SAN DIEGO -- First-line ibrutinib (Imbruvica) with or without rituximab topped standard chemoimmunotherapy in older chronic lymphocytic leukemia (CLL) patients, a phase III trial found.
Among patients ages ≥65, the rate of progression-free survival (PFS) at 24 months was 87% for those on ibrutinib alone compared with 74% for those treated with bendamustine (Treanda, Bendeka) and rituximab (HR 0.39, 95% CI 0.26-0.58, P<0.001), reported Jennifer Woyach, MD, of The Ohio State University Comprehensive Cancer Center in Columbus.
The study also looked at adding rituximab (Rituxan) to ibrutinib, and while the PFS rate at 2 years with the combination also proved superior to bendamustine and rituximab (88% vs 74%, HR 0.38, 95% CI 0.25-0.59, P<0.001), it was no better than ibrutinib monotherapy (HR 1.00, 95% CI 0.62-1.62, P=0.49).
At a press briefing at the American Society of Hematology (ASH) annual meeting, Woyach said no significant differences were seen with regard to overall survival (OS), likely due to the short follow-up (median 38 months) and cross-over design of the trial -- patients that progressed in the chemoimmunotherapy arm then received ibrutinib. Estimates of OS at 2 years were 95% in the chemoimmunotherapy arm, 90% in the ibrutinib-alone arm, and 94% in the ibrutinib-rituximab arm.
The results were published simultaneously in the .
Despite widespread use, the Bruton tyrosine kinase (BTK) inhibitor ibrutinib had never been compared directly to the modern standard treatment of bendamustine plus rituximab. The pivotal trial that led to its approval in untreated CLL and small lymphocytic lymphoma compared it with chlorambucil, a less effective therapy than bendamustine plus rituximab.
ASH briefing moderator David Steensma, MD, of Dana-Farber Cancer Institute in Boston, pointed out that ibrutinib upfront is already being used in the clinic.
"I think this really does indicate that ibrutinib as frontline therapy, which many clinicians have been doing, is a very reasonable practice," he said.
Significant benefit with ibrutinib alone was seen across various subgroups compared with chemoimmunotherapy:
- Intermediate Rai stage: HR 0.44
- High Rai stage: HR 0.33
- With del(17p) or del(11q): HR 0.26
- Without del(17p) or del(11q): HR 0.44
In general, Woyach told 51˶ patients should be treated with ibrutinib in the frontline setting given the PFS advantage in the trial, but offered a couple caveats -- one being for patients who have a strong desire for time-limited therapy.
"If they're in a very low-risk group and really don't want to take therapy beyond six cycles; I suppose bendamustine plus rituximab is still a reasonable option for them," she said.
She also said that for patients with certain comorbid conditions -- such as poorly controlled atrial fibrillation or a history of arrhythmias -- a chemoimmunotherapy regimen may be more appropriate.
Woyach said that in this older group, there does not appear to be any patients that benefit from the addition of rituximab, though she noted that based on anecdotal evidence, she could still see using the CD20-directed antibody if trying to control autoimmune hemolytic anemia, or potentially for those with a very high white blood cell count at baseline.
As for any potential for bendamustine plus ibrutinib in the upfront setting, Woyach said there's no reason to evaluate the two together.
"There's been no studies that have shown that there's an added benefit of bendamustine to ibrutinib," she said. "Certainly ibrutinib helps bendamustine, but the other way around I don't think we know that is the case."
In terms of hematologic adverse events (AEs) -- such as anemia, neutropenia, and thrombocytopenia -- 61% of the patients in the chemoimmunotherapy arm experienced grade ≥3 events, compared with 39% of those in the ibrutinib-rituximab group and 41% of those on ibrutinib alone. Neutropenia was the most common of these, occurring in 40%, 21%, and 15% of the three arms, respectively.
Grade ≥3 non-hematologic AEs were lower in the chemoimmunotherapy arm (63% vs 74% for each of the ibrutinib arms).
"BTK inhibition is not without toxicity in this age group, including significant toxicity, so close monitoring is warranted," said Woyach.
The Alliance North American Intergroup Study A041202 randomized 547 patients 1:1:1 to the three regimens. All patients met International Workshop Group on CLL criteria for treatment.
Patients in the ibrutinib monotherapy arm received a 420-mg daily dose until disease progression, and those in the ibrutinib plus rituximab group also received weekly rituximab at 375 mg/m2 for 4 weeks starting on cycle 2, then just on the first day of cycles 3-6.
In the chemoimmunotherapy group, patients received 90-mg/m2 bendamustine on the first 2 days of each 28-day cycle plus rituximab at a dose of 375 mg/m2 in the first cycle and 500 mg/m2 in cycles 2-6.
Arms were well balanced by sex, age (median 70-71), as well as del(17p) or del(11q), TP53 mutation, complex karyotype, IgVH mutation, and Zap-70 methylation status. Nearly all patients had good performance status (ECOG 0-1). Men made up the majority (67%) of study participants.
Disclosures
The study was funded by Pharmacyclics and the National Cancer Institute.
Woyach disclosed relevant relationships with Janssen, Karyopharm, MorphoSys, AbbVie, and Acerta. Co-authors disclosed multiple relevant relationships with industry including Pharmacyclics, Janssen, Seattle Genetics, AstraZeneca, Merck, Genentech, Teva, AbbVie, Celgene, Gilead, Pfizer, and Novartis.
Primary Source
New England Journal of Medicine
Woyach JA, et al "Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL" N Eng J Med 2018; DOI: 10.1056/NEJMoa1812836.