Single-agent ibrutinib in treatment-naïve and relapsed/refractory chronic lymphocytic leukemia: a 5-year experience

O’Brien, Susan; Furman, Richard R.; Coutré, Steven; Flinn, Ian W.; Burger, Jan A.; Blum, Kristie A.; Sharman, Jeff P.; Wierda, William G.; Jones, Jeffrey A.; Zhao, Weiquiang; Heerema, Nyla A.; Johnson, Amy J.; Luan, Ying; James, Danelle F.; Chu, Alvina D.; Byrd, John C.

doi:10.1182/blood-2017-10-810044

Cited by 353 publications

(385 citation statements)

References 27 publications

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“…There were 15% grade 3‐4 neutropenia events but these did not lead to any treatment discontinuations . The follow‐up data at up to 7 years of this phase Ib/II trial ibrutinib trial continues to look promising . Similarly to results reported after 5‐year follow‐up, the median PFS and OS were shortest (26 and 57 months), in R/R patients with del(17p) when compared with those obtained in lower‐risk cytogenetic groups .…”

Section: Early Trials Of Ibrutinib Single Agent In the Setting Of R/rsupporting

confidence: 51%

Ibrutinib in the treatment of chronic lymphocytic leukemia: 5 years on

Molica

Matutes

Tam

et al. 2019

Hematological Oncology

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A major revolution in the treatment of chronic lymphocytic leukemia (CLL) began with the approval of ibrutinib, a first‐in‐class oral inhibitor of Bruton tyrosine kinase (BTK), for the treatment of relapsed/refractory (R/R) and/or TP53 mutated patients with CLL. However, 5 years later, some issues relating to this disorder still remain including the fact that with ibrutinib only a relatively small proportion of patients achieve complete remission and that ibrutinib‐resistant CLL clones can develop in about 20% of patients. In addition, therapy must still be given continuously, and toxicities leading to drug discontinuation occur in about 30% of patients. In the meantime second‐generation BTK inhibitors have already aroused considerable interest and gathered momentum. A possible strategy to overcome some of these obstacles is to combine ibrutinib with other targeted agents especially in high‐risk disease, such as previously treated refractory patients or those with TP53 aberrations or complex karyotypes, in whom rapid eradication of disease is most desirable. Therapy with single agent ibrutinib should be part of a sequential approach for patients with low risk disease, especially in older patients (aged >70 years) with a higher burden of comorbidities. Long‐term results of ongoing studies combining Ibrutinib with (chemo)‐immunotherapy or other targeted agents are eagerly awaited. Future clinical trials are indeed still needed to provide answers to these open questions.

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Section: Early Trials Of Ibrutinib Single Agent In the Setting Of R/rsupporting

confidence: 51%

Ibrutinib in the treatment of chronic lymphocytic leukemia: 5 years on

Molica

Matutes

Tam

et al. 2019

Hematological Oncology

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“…Ibrutinib, an oral inhibitor of BTK, has shown considerable single‐agent efficacy in CLL . However, the high cost of long‐term ibrutinib treatment together with potential adverse effects has raised concerns .…”

Section: Discussionmentioning

confidence: 99%

Itraconazole Increases Ibrutinib Exposure 10‐Fold and Reduces Interindividual Variation—A Potentially Beneficial Drug‐Drug Interaction

Tapaninen

Olkkola

Tornio

et al. 2019

Clinical Translational Sci

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The oral bioavailability of ibrutinib is low and variable, mainly due to extensive first‐pass metabolism by cytochrome P450 (CYP) 3A4. The unpredictable exposure can compromise its safe and effective dosing. We examined the impact of itraconazole on ibrutinib pharmacokinetics. In a randomized crossover study, 11 healthy subjects were administered itraconazole 200 mg or placebo twice on day 1, and once on days 2–4. On day 3, 1 hour after itraconazole (placebo) and breakfast, ibrutinib (140 mg during placebo; 15 mg during itraconazole) was administered. Itraconazole increased the dose‐adjusted geometric mean area under the concentration‐time curve from zero to infinity (AUC0–∞) of ibrutinib 10.0‐fold (90% confidence interval (CI) 7.2–13.9; P < 0.001) and peak plasma concentration (Cmax) 8.8‐fold (90% CI 6.3–12.1; P < 0.001). During itraconazole, the intersubject variation for the AUC0–∞ (55%) and Cmax (53%) was around half of that during placebo (104%; 99%). In conclusion, itraconazole markedly increases ibrutinib bioavailability and decreases its interindividual variability, offering a possibility to improved dosing accuracy and cost savings.

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“…Single‐agent ibrutinib given continuously confers prolonged progression‐free survival (PFS) with high overall response rates in relapsed/refractory (R/R) and treatment‐naïve (TN) patients with CLL (Byrd et al , , ; Burger et al , ). Complete remission is infrequent early on and increases with ongoing treatment (Barr et al , ; O'Brien et al , ), but few patients ever achieve undetectable minimal residual disease (MRD) (Burger et al , ). The oral BCL2 inhibitor, venetoclax, has demonstrated efficacy and deep responses in patients with R/R del(17p) CLL (Stilgenbauer et al , ), with up to an 83·5% undetectable MRD rate achieved in peripheral blood in combination with rituximab (Seymour et al , ).…”

Section: Baseline Measurements By Genomic Characteristicsmentioning

confidence: 99%

Tumour debulking and reduction in predicted risk of tumour lysis syndrome with single‐agent ibrutinib in patients with chronic lymphocytic leukaemia

et al. 2019

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Single-agent ibrutinib in treatment-naïve and relapsed/refractory chronic lymphocytic leukemia: a 5-year experience

Abstract: Key Points Our 5-year experience shows sustained single-agent efficacy of ibrutinib in CLL patients, with complete response rates increasing over time. Long-term ibrutinib was well tolerated with no new safety signals; rates of grade ≥3 cytopenias decreased with continued therapy.

Cited by 353 publications

References 27 publications

Ibrutinib in the treatment of chronic lymphocytic leukemia: 5 years on

Ibrutinib in the treatment of chronic lymphocytic leukemia: 5 years on

Itraconazole Increases Ibrutinib Exposure 10‐Fold and Reduces Interindividual Variation—A Potentially Beneficial Drug‐Drug Interaction

Tumour debulking and reduction in predicted risk of tumour lysis syndrome with single‐agent ibrutinib in patients with chronic lymphocytic leukaemia

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