Depth and durability of response to ibrutinib in CLL: 5-year follow-up of a phase 2 study

Abstract

The safety and efficacy of ibrutinib (420 mg) in chronic lymphocytic leukemia (CLL) were evaluated in a phase 2 study; 51 patients had TP53 aberration (TP53 cohort) and 35 were enrolled because of age 65 years or older (elderly cohort). Both cohorts included patients with treatment-naive (TN) and relapsed/refractory (RR) CLL. With the median follow-up of 4.8 years, 49 (57.0%) of 86 patients remain on study. Treatment was discontinued for progressive disease in 20 (23.3%) patients and for adverse events in 5 (5.8%). Atrial fibrillation occurred in 18 (20.9%) patients for a rate of 6.4 per 100 patient-years. No serious bleeding occurred. The overall response rate at 6 months, the primary study endpoint, was 95.8% for the TP53 cohort (95% confidence interval, 85.7%-99.5%) and 93.9% for the elderly cohort (95% confidence interval, 79.8%-99.3%). Depth of response improved with time: at best response, 14 (29.2%) of 48 patients in the TP53 cohort and 9 (27.3%) of 33 in the elderly cohort achieved a complete response. Median minimal residual disease (MRD) in peripheral blood was 3.8 × 10^-2 at 4 years, with MRD-negative (<10^-4) remissions in 5 (10.2%) patients. In the TP53 cohort, the estimated 5-year progression-free survival (PFS) was 74.4% in TN-CLL compared with 19.4% in RR-CLL (P = .0002), and overall survival (OS) was 85.3% vs 53.7%, respectively (P = .023). In the elderly cohort, the estimated 5-year PFS and OS in RR-CLL were 64.8% and 71.6%, respectively, and no event occurred in TN-CLL. Long-term administration of ibrutinib was well tolerated and provided durable disease control for most patients. This trial was registered at www.clinicaltrials.gov as #NCT01500733.

Graphical abstract

Figure 1.

Complete response on ibrutinib. (A) Cumulative best response in 81 evaluable patients. (B) Forest plot showing CR rates at best response in subgroups divided by clinical and laboratory criteria; the dashed line marks the CR rate in all patients (23.5%). Whiskers indicate 95% CI. *Trend in CR rate difference between low and advanced Rai stages (P = .054). **Spleen size was not evaluated in 2 patients with history of splenectomy. (C) Status of CR criteria in 79 patients; spleen (volume assessed by CT), target lymph nodes (LN), absolute lymphocyte count (ALC), bone marrow infiltration and cellularity (Marrow), and hematologic recovery (Heme). Twenty-three (28%) patients met all CR criteria (blue blocks); red blocks mark CR criteria not met. B2M, β2-microglobulin; IGHV-M, IGHV mutated; IGHV-U, IGHV unmutated.

Figure 2.

MRD assessment in blood and bone marrow. (A-B) MRD was measured by flow cytometry in peripheral blood (PB) and bone marrow (BM). One patient who had undetectable PB MRD at 4 years was plotted at the lowest margin of detection (10⁻⁶). Patients were stratified by IGHV subgroups: M for mutated, U for unmutated. Red lines indicate median, boxes indicate interquartile ranges. *P < .05; **P < .01; n.s., not significant. (C-E) PB and BM MRD in matched samples at 24, 36, and 48 months. (F) Correlation between PB and BM MRD measurements.

Figure 3.

PFS and OS. Kaplan-Meier estimates of PFS and OS of all patients on study (A-B), and by cohort and treatment status (C-D and E-F, respectively); (C-D) for the TP53 cohort and (E-F) for the elderly cohort B. RR, relapsed and/or refractory CLL; TN, treatment-naïve CLL.