Optimizing Treatment Approaches for Chronic Lymphocytic Leukemia

Matthew S. Davids, MD, MMSc

OncLive^®: How would you characterize the significance of the ALLIANCE, ECOG E1912, and iLLUMINATE trials within the broader treatment spectrum for chronic lymphocytic leukemia (CLL)?

Davids: At a high-level, it was an exciting opportunity, because we had 3 large randomized trials reading out at the same time, and all 3 looked different CLL patient populations. ECOG1912¹ for younger patients, ALLIANCE² for more typical older patients, and iLLUMINATE,³ with an older, frailer population.

The comparative arms for the trials were appropriate standards of care: for the young patients it was FCR [fludarabine, cyclophosphamide, and rituximab], for the middle group of patients it was bendamustine (BR), and then for the older, frailer patients it was chlorambucil with obinutuzumab.

Earlier this year, the FDA approved ibrutinib plus obinutuzumab. To what extend might approved combination regimens become a trend in CLL treatment?

We are all curious about how ibrutinib/obinutuzumab compares to ibrutinib monotherapy. I think that is a crucial question in light of the fact that the ALLIANCE study taught us that rituximab doesn’t add any benefit to ibrutinib. Obinutuzumab is a different antibody from rituximab mechanistically; has been shown to be superior in prior studies, so it may, in fact, add to ibrutinib. Unfortunately, due to a lack of an ibrutinib monotherapy arm, iLLUMINATE doesn’t answer that question, which is a limitation of that study.

In general, combination therapies appear to be where the field is headed. Among the many ongoing novel agent combination trials, some of the most exciting are those exploring the ibrutinib plus venetoclax combination. We’re seeing all sorts of variations on that with or without the obinutuzumab antibody, and ALLIANCE and ECOG have designed their next wave of phase III CLL trials to explore variations on those combinations.

There’s a number of other promising combination studies going on. For example, we are doing a study of duvelisib with venetoclax for patients with relapsed or refractory CLL. In the long run, it will be helpful if we have data comparing combination regimens to single agent-based therapy, because even though the depth of response may be better with the combinations, you still get very good progression-free survival (PFS) from novel agent monotherapy. It is also important to note and there is more expense with combinations upfront; however, the idea is that if you can use a potent enough combination, you may be giving 2 or 3 drugs, but if you only have to do it for a year or 2, that might actually save money compared to many years of novel agent monotherapy, where the agent needs to be given continuously to maintain response.

As we’re seeing more emphasis on combinations, could you discuss the findings from ALLIANCE that led to the elevation of ibrutinib monotherapy to category 1 in certain populations?

From the preclinical side, we knew that there was a theoretical concern for possible antagonism of ibrutinib and rituximab, which may relate to some of the off-target effects that ibrutinib has on natural killer cells, which are important for killing CLL cells with rituximab, an antibody that relies on other immune effector cells to kill CLL cells. In the clinical data on the ALLIANCE study, it doesn’t look like these agents are necessarily antagonistic, but these preclinical data provide a possible rationale for why ibrutinib/rituximab combination is not more efficacious than ibrutinib on its own.

I think an important thing to note is that we learned from ALLIANCE that ibrutinib and rituximab are not better than ibrutinib alone, but we can’t extrapolate this finding to other BTK [Bruton tyrosine kinase] inhibitors, for example acalabrutinib, which doesn’t have the same degree of off-target effects on natural killer cells. It also doesn’t say anything about obinutuzumab, which can kill CLL cells directly, without these immune effector cells. We’re going to need clinical trial data with these different agents before we know that. Fortunately, several ongoing studies will be able to address these questions.

What do these trials tell us about the possibility of stopping therapy?

All 3 of these studies of ibrutinib have been designed as continuous therapy studies. At this point we only have anecdotal experience with patients who discontinue ibrutinib, for example, in patients who develop an ibrutinib-related toxicity and come off drug for that reason. Down the road, that could be an interesting subgroup analysis to look at from the ALLIANCE study, for example, over time those patients who discontinued ibrutinib not due to disease progression but due to use toxicity: how long did they stay progression-free off ibrutinib and what were the characteristics of patients who may have had a longer progression-free interval off ibrutinib? It would be interesting to see a prospective study that discontinues ibrutinib and looks at the natural history of the disease, but that is unlikely to happen. What the field is focusing on now is combination approaches to deepen the response to ibrutinib to get to a minimal residual disease undetectable state and then stopping. There are a number of such studies now underway, including our study of ibrutinib plus FCR chemoimmunotherapy in younger, fit patients, and several studies combining ibrutinib with venetoclax.

What directions for future research do these trials signal?

One important point to mention from the ECOG 1912 study is that after a relatively short amount of follow-up for a frontline study, the ibrutinib plus rituximab arm is already showing an overall survival benefit over FCR alone. The benefit of the ibrutinib regimen seems greatest patients with IGHV unmutated CLL. I think for younger patients with mutated IGHV CLL, the story is less clear, as over half of these patients would be expected to have functional cure with FCR alone. As such, I believe the FCR should still be considered standard of care for such patients, until longer term follow-up is available for ECOG 1912.

Although the [data from the 2018 American Society of Hematology Annual Meeting] has made ibrutinib the preferred frontline therapy for most CLL patients, things are already changing quickly. The CLL14 trial, which is the venetoclax plus obinutuzumab randomized registration trial just recently led to its FDA approval in May 2019 as a frontline therapy in CLL. The venetoclax/obinutuzumab regimen is kind of the best of both worlds. because it’s designed as a time-limited therapy like chemotherapy, but with fewer [adverse] effects because it’s a novel agent only approach, and unlike single agent novel therapies it is showing promise as a time-limited 1-year therapy. Given the availability of this regimen, I think it will be important for oncologists to discuss the pros and cons of venetoclax plus obinutuzumab versus ibrutinib (and, in some cases, chemoimmunotherapy) with patients before selecting frontline therapy.

We now are able to individualize the therapeutic approach depending on the patient’s profile. For example, a patient with significant cardiac issues already on anticoagulation may be at risk for cardiac or bleeding events on ibrutinib, so that might be a good patient for venetoclax/obinutuzumab. Or maybe you have a patient who has poor renal function and you’re worried about tumor lysis syndrome with venetoclax, then maybe ibrutinib is a good option. Although things are getting more complicated, I think it’s a good thing for patients that we have all these options.

Down the road, we’re probably also going to have an FDA approval for ibrutinib plus venetoclax. Then we’re going to have to decide if it is better to start with these 2 drugs upfront and use our best 2 drugs right away (maybe even a 3-drug regimen with an antibody), or to use them sequentially and maybe save drug one for later? There are still many unanswered questions and we have a lot of trials that still need to be done to optimize the sequence of administration and when to use combinations, and so forth.

What is your perspective on the 2019 updates to the National Comprehensive Cancer Network (NCCN) guidelines?

The NCCN guidelines are pretty dynamic, so it would not be surprising if venetoclax/obinutuzumab is added to the guidelines by the end of this year. In terms of the overall utilization of the guidelines, I think that oncologists do look to the guidelines, but on the other hand, there are still oncologists who are more comfortable treating based on the regimens they have traditionally been most comfortable with. For example, we still see rituximab monotherapy used in the older population even though it is not a very effective therapy on its own for CLL. Similarly, bendamustine and rituximab is a regimen many oncologists are accustomed to using for indolent lymphomas and I think that’s going to be continued to be used widely for frontline therapy. So there is a lag in terms of when the NCCN guidelines change and when it really impacts practice. But I do believe that over time the use of novel agents in CLL will grow as community oncologists gain more experience and see firsthand the great power and tolerability of these agents.

How would you sum up the current moment we are in in CLL research and what are your thoughts on the future of treatment?

We are in an enviable position now as CLL specialists; we have so many great drugs now and the challenge is how do we put them together optimally in an individualized way for patients while also trying to keep costs down and minimizing long-term toxicities. I think that for older CLL patients, using novel agent monotherapies sequentially may be fine, but I do think for the younger fitter patients, especially if they have higher-risk disease, that’s where it is particularly important to be pursuing combination novel agent approaches. It’s certainly an exciting time in CLL, with all these new treatment options, and one of the challenges for us as clinical investigators is about how to generate the right data to help us optimize approaches for each individual patient. 

References

1. Shanafelt TD, Wang V, Kay NE, et al. A randomized phase III study of ibrutinib (PCI-32765)-based therapy vs. standard fludarabine, cyclophosphamide, and rituximab (FCR) chemoimmunotherapy in untreated younger patients with chronic lymphocytic leukemia (CLL): a trial of the ECOG-ACRIN cancer research group (E1912). Blood. 2018;132:abstr LBA-4. doi: 10.1182/blood-2018-120779.
2. 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.
3. Moreno C, Greil R, Demirkan F, et al.Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial [Correction appears in Lancet Oncol. 2019;20:43-46]. Lancet Oncol. 2019;20(1):43-56. doi: 10.1016/S1470-2045(18)30788-5.