Adding Copiktra to Standard of Care Chemotherapy Combination in CLL Could Improve Outcomes, But Not Without Toxicities

For many years, the combination therapy of chemotherapies fludarabine, cyclophosphamide and Rituxan (rituximab) (FCR) has been the standard of care for younger patients with chronic lymphocytic leukemia (CLL). Some subsets of patients benefit more than others, however, prompting researchers to investigate the addition of other agents in a bid to improve outcomes.

In an interview with CURE®, Dr. Matthew S. Davids explained how one such study he is currently working on found that the addition of Copiktra (duvelisib) to this three-drug combination did, in fact, improve patient outcomes, with over half of patients achieving complete remission. However, the toxicities experienced when this drug is added to therapy were troublesome enough to highlight the need for further study, Davids explained.

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FCR has been our gold standard chemo immunotherapy regimen for these younger, fit patients under the age of 65 for many years now. And around the time that this study was designed, we were learning that patients could have very long remissions from FCR. We're talking about 12 to 15 years of remission, after getting just six months of the chemo immunotherapy regimen alone. And so, you know, we basically would consider some of these patients to be functionally cured of their CLL, with it being very unlikely that it would ever come back.

Now, the group of patients who have that durable benefit from FCR alone tend to be those with the mutated IGHV, which is a less common type of CLL that needs treatment. And so, the aims of the combination studies with FCR were kind of twofold.

One was to bring the patients who did not have that potential for long term remission, in other words, the 60-65% or so of patients who have unmutated IGHV, to bring those into the category of patients who may have these durable responses and long-term functional cure.

But then the second goal was also to take that group of mutated IGHV patients who already have some potential for cure, but actually increase the odds that they would be cured. Right now, it's only about 50-60% of those patients who have long term functional cure. And the hope would be we could bring that number up by adding additional active agents.

And the duvelisib, at the time, was called IPI-145, it was a new delta/gamma PI3K inhibitor being developed at that time by Infinity Pharmaceuticals, and was showing great promise as a single agent in CLL, even in some very refractory patients. And so, the idea was to put this very active agent in combination with FCR.

And this was a very attractive concept because sort of from a conceptual standpoint, we know that this drug can help to release CLL cells out from the lymph nodes in the bone marrow where they tend to be in a protected micro-environment. And the idea we used to say to the patients, as we were kind of explaining it to them, you're kind of flushing the cells out of the bushes where they're hiding and into the open where they can then be more effectively killed off by the chemo immunotherapy.

What we've learned from the study was that this is a highly effective combination. Well over half of the patients achieved complete remission, and about two thirds of the patients got to an undetectable minimal residual disease state or undetectable MRD in the bone marrow, which is a very powerful regimen.

But we also learned that there's some toxicities associated with the regimen. With duvelisib, we know that there are some risks around liver inflammation, diarrhea, and even colitis in some patients. We saw some rash and other issues arising with the FCR. We saw infections, as we commonly see with the regimen, we saw myelosuppression, meaning that the blood counts were suppressed on some patients for longer periods of time. And so not all the patients made it through the entire regimen without having to stop early. Some patients did have to come off study early because of side effects.

And so, you know, I think what we've learned is that this this can be a good option to consider studying further, but I think if we're studying it further, we need to do so in ways that might help to mitigate some of the toxicities.