Expert Discusses Promising Findings With Ibrutinib, Venetoclax, and Obinutuzumab in CLL


Kerry A. Rogers, MD, discusses phase II findings with obinutuzumab, ibrutinib, and venetoclax and the future of dose-limited regimens in CLL.

Kerry A. Rogers, MD

The combination of obinutuzumab (Gazyva), ibrutinib (Imbruvica), and venetoclax (Venclexta) demonstrated exciting phase II findings in treatment-naïve and relapsed/refractory patients with chronic lymphocytic leukemia (CLL), said lead study author Kerry A. Rogers, MD.  

The study included a total of 50 patients, half were treatment-naïve and the other half were relapsed/refractory. Rogers presented mid-therapy findings for the relapsed/refractory cohort during the 2018 ASH Annual Meeting.

At a median follow-up of 18 months, 23 of the 25 relapsed/refractory patients remained on study and achieved a response. There was 3 complete responses (CRs), 3 patients achieved a CR with incomplete marrow recovery, and 17 had a partial response (PR). The overall response rate (ORR) for this population was 92% (95% CI, 74%-99%). Additionally, 2 patients had minimal residual disease (MRD) in the bone, 2 had it in the marrow, and 3 had it both in the blood and the marrow.

In an interview withTargeted Oncologyat the 2018 ASH Annual Meeting, Rogers, assistant professor, Internal Medicine, Division of Hematology, The Ohio State University Comprehensive Cancer Center, discussed the phase II findings of this trial and the future of dose-limited regimens in CLL.

TARGETED ONCOLOGY:Could you please provide some background on this study?

Rogers:As everyone probably knows, combination regimens are a well-proven and effective strategy in CLL, but that was established in the era of chemoimmunotherapy. Since we have highly effective oral targeted agents now, the goal of this study was to combine an anti-CD20 monoclonal antibody with 2 oral targeted drugs: ibrutinib and venetoclax. In preclinical and clinical studies, these agents have shown to have complimentary mechanisms and nonoverlapping toxicities, except for neutropenia and hematologic toxicities. We combined this with obinutuzumab with the goal of developing a regimen that could achieve very deep remissions and have a fixed duration. Extended monotherapy can lead to extended toxicities over time and increases cost of treatments. We want to use our most effective agents in combination for a defined amount of time and see how long the remissions last, and if we can achieve deep responses.

TARGETED ONCOLOGY:How was the trial designed?

Rogers:This is a study that had a phase Ib cohort, which included 12 patients with relapsed/refractory CLL. All 3 drugs are given at the FDA-approved dosing schedule except venetoclax, which was given between 100 mg and 400 mg. The phase Ib portion identified 400 mg as the optimal dose to be using in combination with obinutuzumab and ibrutinib. That portion of the study has already been reported. There are no dose-limiting toxicities, so we were able to get to 400 mg in all patients. There is a staggered start to the 3 drugs to reduce the tumor burden and the risk of tumor lysis syndrome. It does use the venetoclax ramp-up [schedule] as per the FDA label.

After our 12 patients in the phase Ib portion were treated, and we determined that this was the dose going forward, 2 phase II cohorts accrued. These cohorts were all treated at the recommended phase II dose for the phase Ib part. It was 25 patients with relapsed/refractory CLL, and 25 patients who were treatment-naïve. The goal of these phase II cohorts was to see how effective this is and get a response rate. The primary endpoint for both of these phase II cohorts is the rate of MRD-negative remission. They were developed to be analyzed independently.

TARGETED ONCOLOGY:What are the updated results?

Rogers:I presented the results of the primary endpoint and the end-of-treatment results of these 2 phase II cohorts. These are the responses of the patients who completed treatment, and I also reported some of the adverse events (AEs). There was not anything unexpected in terms of AEs. For the final treatment responses, we had everyone who reached the response assessment and was assessed had an objective response according to International Workshop Group on CLL [iwCLL] criteria. The design was to be an intention-to-treat analysis, meaning patients who discontinued study treatment before the planned response assessment were considered not to respond. Therefore, everyone who made it there and was assessed had a response in both cohorts, but the overall response rate is lower, simply because not everyone reached that.

In the treatment-naïve cohort, the ORR was 84%; for the relapsed/refractory cohort, it was 88% at the end of treatment. That accounts for those who did not reach the response assessment. We had 8 CRs in the treatment-naïve cohort, including 1 with incomplete marrow recovery. That means that their bone marrow was either hypercellular, or their counts were not above the threshold, but they met other criteria for CR. In the relapsed/refractory cohort, we had 11 CRs, one of which had incomplete marrow recovery. These are very good response rates, and all our patients who had a PR had very small residual lymph nodes. With the iwCLL criteria, you cannot have a lymph node bigger than 1.5 cm for a CR. The patients in PR did not have a lot of residual disease left, they just had lymph nodes that were greater than 1.5 cm. In many cases, it was just slightly bigger than that.

The other thing that is exciting about our results is that we did have a lot of cases of MRD-negative responses. When we defined MRD negativity for this study, both the blood and bone marrow had to have no detectable leukemia. Therefore, it could not be one or the other—it had to be both. At the end of treatment, we had 67% of the patients in the treatment-naïve cohort achieve this, and 50% of relapsed/refractory. This means both CR and PR patients can achieve these MRD-negative responses, which is great. This is hopefully going to be meaningful for our PR patients who are MRD negative. There is some evidence from other studies showing that an MRD-negative partial remission could be even better than an MRD-positive CR. I am very excited to see that.

Our primary endpoint was the rate of MRD negative CR at the end of treatment, so that is 2 months after completing 14 cycles of treatment. That was 28% and the same in both cohorts. It was 7 of 25 patients in both the treatment-naïve as well as the relapsed/refractory cohorts. I thought that was cool to see.

TARGETED ONCOLOGY:Is a fixed duration of treatment something that is being done more now?

Rogers:When these oral targeted therapies were developed, especially the BTK inhibitor ibrutinib, it is very uncommon to have it eliminate all the leukemia, or to get an MRD-negative status. Since there are residual leukemia cells, patients need to continue taking the treatment. If they stop, those leukemia cells are going to cause problems again at some point. That is how things were when these agents were first developed. Now, we are starting to see longer follow-up now with venetoclax in a large study where it was only given for a period of 2 years.

As we are seeing how good these agents are, we are learning how to use them to try to deepen the response—or get less MRD—with the hope that fixed durations will be a better possibility. The problem right now is that while the strategy seems to be working, the amount of follow-up we have after people have completed treatment for this study that I am talking about is still a median of less than 1 year for both cohorts.

It is going to take several more years to see how long people remain in remission, and how long it is before they require additional treatment. That is going to be the most important thing in determining the value in this and other fixed duration treatment, because it is expensive to combine 3 drugs, and the side effects are more than with single agents. That could be worthwhile depending on how long people can be followed off-treatment. We are going to need to know what the progression-free survival is to know the real value. This fixed duration of treatment is relatively new, and it is relatively early to say whether this is going to be the most valuable strategy for patients as a standard.

This regimen that I am discussing is going to open in December 2018 in untreated patients with CLL, and I think that is going to better answer this question.

TARGETED ONCOLOGY:What about these preliminary findings is important for clinicians to understand?

Rogers:There are a couple things. First, these results are very exciting. If you think about it, this treatment length is 14 cycles and the cycles are 28 days—so this is just over 1 year of treatment, and 28% of the patients with a CR and no detectable leukemia. I do think that this is more tolerability than chemoimmunotherapy. People should know that this is something that is exciting and will hopefully offer us an advantage for our patients who could otherwise be stuck taking pills indefinitely. Over the next couple of years, we are going to have a better handle on the approaches.


Rogers KA, Huang Y, Ruppert AS, et al. Phase 2 study of combination obinutuzumab, ibrutinib, and venetoclax in treatment-naive and relapsed/refractory chronic lymphocytic leukemia. In: Proceedings from the 2018 ASH Annual Meeting; December 1-4, 2018; San Diego, California. Abstract 693.

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