Key Clinical Data in Relapsed/Refractory CLL


An in-depth analysis of current therapeutic options in relapsed/refractory chronic lymphocytic leukemia.

John C. Byrd, MD: For relapsed and refractory patients, many of the patients we’re seeing are those who have received chemoimmunotherapy and have been in remission for some time but their disease is coming back. Or patients who have received venetoclax or another targeted therapy. In both settings, a BTK [Bruton tyrosine kinase] inhibitor is a good choice. The RESONATE study and ASCEND study both showed that single agent, either ibrutinib or acalabrutinib, was better than alternative controls. Bendamustine, rituximab, ofatumumab, or idelalisib rituximab and all things we used in the past. In both studies, there was a survival advantage, and that in part equates from the BTK inhibitors, which are much better therapy.

A question that I’m asked in this patient population is, what is the better BTK inhibitor? Who wins the beauty contest? Between first-generation ibrutinib and second-generation acalabrutinib or zanubrutinib, we have randomized, equivalent studies that were done with both drugs, as compared with ibrutinib that have shown that there’s at least equivalence with these drugs. The ELEVATE TN relapsed/refractory study demonstrated that there was the hazard ratio for progression-free survival [PFS] by an IRC [intrinsic reaction coordinate], which had a hazard ratio of 1.0. The curves were on top of one another. Survival favored acalabrutinib, in part because there was diminished cardiac toxicity, atrial fibrillation, grade 3/4 hypertension, and a bunch of other adverse events.

A similar study done with zanubrutinib vs ibrutinib in all patients with relapsed disease—not just high risk, like the ELEVATE TN relapsed/refractory study—showed similar findings in terms of diminished cardiac toxicity and improvement over ibrutinib. In this setting, there are strong data that the second-generation BTK inhibitor is the best way to go.

A common question is in the setting of relapsed/refractory disease because we have reversible inhibitors, ARQ 531 and LOXO-305, which are in phase 3 studies. And the question comes up, should I put my patient on a reversible BTK inhibitor or an irreversible BTK inhibitor? It’s important to test this in clinical trials, but we don’t need a ton of clinical trials, testing this until we’re sure that the patterns of resistance match the best way to treat patients. By that I mean that we know with ibrutinib, acalabrutinib, and zanubrutinib, the common mechanism of resistance is acquisition of a CYC41S mutation in BTK where the drug binds. When that happens, we know that the reversible inhibitors, the LOXO-305 or ARQ 531, work in that setting. You can clearly go from 1 to the other, irreversible to reversible.

With reversible BTK inhibitors, the pattern of resistance hasn’t been well described. But when you look at other reversible inhibitors of other kinases—let’s say FLT3 in AML [acute myeloid leukemia]—what we see is patients who develop gatekeeper mutations. And there’s a brand-new preclinical paper showing that gatekeeper mutations, which you’d predict to develop on LOXO-305 or ARQ 531, promote resistance to both reversible inhibitors but also irreversible inhibitors. If you gave a reversible inhibitor in the up-front setting or a second line even before an irreversible inhibitor, then there’s the hypothetical potential that you would promote resistance to the other possible BTK inhibitor. That’s going to be something important as we think of our sequencing of new drugs moving forward.

Paolo Ghia, MD, PhD: PI3 kinase inhibitors are another class of inhibitors that we’ve known for a relatively long time. The first impression that we had with idelalisib is that it’s the first 1 to achieve market with great efficacy. The patients responded very well. That’s been confirmed in the final analysis that was recently published in the JCO [Journal of Clinical Oncology]. For a patient in the phase 3 study enrolled in the relapsed/refractory setting, comparing idelalisib plus rituximab and the anti-CD20 antibody vs rituximab alone together with a placebo, I suspected idelalisib was more effective than rituximab. Indeed, the study has been terminated early because of this overwhelming efficacy. What we learned with time is an idelalisib-based regimen isn’t well tolerated because of severe diarrhea that may be based on colitis.

Also, inflammatory features like pneumonitis can be life-threatening. Many patients would stop treatment, missing the efficacy that could be achieved with a complete treatment. For this reason, though, combination idelalisib-rituximab achieved a median progression-free survival of less than 2 years. That has been confirmed in the ASCEND study in the relapsed/refractory setting, where idelalisib plus rituximab or bendamustine plus rituximab were compared with acalabrutinib, the second-generation BTK inhibitor.

We have another molecule that is a PI3 kinase inhibitor. While idelalisib was a PI3 kinase delta inhibitor, duvelisib is a PI3 kinase gamma and delta inhibitor. That has been proven to be effective compared with ofatumumab, which was a treatment for relapsed/refractory patients. Though effective in terms of overall response, the median PFS has been reached around 13 months. Some issues of tolerability are seen, though less than with idelalisib. But patients may experience elevation of diarrhea.

Anna Schuh, MD, PhD: I remember when we looked at our real-world data on ibrutinib after ibrutinib had gained early access in the United Kingdom. This was before we got access to venetoclax. In the real world of patients relapsing after having a chemoimmunotherapy and then ibrutinib and then relapsing on ibrutinib, the overall survival was 3 months. When then venetoclax monotherapy came along, that number changed to about 2 years after relapsing from ibrutinib. Clearly venetoclax has made a huge difference, even in the setting of patients relapsing after chemoimmunotherapy and relapsing after ibrutinib. But it’s not leading to cure.

The MURANO data were in a very different situation because the inclusion criteria were 1 to 3 lines of therapy. The vast majority of patients had chemoimmunotherapy maybe once or twice and then went into the MURANO study. There were very few patients who had received ibrutinib—only about 6. The results are highly relevant and show very nice response after 24 months of venetoclax and rituximab. That is comparable with using ibrutinib in a KIT-resistant patient. I use venetoclax-rituximab, or ibrutinib or acalabrutinib for that matter, in the relapsed setting after chemoimmunotherapy. It’s difficult to decide which 1 is the right drug. I usually give patients the choice whether they want 24-month duration therapy or continuous therapy. Treating patients with cardiac comorbidities, I’d opt for acalabrutinib rather than ibrutinib. If a patient is well controlled on ibrutinib, I’m not going to switch the patient to acalabrutinib. If I have a patient who’s hardly at any treatment, I’ll lean toward venetoclax and rituximab combination because I know from the MURANO data that this combination is very effective in those patients who haven’t received that much treatment.

Transcript Edited for Clarity

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