In the E1912 trial, eligible patients were aged ≤70 years, did not have 17p deletion, and had not received prior therapy. Patients were randomized 2:1 to receive 420 mg of ibrutinib daily until disease progression or unacceptable toxicity plus rituximab (50 mg/m2 on day 1 of cycle 2, 325 mg/m2 on day 2 of cycle 2, and then 500 mg/m2 on day 1 of cycles 3-7) or standard FCR regimen every 28 days. The primary end point of the trial was PFS; the secondary end point was OS. Analysis was by intention to treat (ITT).
In the ITT population, at a median follow-up of 48 months, 257 of 354 (73%) IR-treated patients remained on ibrutinib. TP53 mutations were noted in 3% of patients in the FCR cohort, and in 9% of patients in the IR cohort.
Grade≥3 treatment-related adverse events (AEs) were experienced by 70% of IR-treated and 80% of FCR-treated patients (odds ratio, 0.56; 95% confidence interval [CI], 0.34-0.90; P = .013). A total of 23 deaths were reported (IR cohort, 11; FCR cohort, 11)
A total of 95 patients discontinued ibrutinib; 23 patients (7% of IR-treated patients; 24% of discontinued patients) discontinued due to progression or death. Among the 72 patients who discontinued ibrutinib for reasons other than progression or death, 48 patients (14% of IR-treated patients; 51% of discontinued patients) discontinued due to AE or complication and 24 patients (7% of IR-treated patients; 25% of discontinued patients) due to withdrawal of consent or other reasons. In multivariable Cox regression analysis, only Cumulative Illness Rating Scale score (range, 0-14) was significantly associated with discontinuation for a reason other than progression (hazard ratio [HR], 1.13 per unit increase; 95% CI, 1.03-1.23; P = .009). The median time from ibrutinib discontinuation to disease progression or death was 23 months.
With extended follow-up (110 PFS events with 15 deaths), the HR for PFS favored IR over FCR (HR, 0.39; 95% CI, 0.26-0.57; P <.0001). Subgroup analysis by IGHV mutation status demonstrated that IR was superior to FCR for IGHV-unmutated patients (HR, 0.28; 95% CI, 0.17-0.48; P <.0001). With current follow-up, the difference is not significant in IGHV-mutated patients (HR, 0.42; 95% CI, 0.16-1.16; P = .086).
Based on these results, the study investigators concluded that, with extended follow-up, IR continued to provide superior PFS and OS compared with FCR for younger patients with previously untreated CLL.
Shanafelt TD, et al. ASH Abstract 33. Session 642.