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CLL/SLL: 2L Therapy
Key Considerations in Selecting Second-line Therapy for Patients With CLL/SLL

Released: May 15, 2024

Expiration: May 14, 2025

Nicole Lamanna
Nicole Lamanna, MD
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Key Takeaways
  • The third-generation BTKi pirtobrutinib and the CAR T-cell therapy liso-cel are now available as treatment options for patients with CLL/SLL who relapsed after ≥2 systemic therapies, including previous BTKi-based regimens and BCL-2i plus anti-CD20 mAb therapy.
  • Key factors in selecting between third-generation BTKi and CAR T-cell therapy include patient preference for either a continuous oral therapy vs a time-limited therapy and the presence of specific patient comorbidities that would render the patient ineligible for either therapy.

Selecting second-line and beyond therapy for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) is a bit more nuanced than selecting first-line treatment. In the second line and beyond, optimal therapy depends on what patients have previously received as part of their first-line therapy, disease characteristics (eg, change or not) at the present time, any new comorbidities, and whether they were intolerant to a previous therapy.

Previous Therapy Considerations
If a patient previously received a BTK inhibitor (BTKi) and now is relapsing, we would opt for venetoclax together with an anti-CD20 monoclonal antibody (mAb) according to the most recent guideline recommendations and supported by results from the phase III MURANO study. In that study, patients with relapsed CLL were randomized to receive either 2 years of venetoclax plus rituximab or bendamustine plus rituximab, with those treated with venetoclax plus rituximab achieving much better outcomes. There also have been suggestions in favor of using obinutuzumab vs rituximab in the relapsed setting given its approval in the frontline setting because it is a more potent anti-CD20 mAb. Although we do not yet have direct evidence for this antibody substitution in the relapsed setting (there are studies ongoing currently), I think this switch is likely fine, but we would need to determine whether in this scenario we should continue venetoclax for 24 months, as in the original MURANO regimen. Another consideration is that if a patient is frail and there are concerns about using obinutuzumab, than rituximab is a logical choice. Thus to summarize, if a patient started a BTKi as initial therapy and progresses, venetoclax and an anti-CD20 mAb combination upon relapse is recommended with clinical trial data to support this choice.

It is important to note that if a patient had started on ibrutinib and experienced disease relapse/progression on that therapy, we would not want to recommend acalabrutinib or zanubrutinib. As a reminder, ibrutinib, acalabrutinib, and zanubrutinib are all covalent BTKis. If a patient fails one of these agents, they are not going to do better on a different one. However, if the patient is intolerant to a covalent BTKi because of adverse events (AEs), one could switch to a different covalent BTKi to extend the use of this drug class. In a patient who develops a rash on ibrutinib, for example, one may try acalabrutinib or zanubrutinib to see if they have improvement of the rash or do not even experience one. I think that is completely reasonable. Conversely, for some serious AEs with a BTKi, one may not want to immediately rechallenge a patient with a different covalent BTKi. For instance, if a patient had a brain bleed—a central nervous system hemorrhage—I would be uncomfortable switching from one covalent BTKi to another one immediately, because they just had a major hemorrhage. By contrast, it is reasonable that for a “minor” AE, one may rechallenge with a different BTKi in the same drug class.

If a patient had progressed on venetoclax plus an anti-CD20 mAb, one could subsequently be treated with one of the covalent BTKis previously mentioned. In addition, one could consider re-challenging on venetoclax-based therapy depending on the amount of time the patient spent off that first-line therapy. For example, if it was very prolonged period of time (eg, ≥4 years off venetoclax), then it is reasonable to rechallenge with the first-line regimen. For a patient who relapses within 1 year of finishing therapy with venetoclax/obinutuzumab in the frontline setting, however, I would usually go to a BTKi as this response duration is shorter than one would hope for in the frontline setting. Here, I also would consider whether the patient has acquired a de novo del(17p) or a TP53 alteration. It is important to check the patient’s cytogenetics/FISH status again upon disease progression/relapse before starting a new line of therapy. These results may also change my opinion on what to do next. If the patient received venetoclax/obinutuzumab as first-line therapy and, upon relapse, has an acquired de novo del(17p) or a TP53 alteration, I might think that a chronic BTKi approach now would be better for that patient.

Recent FDA Approvals
We recently saw 2 new treatments receive FDA accelerated approval for double-relapsed/refractory CLL. The first is pirtobrutinib, a third-generation, noncovalent, reversible BTKi that was approved in adult patients with CLL/SLL who have received ≥2 previous lines of therapy, including a covalent BTKi and a BCL-2 inhibitor (BCL-2i). One could also use this agent in the setting of BTKi intolerance as well. The pirtobrutinib approval was supported by data from the phase I/II BRUIN study in patients with relapsed/recurrent CLL/SLL after ≥2 prior therapies, including a covalent BTKi. In patients with previous covalent BTKi therapy, the overall response rate (ORR) was 82% (95% CI: 76.8%-86.7%); in those with previous BTKi and BCL-2i therapy, ORR was 79.0% (95% CI: 69.7%-86.5%). The other recent approval for CLL/SLL was that of lisocabtagene maraleucel (liso-cel), the first CD19-directed CAR T-cell therapy for adult patients with relapsed/refractory CLL/SLL who have been treated with ≥2 previous lines of therapy, including a BCL-2i and a BTKi. We have been expecting this approval for quite some time based on results from the phase I/II TRANSCEND CLL 004 trial. That study showed that patients who received the CAR T-cell therapy achieved an ORR of 48.0% (95% CI: 32.3%-57.5%), including a complete remission with incomplete blood count recovery (CRi) rate of approximately 20%, with durable responses in those achieving CRi. We generally expect shorter duration of response in these heavily pretreated patients and improved responses as we move these agents earlier in the course of treatment.

Where does CAR T-cell therapy fit in this context? Right now, in my practice, CAR T-cell therapy will still be relegated to patients with CLL with multiply relapsed disease—those who have previously received a BTKi and a BCL-2i. It is important to consider that for patients who have relapsed post covalent BTKi and venetoclax-based therapy, that even the response duration to pirtobrutinib maybe limited and one could utilize this as a bridge to CAR T-cell therapy in this setting. Other factors to consider when deciding between pirtobrutinib and CAR-T cell therapy also include age and comorbidities of the patient when choosing between these options.

Regarding whether to consider pirtobrutinib or liso-cel first for patients with double-refractory disease, that determination is more complex. There are obvious differences in the AE profiles of CAR T-cell therapy (eg, cytokine release syndrome and neurotoxicity) and noncovalent BTKi (eg, cardiac AEs, hypertension, bleeding/hemorrhage). B-cell aplasia has been reported following administration of liso-cel, and there is potential for infections and infection-related complications—although I would argue that we see infections and infection-related complications with all agents used to treat CLL and more-so in our multiply relapsed patients. The toxicity profile for pirtobrutinib so far appears seemingly well tolerated but does have shorter follow-up compared with that of our current covalent BTKis. Moreover, liso-cel CAR T-cell therapy is administered as a one-time treatment (90-110 x 106 CAR-positive viable T-cells) after a conditioning regimen with fludarabine/cyclophosphamide. By contrast, pirtobrutinib is given orally at 200 mg once daily.

Ultimately, we must discuss with the patient the available data from these clinical trials in the multiply relapsed setting together with the toxicity profile of each agent along with the patient’s prior treatment history, comorbidities, and goals of therapy. In all, as we get more experience with these novel agents, we become more successful in mitigating the toxicities and are able to draw from experience in other disease states, such as diffuse large B-cell lymphoma, where CAR T-cells also have been studied. 

Ongoing clinical trials also are exploring pirtobrutinib (NCT05254743; BRUIN-CLL-314) and liso-cel (NCT05873712) in less heavily pretreated patients with CLL/SLL. We eagerly await those data, as well as data for other trials exploring novel mechanisms of action such as BTK degraders (NCT05131022) and anti-CD3xCD20 bispecific mAbs (NCT04623541).

Your Thoughts?
What do you consider when selecting second-line and beyond therapy for patients with CLL/SLL? Join the discussion by posting a comment, and be sure to check back on this page often for additional CLL/SLL education, including an updated online treatment decision support tool for CLL, additional commentaries, and expert text discussions of key topics in the management of patients with CLL.

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