Study: Ibrutinib Produces Superior PFS to Standard Chemoimmunotherapy in Older Patients with CLL

Chronic lymphocytic leukemia (CLL) is a disease of older adults, with a median age of onset of about 70 years. Chemoimmunotherapy has become the gold standard of treatment, with the addition of CD20 antibody to chemotherapy prolonging survival. A study presented at the ASH annual meeting sought to compare standard chemoimmunotherapy against targeted therapy with the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib. The study also sought to evaluate the benefit of adding rituximab to ibrutinib in this patient population.

Ibrutinib has been approved by the U.S. Food and Drug Administration for use in untreated CLL since 2016. The Alliance A041202 study, a multicenter National Cancer Institute National Clinical Trials Network phase III study, evaluated ibrutinib against chemoimmunotherapy using three randomized arms:

• arm 1: the standard, aggressive chemoimmunotherapy regimen of bendamustine plus rituximab (BR)
• arm 2: ibrutinib alone
• arm 3: a combination of ibrutinib plus rituximab

Lead author Jennifer A. Woyach, MD, of Ohio State University Comprehensive Cancer Center in Columbus, Ohio, and her coauthors from Canada and many sites throughout the United States, examined differences in progression-free survival (PFS) among the three groups. They included patients who were 65 years or older with previously untreated CLL that was symptomatic. The sample had no other significant life-limiting illnesses. The median age of the initial sample was 71 years, and 67% of the patients were men.

The eligible sample included in the primary analysis was composed of 525 patients (Arm 1 = 176, Arm 2 = 178, and Arm 3 = 171). At a median follow-up of 32 months, median PFS was 41 months in Arm 1 but had not been reached in Arms 2 or 3. The researchers estimated two-year PFS to be 74% in Arm 1, 87% in Arm 2, and 88% in Arm 3. Of note, patients in Arm 1 could cross over to Arm 2 upon progression. The study had not yet found significant differences in overall survival. Median overall survival had not yet been reached in any arm.

When comparing treatment-emergent adverse events (AEs) among the three arms:

• arm 1:
  • grade 3 or higher hematologic AEs: 61%
  • grade 3 or higher non-hematologic AEs: 60%
  • grade 5 AEs: 2.8%
  • unexplained or unwitnessed death: 1.1%
• arm 2:
  • grade 3 or higher hematologic AEs: 41%
  • grade 3 or higher non-hematologic AEs: 72%
  • grade 5 AEs: 7.8%
  • unexplained or unwitnessed death: 3.9%
• arm 3:
  • grade 3 or higher hematologic AEs: 38%
  • grade 3 or higher non-hematologic AEs: 71%
  • grade 5 AEs: 7.7%
  • unexplained or unwitnessed death: 2.2%

The authors concluded that ibrutinib led to overall better PFS over chemoimmunotherapy in older patients with CLL, supporting its use as standard treatment. They did not find that the addition of rituximab to ibrutinib increased PFS, but they wrote that toxicities and cost limit ibrutinib’s continuous use over the long term.