Dataset Information

Ibrutinib for relapsed/refractory chronic lymphocytic leukemia: a UK and Ireland analysis of outcomes in 315 patients.

ABSTRACT: In 2014, ibrutinib was made available for relapsed/refractory chronic lymphocytic leukemia patients. The UK Chronic Lymphocytic Leukaemia Forum collected data from UK/Ireland patients with a minimum of 1 year follow-up with pre-planned primary endpoints; the number of patients still on therapy at 1 year "discontinuation-free survival" and 1 year overall survival. With a median of 16 months follow up, data on 315 patients demonstrated a 1 year discontinuation-free survival of 73.7% and a 1 year overall survival of 83.8%. Patients with better pre-treatment performance status (0/1 vs. 2+) had superior discontinuation-free survival (77.5% vs. 61.3%; P<0.0001) and overall survival (86.3% vs. 76.0%; P=0.0001). In univariable analysis, overall survival and discontinuation-free survival were not associated with the number of prior lines of therapy or 17p deletion. However, multivariable analysis identified an interaction between prior lines of therapy, age and 17p deletion, suggesting that older patients with 17p deletion did worse when treated with ibrutinib beyond the second line. Overall, 55.6% of patients had no first year dose reductions or treatment breaks of >14 days and had an overall survival rate of 89.7%, while 26% of patients had dose reductions and 13% had temporary treatment breaks of >14 days. We could not demonstrate a detrimental effect of dose reductions alone (1 year overall survival: 91.7%), but patients who had first year treatment breaks of >14 days, particularly permanent cessation of ibrutinib had both reduced 1 year overall survival (68.5%), and also a statistically significant excess mortality rate beyond one year. Although outcomes appear inferior to the RESONATE trial (1 year overall survival; 90%: progression-free survival; 84%), this may partly reflect the inclusion of performance status 2+ patients, and that 17.5% of patients permanently discontinued ibrutinib due to an event other than disease progression.

SUBMITTER: UK CLL Forum

PROVIDER: S-EPMC5479600 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Ibrutinib for relapsed/refractory chronic lymphocytic leukemia: a UK and Ireland analysis of outcomes in 315 patients.

Haematologica 20161018 12

In 2014, ibrutinib was made available for relapsed/refractory chronic lymphocytic leukemia patients. The UK Chronic Lymphocytic Leukaemia Forum collected data from UK/Ireland patients with a minimum of 1 year follow-up with pre-planned primary endpoints; the number of patients still on therapy at 1 year "discontinuation-free survival" and 1 year overall survival. With a median of 16 months follow up, data on 315 patients demonstrated a 1 year discontinuation-free survival of 73.7% and a 1 year o ...[more]

PMID: 27756834

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Project description:Purpose of reviewThere have been significant advances in the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL) over the past two decades. However, the intention of treatment remains control of the disease and delay of progression rather than a cure which remains largely elusive. Considering that CLL is mostly seen in older patients, there are multiple factors that play a role in the selection of CLL beyond the frontline treatment. Here, we review the concept of relapsed CLL, factors that predispose to relapse, and therapeutic options available to this patient population. We also review investigational therapies and provide a framework for selection of therapies in this setting.Recent findingsPlease check if the affiliations are presented correctly.Targeted therapies with continuous BTK inhibitors (BTKi) or fixed duration venetoclax plus anti-CD20 monoclonal antibody therapy have established superiority over chemoimmunotherapy in relapsed CLL and have become the preferred standard of care treatment. The second-generation more selective BTK inhibitors (acalabrutinib and zanubrutinib) have shown improved safety profile compared to ibrutinib. However, resistance to the covalent BTK inhibitors may emerge and is commonly associated with mutations in BTK or other downstream enzymes. The novel non-covalent BTK inhibitors such as pirtobrutinib (Loxo-305) and nemtabrutinib (ARQ 531) are showing promising activities for relapsed CLL refractory to prior covalent BTKi. Other novel therapies such as chimeric antigen receptor (CAR) T cell therapy have also shown significant activities for relapsed and refractory CLL. Measurable residual disease (MRD) assessment has a growing importance in venetoclax-based limited-duration therapy and there is mounting evidence that MRD negativity improves outcomes. However, it remains to be seen if this will become an established clinically significant endpoint. Further, the optimal sequence of various treatment options remains to be determined. Patients with relapsed CLL now have more options for the treatment of the disease. The choice of therapy is best individualized especially in the absence of direct comparisons of targeted therapies, and the coming years will bring more data on the best sequence of use of the therapeutic agents.

Project description:PurposeZanubrutinib is a potent, irreversible next-generation Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupancy and minimize off-target kinase inhibition. We hypothesized that complete/sustained BTK occupancy may improve efficacy outcomes and increased BTK specificity may minimize off-target inhibition-related toxicities.Patients and methodsALPINE (ClinicalTrials.gov identifier: NCT03734016) is a global, randomized, open-label phase III study of zanubrutinib versus ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia. The primary end point was investigator-assessed overall response rate (ORR). The preplanned interim analysis was scheduled approximately 12 months after the first 415 patients were enrolled.ResultsBetween November 1, 2018, and December 14, 2020, 652 patients were enrolled. We present the interim analysis of the first 415 enrolled patients randomly assigned to receive zanubrutinib (n = 207) or ibrutinib (n = 208). At 15 months of median follow-up, ORR (partial or complete response) was significantly higher with zanubrutinib (78.3%; 95% CI, 72.0 to 83.7) versus ibrutinib (62.5%; 95% CI, 55.5 to 69.1; two-sided P < .001). ORR was higher with zanubrutinib versus ibrutinib in subgroups with del(17p)/TP53 mutations (80.5% v 50.0%) and del(11q) (83.6% v 69.1%); 12-month progression-free survival in all patients was higher with zanubrutinib (94.9%) versus ibrutinib (84.0%; hazard ratio, 0.40; 95% CI, 0.23 to 0.69). Atrial fibrillation rate was significantly lower with zanubrutinib versus ibrutinib (2.5% v 10.1%; two-sided P = .001). Rates of cardiac events, major hemorrhages, and adverse events leading to treatment discontinuation/death were lower with zanubrutinib.ConclusionZanubrutinib had a significantly higher ORR, lower atrial fibrillation rate, and improved progression-free survival and overall cardiac safety profile versus ibrutinib. These data support improved efficacy/safety outcomes with selective BTK inhibition.

Dataset Information

Ibrutinib for relapsed/refractory chronic lymphocytic leukemia: a UK and Ireland analysis of outcomes in 315 patients.

Publications

Ibrutinib for relapsed/refractory chronic lymphocytic leukemia: a UK and Ireland analysis of outcomes in 315 patients.

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