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Ibrutinib is superior to chemo-immunotherapy in older patients with chronic lymphocytic leukemia

Results of a phase III trial presented during the Presidential symposium of the 2018 annual meeting of the American Society of Hematology (ASH) show that older patients with chronic lymphocytic leukemia (CLL) have a significantly lower rate of disease progression if they are treated with the targeted therapy ibrutinib rather than with the combination of bendamustine and rituximab. In addition, this trial demonstrated that adding rituximab to ibrutinib does not add benefits beyond those seen with ibrutinib alone. As such, these results establish ibrutinib as a new standard of care for older patients with CLL.

Chemo-immunotherapy (CIT) has been the gold standard for CLL since studies showed that addition of an anti-CD20 antibody to chemotherapy prolongs survival. In younger, fit patients this CIT regimen normally consists of fludarabine-cyclophosphamide and rituximab (FCR), while in elderly patients (>65 years) the combination of bendamustine with rituximab (BR) is an established standard of care. Since 2016, the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib is approved by the FDA and the EMA for untreated CLL patients. However, ibrutinib has only been compared to chlorambucil, which is a relatively ineffective treatment, and it has never been compared to a more aggressive CIT regimen. Additionally, the benefit of combining ibrutinib with rituximab in this setting has not been prospectively studied in a phase III trial. The phase III, Alliance North American Intergroup Study A041202 sought to answer these important clinical questions.

In the study at hand, 547 patients with previously untreated, symptomatic CLL aged 65 years or older were randomly assigned to receive bendamustine (90 mg/m2 days 1 and 2 of each 28-day cycle) plus rituximab (375 mg/m2 day 0 of cycle 1, then 500 mg/m2 on day 1 of cycles 2-6; arm A: BR), ibrutinib alone (420 mg daily until disease progression; arm B: I), or ibrutinib at the same dose in combination with rituximab (375 mg/m2 weekly for 4 weeks starting cycle 2 day 1, then day 1 of cycles 3-6; arm C: IR). The primary endpoint of the study was progression-free survival (PFS). The median age of patients in the study was 71 years (range 65-89), 67% was male and 97% had an ECOG performance status 0-1. The median white blood cell count was 82 x 103/μL, 6% of patients harboured a del(17p) and 19% had a del(11q). High-risk RAI stage (stage III/IV) was seen in 54%, 10% had a TP53 mutation and IGHV was unmutated in 61% of patients.

The PFS was found to be significantly longer in patients treated with I compared to BR (median not reached vs. 41 months; HR[95%CI]: 0.37[0.25-0.56]). Also with IR, the median PFS was not reached (IR vs. BR, HR: 0.41, p<0.0001). At 2 years, the PFS estimates were 74%, 87% and 88% for BR, I and IR, respectively. As such, both ibrutinib-containing treatment regimens were found to be superior to BR. In contrast, the addition of rituximab to ibrutinib did not appear to improve outcomes compared with ibrutinib alone. The PFS benefit of I over BR was seen in all investigated subgroups and was found to be more pronounced in patients with worse prognostic features, including patients with a high-risk RAI disease (HR[95%CI]: 0.33[0.18-0.60]), and patients with a del(17p) or del(11q) (HR[95%CI]: 0.26[0.12-0.56]). There was no difference in overall survival (OS) among the three groups at two years. Of note, patients with disease progression after receiving BR crossed over to receive I as a second-line treatment, which will have an important impact on the OS analysis in this study. Overall, patients responded well to all three treatment regimens, with an overall response rate (ORR) of 94% with I alone, 93% with IR and 81% in the BR arm.

Compared to BR, I alone was associated with a lower rate of hematological toxicity (41% vs. 61%) especially with respect to neutropenia (15% vs. 40%). The incidence of non-hematological toxicity was slightly higher with ibrutinib than with BR at 74% vs. 63%. Particularly the higher incidence of atrial fibrillation (9% vs. 3%) and hypertension (29% vs. 15%) warrant further study and caution in using this drug in all older patients.

In summary, ibrutinib or ibrutinib plus rituximab were found to be significantly more effective than BR in the frontline treatment of older CLL patients. Rituximab does not improve PFS over ibrutinib alone. Importantly, BTK inhibition with ibrutinib is not without significant toxicity in older patients, so close monitoring is still warranted. In this respect, strategies to discontinue therapy are of great interest.


J. Woyach, Ruppert AS, Heerema NA, et al. Ibrutinib alone or in combination with rituximab produces superior progression free survival (PFS) compared with bendamustine plus rituximab in untreated older patients with chronic lymphocytic leukemia (CLL): results of Alliance North American Intergroup Study A041202. Presented at ASH 2018; Abstract 6.

Speaker Jennifer Woyach


Jennifer A. Woyach, MD The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA,


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