Upfront Ibrutinib in CLL

Jan A. Burger, MD, PhD:The RESONATE-3 study was a frontline study for previously untreated patients—elderly, unfit—and it’s been positive. The comparator arm, chlorambucil, had shorter progressive-free survival and overall survival. Based on these data, ibrutinib was approved by the FDA for frontline use in elderly patients, but also in younger patients. There’s no age restriction on the label. The drug got here in the United States. I think with the practical consequences, now we can offer that, can discuss it with patients, and some patients might like it. But other patients may say, “I don’t want to be on a continuous, indefinite treatment.” So, it’s great to have an additional option, but it might not be the best choice for everybody. Certainly, for many elderly patients and for high-risk patients, it’s a great choice.

Clinical practice has been in the last, maybe, decade still heavily geared toward chemoimmunotherapy. I believe FCR, bendamustine-based treatment, and antibodies have been dominating the therapeutic arena. But now there’s the competition by the new kinase inhibitors, and I think we just see a shift of some patients—especially the patient groups we already talked about earlier, high-risk patients, frail patients—toward the new agents. And the other thing is in the relapse setting, where patients have failed previous treatments: we see great benefit from these new drugs.

The question is: what do you do if a patient responded to ibrutinib, has been on the drug, responded well, but then develops disease progression? It seems like that’s a straightforward question, but, in reality, there might be different setting. Patients can progress with Richter’s transformation, which is transformation into aggressive lymphoma, where patients develop rapidly progressive disease, high LDH (lactate dehydrogenase), rapidly enlarging lymph nodes, for example. And those patients need different treatment. For those patients, the currently accepted standard is intensive chemotherapy, similar to high-grade lymphoma. And then if patients are younger, we move them to an allogeneic stem cell transplant. But the survival of these patients is not good based on our experience with Richter’s transformation in the setting of kinase inhibitors or chemoimmunotherapy. So, unfortunately, for those patients, we still sometimes struggle to get them into longer remissions and new concepts are being developed. One hope is that maybe new agents like venetoclax, ABT-199, is an option for these patients.

Richter’s transformation continues to be a problem. It’s not common. We don’t think it has increased in its frequency in patients who are on targeted agents versus patients who historically were on chemoimmunotherapy. But it continues to be an issue. And those patients typically present and progress, oftentimes early on, at least from the published clinical trial data. Oftentimes, within a year or two, patients can progress with this more aggressive lymphoma. I think in the community of treating physicians and physicians participating in these studies, the feeling was that the ibrutinib treatment unmasked an underlying, already-in-progression high-grade lymphoma. So, that’s the feeling. The other issue is patients who responded, but then progressed with their CLL. And there, we are still in early stages of learning what the genetic makeup is. There are some published data, but there’s no consensus treatment. The most promising data, which were presented at the ASH meeting last year, were with venetoclax in this setting, which induces remissions in many patients. But the durability is unknown. And probably those patients, if fit for transplant, should also be considered for stem cell transplant.

Case 1:A Fit Elderly Patient with Newly-Diagnosed Chronic Lymphocytic Leukemia.