scholarly journals Incidence of Serious Adverse Events, Pneumonitis, Infection and Sepsis in Patients with Relapsed and Refractory Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma Treated with Phosphatidylinositol 3-Kinase (PI3K) Inhibitors

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 798-798
Author(s):  
Sriman Swarup ◽  
Donald P. Quick ◽  
Anita Sultan ◽  
Myint Aung Win ◽  
Ei Moe Phyu ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Adverse Events ◽  
Lymphocytic Leukemia ◽  
Control Group ◽  
Study Group ◽  
Phosphatidylinositol 3 Kinase ◽  
Small Lymphocytic Lymphoma ◽  
Phase 3 ◽  
Serious Adverse Events ◽  
Pi3k Inhibitors

Introduction: Phosphatidylinositol 3-kinase (PI3K) is a kinase protein involved in downstream signaling for multiple pathways in B cells and is important for B cell survival, proliferation and metabolism. Hence, PI3K inhibitors have become an attractive therapeutic option for treatment of B cell malignancies. Two prominent PI3K inhibitors, (PI3Kδ-selective inhibitor) and duvelisib (PI3Kδ/γ-combinatorial inhibitor), are currently being studied in relapsed and refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) and have shown to improve survival in recent trials with notable toxicities. We analyzed phase 3 trials to assess the incidence of serious adverse events, pneumonitis, infection and sepsis associated with PI3K inhibitors in this susceptible population. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 2019. Phase 3 RCTs utilizing PI3K inhibitors in patients with relapsed and refractory CLL/SLL that mention serious adverse events, pneumonitis, infection and sepsis as adverse effects were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR), and risk difference (RD) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Random effects model was applied. Results: Four phase 3 RCTs with a total of 1,216 patients with relapsed and refractory CLL/SLL were included in analysis. Studies compared ofatumumab vs idelalisib+ofatumumab, rituximab vs idelalisib+rituximab, bendamustine+ rituximab vs idelalisib+bendamustine+rituximab and ofatumumab vs duvelisib. The randomization ratio was 2:1 in Jones et al. study and 1:1 in other studies. The I2 statistic for heterogeneity was 49, suggesting some heterogeneity among RCTs. The incidence of serious adverse events was 479 (73.69%) in study group vs 252 (44.92%) in control group (RR, 1.58; 95% CI: 1.37 - 1.83; P < 0.0001 and RD, 0.26; 95% CI: 0.13 - 0.40; P = 0.0002). Pneumonitis was noted in 20 (3.07%) vs 1 (0.18%) in control group with RR of 6.53 (95% CI: 1.74 -24.53; P = 0.005) and RD of 0.02 (95% CI: 0.01 - 0.04; P = 0.0004). The incidence of any-grade pneumonia was 107 (16.46%) in study group vs 54 (9.63%) in control group (RR, 1.61; 95% CI: 1.00 - 2.58; P = 0.05). High-grade pneumonia was reported in 81 (12.46%) in idelalisib arm versus 35 (6.24%) in control group with RR of 1.84 (95% CI: 0.82 - 4.13; P = 0.14). Pneumocystis jiroveci pneumonia (PJP) rate was 2.24% higher in study group compared to control arm (RR, 3.87; 95% CI: 1.22 - 12.29; P = 0.02). Any-grade upper respiratory tract infection (URTI) was 14% in study group versus 7.84% in control arm (RR, 1.65; 95% CI: 1.17 - 2.34; P = 0.005). Sepsis rate was 2.88% higher in idelalisib group compared to control arm and the pooled RR was statistically significant at 2.68 (95% CI: 1.19 - 6.04, P = 0.02). Treatment-related deaths were 64 (11.85%) in study arm vs 28 (6.17%) in control arm according to analysis of 3 trials. The pooled RR was also statistically significant at 1.87 (95% CI: 1.21 -2.88; P = 0.005). Conclusions: Our meta-analysis showed that the incidence of serious adverse events, pneumonitis, PJP pneumonia, any-grade URTI and sepsis was significantly higher in PI3K inhibitors group with RR of 1.58 for serious adverse events, RR of 6.53 for pneumonitis, RR of 3.87 for PJP pneumonia and RR of 2.68 for sepsis respectively. Moreover, patients on PI3K inhibitors experienced 5.68% higher incidence of treatment-related deaths with RR of 1.87, compared to control arm. Since treatment-related serious toxicities and deaths are higher amongst patients treated with these agents, extra caution should be observed and recommended with their use. Disclosures No relevant conflicts of interest to declare.

scholarly journals Risk of Serious Adverse Events, Infection and Sepsis in Patients with Relapsed and Refractory Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma Treated with Idelalisib

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5489-5489
Author(s):  
Jonathan Kopel ◽  
Sriman Swarup ◽  
Anita Sultan ◽  
Lukman Tijani ◽  
Ei Moe Phyu ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Adverse Events ◽  
Conflicts Of Interest ◽  
Group Versus ◽  
Lymphocytic Leukemia ◽  
Control Group ◽  
Study Group ◽  
Small Lymphocytic Lymphoma ◽  
Phase 3 ◽  
Serious Adverse Events

Introduction: Idelalisib is a first-in-class potent, oral, selective small-molecule inhibitor of δ isoform of phosphatidylinositol 3-kinase (PI3Kδ), which involves in the signaling of B-cell receptor pathways via activation of downstream serine threonine kinases AKT and mammalian target of rapamycin (mTOR), and has been implicated in the pathogenesis of chronic lymphocytic leukemia/ small lymphocytic lymphoma (CLL/SLL). Yet, there are considerable safety concerns. We undertook a systematic review and combined analysis of phase 3 randomized controlled trials to determine the risk of serious adverse events, infection and sepsis in patients with relapsed/ refractory CLL/SLL treated with idelalisib. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 2019. Phase 3 RCTs utilizing idelalisib in patients with relapsed and refractory CLL/SLL that mention serious adverse events, infection and sepsis as adverse effects were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Random effects model was applied. Results: Three phase 3 RCTs with a total of 892 patients with relapsed and refractory CLL/SLL were eligible for analysis. Studies compared ofatumumab vs idelalisib+ofatumumab, rituximab vs idelalisib+rituximab, bendamustine+ rituximab vs idelalisib+bendamustine+rituximab and ofatumumab vs duvelisib. The randomization ratio was 2:1 in Jones et al. study and 1:1 in other studies. The I2 statistic for heterogeneity was 83, suggesting moderate heterogeneity among RCTs. The incidence of serious adverse events was 341 (69.59%) in study group vs 177 (44.03%) in control group with RR of 1.50 (95% CI: 1.28-1.75; p < 0.0001). Pneumonitis was noted in 14 (2.86%) vs 1 (0.25%) in control group (RR, 5.42; 95% CI: 1.22-24.13; p = 0.03). The incidence of any-grade pneumonia was 78 (15.92%) in study group vs 45 (11.19%) in control group (RR, 1.38; 95% CI: 0.98 - 1.96; P = 0.07). High-grade pneumonia was reported in 59 (12.04%) in idelalisib arm versus 33 (8.21%) in control group with RR of 1.36 (95% CI: 0.82 - 2.27; P = 0.23). Pneumocystis jiroveci (PJP) pneumonia rate was 2.56% higher in study group compared to control arm (RR, 4.25; 95% CI: 1.10 - 16.34; P = 0.04). Febrile neutropenia was noted in 13.47% in study group versus 4.73% in control arm (RR, 2.39; 95% CI: 0.90-6.34; p = 0.08). Sepsis rate was 3.36% higher in idelalisib group compared to control arm and the pooled RR was statistically significant at 2.64 (95% CI 1.10-6.30; p = 0.03). Treatment-related deaths were 45 (6.92%) in idelalisib arm vs 21 (3.74%) in control arm according to analysis of 2 trials. The pooled RR was not statistically significant at 1.64 (95% CI: 0.99 -2.71; P = 0.06). Conclusion: Patients on idelalisib experienced higher risk of serious adverse events, pneumonitis, PJP pneumonia, and sepsis, with RR of 1.50 for serious adverse events, RR of 5.42 for pneumonitis, RR of 4.25 for PJP pneumonia and RR of 2.64 for sepsis respectively. Nevertheless, there was no significant increase in treatment-related deaths due to TRAE in the idelalisib group, compared to control arm. Preemptive measures with proper supportive care are required to reduce those toxicities which can ultimately improve patients' quality of life and may probably affect patients' compliance. Disclosures No relevant conflicts of interest to declare.

scholarly journals Efficacy of Phosphatidylinositol 3-Kinase (PI3K) Inhibitors in Patients with Relapsed and Refractory Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5480-5480
Author(s):  
Anita Sultan ◽  
Bradley J. Grant ◽  
Donald P. Quick ◽  
Chandler Graf ◽  
Sriman Swarup ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Selective Inhibitor ◽  
Lymphocytic Leukemia ◽  
Phosphatidylinositol 3 Kinase ◽  
Small Lymphocytic Lymphoma ◽  
Phase 3 ◽  
Pi3k Inhibitors ◽  
Tp53 Status ◽  
Phosphatidylinositol 3

Introduction: Chronic lymphocytic leukemia/ small lymphocytic lymphoma (CLL/ SLL) is the most common adult lymphoproliferative disorder in western countries and the B-cell receptor signaling pathway has been shown to be involved in the pathogenesis of CLL/ SLL. Phosphatidylinositol 3-kinase (PI3K) is a kinase protein in downstream signaling for multiple pathways in B cells, promoting B-cell survival, proliferation and metabolism. Two prominent PI3K inhibitors, idelalisib (PI3Kδ-selective inhibitor) and duvelisib (PI3Kδ/γ-combinatorial inhibitor), are currently being studied in the treatment of relapsed and refractory CLL/ SLL. The purpose of our study is to explore and consolidate the efficacy of PI3K inhibitors in patients with relapsed and refractory CLL/SLL. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 2019. Phase 3 RCTs utilizing PI3K inhibitors in patients with relapsed and refractory CLL/SLL were incorporated in the analysis. A generic inverse variance method was used to calculate the estimated pooled hazard ratio (HR) for progression-free survival (PFS) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q -statistic. Random effects model was applied. Results: Four phase 3 RCTs with a total of 1,216 patients with relapsed and refractory CLL/SLL were eligible for analysis. Studies compared ofatumumab vs idelalisib+ofatumumab, rituximab vs idelalisib+rituximab, bendamustine+ rituximab vs idelalisib+bendamustine+rituximab and ofatumumab vs duvelisib. The randomization ratio was 2:1 in the study by Jones et al. and 1:1 in other studies. The I2 statistic for heterogeneity was 82%, suggesting moderate heterogeneity among RCTs. The overall pooled HR for PFS was statistically significant at 0.30 (95% CI: 0.20- 0.47; P < 0.0001). The PFS benefit was observed across all ages and regardless of del 17p or TP53 status; age <65 (HR, 0.35; 95% CI: 0.27- 0.46; P < 0.0001), age ≥65 (HR, 0.32; 95% CI: 0.19- 0.54; P < 0.0001), either del 17p or TP53 cohort (HR, 0.33; 95% CI: 0.21- 0.52; P < 0.0001), and neither del 17p nor TP53 cohort (HR, 0.32; 95% CI: 0.19- 0.54; P < 0.0001). In the subset of patients with CLL treated with idelalisib, the pooled HR for PFS was statistically significant at 0.26 (95% CI: 0.18-0.37; P < 0.0001) and the PFS benefit was observed across all ages, and regardless of del17p or TP53 status and IGHV mutation status; age <65 (HR, 0.32; 95% CI: 0.24- 0.43; P < 0.0001), age ≥65 (HR, 0.26; 95% CI: 0.14- 0.47; P < 0.0001), either del17p or TP53 cohort (HR, 0.29; 95% CI: 0.15- 0.57; P = 0.0003), neither del17p nor TP53 cohort (HR, 0.26; 95% CI: 0.20- 0.35; P < 0.0001), IGHV mutated cohort (HR, 0.29; 95% CI: 0.17- 0.51; P < 0.0001), and IGHV unmutated cohort (HR, 0.25; 95% CI: 0.15- 0.40; P < 0.0001). Conclusions: Our study showed that PI3K inhibitors, idelalisib (PI3Kδ-selective inhibitor) and duvelisib (PI3Kδ/γ-combinatorial inhibitor), significantly improved PFS in patients with relapsed and refractory CLL/ SLL regardless of age and poor prognostic features such as del17p or TP53 and IGHV unmutated status, compared to control arm. The efficacy of these drugs must be balanced against the possible side effects. Disclosures No relevant conflicts of interest to declare.

scholarly journals Phosphatidylinositol 3-Kinase (PI3K) Inhibitors-Related Hematological Toxicities in Patients with Relapsed and Refractory Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5877-5877
Author(s):  
Bradley J. Grant ◽  
Anita Sultan ◽  
Nicholas D'Cunha ◽  
Chandler Graf ◽  
Sriman Swarup ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Adverse Effects ◽  
Febrile Neutropenia ◽  
B Cell ◽  
Selective Inhibitor ◽  
Lymphocytic Leukemia ◽  
Phosphatidylinositol 3 Kinase ◽  
Small Lymphocytic Lymphoma ◽  
Phase 3 ◽  
Pi3k Inhibitors

Introduction: Chronic lymphocytic leukemia is the most prevalent adult leukemia in western countries. Phosphatidylinositol 3-kinase (PI3K) is a kinase protein involved in downstream signaling for the B-cell receptor signaling pathway and has been shown to involve in the pathogenesis of chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL/ SLL) by promoting B-cell survival, proliferation and metabolism. Two prominent PI3K inhibitors, idelalisib (PI3Kδ-selective inhibitor) and duvelisib (PI3Kδ/γ-combinatorial inhibitor), have recently shown to improve survival in patients with relapsed and refractory CLL/ SLL. We undertook a systematic review and meta-analysis of phase 3 randomized controlled trials to determine the risk of hematological toxicities associated with PI3K inhibitors. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 2019. Phase 3 RCTs utilizing PI3K inhibitors in patients with relapsed and refractory CLL/SLL that mention hematological toxicities as adverse effects were incorporated in the analysis. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Random effects model was applied. Results: Four phase 3 RCTs with a total of 1,216 patients with relapsed and refractory CLL/SLL were included. Studies compared ofatumumab vs idelalisib+ofatumumab, rituximab vs idelalisib+rituximab, bendamustine+ rituximab vs idelalisib+bendamustine+rituximab and ofatumumab vs duvelisib. The randomization ratio was 2:1 in Jones et al. study and 1:1 in other studies. The I2 statistic for heterogeneity was 49, suggesting some heterogeneity among RCTs. The RR of all-grade side effects were as follows: anemia, 1.39 (95% CI: 0.89 - 2.17; p = 0.15); neutropenia, 1.33 (95% CI: 1.06 - 1.67; p = 0.02); and thrombocytopenia, 1.23 (95% CI: 0.69 - 2.18; p = 0.48). The RR of high-grade adverse effects were as follows: anemia, 1.29 (95% CI: 0.62 - 2.67, p = 0.50); neutropenia, 1.51 (95% CI: 1.22 - 1.88; p = 0.0001); and thrombocytopenia, 1.21 (95% CI: 0.66 - 2.22; p = 0.53). The incidence of febrile neutropenia was 76 (11.69%) in study group vs 22 (3.92%) in control group with RR of 2.62 (95% CI: 1.27 -5.41, P = 0.009). Conclusions: PI3K inhibitors, idelalisib (PI3Kδ-selective inhibitor) and duvelisib (PI3Kδ/γ-combinatorial inhibitor), increased the risk of all grades of neutropenia and febrile neutropenia, with RR of 2.62 for febrile neutropenia, in patients with relapsed and refractory CLL/SLL. Vigilant monitoring is warranted, and proper supportive care and dose modifications should be followed. Disclosures No relevant conflicts of interest to declare.

scholarly journals First-line treatment of chronic lymphocytic leukemia with ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab: final analysis of the randomized, phase 3 iLLUMINATE trial

Haematologica ◽  
2022 ◽  
Author(s):  
Carol Moreno ◽  
Richard Greil ◽  
Fatih Demirkan ◽  
Alessandra Tedeschi ◽  
Bertrand Anz ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Final Analysis ◽  
Lymphocytic Leukemia ◽  
Small Lymphocytic Lymphoma ◽  
First Line ◽  
Open Label ◽  
Phase 3 ◽  
First Line Therapy ◽  
Line Therapy ◽  
Open Label Phase

iLLUMINATE is a randomized, open-label phase 3 study of ibrutinib plus obinutuzumab (n=113) versus chlorambucil plus obinutuzumab (n=116) as first-line therapy for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma. Eligible patients were aged ≥65 years, or

scholarly journals Safety findings from CENTURION, a phase 3 consistency study of lasmiditan for the acute treatment of migraine

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
C Tassorelli ◽  
S Bragg ◽  
JH Krege ◽  
EG Doty ◽  
PA Ardayfio ◽  
...  
Keyword(s):  
Adverse Events ◽  
Acute Treatment ◽  
Motor Vehicle ◽  
Specific Treatment ◽  
Study Drug ◽  
Control Group ◽  
Phase 3 ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Vehicle Accidents

Abstract Background Lasmiditan (LTN) is a selective 5-HT1F receptor agonist for the acute treatment of migraine in adults. We present detailed safety findings from the placebo-controlled, double-blind Phase 3 study, of LTN treatment across 4 attacks (CENTURION). Methods Patients were randomized 1:1:1 to LTN 200 mg (LTN200), LTN100, or a control group that received placebo for 3 attacks and LTN50 for either the 3rd or 4th attack (1:1). Safety analyses were conducted for patients who took ≥1 dose of study drug and, in some cases, those who took all 4 doses. Results Overall, 1471 patients treated 4494 attacks. The incidences of treatment-emergent serious adverse events (SAEs) were - placebo, n=2 (0.4 %); LTN100, n=1 (0.2 %); LTN200, n=2 (0.4 %); no specific treatment-emergent SAE was reported in more than one patient. The most common treatment emergent adverse events (TEAEs) with lasmiditan were dizziness, paresthesia, fatigue, nausea, vertigo, and somnolence; the vast majority were mild or moderate in severity. The incidences of these TEAEs were highest during the first attack and decreased during subsequent attacks. For patients who experienced a common TEAE with the first attack, less than 45 % experienced the same event in subsequent attacks. Patients who did not experience an event in the 1st attack infrequently experienced the same event in subsequent attacks. The time of onset of the common TEAE ranged from ~40 min to 1 h (dependent upon TEAE) and, for individual TEAE, the onset was similar across attacks. Duration was dependent upon TEAE and attack. It was shortest for paresthesia (< 2 h for all attacks); it ranged from 1.8 to 5.5 h for other common TEAEs and was generally similar across attacks. Serotonin syndrome was reported for 2 patients post LTN dosing; there were no meaningful differences across treatment groups in suicidality; there was no evidence of an increase in motor vehicle accidents. Conclusion In this blinded, controlled, multiple-attack study, LTN was associated with generally mild or moderate CNS-related TEAEs of short duration. TEAEs tended to decrease in frequency across the 4 attacks. Trial registration NCT03670810

scholarly journals Managing toxicities of phosphatidylinositol-3-kinase (PI3K) inhibitors

Hematology ◽  
2020 ◽  
Vol 2020 (1) ◽  
pp. 346-356
Author(s):  
Ashley Hanlon ◽  
Danielle M. Brander
Keyword(s):  
Late Onset ◽  
Pi3k Pathway ◽  
Lymphocytic Leukemia ◽  
Phosphatidylinositol 3 Kinase ◽  
Small Lymphocytic Lymphoma ◽  
Pi3k Inhibitors ◽  
Novel Treatment ◽  
Immune Mediated ◽  
The Common ◽  
Phosphatidylinositol 3

Abstract Despite the proven effective approach to targeting the phosphatidylinositol-3-kinase (PI3K) pathway in B-cell malignancies, the approved PI3K inhibitors idelalisib and duvelisib have been less commonly selected for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), given the availability of other more tolerable agents. However, patients with CLL/SLL can experience a disease course that is multiply relapsed, refractory, or intolerant to treatment, and PI3K inhibitors can achieve meaningful responses. This article reviews the common early- and late-onset (considered immune-mediated) toxicities with PI3K inhibitors, including infections, hepatotoxicity, diarrhea and/or colitis, and pneumonitis. Data on pretreatment considerations, toxicity management, and drug rechallenge are presented. In addition, next-generation PI3K inhibitors and novel treatment approaches with PI3K inhibitors, including combinations, time-limited treatments, and intermittent dosing, are highlighted.

The CLL12 trial: Ibrutinib versus placebo in treatment-naïve, early stage chronic lymphocytic leukemia

Blood ◽  
2021 ◽  
Author(s):  
Petra Langerbeins ◽  
Can Zhang ◽  
Sandra Robrecht ◽  
Paula Cramer ◽  
Moritz Fürstenau ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Adverse Events ◽  
Early Stage ◽  
Oral Anticoagulants ◽  
Lymphocytic Leukemia ◽  
Current Standard ◽  
Serious Adverse Events ◽  
Increased Risk ◽  
Risk Of Progression ◽  
Treatment Naïve

Observation is the current standard of care for patients with early stage asymptomatic chronic lymphocytic leukemia (CLL), as chemotherapy-based interventions have failed to prolong survival. We hypothesized that early intervention with ibrutinib would be well tolerated and lead to superior disease control in a subgroup of early stage patients with CLL. The phase 3, double-blind, placebo-controlled CLL12 trial randomly assigned asymptomatic, treatment-naïve Binet stage A CLL patients at increased risk of progression in a 1:1 ratio to receive ibrutinib (N=182) or placebo (N=181) at a dose of 420 mg daily. At a median follow up of 31 months the study met its primary endpoint by significantly improving event-free survival in the ibrutinib group (median, not reached vs. 47.8 months; hazard ratio=0.25; 95% confidence interval=0.14-0.43, P&lt;0.0001). Compared to placebo, ibrutinib did not increase overall toxicity, yielding similar incidence and severity of adverse events. The most common serious adverse events were atrial fibrillation, pneumonia and rash in the ibrutinib group, and basal cell carcinoma, pneumonia and myocardial infarction in the placebo group. Ibrutinib-associated risk for bleeding (33.5%) was decreased by prohibiting use of oral anticoagulants through an amendment of the study protocol and by avoiding CYP3A4 drug-drug interactions. Taken together, ibrutinib confirms efficacy in CLL patients at early stage with increased risk of progression. However, the results do not justify to change the current standard of 'watch and wait'. The trial is registered at clinicaltrials.gov as NCT02863718.

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