An Investigator's Perspective on the Chronic Lymphocytic Leukemia Research Front

Jennifer A. Woyach, MD

OncLive: How would you assess the current treatment spectrum for CLL? What are the most prominent management challenges?

Woyach: We have a number of outstanding management options for patients with CLL right now, with multiple targeted therapies showing great success. In the frontline, our challenge now is to determine whether these therapies are best used in sequence or in combination. Phase III clinical trials—A041702 [NCT03737981] and EA9161 [NCT03701282], specifically–are trying to address this question. These trials are investigating ibrutinib/obinutuzumab with indefinite ibrutinib versus ibrutinib/venetoclax/obinutuzumab. In A041702, in older patients, those on the triple-therapy arm will have ibrutinib discontinued in a response-adapted manner,¹ and in EA9161, for younger patients, ibrutinib will be discontinued in all patients.² Also, we still have real needs to develop new therapies for patients who relapse after Bruton tyrosine kinase [BTK] inhibitors and venetoclax, as well as for those patients who develop Richter transformation.

Can you discuss the goals and the rationale for the design of the ALLIANCE trial, on which you served as lead investigator?

[In the ALLIANCE trial] our goal was to determine whether ibrutinib was better than our best chemoimmunotherapy regimen in CLL, and to determine whether the drug was best alone or in combination with rituximab.³ At the time the trial was designed, we had excellent data on ibrutinib from single-arm clinical studies, mostly in relapsed/refractory disease. The RESONATE-2 study was getting started, and we knew that [it] was going to be comparing ibrutinib with chlorambucil, which was a test that ibrutinib was sure to win, but it still didn’t answer the question of whether ibrutinib was better than standard treatment.

What are the most important takeaways from the ALLIANCE trial?

First is that ibrutinib is more effective than [bendamustine], with a significantly longer progression-free survival. When discussing clinical options with older patients, we can say that we know for sure that ibrutinib is the more effective agent. As well, the trial shows that ibrutinib should be given as a single agent in most cases. We do not have any data with ibrutinib to suggest that it is more effective when given in combination with a monoclonal antibody. Because of this, outside of certain situations, I would favor giving ibrutinib as a single agent. The situations where I might give rituximab or obinutuzumab outside of a clinical trial would be in those with an active autoimmune condition or those with very high white blood cell counts at the start of therapy.

Can you share your investigator’s perspective on the relevance and implications of the findings within the broader context of ibrutinib and the treatment of CLL?

Unless a patient has a contraindication to ibrutinib, this should be considered the standard of care for frontline CLL, and it, rather than chemoimmunotherapy, should be the standard comparison for future studies. This is very significant, because most patients who are diagnosed with CLL now will not receive chemotherapy during the course of their treatment. I also would foresee that studies designed now will usually include ibrutinib or ibrutinib/antibody as the standard-of-care arm, rather than using chemoimmunotherapy. This will also mean that new agents or combinations will need to be very good, because the bar is set very high.

Given the findings from ALLIANCE and other key recent trials, how do you expect the treatment spectrum to take shape over the short term?

Ibrutinib is already used quite often in the frontline setting, and I expect this use will expand. New data from CLL14 also put venetoclax/obinutuzumab into the discussion as well.⁴ It is hard to say right now how the results of this trial will affect practice patterns, but it is very exciting to have another option for therapy.

How would you characterize the shift in the therapeutic landscape, particularly in light of the recent changes to the National Comprehensive Cancer Network treatment guidelines as a result of ALLIANCE and other recent trials?

The recent trials shift the paradigm in CLL away from chemotherapy. Most patients who are diagnosed with CLL will not receive chemotherapy during the course of their treatment.

Given the rapid changes taking place in the CLL spectrum, what would you like to see emphasized in ongoing and future research?

I think the most important question to answer right now is whether combinations are better than single agents. A041702 and EA9161, the new National Clinical Trials Network cooperative group trials, are comparing ibrutinib/obinutuzumab with ibrutinib/obinutuzumab/venetoclax. I think these are excellent trials that will hopefully answer this question.

References

1. ClinicalTrials.gov. Ibrutinib and obinutuzumab with or without venetoclax in treating older patients with untreated chronic lymphocytic leukemia. clinicaltrials.gov/ct2/show/NCT03737981. Updated May 27, 2019. Accessed May 28, 2019.
2. ClinicalTrials.gov. Ibrutinib and obinutuzumab without without venetoclax in treating patients with chronic lymphocytic leukemia. clinicaltrials.gov/ct2/show/NCT03701282. Updated May 27, 2019. Accessed May 28, 2019.
3. Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018;379(26):2517-2528. doi: 10.1056/NEJMoa1812836.
4. ClinicalTrials.gov. A study to compare the efficacy and safety of obinutuzumab + venetoclax (GDC-0199) versus obinutuzumab + chlorambucil in participants with chronic lymphocytic leukemia.