Ibrutinib-based regimen superior to standard chemoimmunotherapy in chronic lymphocytic leukemia

Issue: February 25, 2019

Tait D. Shanafelt

SAN DIEGO — The combination of ibrutinib and rituximab conferred superior PFS and OS compared with standard chemoimmunotherapy among previously untreated younger patients with chronic lymphocytic leukemia, according to a phase 3 randomized study presented during the late-breaking abstract session at ASH Annual Meeting and Exposition.

Researchers say these findings have immediate practice-changing implications and establish ibrutinib (Imbruvica; Pharmacyclics, Janssen)-based therapy as the most effective first-line treatment for patients with CLL.

“Over the last 5 years we’ve had better understanding of the B-cell receptor signaling pathway in CLL, which is really the Achilles heel of CLL,” Tait D. Shanafelt, MD, chief wellness officer and director for the WellMD Center at Stanford Medicine, said during a press conference. “This pill-based therapy targets… that pathway. Although the agent has been shown to be effective as an initial treatment for older patients, we have never had good trials comparing it to our most effective chemoimmunotherapy regimen.”

Shanafelt and colleagues randomly assigned 529 treatment-naive patients with CLL who were aged 70 years or younger in a 2:1 ratio to ibrutinib and rituximab (Rituxan; Genentech, Biogen; n = 354; median age, 58 years; 33.3% women) or fludarabine, cyclophosphamide and rituximab (n = 175; median age, 57 years; 31.4% women).

Nineteen patients did not initiate protocol therapy.

Patients in the ibrutinib group received the Bruton tyrosine kinase inhibitor at 420 mg a day until disease progression and rituximab at 50 mg/m² on day 1 of cycle 2, 325 mg/m² on day 2 of cycle 2, and 500 mg/m² on day 1 of cycles 3 to 7.

Patients treated with the standard therapy received six courses of IV fludarabine at 25 mg/m² and cyclophosphamide at 250 mg/m² on days 1 to 3 with rituximab at 50 mg/m² on day 1 of cycle 1, 325 mg/m² on day 2 of cycle 1, and 500 mg/m² on day 1 of cycles 2 to 6 every 28 days.

PFS served as the primary endpoint, and OS served as the secondary endpoint.

The first interim analysis was conducted in September.

After median follow-up of 33.4 months, there were 77 PFS events (ibrutinib, 37; vs. chemoimmunotherapy, 40) and 14 deaths (4 vs. 10).

HRs favored the ibrutinib-based therapy over the chemoimmunotherapy combination for PFS (HR = 0.35; 95% CI, 0.22-0.55) and OS (HR = 0.17; 95% CI, 0.05-0.54).

A subgroup analysis for PFS showed that the ibrutinib-based treatment was superior to the standard treatment regardless of age, sex, performance status, disease stage, or in the presence or absence of del11q23.

Researchers also found that the ibrutinib-rituximab combination was superior for IGHV-unmutated patients (HR = 0.26; 95% CI, 0.13-0.49), but not IGHV-mutated patients (HR = 0.43; 95% CI, 0.14-0.13).

Grade 3 and grade 4 treatment-related adverse events occurred among 58.5% of patients who received the ibrutinib-based therapy and 72.1% of patients who received the standard therapy (P = .004).

More patients assigned standard chemoimmunotherapy experienced neutropenia (43.7% vs. 22.7%), anemia (12% vs. 2.6%), thrombocytopenia (13.9% vs. 2.9%) and infectious complications (19% vs. 7.1%; P < .0001 for all).

“The new therapy was less toxic than our historical therapy,” Shanafelt said. “Obviously in cancer trials we want to improve the effectiveness in treatment or reduce its side effects. This trial is one of the rare circumstances, where we’ve done both.”– by John DeRosier

Reference:

Shanafelt T, et al. Presented at: ASH Annual Meeting and Exposition; Dec. 1-4, 2018; San Diego.

Disclosures: Shanafelt reports patents and royalties licensed to Mayo Clinic and research funding from AbbVie, Celgene, Genentech, GlaxoSmithKline, Janssen and Pharmacyclics. Please see the abstract for all other authors’ relevant financial disclosures.