Thomas Kipps, MD, PhD
High-risk patients with chronic lymphocytic leukemia (CLL) who have an 11q deletion—said to be an adverse predictor of poor outcomes—can have durable responses when treated with the BTK inhibitor ibrutinib (Imbruvica), according to pooled analyses of results from the phase III HELIOS, RESONATE, and RESONATE-2 studies presented at the 17th International Workshop on Chronic Lymphocytic Leukemia (iwCLL) Biennial Meeting.
The findings suggest that risk factors typically associated with poor clinical outcomes may be less relevant with ibrutinib treatment, explains lead study author Thomas Kipps, MD, PhD, professor of medicine, Evelyn and Edwin Tasch Chair in Cancer Research, and deputy director of research operations at the UC San Diego Moores Cancer Center, who presented the findings at the meeting. In an interview with OncLive
, Kipps explained the details of the integrated analysis from the iwCLL meeting, his ongoing research with ROR1 as a target in CLL, and pivotal combination studies being conducted with ibrutinib.
OncLive: Please discuss your research presented at the iwCLL conference on outcomes of ibrutinib-treated patients with CLL/small lymphocytic leukemia with high-risk prognostic factors.
We were involved in these clinical trials, but I was the senior author of the trial that we put together of patients being randomized to treatment with ibrutinib versus chlorambucil. These were patients older than age 65 and patients who had some medical comorbidities. Particularly, in Europe, chlorambucil is not a bad choice by European standards, although it is less frequently used in the United States. We had the trial where patients were randomized to receive ibrutinib versus chlorambucil as part of the RESONATE-2 study, and what we observed in that was that patients treated with ibrutinib fared better than patients treated with chlorambucil. There was a significant improvement not only in progression-free survival, but also in overall survival despite the fact there was some crossover. There seemed to be a distinct advantage for patients treated with ibrutinib.
Based on that study, the FDA has approved the use of ibrutinib for patients as initial therapy, independent of age or medical comorbidities, so it was a significant study. What we noted in some of our patients treated on ibrutinib was that we had patients with deletion 11q who did fairly well. It was striking because, historically, patients who have CLL who have deletion 11q tend not to fare as well with chemotherapy or chemoimmunotherapy.
In fact, although patients may achieve a good response to therapy, they seem to have a short period of time before they relapse. Therefore, it has been called an adverse prognostic marker. This marker had been pointed out in the paper by [Harmut] Döhner and colleagues in The New England Journal of Medicine
in 2000, and it showed that patients whose CLL cells had deletion 11q fared second to worst to only the patients who have deletion 17p—in terms of outcomes and survival.
Now, we had cytogenetic and follow-up data on patients treated in the era of chemoimmunotherapy, and we looked at survival rates by virtue of the cytogenetic features. What we found was that the survival of patients with 17p had improved quite substantially, but the survival of patients with 11q had not improved as much as the patients with 17p. It was still an adverse risk marker compared with patients who had other cytogenetic lesions or no detectable cytogenetic lesions.
We published on that, and you can look at those data in comparison to Döhner’s study. It seemed that even with the advent of an antibody added to chemotherapy, in the era of chemoimmunotherapy, these patients were still having a relatively adverse prognosis. The observation that patients with 11q were doing better in the RESONATE-2 study was noteworthy.
We then got the data together for other studies that were done with ibrutinib, mainly the RESONATE study—the original one—which compared patients treated with ibrutinib versus patients treated with ofatumumab (Arzerra). We also had the data from the HELIOS study, in which patients were treated with bendamustine and rituximab (Rituxan; BR) and placebo versus BR and ibrutinib. We wanted to assimilate all of the data for patients treated on the ibrutinib arm and to compare how patients did with these different cytogenetic lesions. The reason we remarked on that was because, in the early phase II studies done of the preregistration studies of ibrutinib, enrolling patients who had multiple rounds of prior therapy, it did appear that the patients with 11q minus were faring worse than the other patients—except for those with 17p.