Therapeutic Sequencing in Relapsed/Refractory CLL

Alan P. Skarbnik, MD: Because CLL [chronic lymphocytic leukemia] is not a curable disease, patients will eventually relapse. The question is what do we do once that happens? This would be defined by what patients received in the first-line or second-line setting. In general terms, we try to change the mechanism of action of the drug we’re giving in the relapsed setting because theoretically, they were either resistant or progressed to whatever they received in the frontline setting. When the patients do present with relapse, we need to remember that it’s not because they have relapsed disease that they need treatment. The criteria for treatment in the second, third, and fourth line are the same as the frontline setting. Patients may relapse, or never achieve full remission with the frontline therapy and stayed away for many years.

At the time the criteria are met for treatment to be reinitiated, then we need to remember to retest those patients for some cytogenetic abnormalities. We don’t need to retest for IGHV, that doesn’t change, whether it’s mutated or unmutated, because it’s the cell of origin. But certainly, we need to recheck for 17p deletion, TP53 mutation because relapsed populations are more enriched for those abnormalities. They are dynamic and can change over time. You can have clonal progression. It’s important to know that.

It’s important to evaluate patients for the risk of high-grade Richter transformation and ensure that hasn’t happened. If their lymph nodes are larger than you would expect, if you have a PET [positron emission tomography] scan that has very hypermetabolic areas, consider a biopsy on those sites, ensuring that the patient doesn’t present with a high-grade transformation, which is not the most common scenario, but we need to exclude that anyway.

The next question after testing this, is what did the patient receive before? Has the patient received a previous BTK [Bruton tyrosine kinase] inhibitor, which is more frequent since it’s been on the market for a longer period? If yes, then next we’re going to try a venetoclax-based regimen, if they haven’t received that before. In the second line, if the patient had a BTK inhibitor [BTKi] first, I use venetoclax with a monoclonal antibody. Even though the MURANO trial used rituximab, I use obinutuzumab in the second-line setting based on the fact that it is a higher carrier of undetectable MRD [minimal residual disease].

I’m trying to use a fixed-duration treatment for those patients, and trying to achieve an undetectable MRD state would be ideal. In the second line, remembering we use venetoclax for 2 years rather than 1 year. If the patients do have 17p deletion or TP53 mutation at that time, I will discuss it with the patients at the time of completion of therapy, when they’re approaching those 2 years, if it would be worthwhile for them to continue venetoclax beyond that time. Remembering that the initial trial with venetoclax for the population with 17p deletion was of continuous therapy, it was not a fixed-duration therapy. There are data to continue with the treatment, particularly remembering that 17p deletion was a predicator of progression in the MURANO relapsed trial. But if the patients don’t have this high-risk abnormality, I stop at 2 years.

If the patients have not received a BTK inhibitor prior, then we ask what they received prior. We have a number of patients who received chemoimmunotherapy before, and then we have the same discussion as in the frontline setting. Who will be better off having a BTK inhibitor versus a venetoclax-based regimen? If the patient had 17p deletion or TP53 mutation, I usually go for a BTK inhibitor continuously. If not, then I can use venetoclax/obinutuzumab for 2 years.

We know, based on retrospective data that were presented at ASH [the American Society of Hematology annual meeting] in 2019, that you can salvage venetoclax-exposed patients who’ve progressed in third line or further but are BTKi naïve. You can use a BTKi at that point, and salvage to the tune of about an 80% response rate. The flip side is also true. If you used a BTK inhibitor for patients who have progressed, we can also salvage them with a venetoclax-based regimen. There’s going to be discussion about who should have fixed-duration vs nonfixed duration therapy, adverse effects, logistics, it goes back to the same discussion at in the frontline setting.

Patients who did receive a venetoclax-based regimen, stopped, and progressed, can receive venetoclax, you can rechallenge them. There are data showing that for those patients who did have an initial response, these are patients who have refractory disease or never responded or progressed while on venetoclax therapy. But for those who received it for a year and then started having progression a year or two later, it is reasonable to treat those patients again with venetoclax.

At that point, I would use venetoclax continuously. I wouldn’t stop it because the disease has already shown its face, progressing after discontinuation. But it’s certainly a reasonable approach, and then if they don’t have a response to the venetoclax, a BTKi will be used.

Very rarely, I use chemotherapy in a relapsed setting. We still have PI3 kinase inhibitors available if patients progress on venetoclax and a BTK inhibitor. Idelalisib and duvelisib have been approved, and there are others coming up soon. I prefer duvelisib because it is better tolerated. But then those are the patients we evaluate for clinical trials, CAR [chimeric antigen receptor] T-cell therapy trials, or even allogeneic stem cell transplantation if they have progressed through all the novel agents.

Catherine C. Coombs, MD: The biggest factor when thinking about sequencing of therapies in CLL is what did the patient get for the first line. There are plenty of patients who have been in remission for a while, they received chemoimmunotherapy 5 years ago as their frontline therapy. BTKi and venetoclax regimens are both very reasonable. We individualize that discussion with the patient to see which is more preferable to them based on toxicity profile and length of therapy. For patients who get a BTK inhibitor in the front line, I usually am going toward venetoclax-based regimens in first relapse. There are some patients for whom doing the tumor lysis monitoring is not feasible due to transportation issues or personal preference, and in those patients PI3 kinase inhibitors are reasonable. They are somewhat limited as far as their toxicity profile, but for the patient who prefers an oral-only regimen, that’s an option. I always discuss clinical trial options with my patients as well.

There was an initial concern about using venetoclax prior to BTKi because there weren’t a lot of data on whether the BTK inhibitors would work as well following venetoclax. I don’t have reservations with that, now we have a bit more data and the BTK inhibitors appear to work quite well following venetoclax. So I don’t have reservations in changing the sequence of therapy for patients who want to give a shot at a time-limited regimen and do the venetoclax before the BTK.

Transcript Edited for Clarity

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