Patients with untreated, IGHV-mutated and -unmutated chronic lymphocytic leukemia experienced better overall survival and progression-free survival with ibrutinib and rituximab compared with fludarabine, cyclophosphamide, and rituximab.
Treatment with ibrutinib (Imbruvica) and rituximab (Rituxan) resulted in superior overall survival (OS) and progression-free survival (PFS) vs fludarabine, cyclophosphamide, and rituximab (FCR) in previously untreated chronic lymphocytic leukemia (CLL) without regard for IGHV mutation status, according to long-term follow-up from the phase 3 E1912 trial (NCT02048813).1
With a median follow-up of 70 months, PFS improvement with ibrutinib and rituximab vs FCR was noted in both the IGHV-mutant (HR, 0.27; P <.001) and IGHV-unmutated populations (HR, 0.27; P <.001). In total, 214 or 354 patients remained on treatment with the ibrutinib regimen as well as 115 of 175 patients in the FCR arm who were on active surveillance. Among those who discontinued treatment with ibrutinib/rituximab (n = 138), 10.5% of patients discontinued due to disease progression or death, 21.9% discontinued due to adverse effects and complications, and 6.8% withdrew for other reasons.
Investigators noted that progression was unusual for patients who were able to remain on ibrutinib. The median time from ibrutinib discontinuation to disease progression or death was 25.0 months for those who stopped treatment for reasons beyond progression. Patients in the ibrutinib arm had notably sustained improvement in OS vs FCR (HR, 0.47; P = .018).
Initial results from the trial established that an ibrutinib-based regimen yielded superior PFS and OS vs FCR at a median follow-up of 34 months.2 However, despite finding a statistically significant OS benefit in the ibrutinib arm, the advantage was small and was feasibly attributable to early deaths in the FCR group. Moreover, although the subgroup analysis indicated that the ibrutinib regimen yielded a PFS benefit vs FCR across all prognostic molecular and biologic subgroups, the threshold for statistical significance in IGVH-mutant patients was not reached at the initial report.
The trial included patients with CLL or small cell leukemia who were 70 years or younger and in need of therapy according to International Workshop on Chronic Lymphocytic Leukemia criteria. Those with deletion 17p13 by fluorescence in situ hybridization (FISH) were excluded from the study because of poor response to FCR. Patients were randomized 2:1 to receive either ibrutinib/rituximab or FCR, with stratification factors including age, disease stage, ECOG performance status, and presence of 11q22.3 deletion by FISH. Those in the experimental arm were treated with 420 mg of ibrutinib until disease progression or unacceptable toxicity along with 6 cycles of concomitant rituximab. Standard supportive care was available for patients in both cohorts. A total of 529 patients were accrued, of whom 498 were eligible for treatment.
In the experimental arm, the median time on treatment was 58.9 months. The median PFS in patients who received ibrutinib for less than 12 months, 12 to 24 months, and more than 24 months was 19.3 months, 30.3 months, and over 25.0 months, respectively, although the differences were not statistically significant (P = .47).
PFS was evaluated by international prognostic index (IPI) risk category in 384 patients. The 5-year PFS rates in the FCR group in patients with low-, intermediate-, and high-risk IPI scores were 80%, 56%, and 30%, respectively (P = .018). In the doublet group, the 5-year PFS rates were 90%, 81%, 70%, and 65% for those in the low-, intermediate, high, and very high-risk categories.
Grade 3 or higher adverse effects were reported in 73.0% of patients in the ibrutinib arm and 83.5% of patients in the FCR arm (OR, 0.53; 95% CI, 0.32-0.88; P = .0097). Grade 3 or higher hemorrhage was reported in 1.1% of patients in the ibrutinib arm. Additionally, the proportion of patients who developed a second primary cancer was higher in the doublet arm (15.3%) vs the triplet arm (9.1%; P = .056).