Adding Targeted Therapy to Chemoimmunotherapy in Patients With Chronic Lymphocytic Leukemia: Questions as to Optimal Strategy Remain

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Jennifer Woyach, MD

Although the HELIOS trial is not likely to immediately change the standard of care, it certainly raises questions as to the optimal strategy for incorporating kinase inhibitors in the treatment of patients with chronic lymphocytic leukemia.

—Jennifer Woyach, MD

The HELIOS study is an international phase III trial of bendamustine (Treanda) plus rituximab (Rituxan) in combination with ibrutinib (Imbruvica) vs placebo in patients with previously treated chronic lymphocytic leukemia. As reported by Chanan-Khan in The Lancet Oncology1 and reviewed in this issue of The ASCO Post, median progression-free survival, the primary endpoint of the study, was significantly longer with bendamustine/riuximab plus ibrutinib than with bendamustine/rituximab alone (not reached vs 13.3 months), and 18-month progression-free survival for the ibrutinib group was 79%, vs 24% in the placebo group. Complete response was achieved in 10% of patients in the bendamustine/riuximab plus ibrutinib group, and 4.2% of patients in this group achieved minimal residual disease negativity in the blood or bone marrow. There were no subgroups of patients for whom ibrutinib did not confer benefit.

These data are important because they are the first to definitively show that addition of a targeted therapy can improve on the results of chemoimmunotherapy in the relapsed setting. The results are perhaps not surprising, however, since reported data suggest that progression-free survival with ibrutinib alone would be better than with bendamustine/riuximab alone, although, of course, these data were not available when the trial was being designed.

Whether progression-free survival with bendamustine/riuximab plus ibrutinib is better than that reported with ibrutinib alone is not evident with this length of follow-up. The complete response rate does appear to be higher in patients treated with bendamustine/rituximab plus ibrutinib than reported in those treated with ibrutinib alone. No safety concerns arose with the combination, suggesting that ibrutinib is likely able to be safely combined with other chemoimmunotherapy regimens.

Practice-Changing Results?

The biggest question after the completion of a phase III study is how the results should change clinical practice. At this point, given the data that are available, it is not clear that there are patients who should be treated with bendamustine/rituximab plus ibrutinib rather than ibrutinib alone. The time to objective response is likely faster, and the complete response rate is likely higher, but no data exist yet to suggest that either of these factors affects long-term outcomes with ibrutinib. At this time, therefore, it would be difficult to recommend bendamustine/rituximab plus ibrutinib over ibrutinib as a single agent.

Questions Raised by HELIOS

There are important questions raised by this study. First, as noted, is whether chemoimmunotherapy improves outcomes in patients treated with ibrutinib, and clinical trials will be required to determine this. However, a potentially more interesting question is whether a combination of chemoimmunotherapy plus ibrutinib, by improving the complete response rate, would allow patients to discontinue ibrutinib. The question of ibrutinib discontinuation in responding patients has not yet been tested and is of great interest to limit toxicity as well as cost. If careful clinical studies determine that patients with a complete response or minimal residual disease–negative complete response can safely discontinue ibrutinib, then regimens such as this one, which likely improve on the complete response rate of ibrutinib alone, would be of great interest. Therefore, a study building upon this regimen by randomizing ibrutinib discontinuation either at a predefined time or at the time of complete response would be very appealing and could change clinical practice.

Thus, although the HELIOS trial is not likely to immediately change the standard of care, it certainly raises questions as to the optimal strategy for incorporating kinase inhibitors in the treatment of patients with chronic lymphocytic leukemia and advances our understanding of the potential to combine ibrutinib with standard chemoimmunotherapy. ■

Disclosure: Dr. Woyach reported no potential conflicts of interest.

Dr. Woyach is Assistant Professor, Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio.


1. Chanan-Khan A, Cramer P, Demirkan F, et al: Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): A randomised, double-blind, phase 3 study. Lancet Oncol 17:200-211, 2016.

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