San Diego, California—Combining ibrutinib therapy with rituximab in young, treatment-naïve patients with chronic lymphocytic leukemia (CLL) led to survival outcomes that outshined those seen with the gold standard of care regimen for untreated CLL, according to results from a clinical trial presented at the 2018 ASH Annual Meeting.

“Over the last 15 years, a series of phase 3 trials have established that chemoimmunotherapy…with fludarabine, cyclophosphamide, and rituximab (FCR) improves both progression free survival (PFS) and overall survival (OS) compared with chemotherapy alone,” explained lead investigator Tait D. Shanafelt, MD, Stanford University, Stanford, California, and colleagues, adding that FCR is considered the gold standard treatment regimen for young, fit, treatment-naïve patients with CLL.

Previous studies demonstrating the robust and durable efficacy of ibrutinib in patients with relapsed or refractory disease have preceded phase 3 trials yielding improved survival rates in older patients with untreated CLL.

“Despite these advances, the efficacy of ibrutinib as a first-line treatment for younger CLL patients (i.e. <70) relative to the most efficacious chemoimmunotherapy regimens, such as FCR, is unknown,” Dr Shanafelt and colleagues said.

Thus, they conducted a phase 3 clinical trial comparing the efficacy of ibrutinib plus rituximab with that of FCR in young, treatment-naïve patients with CLL.

Patients were eligible for enrollment in the trial if they were aged ≤70 years and had untreated CLL that required therapy. Those with 17p deletion were excluded because of the poor response seen in these patients treated with FCR. The primary end point was PFS and the secondary end point was OS.

Dr Shanafelt and colleagues conducted their analysis by intention-to-treat; the first interim analysis for PFS was slated to occur 24 to 27 months after patient accrual was complete, and the first interim analysis for OS was scheduled for when the boundary for PFS was crossed.

They graded hematologic toxicity per the 2008 IWCLL Working Group scale, and all other adverse events according to the National Cancer Institute Common Toxicity Criteria (v.4).

Between January 31, 2014, and June 9, 2016, a total of 529 patients were recruited into the study. These patients were randomized in a 2:1 ratio to receive ibrutinib 420 mg daily until disease progression plus rituximab at varying doses of 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 or 6 courses of FCR.

There were 354 patients assigned to the ibrutinib plus rituximab arm and 175 assigned to receive FCR; protocol therapy was not initiated in 19 patients.

Dr Shanafelt and colleagues carried out the first interim analysis in September 2018.

There were 77 PFS events and 14 deaths by the median follow-up of 33.4 months. The hazard ratio (HR) for PFS (HR, 0.352; 95% confidence interval [CI], 0.223-0.558; P <.0001) favored the ibrutinib and rituximab combination over FCR, thus crossing the pre-specified PFS boundary. The combination of ibrutinib and rituximab was also favored by the HR for OS (HR, 0.168, 95% CI, 0.053-0.538; P = .0003; pre-specified boundary for superiority, P = .0005).

In a subgroup analysis for PFS, Dr Shanafelt and colleagues found that ibrutinib plus rituximab was superior to FCR independent of age, sex, performance status, disease stage, or del11q23 status.

In addition, with current follow-up ibrutinib plus rituximab was superior to FCR among patients without IGHV mutation (HR, 0.262; 95% CI, 0.137-0.498; P <.0001) but not for those with the IGHV mutation (HR, 0.435; 95% CI, 0.140-0.1350; P = .07).

Grade 3 and 4 treatment-related adverse events occurred in 58% and 72% of patients in the ibrutinib plus rituximab and FCR arms, respectively (P = .0042). Of note, FCR was more frequently associated with certain grade 3 and 4 adverse events than ibrutinib plus rituximab—neutropenia (44% vs 23%, respectively; P <.0001) and infectious complications (17.7% vs 7.1%, respectively; P <.0001).

“The combination of ibrutinib and rituximab provides superior PFS and OS relative to FCR for patients with previously untreated CLL age ≤70,” Dr Shanafelt and colleagues concluded.

“These findings have immediate practice changing implications and establish ibrutinib-based therapy as the most efficacious first-line therapy for patients with CLL,” they added.—Hina Khaliq

Shanafelt TD, Wang V, Kay NE, et al. A randomized phase III study of ibrutinib (PCI-32765)-based therapy vs. standard fludarabine, cyclophosphamide, and rituximab (FCR) chemoimmunotherapy in untreated younger patients with chronic lymphocytic leukemia (CLL): a trial of the ECOG-ACRIN Cancer Research Group (E1912). Presented at: the 60th ASH Annual Meeting and Exposition; December 1-4, 2018; San Diego, CA. Abstract LBA-4.