This article is more than 5 years old. Information may no longer be current.
Ibrutinib alone, with rituximab improves PFS in chronic lymphocytic leukemia
Click Here to Manage Email Alerts
SAN DIEGO — The use of ibrutinib alone or with rituximab prolonged PFS compared with bendamustine plus rituximab among previously untreated older patients with chronic lymphocytic leukemia, according to results of a randomized phase 3 study presented during the plenary session at ASH Annual Meeting and Exposition.
Findings of the study — which is the first head-to-head comparison of the targeted Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica; Pharmacyclics, Janssen) with the standard-of-care chemotherapy/antibody regimen for CLL — also suggested the addition of rituximab (Rituxan; Genentech, Biogen) to ibrutinib does not add benefit.
“Our goal in designing this study was to advance therapy for our older patients with CLL, which make up the majority of CLL patients,” Jennifer A Woyach, MD, associate professor in the department of internal medicine at The Ohio State University Comprehensive Cancer Center, told HemOnc Today. “Most of the definitive clinical trials in CLL that have not been specifically designed for this age group have accrued much younger patients, so it is difficult to know if results can be generalized to the entire patient population.”
Researchers enrolled 547 previously untreated patients aged 65 to 89 years (median age, 71 years; 67% men), 54% of whom had high-risk Rai stage, 53% of whom had unmethylated Zap-70, 6% of whom had del(17p), and 19% of whom had del(11q).
Researchers randomly assigned patients to one of three groups:
- bendamustine plus rituximab (n = 183; group 1);
- ibrutinib alone (n = 182; group 2); and
- ibrutinib plus rituximab (n = 182; group 3).
At the time of progression, patients in group 1 could cross over to group 2.
PFS served as the study’s primary endpoint.
Median follow-up was 38 months.
Overall, 525 patients (96%) were eligible for the primary PFS analysis (group 1, n = 176; group 2, n = 178; group 3, n = 171).
A greater proportion of patients assigned ibrutinib plus rituximab achieved 2-year PFS (88%; 95% CI, 81-92) compared with ibrutinib alone (87%; 95% CI, 81-92) or bendamustine and rituximab (74%; 95% CI, 66-80).
Median PFS was 43 months with bendamustine plus rituximab, but was not yet reached for either of the ibrutinib-containing arms.
Ibrutinib alone vs. bendamustine and rituximab significantly reduced the risk for progression (HR = 0.37; 95% CI, 0.25-0.56), with a similar HR observed for the ibrutinib and rituximab arm. This benefit persisted in all patient subgroups except for those with methylated Zap-70, for whom researchers observed a trend toward improved survival with ibrutinib; however, it did not reach statistical significance (HR = 0.82; 95% CI, 0.45-1.48).
Researchers reported no differences in 2-year OS (group 1, 95%; group 2, 90%; group 3, 94%), and median OS had not yet been reached. The lack of OS difference is likely due to short follow-up and cross over between the arms, Woyach said during a press conference.
The addition of rituximab to ibrutinib did not appear to improve outcomes. Overall response rates were 94% for ibrutinib alone, 93% for ibrutinib plus rituximab, and 81% for bendamustine plus rituximab.
“Preclinical data suggest that the interleukin-2–inducible kinase, or ITK, inhibition with ibrutinib prevents natural killer cell-mediated antibody-dependent cell-mediated cytotoxicity, which would make antibodies like rituximab less effective,” Woyach told HemOnc Today. “This has not been shown to be the case in patients, but could explain the lack of benefit.”
Grade 3 or worse treatment-related hematologic adverse events were more common in the bendamustine and rituximab group, occurring among 61% of patients in group 1, 41% in group 2, and 38% in group 3 (P < .0001). Significantly more patients assigned brentuximab vedotin than ibrutinib alone or with rituximab experienced neutropenia (40% vs. 15% vs. 21%; P < .001), thrombocytopenia (15% vs. 7% vs. 5%; P = .008) and febrile neutropenia (7% vs. 2% vs. 1%; P < .001).
Conversely, grade 3 or worse nonhematologic treatment-related adverse events occurred among more of those in the ibrutinib groups, with incidences of 60% in group 1, 72% in group 2, and 71% in group 3 (P = .03).
Specifically, more patients assigned ibrutinib alone or with rituximab than bendamustine and rituximab experienced hypertension (29% vs. 34% vs. 15%; P < .001) and atrial fibrillation (9% vs. 6% vs. 3%; P = .05). Infections and sudden death also were more common in the ibrutinib arms, but the difference did not reach statistical significance.
Grade 5 adverse events occurred in five patients (2.8%) in group 1, 14 (7.8%) in group 2, and 14 (7.7%) in group 3.
“Importantly, Bruton tyrosine kinase inhibition is not without toxicity in this age group, including significant toxicity,” Woyach said during the press conference. “So, close monitoring remains important, and strategies to limit toxicities through the use of more selected Bruton tyrosine kinase inhibitors or potentially limiting the duration of therapy are of great interest.”
Despite these adverse events, the benefits still appear to outweigh the risks, she added.
“Overall survival is not different among the arms, but is not worse with ibrutinib or ibrutinib plus rituximab than for bendamustine plus rituximab,” Woyach told HemOnc Today. “We and other groups are working to try to figure out which patients are more at risk for side effects, so that those patients could potentially be directed toward other therapies.”
The successor to this study, A041702, is scheduled to begin enrollment this month and will evaluate whether ibrutinib given in combination with venetoclax (Venclexta; AbbVie, Genentech) and obinutuzumab (Gazyva, Genentech) with response-directed discontinuation of therapy is better than standard ibrutinib, Woyach said.
“I think this will be a very important study in this age group,” she said. “As well, studies of newer generation Bruton tyrosine kinase inhibitors are also of interest because of the potential for improved safety profiles.” – by Alexandra Todak
Reference:
Woyach JA, et al. Abstract 6. Presented at: ASH Annual Meeting and Exposition; Dec. 1-4, 2018; San Diego.
Disclosures: Woyach reports no relevant financial disclosures. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
Back to Top
Brian Hill, MD, PhD
The median age at CLL diagnosis is 72 years, making the randomized study of frontline bendamustine plus rituximab for six cycles vs. ibrutinib with or without rituximab in CLL patients aged 65 years or older particularly relevant to the oncology community. PFS appeared significantly pronged with ibrutinib with or without rituximab relative to bendamustine plus rituximab. So, does this mean that all patients with CLL in need of treatment should take ibrutinib in perpetuity?
Despite the widespread appeal of a “chemotherapy-free” approach, taking ibrutinib indefinitely does not translate into a “toxicity-free” treatment course. In fact, the rate of cumulative grade 3 or worse nonhematologic adverse events was higher in the ibrutinib arms, at 74% vs. 63% with bendamustine plus rituximab (P = .04). Among the 361 patients who received ibrutinib with or without rituximab, there were deaths due to infection/sepsis (n = 9) and intracranial hemorrhage (n = 3), as well as unexplained or unwitnessed deaths (11 out of 361 with ibrutinib vs. 2 out of 176 with bendamustine plus rituximab). So, despite superior disease control, there was no difference in 2-year OS between bendamustine plus rituximab (95%) and ibrutinib (90%) or ibrutinib with rituximab (94%).
The authors are to be commended for executing a prospective randomized trial that informs treatment decisions about frontline treatment for CLL. The results confirm that bendamustine plus rituximab is a safe and effective time-limited treatment. The study also shows that continuous targeted therapy improves PFS over time-limited therapy, but with an extremely high financial cost as well as ongoing cumulative risk for toxicity with a concerning signal for sudden death, possibly due to ventricular arrhythmias.
For the minority of patients with high-risk cytogenetic features (17p or 11q deletion), the benefit of superior disease control likely outweighs these drawbacks. However, for low-risk disease — such as mutated IgVH and/or 13q deletion — patients and physicians may prefer time-limited therapy with bendamustine plus rituximab and opt for novel agents at progression. This study confirms that doing so will not compromise OS and is associated with lower cumulative rates of adverse events.
What is the optimal treatment for patients who progress after bendamustine plus rituximab? It is worth noting that venetoclax plus rituximab is an emerging time-limited therapy associated with a high rate of deep remissions and may obviate the need to expose all patients with CLL to the cost, risk and toxicity of indefinite ibrutinib.
References:
Guha A, et al. J Am Coll Cardiol. 2018;doi:
Lampson BL, et al. Blood. 2017;doi:10.1182/blood-2016-10-742437.
Seymour JF, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1713976.
Woyach JA, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1812836.
Perspective
Back to Top
David Steensma, MD
Ibrutinib’s approval for CLL is a bit funny — it was compared with chlorambucil, which very few patients use anymore. The standard of care for CLL among older patients has been the combination of bendamustine and rituximab, and the question this study addressed was, does ibrutinib alone, or with rituximab, improve disease progression in comparison with bendamustine?
This practice of using ibrutinib is already being done in the clinic. We’ve had other agents just approved for CLL, such as duvelisib (Copiktra, Verastem Oncology) and venetoclax, but these have been used primarily in the relapsed/refractory setting. This study really does indicate the ibrutinib as frontline therapy, which many clinicians have been doing, is a very reasonable practice.
Click Here to Manage Email Alerts