Patients and Treatment

Table 1. Table 1. Baseline Demographic and Clinical Characteristics of the Patients.

A total of 85 patients were enrolled at eight sites. The baseline characteristics of the patients are listed in Table 1, and in Table S2 in the Supplementary Appendix. The patients, who were generally considered to have high-risk disease, had received a median of four previous therapies. A total of 65% of the patients had advanced-stage disease, 33% had 17p13.1 deletions, and 36% had 11q22.3 deletions. At a median follow-up of 20.9 months (range, 0.7 to 26.7), 54 patients (64%) were still receiving treatment, and 31 (36%) had discontinued treatment. Reasons for treatment discontinuation (detailed in Table S3 in the Supplementary Appendix) included disease progression in 11 patients (13%); the patient's or investigator's decision in 13 (15%), of whom 5 patients then underwent stem-cell transplantation; and adverse events in 7 patients (8%), including 3 patients who had pneumonia, 2 who had sepsis, 1 who had staphylococcal bacteremia without physiological signs of sepsis, and 1 who had gastrointestinal hemorrhage.

Pharmacokinetic and Pharmacodynamic Measurements

The steady-state concentration–time profiles of ibrutinib after administration of 420 mg or 840 mg per day are shown in Fig. S1 in the Supplementary Appendix. The exposure to ibrutinib increased proportionally from a dose of 420 to 840 mg per day. No differences in the time to the peak ibrutinib concentration in the blood (median T max , 2 hours [range, 0.5 to 6]) or the terminal half-life (7.8±3.6 hours with 420 mg per day and 8.1±3.4 hours with 840 mg per day) were apparent between doses.

Post-treatment assessments indicated full occupancy of BTK by ibrutinib at both dose levels. The median level of BTK occupancy was 96 to 99% (Fig. S2 in the Supplementary Appendix); it was observed as early as 4 hours after the dose was administered and was maintained 24 hours after the dose was administered, at both dose levels.

Safety

Table 2. Table 2. Adverse Events.

Long-term therapy with ibrutinib was associated with modest toxicity; most adverse events were grade 1 or 2 (Table 2). The most common adverse events were diarrhea, fatigue, and upper respiratory tract infection, and most adverse events resolved without the need for a suspension of treatment. Adverse events leading to discontinuation of treatment occurred in 2 patients in the 420-mg cohort (4%) and in 4 patients in the 840-mg cohort (12%). Serious adverse events are listed in Table S4 in the Supplementary Appendix. The most common adverse events of grade 3 or higher were pneumonia (in 10 patients [12%]) and dehydration (in 5 patients [6%]). Infections of grade 3 or higher occurred most frequently early in the course of therapy.

The average rate of infection was 7.1 per 100 patient-months during the first 6 months and 2.6 per 100 patient-months thereafter (Table S5 in the Supplementary Appendix). The exposure-adjusted rate of infections that were grade 3 or higher was reduced by more than half after 6 months of treatment (Table S5 in the Supplementary Appendix).

IgG and IgM levels remained relatively stable throughout treatment, whereas IgA levels increased at 3, 6, and 12 months (Fig. S3 in the Supplementary Appendix). Grade 3 or 4 hematologic toxic effects were infrequent; 5 patients (6%) had anemia, 13 patients (15%) had neutropenia, and 5 patients (6%) had thrombocytopenia. Bleeding events that were grade 3 or higher in severity occurred in 4 patients. A total of 8 patients died within 30 days after receiving the last dose of ibrutinib: 3 deaths were from pneumonia, 1 was from the systemic inflammatory response syndrome, 1 was from sarcoma, and 3 were related to CLL progression.

Efficacy

Figure 1. Figure 1. Response to Ibrutinib over Time. Panel A shows the median percent change from baseline in the absolute lymphocyte count (ALC) and the sum of the products of lymph-node diameters (SPD) in all patients. I bars denote distribution-free 95% confidence intervals. Panel B shows the curves for cumulative best response (complete response plus partial response, partial response with lymphocytosis, and stable disease).

The overall response rate based on the standard criteria30,33 was 71% (2 complete responses and 34 partial responses) in the 420-mg cohort and 71% (24 partial responses) in the 840-mg cohort. In addition, 10 patients in the 420-mg cohort (20%) and 5 patients in the 840-mg cohort (15%) had a partial response with persistent lymphocytosis. Blood lymphocytosis was generally noted by day 7 (in 78% of the patients); it peaked at a median of 4 weeks and then slowly declined. In 50 of 63 patients (79%), the lymphocyte count normalized (absolute lymphocyte count, <4×103 cells per cubic millimeter) or was reduced by 50% from the baseline level. Treatment-related lymphocytosis developed at similar frequencies in patients with unmutated and those with mutated immunoglobulin variable-region heavy-chain genes (77% and 83%, respectively). However, in patients with unmutated immunoglobulin genes, lymphocyte counts normalized more rapidly (median, 6.4 vs. 14.8 months) and more frequently (in 85% vs. 50% of the patients). Lymphocytosis occurred concomitantly with a notable reduction in lymph-node size (Figure 1A) and spleen size, as well as frequent improvement in cytopenias (Fig. S4 in the Supplementary Appendix). An improved response was time-dependent (Figure 1B); increasing numbers of partial responses and complete responses occurred during follow-up, whereas the frequency of a partial response with lymphocytosis diminished as the lymphocyte count decreased over time.

Figure 2. Figure 2. Overall Response Rates (ORR) According to Subgroup. Rai stage 0 indicates low risk, stage I or II intermediate risk, and stage III or IV high risk. The dotted line shows the response rate for all 85 patients. IGHV denotes immunoglobulin variable-region heavy-chain gene.

As shown in Figure 2, the response to ibrutinib did not appear to vary according to traditional high-risk prognostic features. The response rate among the patients with a 17p13.1 deletion was 68%, including one complete response, whereas the response rate was 71% among those without this deletion. The only factor associated with a response was the mutation status of the immunoglobulin variable-region heavy-chain gene. Notably, 4 of the 12 patients with a mutated immunoglobulin variable-region heavy-chain gene (33%) had a partial response or complete response and 5 (42%) had a partial response with lymphocytosis. By contrast, 53 of the 69 patients with an unmutated immunoglobulin variable-region heavy-chain gene (77%) had a partial response or complete response and 9 (13%) had a partial response with lymphocytosis. This difference in the overall response rate (partial response plus complete response) was significant (P=0.005), whereas the combined overall response rate plus the rate of partial response with lymphocytosis did not differ significantly according to mutation status.

Sustained improvement in cytopenias, defined as improvement by more than 50% or a hemoglobin level higher than 11 g per deciliter, an absolute neutrophil count higher than 1500 cells per cubic millimeter, or a platelet count higher than 100,000 cells per cubic millimeter (lasting for ≥2 cycles without transfusion or administration of growth factors), was frequently observed during ibrutinib treatment (Fig. S4 in the Supplementary Appendix). Improvement was observed in 32 of 41 patients with baseline thrombocytopenia (78%), 27 of 33 with anemia (82%), and 24 of 31 with neutropenia (77%).

Figure 3. Figure 3. Kaplan–Meier Curves for Progression-free Survival and Overall Survival. Panels A and B show the probability of progression-free survival and overall survival, respectively, for all 85 patients (top graphs) and according to status with respect to the 17p13.1 and 11q22.3 deletions (middle graphs) and IGHV mutation status (bottom graphs). Tick marks indicate censored data.

Ibrutinib treatment promoted durable responses, irrespective of the dose. The 26-month estimated rate of progression-free survival (Figure 3A, top graph) was 75%, and the rate of overall survival (Figure 3B, top graph) was 83%. Disease progression developed in 11 patients (13%) during follow-up, and 7 of those patients had progression by biologic transformation (Richter's syndrome). The median time from the initial diagnosis of CLL to transformation was 98 months (range, 24 to 143). Among the 11 patients in whom progressive disease developed, 10 patients had a 17p13.1 or a 11q22.3 deletion, and 1 patient did not have high-risk cytogenetic abnormalities (Figure 3A). Patients had a prolonged time to progression despite high-risk genomic features. Among the 28 patients with a 17p13.1 deletion — a uniformly poor prognostic factor — the 26-month estimated rate of progression-free survival (Figure 3A) was 57% and the rate of overall survival (Figure 3B) was 70%. Patients who discontinued ibrutinib for reasons other than progression remained in the study and were followed quarterly until disease progression, the initiation of new anticancer therapy, or death. After disease progression or initiation of subsequent anticancer therapy, follow-up was limited to survival status. Treatment at the time of new treatment initiation was left to the discretion of the treating physician.