Ibrutinib outperforms chemoimmunotherapy in older patients with chronic lymphocytic leukaemia

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Published: 1 Dec 2018
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Dr Jennifer Woyach - The Ohio State University Comprehensive Cancer Center, Columbus, USA

Dr Jennifer Woyach gives a press conference at ASH 2018 about results from a trial of ibrutinib vs chemoimmunotherapy in older patients with chronic lymphocytic leukaemia.

Watch her interview with ecancer here.

Read the article about this work here

Good morning everybody. Today I’ll be discussing the results of the Alliance-led NCTN study A041202, a randomised phase III trial of bendamustine plus rituximab versus ibrutinib versus ibrutinib plus rituximab in untreated older patients with chronic lymphocytic leukaemia.

We undertook this study to determine the most effective therapy for older patients with CLL which makes up the majority of CLL patients. They have been traditionally under-represented in clinical trials unless they are designed specifically for this age group. At the time that the study was designed bendamustine plus rituximab was widely used in the community, based upon excellent data in the phase II setting. During this time the BTK inhibitor ibrutinib was just entering the clinic. Despite now widespread use in the front line following FDA approval for this indication in 2016, the efficacy of ibrutinib versus standard chemoimmunotherapy has not previously been investigated. We also designed this trial to answer the question of whether ibrutinib given in combination with the CD20 monoclonal antibody rituximab would be superior to ibrutinib given as a single agent. The addition of rituximab improves both progression free and overall survival when added to chemotherapy in CLL but it has been unknown whether this would improve outcomes with ibrutinib and this is the only phase III trial designed to answer this question.

In this study we enrolled previously untreated patients with CLL who were aged 65 or older and met criteria for the initiation of therapy by iwCLL guidelines. Patients were randomised one to one to one to bendamustine plus rituximab, ibrutinib given as standard daily dosing until disease progression, or ibrutinib given in combination with rituximab. The study did have a crossover design so patients enrolled on bendamustine plus rituximab who progressed had the option of crossing over to single agent ibrutinib.

644 patients were screened for the study and, of those, 547 patients from 219 sites across the United States and Canada were randomised to one of the three arms. The median age across all patients was 71 years, ranging from 65 to 89. 67% were male and 97% had a performance status of zero or one. 6% of patients had deletion of 17p on central FSH and 19% had a deletion of 11q. TP53 mutation on central analysis was seen in 10%. ZAP-70 unmethylated disease, which was defined as less than 20% methylation and equates to IgVH unmutated disease, was seen in 53% of patients. Besides this slightly higher percentage of patients on the ibrutinib plus rituximab arm having a complex karyotype, the three arms were well matched in terms of these baseline characteristics.

In the eligible patient population the progression free survival was significantly higher in the ibrutinib containing arms than the bendamustine plus rituximab arm with a hazard ratio of 0.39 for ibrutinib versus bendamustine/rituximab and 0.38 for ibrutinib plus rituximab versus bendamustine plus rituximab. There is no difference in progression free survival between ibrutinib and ibrutinib plus rituximab. 24 month progression free survival was 74% with bendamustine plus rituximab, 87% with ibrutinib and 88% with ibrutinib plus rituximab. Median progression free survival is 43 months with bendamustine plus rituximab and has not yet been reached for either of the ibrutinib containing arms.

The Forest plot here demonstrates progression free survival relative to our stratification factors, it’s shown for only ibrutinib versus bendamustine plus rituximab because ibrutinib and ibrutinib plus rituximab were similar. You can see that ibrutinib is superior to bendamustine plus rituximab throughout except for in those subgroups of patients with methylated ZAP-70 which equates to mutated IgVH where the trend is towards improved progression free survival with ibrutinib but has not yet reached statistical significance. At this time we do not have a difference in overall survival among the arms which may be due to the short follow-up as well as the crossover design.

Because the safety profile of these agents has been studied extensively our focus was primarily on grade 3 or higher adverse events that were of special interest with ibrutinib or were different among the arms. The adverse events presented here are all regardless of attribution and because of the time difference of the therapies they include all adverse events, both during active treatment as well as follow-up, excluding any crossover patients in the bendamustine/rituximab arm. Hematologic adverse events, specifically neutropenia and thrombocytopenia, were more prevalent with bendamustine plus rituximab whereas overall non-hematologic adverse events were more prevalent on the ibrutinib containing arms. High grade bleeding was uncommon and was not different among the arms. Atrial fibrillation was slightly more prevalent on the ibrutinib containing arms and hypertension was more common on the ibrutinib arms. Infections and sudden death, while numerically higher in the ibrutinib arms, do not reach statistical significance.

In conclusion, ibrutinib and ibrutinib plus rituximab results in a superior progression free survival compared with bendamustine plus rituximab in the front-line setting for older patients with CLL. The addition of rituximab does not improve progression free survival over ibrutinib alone. We do not have an overall survival difference at this time, likely again due to the crossover and relatively short follow-up. Importantly though, BTK inhibition is not without toxicity in this age group, including significant toxicities, so close monitoring remains important as well as strategies to limit toxicity through either the use of more selective BTK inhibitors or potentially limiting the duration of therapy are of great interest. Towards this goal I just would like to mention the next phase III co-operative group studies are the successor to this trial, A041702, and ECOG trial EA9161, which will both open in December 2018 and address the question of whether ibrutinib in combination with venetoclax and obinutuzumab as a strategy for discontinuation is superior to standard ibrutinib therapy. Thank you.