Comparable outcomes in chronic lymphocytic leukaemia (<scp>CLL</scp>) patients treated with reduced‐dose ibrutinib: results from a multi‐centre study

Mato, Anthony R.; Timlin, Colleen; Ujjani, Chaitra S.; Skarbnik, Alan P; Howlett, Christina; Banerjee, Rahul; Nabhan, Chadi; Schuster, Stephen J.

doi:10.1111/bjh.14540

Cited by 55 publications

(59 citation statements)

References 9 publications

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“…This would suggest that the ideal treatment strategy would be to recommend initiation of therapy at standard dosing and interruption as needed as directed in the FDA label. Two studies have reported no negative impact for patients requiring dose reductions 16, 17 , however differences may be attributable to population differences and timing of reductions. The present analyses focus on patients with early incomplete adherence and possibly represents a group that is at greater risk of poor adherence and subsequent poor outcomes.…”

Section: Discussionmentioning

confidence: 99%

Ibrutinib Dose Adherence and Therapeutic Efficacy in Non-Hodgkin Lymphoma: A Single-Center Experience

Williams

Baran

Casulo

et al. 2019

Clinical Lymphoma Myeloma and Leukemia

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Background: As oral targeted agents, such as ibrutinib, become more widely used understanding the impact of suboptimal dosing on overall and progression-free survival outside of clinical trials is imperative. Methods: Data on ibrutinib discontinuation, dose reductions and treatment interruptions were collected on 170 non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL n=115, 64%) patients treated with ibrutinib at a single institution. Ibrutinib dose adherence was calculated as the proportion of days in which ibrutinib was administered out of the total number of days ibrutinib was prescribed in the first 8 weeks. Kaplan-Meier curves and log-rank tests were used to compare conditional survival outcomes beyond 8 weeks in patients ≥80% dose adherence and patients <80% dose adherence. Results: Median overall survival among those that discontinued for progression was poor (n=51, 1.7 months, 95%CI 0.3–3.7). Lower dose adherence (<80%) was associated with significantly worse progression-free (p=0.002) and overall survival (p=0.024). However, among CLL patients, lower dose adherence was only associated with worse progression-free survival (p=0.043). Patients with early dose reductions had significant worse PFS (p=0.004) and OS (p=0.014). Patients with dose interruptions lasting > 1 week had worse PFS (p=0.047) but not OS (p=0.577). Conclusion: In this observational study, NHL and CLL patients demonstrated poor outcomes after discontinuing ibrutinib for disease progression. The inferior survival related to suboptimal dose adherence of ibrutinib was predominantly due to early dose reduction. These data confirm poor survival in CLL and lymphoma patients alike after ibrutinib discontinuation and support recommendations for full dose at treatment initiation.

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Section: Discussionmentioning

confidence: 99%

Ibrutinib Dose Adherence and Therapeutic Efficacy in Non-Hodgkin Lymphoma: A Single-Center Experience

Williams

Baran

Casulo

et al. 2019

Clinical Lymphoma Myeloma and Leukemia

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“…Clinical outcome data at lower doses are limited. One retrospective investigation of 197 ibrutinib-treated patients reported similar ORR, PFS and OS in 37 patients (19%) receiving a reduced median dose of 4.3 mg/kg/day 61 . The UK and Ireland expanded access program also did not report reduced OS in patients who had dose reductions 11 .…”

Section: Is Dose Reduction or Drug Holiday A Good Solution?mentioning

confidence: 99%

How I treat CLL patients with ibrutinib

Brown

2018

Blood

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Ibrutinib is a transformative therapy for high-risk and relapsed refractory chronic lymphocytic leukemia (CLL) patients. In clinical trials in relatively healthy younger patients, ibrutinib has been well tolerated. As its use has become more widespread in the community, however, its full adverse event profile has emerged and proven more challenging than was initially anticipated. Reports of community-based use have estimated discontinuation rates as high as 40% in the first year of therapy. This article therefore reviews my approach to the evaluation and management of a CLL patient starting on ibrutinib, with the goal of minimizing and managing toxicity to maintain patients on ibrutinib. Key topics discussed include bleeding risk; cardiac complications, particularly atrial fibrillation; drug interactions; and infections.

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“…Sustained adherence to Tyrosine Kinase Inhibitor (TKI) has been shown to be an important factor in achieving efficacy of treatment in chronic myeloid leukemia . In CLL, however, it is still unclear whether intermittent interruption of ibrutinib therapy influences clinical outcomes . In the RESONATE trial a mean ibrutinib dose intensity <95% was associated with inferior PFS, but had no effect on OS .…”

Section: Adherence To Ibrutinib: Still An Open Issuementioning

confidence: 99%

“…In a real‐world experience of reduced dose ibrutinib in CLL (n = 197pts). Mato et al demonstrated that ibrutinib dose reduction does not affect clinical outcomes. Given that ibrutinib irreversibly binds to its target, the rate of BTK saturation might have minimal effect on drug efficacy; this is of particular interest during the period of treatment when the amount of ibrutinib required to achieve the same target occupancy may be less .…”

Section: Adherence To Ibrutinib: Still An Open Issuementioning

confidence: 99%

“…38 In CLL, however, it is still unclear whether intermittent interruption of ibrutinib therapy influences clinical outcomes. [39][40][41][42][43] In the RESONATE trial a mean ibrutinib dose intensity <95% was associated with inferior PFS, but had no effect on OS. 39 A real life study by the UK CLL Forum reported that treatment interruptions >14 days within the first year of ibrutinib therapy were associated with inferior OS.…”

Section: Adherence To Ibrutinib: Still An Open Issuementioning

confidence: 99%

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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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Comparable outcomes in chronic lymphocytic leukaemia (CLL) patients treated with reduced‐dose ibrutinib: results from a multi‐centre study

Cited by 55 publications

References 9 publications

Ibrutinib Dose Adherence and Therapeutic Efficacy in Non-Hodgkin Lymphoma: A Single-Center Experience

Ibrutinib Dose Adherence and Therapeutic Efficacy in Non-Hodgkin Lymphoma: A Single-Center Experience

How I treat CLL patients with ibrutinib

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

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