When patients with chronic lymphocytic leukemia (CLL) have disease that is refractory to BTK and Bcl-2 inhibitors, management can be challenging. Our panel of experts discuss US Food and Drug Administration (FDA)–approved therapies and clinical strategies for treating double-exposed/refractory patients with CLL.

If a patient was treated with a venetoclax-based regimen, had a durable remission, and then went on to receive a BTK inhibitor, they might be able to return to the venetoclax-based treatment and achieve a reasonable remission. In my own practice, if a patient experienced remission with a venetoclax-based therapy and maintained that remission for a few years, it might be worthwhile to go back to that treatment. If their remission was shorter than that, I would probably not be excited about retreatment.

At that point, if a patient’s CLL is refractory to both a covalent BTK inhibitor and venetoclax, then I might consider a noncovalent BTK inhibitor. The only option that is currently FDA approved is pirtobrutinib, which was granted accelerated approval, but we will hopefully have other options in the future. Beyond that, we would move to combinations of known agents. There are some small data series looking at the combination of a covalent BTK inhibitor with venetoclax in patients who have already received both of those treatments, and, surprisingly, there was actually some durable remissions. Anecdotally, in my own practice, I have also seen patients experience durable remissions, so I am thankful for those data.

After that, we would get into much more complicated, limited treatments such as cellular therapy, including CAR T-cell therapy. Although CAR T-cell therapy is helpful for a select few patients, hopefully, with other treatment approaches, we will be able to treat the majority of patients for a long time without needing to reach for cellular therapy.

Many patients may have stopped treatment with BTK inhibitors or even venetoclax-based treatment because of toxicity. Regarding the question of whether it is at all possible to go back to those treatments, a lot of data have been published looking at the use of the so-called second-generation covalent BTK inhibitors. These include acalabrutinib and zanubrutinib, which may be more selective and therefore have fewer off-target side effects. I think it is very important to ensure that you have used a class of agents maximally before you move on to noncovalent BTK inhibitors or other options.

In my own practice, I first confirm that a patient truly meets the indications for treatment. A lot of patients, even if they have stopped treatment due to toxicity, may not immediately need therapy because they do not meet some of the traditional criteria for starting treatment. Some data suggest that patients can wait close to 2 years before they need the next line of therapy if they received ibrutinib for a short period of time and stopped because of toxicity. We should note the classes of drugs to which patients may have had toxicities but did not develop true resistance. I think that recycling drugs in these classes is important to consider as a long-term treatment option.

Additionally, despite everything we do, there is a small number of patients for whom we still need to consider allogeneic stem cell transplant if nothing else is available and if all other treatments have failed, besides the options that Dr Flinn discussed previously. That still remains under consideration, particularly for younger patients who have high-risk disease.

For patients whose CLL has progressed on a covalent BTK inhibitor and venetoclax, CLL becomes very likely to be a life span–limiting disease. Until the recent FDA accelerated approvals of pirtobrutinib and lisocabtagene maraleucel, we did not have FDA-approved options that were expected to work well for these patients.

Our institution has published data on the strategy that Dr Flinn discussed regarding retreatment with a covalent BTK inhibitor and venetoclax. We reported that patients can get durable benefit, but relapse is usually very difficult to control if the cells become resistant to the combination. This is when we really need to think. If a patient is younger, are we going to send them for an allogeneic transplant, as Dr Parikh mentioned? Or are we going to send them for CAR T-cell therapy? There is evidence that the bulk of patients who receive CAR T-cell therapy will not achieve disease control for their remaining life span.

Investigational treatment through a clinical trial is an option, and until recently, this used to be the best thing, but some patients are not well enough, and others cannot participate for social reasons. I practice in central Ohio, and I see patients from rural areas who cannot travel to participate in research studies. In double-refractory patients, it is important to have a discussion about how the disease might impact their life span and what the patient’s expectations are, deciding together how much they are willing and able to go through in terms of investigational treatments, cellular therapies, or even transplant. It can be a very real change when patients become accustomed to observation or to taking pills and going about their business but then need more intensive treatment after disease progression. Setting expectations with patients is really important.