Chronic lymphoid leukemia (CLL) is characterized by a variable natural history that is partly predicted by clinical and genomic features.1 Therapy for CLL has evolved from monotherapy with alkylating agents to chemoimmunotherapy.2,3 Each of the combination regimens has shown prolonged rates of progression-free survival, as compared with similar regimens that do not contain antibodies.
Treatment of patients with relapsed CLL often includes regimens such as bendamustine and rituximab,4ofatumumab,5 or investigational agents.6-8 Ofatumumab was approved by the Food and Drug Administration (FDA) and the European Medicines Agency on the basis of a single-group study involving patients who had resistance to fludarabine and alemtuzumab therapy; with an overall response rate of 58%,5 ofatumumab has been recommended in international consensus guidelines as a therapeutic option for patients with previously treated CLL.9,10
A short duration of response to initial therapy or adverse cytogenetic abnormalities have been associated with a poor outcome among patients receiving conventional therapy.9,11,12 Identifying new therapies that prolong survival remains an important need for these patients.
Ibrutinib (Imbruvica, Pharmacyclics and Janssen) is a first-in-class, oral covalent inhibitor of Bruton’s tyrosine kinase, an essential enzyme in B-cell receptor signaling, homing, and adhesion.13-15 On the basis of response rates in single-group, phase 2 studies, ibrutinib was recognized by the FDA as a breakthrough therapy and was granted accelerated approval for patients with mantle-cell lymphoma (in November 2013) and CLL (in February 2014) who had received at least one previous therapy. Among patients with relapsed or refractory CLL or small lymphocytic lymphoma (SLL), those who received ibrutinib had a response rate of 71%, according to investigator assessment, and a progression-free survival rate of 75% at 2 years.13 In this study, drug toxicity did not result in the discontinuation of ibrutinib in most patients. On the basis of early results of the phase 2 trial, we initiated a multicenter, open-label, randomized, phase 3 trial, the Study of Ibrutinib versus Ofatumumab in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (RESONATE), to compare once-daily oral ibrutinib with an active control single-agent therapy, ofatumumab, in patients with relapsed or refractory CLL or SLL.
Among patients with relapsed CLL or SLL, including those who had a short duration of response to prior therapy or who had adverse cytogenetic abnormalities, ibrutinib was superior to ofatumumab with respect to progression-free survival, overall survival, and response rate at a median follow-up of 9.4 months. The positive effect of ibrutinib was observed in subgroups of patients with a high-risk chromosome 17p13.1 deletion and with resistance to previous purine analogue therapy. Similar benefits with respect to progression-free survival were observed regardless of age, clinical stage, and factors such as status with respect to mutations in IGHV. The effect of ibrutinib on overall survival was significant, an effect that was robust despite the crossover of 57 patients to the ibrutinib group after they had disease progression while receiving ofatumumab; this effect was also observed in subgroup and sensitivity analyses.
Except for a few differences, our findings are largely similar to those of other trials of ibrutinib or ofatumumab. In each of the two groups in our study, the response rate as determined by independent assessors was lower than the response rate as determined by investigators. In the phase 2 study of ibrutinib monotherapy,13 in which response was assessed by investigators, the response rate was 71%, which is similar to the 70% response rate assessed by investigators in our study. The independently assessed response rate in the ofatumumab group in our study appears to be lower than that in the pivotal study that was based on 1996 National Cancer Institute guidelines for CLL,23 which did not require CT scanning to confirm response.24 This difference may be due in part to the requirement in our study for serial CT scanning, which was performed every 12 weeks, to confirm response. Another ofatumumab study that compared response assessment between patients who underwent CT scanning and those who did not undergo CT scanning showed substantial differences in the rates of response between the two subgroups, with lower response rates seen in the group that underwent CT scanning.25 Furthermore, the investigator-assessed response rate among patients in the ofatumumab group in our study (21%) was similar to the rate (23%) in a recent study that used 2008 criteria of the International Workshop on Chronic Lymphocytic Leukemia.26 Reassuringly, the results with respect to progression-free survival in the ofatumumab group in our study (median, 8.1 months) are similar to those in historical reports (median, approximately 6 months).5
Previous reports of ofatumumab therapy showed that patients with refractory CLL had a median survival of 12 months26 and 15 months,5 with no plateau in deaths. With a median follow-up of 9.4 months in our study, an early separation in the curves for overall survival favored ibrutinib; however, the median was not reached in either study group. At later time points, the survival curve for ofatumumab began to flatten, which may in part be a reflection of the influence of ibrutinib on patients in the ofatumumab group who crossed over to ibrutinib therapy.
Ibrutinib was associated with toxic effects that were expected on the basis of the results of phase 2 studies. It appears that the drug can be safely administered even in a heavily pretreated and elderly population with baseline coexisting conditions, such as the one in our study. In the ibrutinib group, 32% of the patients had a decreased creatinine clearance, 64% had cytopenias, and 32% had a score on the Cumulative Illness Rating Scale of more than 6 (ranging from 0 to 52, with higher scores indicating worse health status). Toxic effects did not result in frequent dose reductions or treatment discontinuations.
One strength of a randomized, controlled trial is that background disease-related complications may be differentiated from a treatment effect with a new agent. However, it is important to note that patients in the ibrutinib group had a reporting period for adverse events that was more than 3 months longer than that in the ofatumumab group (median duration, 8.6 months vs. 5.3 months), and no exposure-adjusted analysis of adverse events was performed.
The frequencies of renal complications and increased creatinine levels were similar in the two study groups. Although the overall rate of infections was higher in the ibrutinib group, the frequency of infections of grade 3 or higher did not differ significantly between the two groups. Ocular symptoms were collected proactively and were reported more frequently among patients in the ibrutinib group, including a small proportion of patients who reported blurred vision. The development of cataracts in 3% of the patients receiving ibrutinib (as compared with 1% in the control group) bears noting, since longer exposure may be associated with an increased risk.
Atrial fibrillation of any grade was noted in 10 patients in the ibrutinib group, as compared with 1 patient in the ofatumumab group, and led to the discontinuation of ibrutinib in 1 patient. Potential reasons for the higher rate of atrial fibrillation among patients receiving ibrutinib are being explored. In clinical studies in which serial electrocardiographic studies were performed, no evidence of arrhythmias was observed among patients receiving ibrutinib.13,27
An adverse event of interest with ibrutinib from early studies was major hemorrhage, including subdural hematoma. In our study, we excluded patients requiring warfarin but not those requiring other forms of anticoagulation. The rate of major hemorrhage was similar in the two study groups, with one subdural hematoma noted in a patient receiving ibrutinib. Although mild bleeding episodes were more common in the ibrutinib group, adherence to appropriate drug-withholding guidelines perioperatively and precautions regarding the use of antiplatelet agents and anticoagulants resulted in no unexpected major bleeding complications in the ibrutinib group. Further studies of the mechanism of bleeding, including bruising, that was observed among patients receiving ibrutinib have been conducted28 or are planned.
In conclusion, ibrutinib was superior to ofatumumab in difficult-to-treat patients with relapsed or refractory CLL or SLL, as measured by progression-free survival, overall survival, and response. The improvement was observed across all subgroups that were examined, including patients who were resistant to chemoimmunotherapy and those with a chromosome 17p13.1 deletion, which confirms single-agent ibrutinib as an effective therapy for CLL or SLL. Phase 3 studies examining the effect of ibrutinib in previously untreated patients with CLL or SLL are ongoing