Targeted Therapy Options for Frontline CLL

John M. Pagel, MD, PhD:The unmet need that we continue to need to improve on is providing the most tolerable therapy with the most efficacious outcome to patients. In 2020, the way we typically approach that is with standard targeted therapies. We do not typically use chemoimmunotherapy much, if at all, in chronic lymphocytic leukemia [CLL] anymore. This includes both older and younger patients. The disease has clearly evolved to suggest that targeted therapy—in particular, Bruton tyrosine kinase [BTK] inhibitors and BCL2 inhibitors—have really set the stage and landscape for the regimens and approaches that we use in the frontline setting.

We did 2 major studies in the recent past, and actually presented them at the American Society of Hematology [ASH Annual Meeting & Exposition] in 2018. We showed that in comparison with standard chemotherapy regimens—either fludarabine, Cytoxan [cyclophosphamide], Rituxan [rituximab], or FCR; or bendamustine and rituximab [BR]—the BTK inhibitor ibrutinib was superior for progression-free survival. And in younger patients, compared with FCR [fludarabine, cyclophosphamide, rituximab], it actually had an overall survival advantage as well.

We had previous data that suggested that ibrutinib was better than other chemotherapy regimens such as chlorambucil and obinutuzumab, which is a very reasonable regimen in older patients. Again, ibrutinib had a significant improvement in the primary end point in those studies and, in particular, in the iLLUMINATE trial, progression-free survival. Because of that, we have now learned that the frontline therapy is targeted agents over chemoimmunotherapy, either with a Bruton tyrosine kinase inhibitor or with venetoclax, which I’ll talk about a bit more in just a second.

Let me say another word about BTK inhibitors. Certainly, ibrutinib is a standard of care in the frontline setting—I just alluded to that—compared with those randomized studies of FCR [fludarabine, cyclophosphamide, rituximab] or BR [bendamustine, rituximab]. But we also know that a next-generation BTK inhibitor is available, known as acalabrutinib. Acalabrutinib is another BTK inhibitor that’s approved for patients with CLL in the frontline setting as well as in the relapsed setting. The ELEVATE-TN trial that we just reported on at the last ASH meeting in 2019 showed that in this trial, which compared 3 different arms—either acalabrutinib by itself as a single agent, acalabrutinib with obinutuzumab, or chlorambucil and obinutuzumab—the acalabrutinib-containing arms were significantly better compared with the chlorambucil-and-obinutuzumab arm.

Acalabrutinib has also emerged as another important standard of care using BTK inhibitors in the frontline setting for patients with CLL, and not just for high-risk patients. Certainly, we know that if you have a deletion of the short arm of chromosome 17, a 17p deletion, or aTP53mutation, which we should always be screening for as well, BTK inhibitors are clearly the drug of choice in those patients. Or perhaps venetoclax. However, not chemoimmunotherapy.

But it’s not just those -risk patients who should be getting these targeted agents. Rather, it’s probably all patients, with maybe 1 exception. There are patients who are very, very favorable, who have what we call mutated immunoglobulin heavy chain variable region. They’reIGHVmutated. I always like to say it’s good to be a mutant. It means that these cells have undergone somatic hypermutation and are a more mature cell that leads to a more favorable prognosis. The unmutated patients are a bit more aggressive, and unfortunately, they’re usually the vast majority of patients who present with CLL.

Nonetheless, in the more favorable patients, the mutated patients, we do know that FCR [fludarabine, cyclophosphamide, rituximab], at least in younger patients who are fit and can tolerate that regimen, can provide a long-term survival benefit in roughly about half of patients. We have long-term data with a plateau on the curve, out 14, 15 years, suggesting that these people might be cured. The interesting thing is that in the recent ECOG trial [ECOG-ACRIN] comparing ibrutinib with FCR [fludarabine, cyclophosphamide, rituximab], we also showed that those favorable mutated patients do just as well, albeit the follow-up is relatively short—only on the order of a couple of years. We don’t have that 14- or 15-year follow-up data, but that might be a patient population for which we still want to consider chemoimmunotherapy. Otherwise, even for standard-risk patients, or patients who might have favorable cytogenetics, the standard of care has really evolved now to targeted therapies, and we’ve discussed BTK inhibitors.

Transcript edited for clarity.