR, Partial Response; PRO, Prospective; RETRO, Retrospective; SD, Standard Deviation; TTBR, Time to Best Response; TTFR, Time to First Response; TTNT, Time to Next Therapy. a Calculated as the duration from ibrutinib initiation until the end of study date. b From ibrutinib initiation to OS. c 5 missing for retrospective patients, 15 missing and 1 not evaluable for prospective patients. d Including partial response with lymphocytosis. e PFS of patients with at least one ibrutinib dose reduction versus PFS of patients with no ibrutinib dose reduction: p = 0.7971 for retrospective patients and p = 0.3163 for prospective patients. f Calculated as the duration from ibrutinib initiation to dose reduction as first modification. g Calculated as the duration from ibrutinib initiation to permanent discontinuation. Figure 1 Progression free survival for CLL patients by type of inclusion (Effectiveness population, N = 388) Figure 2 Time from ibrutinib initiation to overall survival for CLL patients by type of inclusion (Effectiveness population, N = 388) For prospective patients, the median follow-up duration was 58.5 (range: 0.1–68.7) months with a median PFS of 52.9 (95% CI: 40.3–60.6) months (Table 2 ). PFS rates were 83.5%, 61.1% and 45.1 at month 12, 36 and 60 respectively (Fig. 1). The median OS and the median DOR were not reached (Table 2 , Fig. 2 and Online Resource 3). The OS rates were 87.6%, 74.2% and 63.3% at month 12, 36 and 60 respectively (Fig. 2). The median time to first response, best response and next therapy were 2.8 (95% CI: 2.6–2.9), 8.2 (95% CI: 5.0–10.6) and 50.6 (95% CI: 41.9–58.3) months respectively (Table 2 , Online Resources 4 and 5, and Fig. 3). At 60 months, 96.6% of the prospective patients had a response to ibrutinib treatment: 38.2% had a complete response and 58.4% a partial response (Table 2 ). The disease progressed in 29.4% of the cases (until month 60). Figure 3 Time to next therapy, excluding patients restarting ibrutinib as subsequent therapy, for CLL patients by type of inclusion (Effectiveness population, N = 388) When mutation status (del17p and/or TP53) was taken into account, the median PFS for retrospective patients with a mutation was 47.5 (95% CI: 35.8 – NA) months but was not reached for those without mutation (Fig. 4A). PFS rates were 96.3%, 60.4% and 39.3% at month 12, 36 and 60 respectively for those with mutation versus 91.1%, 74.0% and 58.2% for those without. For prospective patients, the median PFS for those with a mutation was 55.4 (95% CI: (34.8 – NA) months but was not reached for those without mutation (Fig. 4B). PFS rates were 87.4%, 60.9% and 44.1% at month 12, 36 and 60 respectively for those with mutation versus 79.6%, 63.1% and 54.5% for those without. Figure 4 Progression free survival for CLL patients according to mutation status (del17p and/or TP53) for retrospective patients (a) and prospective patients (b) (Effectiveness population, N = 388) Dose reduction of ibrutinib For 91.4% of the retrospective patients and 91.3% of the prospective patients, the daily dose of ibrutinib at initiation was 420mg with a median overall treatment duration of 42.1 (range: 0.7–66.5) months for retrospective and 39.2 (range: 0.0-63.5) months for prospective patients. For retrospective patients, the median duration of treatment by ibrutinib until inclusion was 9.0 (range: 1.0–24.6) months. More than half of the patients had no dose modifications (56.1% of the retrospective and 58.7% of the prospective patients). For those who had at least one dose modification (43.9% retrospective and 41.3% prospective), toxicity was the main reason of dosing change (56.3% retrospective and 64.2% prospective). Among those who had at least one dose reduction (36.1% retrospective and 37.1% prospective patients), the mean number of dose reduction was 1.5 (SD = 0.7) for retrospective patients and 1.3 (SD = 0.7) for prospective patients, and their PFS was 55.2 (95% CI: 39.7 – NA) months for the retrospective group and 49.1 (95% CI: 40.3 – NA) months for the prospective group versus 49.4 (95% CI: 44.5–61.5) and 52.9 (95% CI: 30.9-NA) months, respectively, for those with no dose reduction (63.9% retrospective and 62.9% prospective patients) (p = 0.7971 retrospective and p = 0.3163 prospective) (Table 2 , Figs. 5A and 5B). The median time between treatment instauration and first dose reduction as first dose modification was 7.4 (range: 0.4–60.9) months for retrospective patients (N = 43) and 9.3 (range: 0.4–57.4) months for prospective patients (N = 51) (Table 2 ). Figure 5 Progression free survival for CLL patients with at least one ibrutinib dose reduction versus no dose reduction for retrospective patients (a) and prospective patients (b) (Effectiveness population, N = 388) Overall, permanent ibrutinib discontinuation was observed in 119 retrospective patients (60.1%) and in 127 prospective patients (64.8%) (Table 2 ). The median time from ibrutinib initiation to permanent discontinuation was 28.7 (range: 0.7–62.8) months for retrospective patients and 18.0 (range: 0.1–61.1) months for prospective patients, and the main reasons for discontinuation were toxicity (43.5% retrospective and 42.0% prospective), disease progression (33.0% retrospective and 32.8% prospective) and death (5.2% retrospective and 10.1% prospective). Among retrospective patients who discontinued ibrutinib because of toxicity (N = 50), 5 (10.0%) patients had no prior line of treatment, 18 (36.0%) one prior line and 27 (54.0%) at least two prior lines. Among prospective patients (N = 50), 7 (14.0%) had no prior line of treatment, 21 (42.0%) one prior line and 22 (44.0%) two prior lines or more. After ibrutinib treatment, less than half (41.9% of the retrospective and 33.2% of the prospective patients) received a subsequent therapy (Table 1 ). The most frequent subsequent treatment was Venetoclax +/- Rituximab for 54.2% of the retrospective and for 49.2% of the prospective patients. Ibrutinib was retaken by 14.5% of the retrospective and by 18.4% of the prospective patients. Safety Almost all patients (85.9% of the retrospective and 99.5% of the prospective patients) had at least one TEAE (Table 3 ). For 17.7% of the retrospective and for 30.1% of the prospective patients, TEAEs were related to ibrutinib and considered by the investigators as serious. The most frequent TEAEs of interest were infections (57.6%), diarrhoea (16.2%), and hypertension (14.6%) for retrospective patients and infections (71.4%), diarrhoea (28.6%), and arthralgia/myalgia (26.5%) for prospective patients. A total of 16 retrospective patients (8.1%) and 22 prospective patients (11.2%) had atrial fibrillation or flutter. Regarding treatment-emergent bleeding event, 28.8% of the retrospective patients and 54.1% of the prospective patients had such events, and more bleeding events were noticed among patients under ant-thrombotic treatment. Bleeding events were considered as major for 2.0% of the retrospective patients and for 8.2% of the prospective patients. A total of 14.6% of the retrospective and 22.4% of the prospective patients had at least one AE leading to death with the most important preferred terms being general physical health deterioration for both groups (4.5% for retrospective and 2.0% for prospective patients) as well as septic shock (2.0%), sepsis (2.0%) and Richter’s syndrome (2.0%) for prospective patients (Table 4 ). Other AEs leading to death are detailed in Table 4 . Table 3 Adverse events (AE) and treatment-emergent adverse events (TEAE) of interest by type of inclusion (Safety population, N = 394). RETRO after inclusion (N = 198) a PRO (N = 196) a Patients with at least one AE, N (%) 175 (88.4) 195 (99.5) Patients with TEAE (any severity), N (%) ≥ 1 TEAE 170 (85.9) 195 (99.5) ≥ 1 serious TEAE 100 (50.5) 142 (72.4) ≥ 1 severe TEAE 98 (49.5) 143 (73.0) ≥ 1 TEAE related to ibrutinib b 135 (68.2) 181 (92.3) ≥ 1 serious TEAE related to ibrutinib c 35 (17.7) 59 (30.1) Patients with treatment-emergent bleeding events, N (%) ≥ 1 bleeding 57 (28.8) 106 (54.1) ≥ 1 major bleeding 4 (2.0) 16 (8.2) ≥ 1 bleeding while on anti-thrombotic treatment d 16/39 (41.0) 34/45 (75.6) ≥ 1 major bleeding while on anti-thrombotic treatment d 2/39 (5.1) 7/45 (15.6) ≥ 1 bleeding while NOT on anti-thrombotic treatment e 41/159 (25.8) 72/151 (47.7) ≥ 1 major bleeding while NOT on anti-thrombotic treatment e 2/159 (1.3) 9/151 (6.0) Patients with TEAE of interest (any severity), N (%) ≥ 1 infection 114 (57.6) 140 (71.4) ≥ 1 diarrhoea 32 (16.2) 56 (28.6) ≥ 1 arthralgia/myalgia 27 (13.6) 52 (26.5) ≥1 atrial fibrillation or flutter 16 (8.1) 22 (11.2) ≥ 1 hypertension 29 (14.6) 29 (14.8) ≥ 1 rash 16 (8.1) 22 (11.2) Abbreviations: AE, Adverse Event; CLL, Chronic Lymphocytic Leukaemia; PRO, Prospective; RETRO, Retrospective; TEAE, Treatment-Emergent Adverse Event. a 4 retrospective and 2 prospective patients were included for the safety analysis although they met ≥ 1 exclusion criteria and/or not all inclusion criteria. b 166 (83.8%) retrospective patients had at least one TEAE related to ibrutinib before inclusion. c 16 (8.1%) retrospective patients had at least one serious TEAE related to ibrutinib before inclusion. d Percentage are calculated over the number of patients with antithrombotic treatment (N = 39 for the retrospective patients; N = 45 for the prospective patients). e Percentage are calculated over the number of patients without antithrombotic treatment (N = 159 for the retrospective patients; N = 151 for the prospective patients). Table 4 Adverse events leading to death classified by System Organ Class and Preferred Term, by type of inclusion (Safety population, N = 394). RETRO (N = 198) a PRO (N = 196) a Patients with AE leading to death, N (%) Patients with at least one AE leading to death 29 (14.6) 44 (22.4) Patients with at least one TEAE leading to death 26 (13.1) 41 (20.9) AE leading to death classified by SOC and PT, N (%) SOC PT Blood and lymphatic system disorders 1 (0.5) - Cytopenia 1 (0.5) - Cardiac disorders 2 (1.0) 1 (0.5) Cardiac failure - 1 (0.5) Cardi-respiratory arrest 1 (0.5) - Congestive cardiomyopathy 1 (0.5) - General disorders and administration site conditions 11 (5.6) 7 (3.6) General physical health deterioration 9 (4.5) 4 (2.0) Death 2 (1.0) 3 (1.5) Hepatobiliary disorders - 1 (0.5) Drug-induced liver injury - 1 (0.5) Infections and infestations 8 (4.0) 15 (7.7) Septic choc 2 (1.0) 4 (2.0) Covid-19 1 (0.5) 3 (1.5) Sepsis - 4 (2.0) Cerebral aspergillosis 2 (1.0) - Meningitis - 2 (1.0) Atypical mycobacterial pneumonia - 1 (0.5) Bronchitis 1 (0.5) - Fungaemia - 1 (0.5) Fungal infection - 1 (0.5) Pneumocystis jirovecii pneumonia - 1 (0.5) Pneumonia 1 (0.5) - Pulmonary mucormycosis - 1 (0.5) Rhinocerebral mucormycosis - 1 (0.5) Injury, poisoning and procedural complications - 1 (0.5) Subdural haematoma - 1 (0.5) Metabolism and nutrition disorders - 1 (0.5) Tumour Lysis Syndrome - 1 (0.5) Neoplasms benign, malignant and unspecified (incl. cysts and polyps) 7 (3.5) 11 (5.6) Richter’s syndrome 1 (0.5) 4 (2.0) Prostate cancer 1 (0.5) 1 (0.5) B-cell lymphoma - 1 (0.5) Breast cancer metastatic - 1 (0.5) Chronic lymphocytic leukaemia - 1 (0.5) Colorectal cancer metastatic - 1 (0.5) Cutaneous t-cell lymphoma 1 (0.5) - Lung neoplasm malignant 1 (0.5) - Metastases to central nervous system 1 (0.5) - Metastatic bronchial carcinoma 1 (0.5) - Neuroendocrine carcinoma 1 (0.5) - Oespophageal squamous cell carcinoma stage 0 - 1 (0.5) Pancreatic carcinoma 1 (0.5) - Transitional cell carcinoma - 1 (0.5) Nervous system disorders 2 (1.0) 2 (1.0) Central nervous system lesion 1 (0.5) - Cerebellar haematoma - - Cerebral haemorrhage - 1 (0.5) Intraventicular haemorrage 1 (0.5) 1 (0.5) Respiratory, thoracic and mediastinal disorders 4 (2.0) 4 (2.0) Lung disorder - 3 (1.5) Acute respiratory distress syndrome 1 (0.5) - Dysnopea 1 (0.5) - Pneumonitis 1 (0.5) - Pulmonary embolism 1 (0.5) - Respiratory distress - 1 (0.5) Vascular disorders - 1 (0.5) Infarction - 1 (0.5) Abbreviations: AE, Adverse Event; CLL, Chronic Lymphocytic Leukaemia; PRO, prospective; PT, Preferred term, RETRO, retrospective, SOC, System Organ Class; TEAE, Treatment-Emergent Adverse Event. a 4 retrospective and 2 prospective patients were included for the safety analysis although they met ≥ one exclusion criteria and/or not all inclusion criteria. Discussion Although clinical trials have always been the gold standard of proof regarding effectiveness and safety of new drugs, there is nowadays a great interest in real-world research since they represent patients in real-life settings. To our knowledge, FIRE was the largest French real-word study that assessed the effectiveness and safety of ibrutinib, in accordance with the French marketing authorization in 2016, for the treatment of CLL/SLL in patients who received at least one prior line of treatment, or who were previously untreated and had a del17p and/or TP53 mutation unsuitable for chemoimmunotherapy. In this extensive study, set up in 65 centres, 388 CLL/SLL patients (194 retrospective and 194 prospective) were included in the effectiveness population and followed-up for five years. Our results showed a median PFS of 53.1 months for retrospective patients and of 52.9 months for prospective patients with one-year PFS survival rates of 93.2% and 83.5% and 5-year rates of 45.5% and 45.1% respectively. The median OS was not reached for both groups. The OS rates were 97.9% for retrospective patients and 87.6% for prospective patients at one year, and 64.5% and 63.3%, respectively, at 5 years. Our results are consistent with previous effectiveness findings [ 16 , 17 ]. In a real-world multicenter retrospective study conducted on 205 CLL patients treated with ibrutinib, the 12-months PFS and OS rates were 86.3% and 88.8% respectively [ 16 ]. In another study on long-term efficacy and safety with a median follow-up of 5 years, in which 31 treatment-naïve and 101 R/R patients were included, the median PFS in R/R patients was 51 months with a 5-year PFS rate of 44% [ 17 ]. The median OS was not reached and the OS rate at 5 years was 60%. In a UK/Ireland-based study, the one-year OS was 83.8% [ 18 ]. In the clinical trial RESONATE, only R/R CLL patients were included. When comparing the results at similar timepoints between RESONATE and FIRE, the one-year PFS and OS rates in RESONATE (84% and 90% respectively) as well as the 5-year PFS (40.0%) were similar to those of FIRE [ 7 , 8 , 19 ]. The ORR was also similar: 91% in RESONATE vs. 96.8% and 96.6% for retrospective and prospective patients, respectively, in FIRE [ 8 ] (Online Resource 6). However when comparing median PFS and OS, those in RESONATE were lower: 44.1 (95% CI: 38.5–56.2) months for the median PFS and 67.7 (95% CI: 61.0 – not reached) months for the median OS [ 8 ] (Online Resource 6). One explanation could be the longer follow-up period in RESONATE (6 years vs. 5 years). However, taking the fact that our results are included in the confidence intervals of the PFS and OS of RESONATE, our finding are consistent. Therefore, although the FIRE population is slightly different than the population in RESONATE (e.g. age, ECOG PS, mutations status, number of prior therapies), it is reassuring to see that our effectiveness results are similar to the results of clinical trials. The safety profile of ibrutinib and dose reductions were also assessed. Our results showed that among patients who had a dose modification, 80.5% (70/87) of the retrospective patients and 88.9% (72/81) of the prospective patients had at least one dose reduction, mainly due to toxicity. Efficacy results showed that patients with at least one dose reduction had a similar PFS than patients with no dose reduction, supporting the fact that CLL patients in France are well managed, follow-up and treated. Our results not only confirm those of previous real-world studies [ 18 , 20 , 21 ] but also encourage the idea that ibrutinib can still be administrated to patients presenting AEs. Therefore, if physicians need to modify the dose because of an AE, dose reduction may be the best option. Suggesting dose reduction to patients in need of dose modification will thus reduce treatment discontinuation, increase patient adherence, improve patients outcome and on a long-term strategy decrease financial and economic burden. However, to obtain the best benefit from ibrutinib, it is important to promptly identify and manage AEs, and understand specific AEs that can lead to dose reductions. Identifying specific AEs and other factors that could potentially be associated with the need for dose reduction could be the next step in order to well maintain ibrutinib treatment for patients with AEs at the correct reduced dose. The median time to dose reduction as the first dose modification was 7.4 (range: 0.4–60.9) months for retrospective patients and 9.3 (range: 0.4–57.4) months for prospective patients. One retrospective chart review on first line and R/R CLL patients treated with ibrutinib either in academic practice or community network that assessed the median time to first dose reduction found an overall median time of 3.6 months [ 22 ]. However, when the overall result was stratified by academic/community settings and by first line and R/R patients, the median time to first dose reduction for first line patients treated in academic settings increased to 16.6 months versus 3.6 months for R/R academic-treated patients. Furthermore, a review on ibrutinib dose modifications in the management of CLL mentioned that in real-world settings, dose reductions over the first year was often noticed [ 23 ]. However, addressing the question of time in dose reduction still remains rare and unclear. Therefore, further research on this topic is necessary in order to better understand the role of the time in dose reductions and ibrutinib outcome. Furthermore, the results showed that among patients who discontinued ibrutinib, toxicity was the main reason for 43.5% of the retrospective patients and 42.0% of the prospective patients. These results were similar to the one found in a Swedish retrospective study: 40.4% (19/47) [ 20 ]. However, a Danish retrospective study showed a higher rate: 54.7% (47/86) [ 16 ]. In RESONATE, the discontinuation rate due to toxicity was much lower 21.1% (32/152) (Online Resource 6). One explanation to this lower discontinuation rate due to AEs compared to the FIRE study could be that RESONATE is a clinical trial with eligibility criteria which promote inclusion of selected patient. Although our results on discontinuation rates due to AEs differed from the one found in RESONATE, they illustrate the need of real-world research on long-term safety on heterogeneous population. Among adverse events noticed in our study, patients reported low rate of major bleeding events (2.0% retrospective and 8.2% prospective). This rate was five times less for retrospective patients but similar for prospective patients than the rate reported in RESONATE (10.0%) [ 8 ]. Of note, in FIRE, more patients had a bleeding / major bleeding event when they were under anti-thrombotic treatment. Explanations could be that bleeding events are side effects of such treatments, and in RESONATE, patients under anticoagulation containing warfarin were excluded. In addition, the rate of atrial fibrillation was similar for patients in the two studies (FIRE: 8.1% for retrospective and 11.2% for prospective patients; RESONATE: 12.0%) but the rate of hypertension was lower in FIRE than in RESONATE (FIRE: 14.6% for retrospective and 14.8% for prospective; RESONATE: 21.0%) [ 8 ]. Nevertheless, it is reassuring to see that there was no new AE observed and that the safety profile of ibrutinib in our study seems to be consistent with previous studies. Our study has several strengths and limitations. First, FIRE was an extensive research and the largest French real-word study on the effectiveness and safety of ibrutinib. Second, because of its real-world design, effectiveness and safety parameters were presented through descriptive data in a “real-life condition”, and therefore, our results complement those of clinical trials. Moreover, all consecutive patients who met the eligibility criteria and who had therapy-demanding disease were considered for inclusion in order to reduce selection bias. However, there might have been a bias in effectiveness results between retrospective and prospective patients since retrospective patients who died before enrolment were not included. Therefore, retrospective patients who were included in the study should be considered in “better” health than prospective patients. However, it is reassuring to see that the results between the two groups are quite similar. In addition, because of the exclusion of retrospective patients who died before enrolment, it was difficult to pull data of retrospective patients together with the data of prospective patients. Moreover, the number of adverse events for retrospective patients have been underestimated since TEAEs that occurred before inclusion and that were not related to ibrutinib were not collected for these patients. Finally, our focus was on the effectiveness and safety profile of ibrutinib. Therefore, other aspects such as the quality of life of patients under ibrutinib were not considered in this article. Although such data might have been informative and complement the findings of this article, this whole topic could be discussed in a further paper. Conclusion In conclusion, FIRE was an extensive real-word study that showed the effectiveness of ibrutinib on the PFS and OS for patients with CLL, as well as on other effectiveness parameters. The study indicated high PFS rates, even though R/R CLL patients (i.e. patients with high-risk features, in particular with del17p and/or TP53 mutations) have been included. Dose modifications were mainly attributed to toxicity. However, it is reassuring to see that patients who had at least a dose reduction had a similar PFS than patients with no dose reduction, implying the fact that ibrutinib can still be administrated in case of AEs. No additional safety concerns than those already mentioned in other studies could be noticed. Finally, our results not only complement those of clinical trials but they are also consistent with both results of clinical trials and other real-world studies. Declarations Acknowledgments We would like to thank all patients who participated in this study as well as the FIRE investigators group and staff from the study centres. Medical writing assistance and statistical analysis were provided by ICTA PM (medical writing: Joëlle Castellani, PhD; statistical analysis: Simon Paternotte and Edwige Yon). Funding This study, including statistical support and writing assistance, was sponsored by Janssen-Cilag Ltd. Ethics approval and consent to participate Since this study was non-interventional, no approval from an Ethics Committee was needed in France at the time that the study was set up (before the implementation of the Jardé Law). However, the study was conducted in accordance with the principles stated in the Declaration of Helsinki and an Informed Consent Form was obtained from all patients prior their participation in the study. Author contributions VL provided the study design. Investigation and data collection were performed by CD, AQ, LY, MSD, BA, BS, KLD, ST, ET, HO, LV, SG, JVM, PF and VL. SD and MD contributed to data interpretation. VL, SD and MD contributed to the manuscript preparation. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Competing interests CD has received honoraria from Abbvie, AstraZeneca, Beigene, Janssen and Lilly. AQ has received honoraria from Abbvie, AstraZeneca, Beigene and Janssen. LY has received honoraria from Abbvie, AstraZeneca, Beigene, BMS/Celgene, Gilead/Kite, Janssen and Roche. MSD has receivedhonoraria from Abbvie, Astra Zeneca, Beigene and Janssen. KLD has received honoraria from Janssen, Abbvie, AstraZeneca, Roche, Incyte and Takeda. ET has received honoraria from Abbvie, AstraZeneca, Beigene and Janssen. PF has received honoraria from Abbvie, Amgen, AstraZeneca, Beigene, Gilead, Janssen and LoxoLilly. VL has received honoraria from Abbvie, Astra Zeneca, Amgen, MSD, Janssen, Beigene and Lilly. SD is an employee of Janssen and reports stock ownership of Johnson & Johnson. MD is an employee of Janssen. BA, BS, ST, HO, LV, SG, and JVM have nothing to declare. Data availability The data-sharing policy of the Janssen Pharmaceutical Companies of Johnson & Johnson is available at www.janssen.com/clinical-trials/transparency. Requests for access to the data from selected studies can be submitted through the Yale Open Data Access (YODA) Project site at yoda.yale.edu. References Hallek M (2017) Chronic lymphocytic leukemia: 2017 update on diagnosis, risk stratification, and treatment. Am J Hematol 92:946–965. Ou Y, Long Y, Ji L et al (2022). Trends in Disease Burden of Chronic Lymphocytic Leukemia at the Global, Regional, and National Levels From 1990 to 2019, and Projections Until 2030: A Population-Based Epidemiologic Study. Front Oncol 12:840616. The Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute. Cancer Stat Facts: Leukemia – Chronic Lymphocytic Leukemia (CLL). https://seer.cancer.gov/statfacts/html/clyl.html Accessed 25 April 2023. Janssen-Cilag International NV. IMBRUVICA [Summary of Product Characteristics]. Beerse, Belgium. 2014. EMA. Imbruvica. https://www.ema.europa.eu/en/medicines/human/EPAR/imbruvica Accessed 20 April 2023. Burger JA, Barr PM, Robak T et al (2020) Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia 34:787-798. Byrd JC, Brown JR, O'Brien S et al (2014) Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med 371:213-223. Munir T, Brown JR, O'Brien S et al (2019) Final analysis from RESONATE: Up to six years of follow-up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma. Am J Hematol 94:1353-1363. Woyach JA, Ruppert AS, Heerema NA et al (2018). Ibrutinib Regimens versus Chemoimmunotherapy in Older Patients with Untreated CLL. N Engl J Med 379:2517-2528. Chanan-Khan A, Cramer P, Demirkan F et al (2016) Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study. Lancet Oncol 17:200–211. Moreno C, Greil R, Demirkan F et al (2019) Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in frst-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 20:43-56. Niemann C, Munir T, Moreno C et al (2022) Residual Disease Kinetics Among Patients with High-Risk Factors Treated with First-Line Fixed-Duration Ibrutinib Plus Venetoclax (Ibr+Ven) Versus Chlorambucil Plus Obinutuzumab (Clb+O): The Glow Study. Blood 140(S1):228-230. Dartigeas C, Slama B, Doyle M et al (2022). FIRE Study: Real-World Effectiveness and Safety of Ibrutinib in Clinical Practice in Patients with CLL and MCL. Clin Hematol Int 4:65-74. Dartigeas C, Ysebaert L, Feugier P et al (2022) Overall and subgroup results from the third interim analysis of FIRE, a real-world study of ibrutinib treatment for CLL/SLL in France. Blood 140(S1):9906-9907. Byrd JC, Furman RR, Coutre SE et al (2015) Three-year follow-up of treatment-naive and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood 125:2497-2506. Aarup K, Rotbain EC, Enggaard L et al (2020) Real-world outcomes for 205 patients with chronic lymphocytic leukemia treated with ibrutinib. Eur J Haematol 105:646-654. O'Brien S, Furman RR, Coutre S et al (2018) Single-agent ibrutinib in treatment-naive and relapsed/refractory chronic lymphocytic leukemia: a 5-year experience. Blood 131:1910-1919. UK CLL Forum (2016) Ibrutinib for relapsed/refractory chronic lymphocytic leukemia: a UK and Ireland analysis of outcomes in 315 patients. Haematologica 101:1563-1572. Brown JR, Hillmen P, O'Brien S et al (2014) Updated Efficacy Including Genetic and Clinical Subgroup Analysis and Overall Safety in the Phase 3 RESONATE Trial of Ibrutinib Versus Ofatumumab in Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. Blood 124:3331. Winqvist M, Andersson P-O, Asklid A et al (2019) Long-term real-world results of ibrutinib therapy in patients with relapsed or refractory chronic lymphocytic leukemia: 30-month follow up of the Swedish compassionate use cohort. Haematologica 104:e208-e210. Mato AR, Timlin C, Ujjani C et al (2018) Comparable outcomes in chronic lymphocytic leukaemia (CLL) patients treated with reduced-dose ibrutinib: results from a multi-centre study. Br J Haematol 181:259-261. Hou J-Z, Ryan K, Du S et al (2021) Real-world ibrutinib dose reductions, holds and discontinuations in chronic lymphocytic leukemia. Future Oncol 17:4959-4969. Hardy-Abeloos C, Pinotti R, Gabrilove J (2020) Ibrutinib dose modifications in the management of CLL. J Hematol Oncol 13:66. Additional Declarations Competing interest reported. CD has received honoraria from Abbvie, AstraZeneca, Beigene, Janssen and Lilly. AQ has received honoraria from Abbvie, AstraZeneca, Beigene and Janssen. LY has received honoraria from Abbvie, AstraZeneca, Beigene, BMS/Celgene, Gilead/Kite, Janssen and Roche. MSD has received honoraria from Abbvie, Astra Zeneca, Beigene and Janssen. KLD has received honoraria from Janssen, Abbvie, AstraZeneca, Roche, Incyte and Takeda. ET has received honoraria from Abbvie, AstraZeneca, Beigene and Janssen. PF has received honoraria from Abbvie, Amgen, AstraZeneca, Beigene, Gilead, Janssen and LoxoLilly. VL has received honoraria from Abbvie, Astra Zeneca, Amgen, MSD, Janssen, Beigene and Lilly. SD is an employee of Janssen and reports stock ownership of Johnson & Johnson. MD is an employee of Janssen. BA, BS, ST, HO, LV, SG, and JVM have nothing to declare. 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France","correspondingAuthor":false,"prefix":"","firstName":"Sandrine","middleName":"","lastName":"DUPUIS","suffix":""},{"id":264531721,"identity":"129b2d87-d1a0-4973-9423-6f9744244dd2","order_by":14,"name":"Marine DESLANDES","email":"","orcid":"","institution":"Janssen France","correspondingAuthor":false,"prefix":"","firstName":"Marine","middleName":"","lastName":"DESLANDES","suffix":""},{"id":264531722,"identity":"4d23509b-1e78-4621-9c6c-baccd81e8477","order_by":15,"name":"Pierre FEUGIER","email":"","orcid":"","institution":"Hôpitaux de Brabois, CHU de Nancy","correspondingAuthor":false,"prefix":"","firstName":"Pierre","middleName":"","lastName":"FEUGIER","suffix":""},{"id":264531723,"identity":"9e8b08ff-cff0-48fb-98a4-8d6699266c44","order_by":16,"name":"Véronique LEBLOND","email":"","orcid":"","institution":"AP-HP Hôpital de la Pitié-Salpêtrière","correspondingAuthor":false,"prefix":"","firstName":"Véronique","middleName":"","lastName":"LEBLOND","suffix":""}],"badges":[],"createdAt":"2023-12-26 17:44:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3809070/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3809070/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00277-024-05666-3","type":"published","date":"2024-03-06T15:01:57+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":49135212,"identity":"d62b97ca-8fb1-4729-9056-997079629f54","added_by":"auto","created_at":"2024-01-03 17:03:23","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":271544,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eProgression free survival for CLL patients by type of inclusion (Effectiveness population, N=388)\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-3809070/v1/613da1c75524a2ee86f01509.png"},{"id":49135213,"identity":"00111902-3f94-4da2-b984-c57e3708c487","added_by":"auto","created_at":"2024-01-03 17:03:23","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":249401,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTime from ibrutinib initiation to overall survival for CLL patients by type of inclusion (Effectiveness population, N=388)\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-3809070/v1/a6f4556f7288c7f9771e778b.png"},{"id":49135214,"identity":"5024d203-fa9d-44f3-8be0-976daf11e28d","added_by":"auto","created_at":"2024-01-03 17:03:23","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":239415,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTime to next therapy, excluding patients restarting ibrutinib as subsequent therapy, for CLL patients by type of inclusion (Effectiveness population, N=388)\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Fig3.png","url":"https://assets-eu.researchsquare.com/files/rs-3809070/v1/efeb990bf1605a3045c6a169.png"},{"id":49135700,"identity":"6138b0bc-1704-4858-8094-388b32467b65","added_by":"auto","created_at":"2024-01-03 17:11:23","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":454873,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eProgression free survival for CLL patients according to mutation status (del17p and/or TP53) for retrospective patients (a) and prospective patients (b) (Effectiveness population, N=388)\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Fig4.png","url":"https://assets-eu.researchsquare.com/files/rs-3809070/v1/437daabdac32ffb8f49dbe95.png"},{"id":49135701,"identity":"47676dfc-204b-4133-bacd-6d8ca138aad2","added_by":"auto","created_at":"2024-01-03 17:11:23","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":485733,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eProgression free survival for CLL patients with at least one ibrutinib dose reduction versus no dose reduction for retrospective patients (a) and prospective patients (b) (Effectiveness population, N=388)\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Fig5.png","url":"https://assets-eu.researchsquare.com/files/rs-3809070/v1/f6b16d77097ebef663b83c41.png"},{"id":52431997,"identity":"0c65a430-1c9a-48d5-a214-5949fb75de18","added_by":"auto","created_at":"2024-03-11 15:10:17","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1493705,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3809070/v1/22ba36f9-3aac-4176-8521-ba8d9fb6085e.pdf"},{"id":49135216,"identity":"885957e2-c418-455e-8579-b532658ea8ab","added_by":"auto","created_at":"2024-01-03 17:03:23","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":213592,"visible":true,"origin":"","legend":"","description":"","filename":"OnlineResources.docx","url":"https://assets-eu.researchsquare.com/files/rs-3809070/v1/8fd9a05d7457f91bbdac0966.docx"}],"financialInterests":"Competing interest reported. CD has received honoraria from Abbvie, AstraZeneca, Beigene, Janssen and Lilly.\nAQ has received honoraria from Abbvie, AstraZeneca, Beigene and Janssen.\nLY has received honoraria from Abbvie, AstraZeneca, Beigene, BMS/Celgene, Gilead/Kite, Janssen and Roche.\nMSD has received honoraria from Abbvie, Astra Zeneca, Beigene and Janssen.\nKLD has received honoraria from Janssen, Abbvie, AstraZeneca, Roche, Incyte and Takeda.\nET has received honoraria from Abbvie, AstraZeneca, Beigene and Janssen.\nPF has received honoraria from Abbvie, Amgen, AstraZeneca, Beigene, Gilead, Janssen and LoxoLilly.\nVL has received honoraria from Abbvie, Astra Zeneca, Amgen, MSD, Janssen, Beigene and Lilly.\nSD is an employee of Janssen and reports stock ownership of Johnson \u0026 Johnson. \nMD is an employee of Janssen.\nBA, BS, ST, HO, LV, SG, and JVM have nothing to declare.","formattedTitle":"Final results on effectiveness and safety of Ibrutinib in patients with chronic lymphocytic leukemia from the non-interventional FIRE study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eChronic lymphocytic leukemia (CLL) is the most common leukemia in adults in Western countries [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. In 2019, the global age-standardized incidence rate was 1.28 cases per 100,000 persons [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The median age at diagnosis is 70 years old [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] and the disease is more common in male patients (global sex ratio: 1.4 men/women) [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA decade ago, targeted therapies have been developed with ibrutinib, a first-in-class, oral, once daily Bruton\u0026rsquo;s Tyrosine Kinase inhibitor (BTKi). Such therapies started to progressively replace first chemoimmunotherapy for relapsed CLL patients and then in first line treatment. Ibrutinib has been authorized in Europe in October 2014 and commercialized in France since November 21st, 2014. Currently, it is indicated in Europe for the treatment of all CLL and Waldenstr\u0026ouml;m\u0026rsquo;s macroglobulinaemia adult patients, and for the treatment of relapsed or refractory (R/R) MCL in adult patients [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe efficacy of ibrutinib compared to chemoimmunotherapy-based treatment has been largely demonstrated in several clinical trials. Phase-3 studies (RESONATE-2 and RESONATE) showed that previously untreated patients with CLL and R/R CLL had better progression-free survival (PFS) and overall survival (OS) when treated with ibrutinib than with chlorambucil [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] or ofatumumab [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Other trials showed similar results in CLL (ALLIANCE: ibrutinib alone or in combination with rituximab versus bendamustine with rituximab; ILLUMINATE: ibrutinib in combination with obinutuzumab versus chlorambucil with obinutuzumab; HELIOS: ibrutinib in combination with bendamustine and rituximab versus bendamustine and rituximab; and GLOW: first-line fixed-duration ibrutinib in combination with venetoclax versus chlorambucil with obinutuzumab) [\u003cspan additionalcitationids=\"CR10 CR11\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTo complement these clinical trials results, the FIRE study was set up to investigate, in France, in real-life conditions, the effectiveness and safety of ibrutinib treatment in patients with CLL (including small lymphocytic lymphoma (SLL)), along with those with high-risk features (e.g. deletion (del)17p or TP53 mutation; unmutated immunoglobulin heavy chain (IGHV) genes). Results of the second and third interim analyses were previously reported [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. In the second interim analysis, with a median follow-up of 17.4 months, the findings confirmed effectiveness in R/R patients with high-risk features and did not highlight additional adverse events (AE) than those documented in clinical trials [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. In the third interim analysis, with a median follow-up of 47.2 months, the results showed that ibrutinib was still an effective treatment for CLL patients and that patients who have received ibrutinib in earlier line of treatment had a better PFS [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Again, the effectiveness and safety profiles in this third interim analysis were consistent with the results of clinical trials. In this article, the objective was to report the final results of the FIRE study on effectiveness and safety outcomes for CLL patients, after a maximum follow-up of five years.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eStudy design\u003c/p\u003e \u003cp\u003eFIRE was a retro-prospective, non-interventional, multicenter study, implemented in France through specialized onco-haematology centres. A total of 65 centres participated in the study. The first CLL patient was included on May 12th, 2016, and the last visit of the last CLL patient occurred on July 26th, 2022. Patients were recruited in the study for about one year and were followed for up to five years.\u003c/p\u003e \u003cp\u003ePatients could have initiated ibrutinib more than 30 days prior their enrolment in the study and been enrolled regardless of whether or not they were still receiving ibrutinib at the time of inclusion (i.e. retrospective patients), or they could have started ibrutinib between 30 days before and 14 days after their inclusion (i.e. prospective patients). The overall design of the study has been provided in Online Resource 1.\u003c/p\u003e \u003cp\u003eStudy participants\u003c/p\u003e \u003cp\u003eAdults with a confirmed diagnosis of CLL and who initiated ibrutinib therapy on or after November 21st, 2014, or who planned to initiate ibrutinib within the next 14 days could participate in the study. Patients were included according to the French marketing authorization in 2016, corresponding either to patients with R/R CLL or to previously untreated CLL patients with del17p and/or TP53 mutations unsuitable for chemoimmunotherapy. Patients who were part of the ibrutinib Temporary Authorization for Use, who participated at the same time in another research study and who did not sign the Informed Consent Form were not eligible.\u003c/p\u003e \u003cp\u003eOutcomes\u003c/p\u003e \u003cp\u003eThe primary outcome was the progression-free survival (PFS). Secondary outcomes included overall survival (OS), treatment responses, duration of response (DOR), time to best response / first response / next treatment, treatment discontinuation (permanent), dose reductions, and safety. The definition of the different endpoints is provided in Online Resource 2. The safety analyses included treatment-emergent adverse events (TEAE), treatment-emergent bleeding events and AEs leading to death.\u003c/p\u003e \u003cp\u003eData collection\u003c/p\u003e \u003cp\u003eAll data were collected through the medical records of the patients. The data were collected at different time points between inclusion and the end of the study (Online Resource 1). For patients who initiated ibrutinib therapy at least 31 days before their enrolment, data were also collected retrospectively except for AEs not related to ibrutinib. All investigators were trained to fill in the Electronic Case Report Form and on the use of the Electronic Data Capture System.\u003c/p\u003e \u003cp\u003eSample size\u003c/p\u003e \u003cp\u003eWe used the following hypothesis to calculate our sample size: a 30-month PFS rate of 76% [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Therefore, the PFS at 24 months was estimated to be 80%. Considering this 24-month PFS rate, a rate of censored patients during the first 24 months of 10% and a Confidence Interval (CI) half-width of 4.1%, 400 CLL patients needed to be included to estimate a two-sided 95% CIs for a PFS rate.\u003c/p\u003e \u003cp\u003eData analysis and statistics\u003c/p\u003e \u003cp\u003eThe statistical analysis on effectiveness parameters (e.g. PFS, OS, DOR, etc.) was performed on all included patients who met the inclusion and non-inclusion criteria and who took at least one dose of ibrutinib (effectiveness population). The statistical analysis on safety parameters was performed on all included patients who took at least one dose of ibrutinib (safety population).\u003c/p\u003e \u003cp\u003eDemographic information (i.e. age, gender), medical history and comorbidities, treatment history and subsequent treatment were obtained and summarized as frequency and percentage.\u003c/p\u003e \u003cp\u003eAll time-to-event variables (i.e. PFS, OS, DOR, time to first response / best response / next therapy) were analysed using standard survival analysis methods, including Kaplan-Meier product-limit survival curve. Responses were assessed by physicians. The median time to event with two-sided 95% CIs was estimated. In addition, the PFS was also analysed by mutation status (i.e. mutated (del17p and/or TP53) vs. not mutated) and by dose reduction (i.e. patients with at least one dose reduction vs. no dose reduction). For the PFS by dose reduction, an exploratory logrank test with a level of significance of p\u0026thinsp;=\u0026thinsp;0.05 was used to determine the effectiveness of ibrutinib among those who had at least one dose reduction vs. those who did not. All data were analysed by inclusion type (i.e. retrospective / prospective) with SAS\u0026reg; version 9.4 (SAS Institute, North Carolina, USA).\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u0026rsquo; characteristics at ibrutinib initiation\u003c/h2\u003e \u003cp\u003eA total of 388 patients was included in the effectiveness analysis (194 retrospective and 194 prospective) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Most patients were male (66.5%), \u0026le;\u0026thinsp;75 years old (64.9%) and with an ECOG performance status of 0 or 1 (89.6%). Almost half of the patients (48.5%) had at least one medical history and comorbidity. Of those who underwent molecular and cytogenetic assessment, 58.2% (N\u0026thinsp;=\u0026thinsp;156/268) had del17p and/or TP53 mutation and 30.0% (N\u0026thinsp;=\u0026thinsp;81/270) del11q mutation. The median time between the initial diagnosis and the start of ibrutinib was 7.0 (range: 0.0\u0026ndash;35.0) years. Most patients (85.3%, N\u0026thinsp;=\u0026thinsp;331) were R/R patients. Among those who were previously treated, the median number of prior therapies was 2 (range: 1\u0026ndash;7). All those who were previously untreated for CLL had del17p and/or TP53 mutations.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient and illness characteristics by type of inclusion (Effectiveness population, N\u0026thinsp;=\u0026thinsp;388).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRETRO (N\u0026thinsp;=\u0026thinsp;194)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePRO (N\u0026thinsp;=\u0026thinsp;194)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTOTAL (N\u0026thinsp;=\u0026thinsp;388)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eType of hematologic malignance, N (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCLL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e185 (95.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e186 (95.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e371 (95.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSLL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (4.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (4.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e17 (4.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDemographic data\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at ibrutinib initiation, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026le;\u0026thinsp;75 years old\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e128 (66.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e124 (63.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e252 (64.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;75 years old\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e66 (34.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e70 (36.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e136 (35.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e122 (62.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e136 (70.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e258 (66.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e72 (37.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e58 (29.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e130 (33.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eClinical assessment at ibrutinib initiation\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eECOG PS, N (%)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e79 (53.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e76 (48.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e155 (50.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e56 (37.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e63 (40.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e119 (38.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (7.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15 (9.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e26 (8.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (2.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (1.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6 (2.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMedical history and comorbidity at ibrutinib initiation\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAt least one medical history or comorbidity, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95 (49.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e93 (47.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e188 (48.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrior bleeding event, N (%)\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (1.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (3.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10 (2.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHistory of significant cardiovascular disease, N (%)\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (7.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22 (11.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e37 (9.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOngoing malignancy (other than CLL), N (%)\u003csup\u003ed\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (2.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (2.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9 (2.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOngoing active infection with hepatitis B or C, N (%)\u003csup\u003ee\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 (0.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOngoing autoimmune haemolytic anaemia, N (%)\u003csup\u003ef\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (1.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (4.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e11 (2.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOngoing atrial fibrillation, N (%)\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (2.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (3.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e11 (2.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther ongoing cardiovascular disease, N (%)\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (3.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 (5.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16 (4.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOngoing respiratory disease, N (%)\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (7.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16 (8.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e30 (7.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOngoing uncontrolled active systemic infection or grade 3\u0026ndash;4 infection, N (%)\u003csup\u003eg\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (1.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 (0.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCreatinine clearance\u0026thinsp;\u0026lt;\u0026thinsp;30 mL/min, N (%)\u003csup\u003eh\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (1.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4 (1.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCreatinine clearance\u0026thinsp;\u0026ge;\u0026thinsp;30 mL/min and \u0026lt;\u0026thinsp;70 mL/min, N (%)\u003csup\u003eh\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e39 (21.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e43 (23.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e82 (22.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMolecular \u0026amp; cytogenetic at ibrutinib initiation\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDel(17p) present and/or mutated TP53, N (%)\u003csup\u003ei\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e83 (59.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e73 (57.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e156 (58.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDel(17p) present, N (%)\u003csup\u003ej\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e70 (45.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e52 (36.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e122 (40.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDel(13q) present, N (%)\u003csup\u003ek\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e51 (41.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e40 (37.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e91 (39.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDel(11q) present, N (%)\u003csup\u003el\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e44 (30.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e37 (29.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e81 (30.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTrisomy 12 present, N (%)\u003csup\u003em\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27 (22.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25 (27.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e52 (24.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTP53 mutated, N (%)\u003csup\u003en\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e59 (43.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e50 (42.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e109 (43.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIGHV unmutated, N %)\u003csup\u003eo\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e39 (81.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21 (72.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e60 (77.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eComplex karyotype, N (%)\u003csup\u003ep\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e60 (51.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e62 (62.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e122 (56.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTreatment history at ibrutinib initiation\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian time between initial diagnosis and ibrutinib initiation, median (range), years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.48 (0.0\u0026ndash;35.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7.24 (0.1\u0026ndash;27.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.98 (0.0\u0026ndash;35.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian number of prior therapy among those previously treated (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (1\u0026ndash;7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (1\u0026ndash;6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 (1\u0026ndash;7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of prior line of therapies, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24 (12.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e33 (17.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e57 (14.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e72 (37.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e68 (35.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e140 (36.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e56 (28.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e55 (28.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e111 (28.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e42 (21.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e38 (19.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e80 (20.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eType of therapy previously received, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCombination therapies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e113 (66.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e118 (73.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e231 (69.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMonotherapies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (7.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 (3.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e18 (5.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBoth\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e44 (25.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e38 (23.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e82 (24.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatients with prior stem cell transplant, N (%)\u003csup\u003eq\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (2.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (4.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12 (3.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreatment-free period between last therapy and\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;36 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e118 (76.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e97 (66.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e215 (71.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eibrutinib initiation, N (%)\u003csup\u003er\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;36 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37 (23.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e48 (33.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e85 (28.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eConcomitant medications\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAt least one concomitant systemic anti-cancer therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (4.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17 (8.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e26 (6.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAt least one anti-thrombotic therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40 (20.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e46 (23.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e86 (22.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSubsequent treatment\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;198\u003csup\u003es\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;196\u003csup\u003es\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;394\u003csup\u003es\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInitiation of a subsequent treatment, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e83 (41.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e65 (33.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e148 (37.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eChemotherapy / Immunochemotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 (25.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18 (27.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e39 (26.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVenetoclax +/- Rituximab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e45 (54.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e32 (49.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e77 (52.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIbrutinib\u003csup\u003et\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (14.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12 (18.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e24 (16.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIdealisib \u0026ndash; R\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (3.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (4.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6 (4.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAllotransplantation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (2.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 (1.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003cem\u003eAbbreviations: CLL, Chronic Lymphocytic Leukaemia; Del, Deletion; ECOG PS, Eastern Cooperative Oncology Group Performance Status; IGHV, Immunoglobulin Heavy Chain Variable Region; PRO, Prospective; RETRO, Retrospective; SLL, Small Lymphocytic Lymphoma; TP53, Tumour Protein P53.\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eNote: The percentages were presented on non-missing values. They are rounded and sometimes do not add to 100%.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ea\u0026nbsp;\u003c/sup\u003eMissing data: 45 retrospective, 37 prospective, 82 total.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003eb\u0026nbsp;\u003c/sup\u003eMissing data: 1 retrospective, 5 prospective, 6 total.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ec\u0026nbsp;\u003c/sup\u003eMissing data: 2 prospective, 2 total.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ed\u0026nbsp;\u003c/sup\u003eMissing data: 1 retrospective, 3 prospective, 4 total.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ee\u0026nbsp;\u003c/sup\u003eMissing data: 9 retrospective, 7 prospective, 16 total.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ef\u0026nbsp;\u003c/sup\u003eMissing data: 2 retrospective, 5 prospective, 7 total.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003eg\u003c/sup\u003e Missing data: 2 retrospective, 3 prospective, 5 total.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003eh\u0026nbsp;\u003c/sup\u003eMissing data: 9 retrospective, 8 prospective, 17 total.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003csup\u003eI\u0026nbsp;\u003c/sup\u003eMissing data: 54 retrospective, 66 prospective, 120 total.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ej\u0026nbsp;\u003c/sup\u003eMissing data: 39 retrospective, 51 prospective, 90 total.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ek\u0026nbsp;\u003c/sup\u003eMissing data: 70 retrospective, 88 prospective, 158 total.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003el\u0026nbsp;\u003c/sup\u003eMissing data: 51 retrospective, 67 prospective, 118 total.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003em\u0026nbsp;\u003c/sup\u003eMissing data: 72 retrospective, 102 prospective, 174 total.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003en\u0026nbsp;\u003c/sup\u003eMissing data: 59 retrospective, 76 prospective, 135 total.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003eo\u0026nbsp;\u003c/sup\u003eMissing data: 146 retrospective, 165 prospective, 311 total.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ep\u0026nbsp;\u003c/sup\u003eMissing data: 78 retrospective, 95 prospective, 173 total.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003eq\u0026nbsp;\u003c/sup\u003eMissing data: 9 retrospective, 31 prospective, 40 total.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003er\u003c/sup\u003e Missing data: 15 retrospective, 16 prospective, 31 total.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003es\u0026nbsp;\u003c/sup\u003eSafety analysis: 4 retrospective and 2 prospective patients were included although they met \u0026ge; 1 exclusion criteria and/or not all inclusion criteria.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003et\u0026nbsp;\u003c/sup\u003eIncluding restart of ibrutinib therapy after permanent discontinuation of ibrutinib (i.e. for more than three months).\u003c/p\u003e\u003cp\u003e\u0026lt; Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e near here \u0026gt;\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eEffectiveness\u003c/h2\u003e \u003cp\u003eFor retrospective patients, the median follow-up duration was 59.2 (range: 3.7\u0026ndash;72.0) months with a median PFS of 53.1 (95% CI: 44.5\u0026ndash;60.5) months (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). PFS rates were 93.2%, 68.1% and 45.5% at month 12, 36 and 60 respectively (Fig.\u0026nbsp;1). The median OS was not reached (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and Fig.\u0026nbsp;2). The OS rates were 97.9%, 79.7% and 64.5% at month 12, 36 and 60 respectively. The median DOR was 59.5 (95% CI: 56.6 \u0026ndash; NA) months (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and Online Resource 3). The median time to first response, best response and next therapy were 2.8 (95% CI: 2.4\u0026ndash;3.0), 8.4 (95% CI: 6.7\u0026ndash;9.4) and 50.1 (95% CI: 41.9\u0026ndash;60.1) months (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, Online Resources 4 and 5, and Fig.\u0026nbsp;3). At 60 months, 96.8% of the retrospective patients had a response to ibrutinib treatment: 40.7% had a complete response and 56.1% a partial response (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The disease progressed in 34.0% of the cases (until month 60).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSurvival, best response and treatment modifications by type of inclusion.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEffectiveness population\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRETRO (N\u0026thinsp;=\u0026thinsp;194)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePRO (N\u0026thinsp;=\u0026thinsp;194)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSurvival\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian follow-up duration (range), months\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e59.24 (3.7\u0026ndash;72.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e58.53 (0.1\u0026ndash;68.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian PFS (95% CI), months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e53.06 (44.52\u0026ndash;60.45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e52.93 (40.34\u0026ndash;60.58)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian OS (95% CI) \u003csup\u003eb\u003c/sup\u003e, months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNot reached\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNot reached\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian DOR (95% CI), months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e59.50 (56.61-NA)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNot reached\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian TTBR (95% CI), months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.44 (6.74\u0026ndash;9.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8.21 (5.03\u0026ndash;10.55)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian TTFR (95% CI), months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.76 (2.43\u0026ndash;2.99)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.76 (2.60\u0026ndash;2.92)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian TTNT (95% CI), months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e50.14 (41.86\u0026ndash;60.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e50.63 (41.89\u0026ndash;58.28)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBest response at 60 months, N (%)\u003c/b\u003e\u003csup\u003e\u003cb\u003ec\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e189\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e178\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOverall response\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e183 (96.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e172 (96.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e77 (40.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e68 (38.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePR\u003csup\u003ed\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e106 (56.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e104 (58.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eStable disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (2.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (1.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDisease progression\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (1.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (2.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDose reduction\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatients with no ibrutinib dose reduction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;124\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;122\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMedian PFS (95% CI), months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e49.35 (44.45\u0026ndash;61.54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e52.93 (30.85-NA)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatients with at least one ibrutinib dose reduction\u003csup\u003ee\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;72\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMedian PFS (95% CI), months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e55.23 (39.66-NA)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e49.08 (40.34-NA)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSafety population\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eRETRO (N\u0026thinsp;=\u0026thinsp;198)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003ePRO (N\u0026thinsp;=\u0026thinsp;196)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDose reduction\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime to dose reduction as first dose modification\u003csup\u003ef\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;51\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMedian time (range), months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.39 (0.39\u0026ndash;60.88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9.30 (0.39\u0026ndash;57.43)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePermanent discontinuation\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime to permanent discontinuation\u003csup\u003eg\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;119\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;127\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMedian time (range), months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28.65 (0.7\u0026ndash;62.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18.00 (0.1\u0026ndash;61.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003cem\u003eAbbreviations: CI, Confidence Interval; CLL, Chronic Lymphocytic Leukaemia; CR, Complete Response; DOR, Duration of Response; NA, Not Available; OS, Overall Survival; PFS, Progression-Free Survival; PR, Partial Response; PRO, Prospective; RETRO, Retrospective; SD, Standard Deviation; TTBR, Time to Best Response; TTFR, Time to First Response; TTNT, Time to Next Therapy.\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003csup\u003ea\u003c/sup\u003e Calculated as the duration from ibrutinib initiation until the end of study date.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003csup\u003eb\u003c/sup\u003e From ibrutinib initiation to OS.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003csup\u003ec\u003c/sup\u003e 5 missing for retrospective patients, 15 missing and 1 not evaluable for prospective patients.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003csup\u003ed\u003c/sup\u003e Including partial response with lymphocytosis.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003csup\u003ee\u003c/sup\u003e PFS of patients with at least one ibrutinib dose reduction versus PFS of patients with no ibrutinib dose reduction: p\u0026thinsp;=\u0026thinsp;0.7971 for retrospective patients and p\u0026thinsp;=\u0026thinsp;0.3163 for prospective patients.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003csup\u003ef\u003c/sup\u003e Calculated as the duration from ibrutinib initiation to dose reduction as first modification.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003csup\u003eg\u003c/sup\u003e Calculated as the duration from ibrutinib initiation to permanent discontinuation.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e\u0026lt; Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e near here \u0026gt;\u003c/p\u003e \u003cp\u003e \u003cb\u003eFigure\u0026nbsp;1 Progression free survival for CLL patients by type of inclusion (Effectiveness population, N\u0026thinsp;=\u0026thinsp;388)\u003c/b\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eFigure\u0026nbsp;2 Time from ibrutinib initiation to overall survival for CLL patients by type of inclusion (Effectiveness population, N\u0026thinsp;=\u0026thinsp;388)\u003c/b\u003e \u003c/p\u003e \u003cp\u003eFor prospective patients, the median follow-up duration was 58.5 (range: 0.1\u0026ndash;68.7) months with a median PFS of 52.9 (95% CI: 40.3\u0026ndash;60.6) months (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). PFS rates were 83.5%, 61.1% and 45.1 at month 12, 36 and 60 respectively (Fig.\u0026nbsp;1). The median OS and the median DOR were not reached (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, Fig.\u0026nbsp;2 and Online Resource 3). The OS rates were 87.6%, 74.2% and 63.3% at month 12, 36 and 60 respectively (Fig.\u0026nbsp;2). The median time to first response, best response and next therapy were 2.8 (95% CI: 2.6\u0026ndash;2.9), 8.2 (95% CI: 5.0\u0026ndash;10.6) and 50.6 (95% CI: 41.9\u0026ndash;58.3) months respectively (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, Online Resources 4 and 5, and Fig.\u0026nbsp;3). At 60 months, 96.6% of the prospective patients had a response to ibrutinib treatment: 38.2% had a complete response and 58.4% a partial response (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The disease progressed in 29.4% of the cases (until month 60).\u003c/p\u003e \u003cp\u003e \u003cb\u003eFigure\u0026nbsp;3 Time to next therapy, excluding patients restarting ibrutinib as subsequent therapy, for CLL patients by type of inclusion (Effectiveness population, N\u0026thinsp;=\u0026thinsp;388)\u003c/b\u003e \u003c/p\u003e \u003cp\u003eWhen mutation status (del17p and/or TP53) was taken into account, the median PFS for retrospective patients with a mutation was 47.5 (95% CI: 35.8 \u0026ndash; NA) months but was not reached for those without mutation (Fig.\u0026nbsp;4A). PFS rates were 96.3%, 60.4% and 39.3% at month 12, 36 and 60 respectively for those with mutation versus 91.1%, 74.0% and 58.2% for those without. For prospective patients, the median PFS for those with a mutation was 55.4 (95% CI: (34.8 \u0026ndash; NA) months but was not reached for those without mutation (Fig.\u0026nbsp;4B). PFS rates were 87.4%, 60.9% and 44.1% at month 12, 36 and 60 respectively for those with mutation versus 79.6%, 63.1% and 54.5% for those without.\u003c/p\u003e \u003cp\u003e \u003cb\u003eFigure\u0026nbsp;4 Progression free survival for CLL patients according to mutation status (del17p and/or TP53) for retrospective patients (a) and prospective patients (b) (Effectiveness population, N\u0026thinsp;=\u0026thinsp;388)\u003c/b\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eDose reduction of ibrutinib\u003c/h2\u003e \u003cp\u003eFor 91.4% of the retrospective patients and 91.3% of the prospective patients, the daily dose of ibrutinib at initiation was 420mg with a median overall treatment duration of 42.1 (range: 0.7\u0026ndash;66.5) months for retrospective and 39.2 (range: 0.0-63.5) months for prospective patients. For retrospective patients, the median duration of treatment by ibrutinib until inclusion was 9.0 (range: 1.0\u0026ndash;24.6) months. More than half of the patients had no dose modifications (56.1% of the retrospective and 58.7% of the prospective patients).\u003c/p\u003e \u003cp\u003eFor those who had at least one dose modification (43.9% retrospective and 41.3% prospective), toxicity was the main reason of dosing change (56.3% retrospective and 64.2% prospective). Among those who had at least one dose reduction (36.1% retrospective and 37.1% prospective patients), the mean number of dose reduction was 1.5 (SD\u0026thinsp;=\u0026thinsp;0.7) for retrospective patients and 1.3 (SD\u0026thinsp;=\u0026thinsp;0.7) for prospective patients, and their PFS was 55.2 (95% CI: 39.7 \u0026ndash; NA) months for the retrospective group and 49.1 (95% CI: 40.3 \u0026ndash; NA) months for the prospective group versus 49.4 (95% CI: 44.5\u0026ndash;61.5) and 52.9 (95% CI: 30.9-NA) months, respectively, for those with no dose reduction (63.9% retrospective and 62.9% prospective patients) (p\u0026thinsp;=\u0026thinsp;0.7971 retrospective and p\u0026thinsp;=\u0026thinsp;0.3163 prospective) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, Figs.\u0026nbsp;5A and 5B). The median time between treatment instauration and first dose reduction as first dose modification was 7.4 (range: 0.4\u0026ndash;60.9) months for retrospective patients (N\u0026thinsp;=\u0026thinsp;43) and 9.3 (range: 0.4\u0026ndash;57.4) months for prospective patients (N\u0026thinsp;=\u0026thinsp;51) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cb\u003eFigure\u0026nbsp;5 Progression free survival for CLL patients with at least one ibrutinib dose reduction versus no dose reduction for retrospective patients (a) and prospective patients (b) (Effectiveness population, N\u0026thinsp;=\u0026thinsp;388)\u003c/b\u003e \u003c/p\u003e \u003cp\u003eOverall, permanent ibrutinib discontinuation was observed in 119 retrospective patients (60.1%) and in 127 prospective patients (64.8%) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The median time from ibrutinib initiation to permanent discontinuation was 28.7 (range: 0.7\u0026ndash;62.8) months for retrospective patients and 18.0 (range: 0.1\u0026ndash;61.1) months for prospective patients, and the main reasons for discontinuation were toxicity (43.5% retrospective and 42.0% prospective), disease progression (33.0% retrospective and 32.8% prospective) and death (5.2% retrospective and 10.1% prospective). Among retrospective patients who discontinued ibrutinib because of toxicity (N\u0026thinsp;=\u0026thinsp;50), 5 (10.0%) patients had no prior line of treatment, 18 (36.0%) one prior line and 27 (54.0%) at least two prior lines. Among prospective patients (N\u0026thinsp;=\u0026thinsp;50), 7 (14.0%) had no prior line of treatment, 21 (42.0%) one prior line and 22 (44.0%) two prior lines or more. After ibrutinib treatment, less than half (41.9% of the retrospective and 33.2% of the prospective patients) received a subsequent therapy (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The most frequent subsequent treatment was Venetoclax +/- Rituximab for 54.2% of the retrospective and for 49.2% of the prospective patients. Ibrutinib was retaken by 14.5% of the retrospective and by 18.4% of the prospective patients.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eSafety\u003c/h2\u003e \u003cp\u003eAlmost all patients (85.9% of the retrospective and 99.5% of the prospective patients) had at least one TEAE (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). For 17.7% of the retrospective and for 30.1% of the prospective patients, TEAEs were related to ibrutinib and considered by the investigators as serious. The most frequent TEAEs of interest were infections (57.6%), diarrhoea (16.2%), and hypertension (14.6%) for retrospective patients and infections (71.4%), diarrhoea (28.6%), and arthralgia/myalgia (26.5%) for prospective patients. A total of 16 retrospective patients (8.1%) and 22 prospective patients (11.2%) had atrial fibrillation or flutter. Regarding treatment-emergent bleeding event, 28.8% of the retrospective patients and 54.1% of the prospective patients had such events, and more bleeding events were noticed among patients under ant-thrombotic treatment. Bleeding events were considered as major for 2.0% of the retrospective patients and for 8.2% of the prospective patients. A total of 14.6% of the retrospective and 22.4% of the prospective patients had at least one AE leading to death with the most important preferred terms being general physical health deterioration for both groups (4.5% for retrospective and 2.0% for prospective patients) as well as septic shock (2.0%), sepsis (2.0%) and Richter\u0026rsquo;s syndrome (2.0%) for prospective patients (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Other AEs leading to death are detailed in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAdverse events (AE) and treatment-emergent adverse events (TEAE) of interest by type of inclusion (Safety population, N\u0026thinsp;=\u0026thinsp;394).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRETRO after inclusion (N\u0026thinsp;=\u0026thinsp;198)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePRO (N\u0026thinsp;=\u0026thinsp;196)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatients with at least one AE, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e175 (88.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e195 (99.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatients with TEAE (any severity), N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;1 TEAE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e170 (85.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e195 (99.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;1 serious TEAE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e100 (50.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e142 (72.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;1 severe TEAE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e98 (49.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e143 (73.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;1 TEAE related to ibrutinib\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e135 (68.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e181 (92.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;1 serious TEAE related to ibrutinib\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e35 (17.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e59 (30.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatients with treatment-emergent bleeding events, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;1 bleeding\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e57 (28.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e106 (54.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;1 major bleeding\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4 (2.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e16 (8.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;1 bleeding while on anti-thrombotic treatment\u003csup\u003ed\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e16/39 (41.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e34/45 (75.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;1 major bleeding while on anti-thrombotic treatment\u003csup\u003ed\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2/39 (5.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7/45 (15.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;1 bleeding while NOT on anti-thrombotic treatment\u003csup\u003ee\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e41/159 (25.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e72/151 (47.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;1 major bleeding while NOT on anti-thrombotic treatment\u003csup\u003ee\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2/159 (1.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9/151 (6.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatients with TEAE of interest (any severity), N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;1 infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e114 (57.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e140 (71.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;1 diarrhoea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e32 (16.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e56 (28.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;1 arthralgia/myalgia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e27 (13.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e52 (26.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;1 atrial fibrillation or flutter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e16 (8.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e22 (11.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;1 hypertension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e29 (14.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e29 (14.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;1 rash\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e16 (8.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e22 (11.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eAbbreviations: AE, Adverse Event; CLL, Chronic Lymphocytic Leukaemia; PRO, Prospective; RETRO, Retrospective; TEAE, Treatment-Emergent Adverse Event.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003csup\u003ea\u003c/sup\u003e 4 retrospective and 2 prospective patients were included for the safety analysis although they met\u0026thinsp;\u0026ge;\u0026thinsp;1 exclusion criteria and/or not all inclusion criteria.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003csup\u003eb\u003c/sup\u003e 166 (83.8%) retrospective patients had at least one TEAE related to ibrutinib before inclusion.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003csup\u003ec\u003c/sup\u003e 16 (8.1%) retrospective patients had at least one serious TEAE related to ibrutinib before inclusion.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003csup\u003ed\u003c/sup\u003e Percentage are calculated over the number of patients with antithrombotic treatment (N\u0026thinsp;=\u0026thinsp;39 for the retrospective patients; N\u0026thinsp;=\u0026thinsp;45 for the prospective patients).\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003csup\u003ee\u003c/sup\u003e Percentage are calculated over the number of patients without antithrombotic treatment (N\u0026thinsp;=\u0026thinsp;159 for the retrospective patients; N\u0026thinsp;=\u0026thinsp;151 for the prospective patients).\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAdverse events leading to death classified by System Organ Class and Preferred Term, by type of inclusion (Safety population, N\u0026thinsp;=\u0026thinsp;394).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRETRO (N\u0026thinsp;=\u0026thinsp;198)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePRO (N\u0026thinsp;=\u0026thinsp;196)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatients with AE leading to death, N (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatients with at least one AE leading to death\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29 (14.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e44 (22.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatients with at least one TEAE leading to death\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26 (13.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e41 (20.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAE leading to death classified by SOC and PT, N (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSOC\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003ePT\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlood and lymphatic system disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCytopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCardiac disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (1.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCardiac failure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCardi-respiratory arrest\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCongestive cardiomyopathy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGeneral disorders and administration site conditions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (5.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (3.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGeneral physical health deterioration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (4.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (2.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDeath\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (1.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (1.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHepatobiliary disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDrug-induced liver injury\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInfections and infestations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (4.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15 (7.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSeptic choc\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (1.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (2.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCovid-19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (1.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSepsis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (2.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCerebral aspergillosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (1.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMeningitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (1.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAtypical mycobacterial pneumonia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBronchitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFungaemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFungal infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePneumocystis jirovecii pneumonia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePneumonia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePulmonary mucormycosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRhinocerebral mucormycosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInjury, poisoning and procedural complications\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSubdural haematoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMetabolism and nutrition disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTumour Lysis Syndrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeoplasms benign, malignant and unspecified (incl. cysts and polyps)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (3.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11 (5.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRichter\u0026rsquo;s syndrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (2.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eProstate cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eB-cell lymphoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBreast cancer metastatic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eChronic lymphocytic leukaemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eColorectal cancer metastatic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCutaneous t-cell lymphoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLung neoplasm malignant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMetastases to central nervous system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMetastatic bronchial carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNeuroendocrine carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOespophageal squamous cell carcinoma stage 0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePancreatic carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTransitional cell carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNervous system disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (1.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (1.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCentral nervous system lesion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCerebellar haematoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCerebral haemorrhage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIntraventicular haemorrage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRespiratory, thoracic and mediastinal disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (2.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (2.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLung disorder\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (1.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAcute respiratory distress syndrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDysnopea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePneumonitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePulmonary embolism\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRespiratory distress\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVascular disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInfarction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003cem\u003eAbbreviations: AE, Adverse Event; CLL, Chronic Lymphocytic Leukaemia; PRO, prospective; PT, Preferred term, RETRO, retrospective, SOC, System Organ Class;\u003c/em\u003e TEAE, Treatment-Emergent Adverse Event.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003csup\u003ea\u003c/sup\u003e 4 retrospective and 2 prospective patients were included for the safety analysis although they met\u0026thinsp;\u0026ge;\u0026thinsp;one exclusion criteria and/or not all inclusion criteria.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e\u0026lt; Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e near here \u0026gt;\u003c/p\u003e \u003cp\u003e\u0026lt; Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e near here \u0026gt;\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eAlthough clinical trials have always been the gold standard of proof regarding effectiveness and safety of new drugs, there is nowadays a great interest in real-world research since they represent patients in real-life settings. To our knowledge, FIRE was the largest French real-word study that assessed the effectiveness and safety of ibrutinib, in accordance with the French marketing authorization in 2016, for the treatment of CLL/SLL in patients who received at least one prior line of treatment, or who were previously untreated and had a del17p and/or TP53 mutation unsuitable for chemoimmunotherapy. In this extensive study, set up in 65 centres, 388 CLL/SLL patients (194 retrospective and 194 prospective) were included in the effectiveness population and followed-up for five years.\u003c/p\u003e \u003cp\u003eOur results showed a median PFS of 53.1 months for retrospective patients and of 52.9 months for prospective patients with one-year PFS survival rates of 93.2% and 83.5% and 5-year rates of 45.5% and 45.1% respectively. The median OS was not reached for both groups. The OS rates were 97.9% for retrospective patients and 87.6% for prospective patients at one year, and 64.5% and 63.3%, respectively, at 5 years. Our results are consistent with previous effectiveness findings [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. In a real-world multicenter retrospective study conducted on 205 CLL patients treated with ibrutinib, the 12-months PFS and OS rates were 86.3% and 88.8% respectively [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. In another study on long-term efficacy and safety with a median follow-up of 5 years, in which 31 treatment-na\u0026iuml;ve and 101 R/R patients were included, the median PFS in R/R patients was 51 months with a 5-year PFS rate of 44% [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. The median OS was not reached and the OS rate at 5 years was 60%. In a UK/Ireland-based study, the one-year OS was 83.8% [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. In the clinical trial RESONATE, only R/R CLL patients were included. When comparing the results at similar timepoints between RESONATE and FIRE, the one-year PFS and OS rates in RESONATE (84% and 90% respectively) as well as the 5-year PFS (40.0%) were similar to those of FIRE [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. The ORR was also similar: 91% in RESONATE vs. 96.8% and 96.6% for retrospective and prospective patients, respectively, in FIRE [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] (Online Resource 6). However when comparing median PFS and OS, those in RESONATE were lower: 44.1 (95% CI: 38.5\u0026ndash;56.2) months for the median PFS and 67.7 (95% CI: 61.0 \u0026ndash; not reached) months for the median OS [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] (Online Resource 6). One explanation could be the longer follow-up period in RESONATE (6 years vs. 5 years). However, taking the fact that our results are included in the confidence intervals of the PFS and OS of RESONATE, our finding are consistent. Therefore, although the FIRE population is slightly different than the population in RESONATE (e.g. age, ECOG PS, mutations status, number of prior therapies), it is reassuring to see that our effectiveness results are similar to the results of clinical trials.\u003c/p\u003e \u003cp\u003eThe safety profile of ibrutinib and dose reductions were also assessed. Our results showed that among patients who had a dose modification, 80.5% (70/87) of the retrospective patients and 88.9% (72/81) of the prospective patients had at least one dose reduction, mainly due to toxicity. Efficacy results showed that patients with at least one dose reduction had a similar PFS than patients with no dose reduction, supporting the fact that CLL patients in France are well managed, follow-up and treated. Our results not only confirm those of previous real-world studies [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] but also encourage the idea that ibrutinib can still be administrated to patients presenting AEs. Therefore, if physicians need to modify the dose because of an AE, dose reduction may be the best option. Suggesting dose reduction to patients in need of dose modification will thus reduce treatment discontinuation, increase patient adherence, improve patients outcome and on a long-term strategy decrease financial and economic burden. However, to obtain the best benefit from ibrutinib, it is important to promptly identify and manage AEs, and understand specific AEs that can lead to dose reductions. Identifying specific AEs and other factors that could potentially be associated with the need for dose reduction could be the next step in order to well maintain ibrutinib treatment for patients with AEs at the correct reduced dose.\u003c/p\u003e \u003cp\u003eThe median time to dose reduction as the first dose modification was 7.4 (range: 0.4\u0026ndash;60.9) months for retrospective patients and 9.3 (range: 0.4\u0026ndash;57.4) months for prospective patients. One retrospective chart review on first line and R/R CLL patients treated with ibrutinib either in academic practice or community network that assessed the median time to first dose reduction found an overall median time of 3.6 months [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. However, when the overall result was stratified by academic/community settings and by first line and R/R patients, the median time to first dose reduction for first line patients treated in academic settings increased to 16.6 months versus 3.6 months for R/R academic-treated patients. Furthermore, a review on ibrutinib dose modifications in the management of CLL mentioned that in real-world settings, dose reductions over the first year was often noticed [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. However, addressing the question of time in dose reduction still remains rare and unclear. Therefore, further research on this topic is necessary in order to better understand the role of the time in dose reductions and ibrutinib outcome.\u003c/p\u003e \u003cp\u003eFurthermore, the results showed that among patients who discontinued ibrutinib, toxicity was the main reason for 43.5% of the retrospective patients and 42.0% of the prospective patients. These results were similar to the one found in a Swedish retrospective study: 40.4% (19/47) [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. However, a Danish retrospective study showed a higher rate: 54.7% (47/86) [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. In RESONATE, the discontinuation rate due to toxicity was much lower 21.1% (32/152) (Online Resource 6). One explanation to this lower discontinuation rate due to AEs compared to the FIRE study could be that RESONATE is a clinical trial with eligibility criteria which promote inclusion of selected patient. Although our results on discontinuation rates due to AEs differed from the one found in RESONATE, they illustrate the need of real-world research on long-term safety on heterogeneous population.\u003c/p\u003e \u003cp\u003eAmong adverse events noticed in our study, patients reported low rate of major bleeding events (2.0% retrospective and 8.2% prospective). This rate was five times less for retrospective patients but similar for prospective patients than the rate reported in RESONATE (10.0%) [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Of note, in FIRE, more patients had a bleeding / major bleeding event when they were under anti-thrombotic treatment. Explanations could be that bleeding events are side effects of such treatments, and in RESONATE, patients under anticoagulation containing warfarin were excluded. In addition, the rate of atrial fibrillation was similar for patients in the two studies (FIRE: 8.1% for retrospective and 11.2% for prospective patients; RESONATE: 12.0%) but the rate of hypertension was lower in FIRE than in RESONATE (FIRE: 14.6% for retrospective and 14.8% for prospective; RESONATE: 21.0%) [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Nevertheless, it is reassuring to see that there was no new AE observed and that the safety profile of ibrutinib in our study seems to be consistent with previous studies.\u003c/p\u003e \u003cp\u003eOur study has several strengths and limitations. First, FIRE was an extensive research and the largest French real-word study on the effectiveness and safety of ibrutinib. Second, because of its real-world design, effectiveness and safety parameters were presented through descriptive data in a \u0026ldquo;real-life condition\u0026rdquo;, and therefore, our results complement those of clinical trials. Moreover, all consecutive patients who met the eligibility criteria and who had therapy-demanding disease were considered for inclusion in order to reduce selection bias. However, there might have been a bias in effectiveness results between retrospective and prospective patients since retrospective patients who died before enrolment were not included. Therefore, retrospective patients who were included in the study should be considered in \u0026ldquo;better\u0026rdquo; health than prospective patients. However, it is reassuring to see that the results between the two groups are quite similar. In addition, because of the exclusion of retrospective patients who died before enrolment, it was difficult to pull data of retrospective patients together with the data of prospective patients. Moreover, the number of adverse events for retrospective patients have been underestimated since TEAEs that occurred before inclusion and that were not related to ibrutinib were not collected for these patients. Finally, our focus was on the effectiveness and safety profile of ibrutinib. Therefore, other aspects such as the quality of life of patients under ibrutinib were not considered in this article. Although such data might have been informative and complement the findings of this article, this whole topic could be discussed in a further paper.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, FIRE was an extensive real-word study that showed the effectiveness of ibrutinib on the PFS and OS for patients with CLL, as well as on other effectiveness parameters. The study indicated high PFS rates, even though R/R CLL patients (i.e. patients with high-risk features, in particular with del17p and/or TP53 mutations) have been included. Dose modifications were mainly attributed to toxicity. However, it is reassuring to see that patients who had at least a dose reduction had a similar PFS than patients with no dose reduction, implying the fact that ibrutinib can still be administrated in case of AEs. No additional safety concerns than those already mentioned in other studies could be noticed. Finally, our results not only complement those of clinical trials but they are also consistent with both results of clinical trials and other real-world studies.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank all patients who participated in this study as well as the FIRE investigators group and staff from the study centres. Medical writing assistance and statistical analysis were provided by ICTA PM (medical writing: Joëlle Castellani, PhD; statistical analysis: Simon Paternotte and Edwige Yon).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study, including statistical support and writing assistance, was sponsored by Janssen-Cilag Ltd.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSince this study was non-interventional, no approval from an Ethics Committee was needed in France at the time that the study was set up (before the implementation of the Jardé Law). However, the study was conducted in accordance with the principles stated in the Declaration of Helsinki and an Informed Consent Form was obtained from all patients prior their participation in the study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eVL\u0026nbsp;provided the study design. Investigation and data collection were performed by\u0026nbsp;CD, AQ, LY, MSD, BA, BS, KLD, ST, ET,\u0026nbsp;HO,\u0026nbsp;LV,\u0026nbsp;SG, JVM,\u0026nbsp;PF and\u0026nbsp;VL.\u0026nbsp;SD and\u0026nbsp;MD\u0026nbsp;contributed to data interpretation.\u0026nbsp;VL, SD and MD\u0026nbsp;contributed to the manuscript preparation.\u0026nbsp;All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCD has received honoraria from Abbvie, AstraZeneca, Beigene, Janssen and Lilly.\u003c/p\u003e\n\u003cp\u003eAQ has received honoraria from Abbvie, AstraZeneca, Beigene and Janssen.\u003c/p\u003e\n\u003cp\u003eLY has received honoraria from\u0026nbsp;Abbvie, AstraZeneca, Beigene, BMS/Celgene, Gilead/Kite, Janssen and Roche.\u003c/p\u003e\n\u003cp\u003eMSD has receivedhonoraria from\u0026nbsp;Abbvie, Astra Zeneca, Beigene and Janssen.\u003c/p\u003e\n\u003cp\u003eKLD has received honoraria from Janssen, Abbvie, AstraZeneca, Roche, Incyte and Takeda.\u003c/p\u003e\n\u003cp\u003eET has received honoraria from Abbvie, AstraZeneca, Beigene and Janssen.\u003c/p\u003e\n\u003cp\u003ePF has received honoraria from\u0026nbsp;Abbvie, Amgen, AstraZeneca, Beigene, Gilead, Janssen and LoxoLilly.\u003c/p\u003e\n\u003cp\u003eVL has received honoraria from Abbvie, Astra Zeneca, Amgen, MSD, Janssen, Beigene and Lilly.\u003c/p\u003e\n\u003cp\u003eSD is an employee of Janssen and reports stock ownership of Johnson \u0026amp; Johnson.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMD is an employee of Janssen.\u003c/p\u003e\n\u003cp\u003eBA, BS, ST, HO, LV, SG, and JVM have nothing to declare.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data-sharing policy of the Janssen Pharmaceutical Companies of Johnson \u0026amp; Johnson is available at www.janssen.com/clinical-trials/transparency. Requests for access to the data from selected studies can be submitted through the Yale Open Data Access (YODA) Project site at yoda.yale.edu.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eHallek M (2017) Chronic lymphocytic leukemia: 2017 update on diagnosis, risk stratification, and treatment. Am J Hematol 92:946\u0026ndash;965.\u003c/li\u003e\n\u003cli\u003eOu Y, Long Y, Ji L et al (2022). Trends in Disease Burden of Chronic Lymphocytic Leukemia at the Global, Regional, and National Levels From 1990 to 2019, and Projections Until 2030: A Population-Based Epidemiologic Study. Front Oncol 12:840616.\u003c/li\u003e\n\u003cli\u003eThe Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute. Cancer Stat Facts: Leukemia \u0026ndash; Chronic Lymphocytic Leukemia (CLL). https://seer.cancer.gov/statfacts/html/clyl.html Accessed 25 April 2023.\u003c/li\u003e\n\u003cli\u003eJanssen-Cilag International NV. IMBRUVICA [Summary of Product Characteristics]. Beerse, Belgium. 2014.\u003c/li\u003e\n\u003cli\u003eEMA. Imbruvica. https://www.ema.europa.eu/en/medicines/human/EPAR/imbruvica Accessed 20 April 2023.\u003c/li\u003e\n\u003cli\u003eBurger JA, Barr PM, Robak T et al (2020) Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia 34:787-798.\u003c/li\u003e\n\u003cli\u003eByrd JC, Brown JR, O\u0026apos;Brien S et al (2014) Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med 371:213-223.\u003c/li\u003e\n\u003cli\u003eMunir T, Brown JR, O\u0026apos;Brien S et al (2019) Final analysis from RESONATE: Up to six years of follow-up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma. Am J Hematol 94:1353-1363.\u003c/li\u003e\n\u003cli\u003eWoyach JA, Ruppert AS, Heerema NA et al (2018). Ibrutinib Regimens versus Chemoimmunotherapy in Older Patients with Untreated CLL. N Engl J Med 379:2517-2528.\u003c/li\u003e\n\u003cli\u003eChanan-Khan A, Cramer P, Demirkan F et al (2016) Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study. Lancet Oncol 17:200\u0026ndash;211.\u003c/li\u003e\n\u003cli\u003eMoreno C, Greil R, Demirkan F et al (2019) Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in frst-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 20:43-56.\u003c/li\u003e\n\u003cli\u003eNiemann C, Munir T, Moreno C et al (2022) Residual Disease Kinetics Among Patients with High-Risk Factors Treated with First-Line Fixed-Duration Ibrutinib Plus Venetoclax (Ibr+Ven) Versus Chlorambucil Plus Obinutuzumab (Clb+O): The Glow Study. Blood 140(S1):228-230.\u003c/li\u003e\n\u003cli\u003eDartigeas C, Slama B, Doyle M et al (2022). FIRE Study: Real-World Effectiveness and Safety of Ibrutinib in Clinical Practice in Patients with CLL and MCL. Clin Hematol Int 4:65-74.\u003c/li\u003e\n\u003cli\u003eDartigeas C, Ysebaert L, Feugier P et al (2022) Overall and subgroup results from the third interim analysis of FIRE, a real-world study of ibrutinib treatment for CLL/SLL in France. Blood 140(S1):9906-9907.\u003c/li\u003e\n\u003cli\u003eByrd JC, Furman RR, Coutre SE et al (2015) Three-year follow-up of treatment-naive and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood 125:2497-2506.\u003c/li\u003e\n\u003cli\u003eAarup K, Rotbain EC, Enggaard L et al (2020) Real-world outcomes for 205 patients with chronic lymphocytic leukemia treated with ibrutinib. Eur J Haematol 105:646-654.\u003c/li\u003e\n\u003cli\u003eO\u0026apos;Brien S, Furman RR, Coutre S et al (2018) Single-agent ibrutinib in treatment-naive and relapsed/refractory chronic lymphocytic leukemia: a 5-year experience. Blood 131:1910-1919.\u003c/li\u003e\n\u003cli\u003eUK CLL Forum (2016) Ibrutinib for relapsed/refractory chronic lymphocytic leukemia: a UK and Ireland analysis of outcomes in 315 patients. Haematologica 101:1563-1572.\u003c/li\u003e\n\u003cli\u003eBrown JR, Hillmen P, O\u0026apos;Brien S et al (2014) Updated Efficacy Including Genetic and Clinical Subgroup Analysis and Overall Safety in the Phase 3 RESONATE Trial of Ibrutinib Versus Ofatumumab in Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. Blood 124:3331.\u003c/li\u003e\n\u003cli\u003eWinqvist M, Andersson P-O, Asklid A et al (2019) Long-term real-world results of ibrutinib therapy in patients with relapsed or refractory chronic lymphocytic leukemia: 30-month follow up of the Swedish compassionate use cohort. Haematologica 104:e208-e210.\u003c/li\u003e\n\u003cli\u003eMato AR, Timlin C, Ujjani C et al (2018) Comparable outcomes in chronic lymphocytic leukaemia (CLL) patients treated with reduced-dose ibrutinib: results from a multi-centre study. Br J Haematol 181:259-261.\u003c/li\u003e\n\u003cli\u003eHou J-Z, Ryan K, Du S et al (2021) Real-world ibrutinib dose reductions, holds and discontinuations in chronic lymphocytic leukemia. Future Oncol 17:4959-4969.\u003c/li\u003e\n\u003cli\u003eHardy-Abeloos C, Pinotti R, Gabrilove J (2020) Ibrutinib dose modifications in the management of CLL. J Hematol Oncol 13:66.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"annals-of-hematology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"aohe","sideBox":"Learn more about [Annals of Hematology](http://link.springer.com/journal/277)","snPcode":"277","submissionUrl":"https://submission.nature.com/new-submission/277/3","title":"Annals of Hematology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Chronic Lymphocytic Leukemia, Ibrutinib, Real-World Evidence, Effectiveness, Safety","lastPublishedDoi":"10.21203/rs.3.rs-3809070/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3809070/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eWe conducted an observational study (FIRE) to understand the effectiveness and safety outcomes of ibrutinib in patients with chronic lymphocytic leukemia (CLL) in France, after a maximum follow-up of five years. Patients were included according to the French marketing authorization in 2016 (i.e. patients with relapsed or refractoryCLL or to previously untreated CLL patients with deletion 17p and/or TP53 mutations unsuitable for chemoimmunotherapy) and could have initiated ibrutinib more than 30 days prior their enrolment in the study (i.e. retrospective patients) or between 30 days before and 14 days after their enrolment (i.e. prospective patients). The results showed that in the effectiveness population (N=388), the median progression-free survival (PFS) was 53.1 (95% CI: 44.5-60.5) months for retrospective patients and 52.9 (95% CI: 40.3-60.6) months for prospective patients and no difference was shown between the PFS of patients who had at least one dose reduction versus the PFS of patients without dose reduction (p=0.7971 for retrospective and p=0.3163 for prospective patients). For both retrospective and prospective patients, the median overall survival was not reached. The most frequent treatment-emergent adverse event of interest was infections (57.6% retrospective; 71.4% prospective). A total of 14.6% of the retrospective patients and 22.4% of the prospective patients had an adverse event leading to death. Our findings on effectiveness were consistent with other studies and the fact that patients with dose reductions had similar PFS than patients without dose reduction is reassuring. No additional safety concerns than those already mentioned in previous studies could be noticed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eClinicalTrials.gov, NCT03425591. Registered 1 February 2018 – Retrospectively registered.\u003c/p\u003e","manuscriptTitle":"Final results on effectiveness and safety of Ibrutinib in patients with chronic lymphocytic leukemia from the non-interventional FIRE study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-03 17:03:18","doi":"10.21203/rs.3.rs-3809070/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-01-14T15:57:50+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-01-14T15:43:50+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-01-04T05:22:35+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"14ac42f2-fc2b-4b4a-9014-44fdc67b988a","date":"2024-01-03T15:38:30+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"ab4c2f8c-2908-4185-afb1-f6a7cdf5cfc8","date":"2024-01-03T11:01:30+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2023-12-31T07:32:43+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2023-12-29T08:14:08+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-12-29T08:14:08+00:00","index":"","fulltext":""},{"type":"submitted","content":"Annals of Hematology","date":"2023-12-26T17:33:42+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"annals-of-hematology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"aohe","sideBox":"Learn more about [Annals of Hematology](http://link.springer.com/journal/277)","snPcode":"277","submissionUrl":"https://submission.nature.com/new-submission/277/3","title":"Annals of Hematology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"aeded81a-7a86-4f30-8a17-aa3fb58d7ff1","owner":[],"postedDate":"January 3rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-03-11T15:06:18+00:00","versionOfRecord":{"articleIdentity":"rs-3809070","link":"https://doi.org/10.1007/s00277-024-05666-3","journal":{"identity":"annals-of-hematology","isVorOnly":false,"title":"Annals of Hematology"},"publishedOn":"2024-03-06 15:01:57","publishedOnDateReadable":"March 6th, 2024"},"versionCreatedAt":"2024-01-03 17:03:18","video":"","vorDoi":"10.1007/s00277-024-05666-3","vorDoiUrl":"https://doi.org/10.1007/s00277-024-05666-3","workflowStages":[]},"version":"v1","identity":"rs-3809070","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3809070","identity":"rs-3809070","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}