Jacobs and Peers Consider Third-Line Treatment in Relapsed/Refractory CLL

Ryan W. Jacobs, MD

MODERATOR

Assistant Professor of Medicine

Levine Cancer Institute

Atrium Health

Charlotte, NC

EVENT REGION Florida and North Carolina

PARTICIPANT LIST Alexandra Stefanovic, MD | Hakam Khazrik, MD | Omar Castaneda Puglianini, MD | Jorge Hurtado-Cordovi, MD | Nuruddin Jooma, MD, MPH | Ashok Kumar, MD | Margaret Howard, MD, MSc | Uday Dandamudi, MD

DISCUSSION QUESTIONS

• What clinical factors would trigger the need for a change in therapy for your patients?
• Would your treatment change be based on worsening laboratory results, awaiting symptoms, or both?
• What would motivate you to make your treatment decision sooner?
• For which patients would you consider rechallenging with a previous agent in the third-line setting?

JACOBS: When you have a patient who’s experiencing progression on second-line treatment, do you wait for them to be symptomatic or do you start third-line treatment at the point where you start to see the lymphocyte level rise or the lymph nodes grow, even if the patient may not necessarily be symptomatic?

STEFANOVIC: Whenever we see patients who have experienced progression after both a Bruton tyrosine kinase [BTK] inhibitor and a BCL2 inhibitor, this is no longer indolent disease and it’s quite easy to miss the point between progression and symptoms. At this time, I think starting a new line of treatment earlier rather than later is probably prudent. I was the one who suggested the chimeric antigen receptor [CAR] T-cell therapy with lisocabtagene maraleucel [liso-cel; Breyanzi]. I think the bridging with pirtobrutinib [Jaypirca] would be an idea too, and hopefully the patient can be one of the luckier ones who respond. My answer to the question is in the third line, I would start treatment sooner rather than later.

JACOBS: I would agree that in a patient like this, it might make sense to at least start the conversation about liso-cel with initially getting the disease under control again with pirtobrutinib. Because unfortunately, in the third-line setting or later, the progression-free survival [PFS] expectations get much shorter and we don’t get these long PFSs like we see in first-line setting with covalent Bruton tyrosine kinase inhibitors, for example.

The answer to this question depends on what the patients are getting at the time of progression. It’s a very different thing to treat a patient who is experiencing progression in the third-line setting if they originally received treatment—let’s say in the second-line setting—with venetoclax and they happen to be on a treatment holiday. You’re taking a patient who is not on any treatment who experiences progression and experiences progression asymptomatically. You might not necessarily jump into treatment as soon as you would for a patient who is on active indefinite therapy with a covalent BTK inhibitor and we start to see the lymphocytosis. It’s a bit of a different consideration.

One unique element with venetoclax is the consideration for rechallenge. This would also be potentially relevant if you had a patient who had been on a covalent BTK inhibitor and had stopped for some reason other than disease progression. Maybe it was a personal decision the patient made, or maybe they had intolerance to one of the covalent BTK inhibitors but had not tried one of the other newer BTK inhibitors, for example, like if a patient had previously been treated with ibrutinib [Imbruvica] and stopped and was now experiencing progression again.

For the last question, for this patient who had been treated in the second-line setting with venetoclax and went through their 2-year course and had been off therapy for 6 months and was then found to experience progression, would you consider rechallenging with venetoclax again in this setting?

KHAZRIK: Probably not. I think it’s a very short period.

JACOBS: In the days before pirtobrutinib, I often did [because of] lack of other options if I didn’t have a clinical trial. I would usually get a few more months, but with pirtobrutinib, I think it’s probably worth giving that a try.

If a patient had ibrutinib in the past, came off, and experienced progression and now is experiencing progression on venetoclax but the reason they had stopped ibrutinib previously was for a toxicity issue, would you consider giving acalabrutinib or zanubrutinib [Brukinsa] a try? Or would you prefer to go on to pirtobrutinib after venetoclax?

CASTANEDA PUGLIANINI: Zanubrutinib would be an option, but if we have pirtobrutinib available and [it] can be approved, then pirtobrutinib would be started. Then [we would be] thinking about [using] pirtobrutinib [for] bridging for CAR T-cell therapy and potentially restarting it after CAR T if toxicities allow.

JACOBS: There are data out there for acalabrutinib after ibrutinib intolerance as well as zanubrutinib after acalabrutinib intolerance. For all those scenarios, about three-quarters of the time, you can try the alternative BTK inhibitor and they’ll tolerate it. There are some situations where you wouldn’t want to do that. If a patient had a significant bleed, that would be one [for whom] I would maybe not retry. But [in] a lot of situations, I think it would be safe.

DISCUSSION QUESTIONS

• Do you have any trial or clinical experience using pirtobrutinib?
• When would you select pirtobrutinib for your patients with relapsed/refractory CLL based on findings from the BRUIN trial (NCT03740529)?1

JACOBS: Do you have any trial or clinical experience using pirtobrutinib?

HURTADO-CORDOVI: No, I have not used pirtobrutinib yet myself. I am aware of the data, and I’m eager to use it, but I haven’t had the chance yet.

JACOBS: It’s also available in the mantle cell lymphoma setting. It was available for a while before the CLL approval, so it’s possible some have had some experience there.

JOOMA: I have [experience with it] in the mantle cell setting for an older patient. It was a fairly well-tolerated drug.

JACOBS: That’s been my experience as well. Dr Kumar, when would you select pirtobrutinib for your patients with relapsed CLL?

KUMAR: If they had already received BCL2 or BTK therapies, I think they are good candidates. I have never used it. I have not had an opportunity to use the drug, but I think it’s a good drug at this point.

HOWARD: I have not used it either, but it’s on my radar. I have an 88-year-old patient who is on zanubrutinib, so some therapies are not options for her. We’re having some challenges with regard to overall tolerance and adverse events, having to use growth factor support because she frequently has an absolute neutrophil count of 0. We’re getting through it, but at the same time, I know that it’s an option. Does anyone have any thoughts with regard to when you might transition at that point?

JACOBS: You have a patient who is responding to zanubrutinib but has been intolerant?

HOWARD: Technically, yes. It’s been slow going with regard to that.

JACOBS: Luckily, with zanubrutinib, you have multiple options for dose reduction, which you may have already tried. Particularly with the neutropenia that gets to 0, zanubrutinib is the one that seems to do that from time to time. You’ll have a patient show up with an absolute neutrophil count of 0, and you get nervous. I certainly hold treatment, [use] growth factor support, and allow for recovery. If it’s a recurrent issue, particularly if they’ve been on treatment for a bit and I didn’t just start them on treatment, then I’ll go for dose reductions. You can go all the way down to 80 mg a day with zanubrutinib, and that is considered acceptable. If they experience progression on that, in the discussion of what to do with a patient who has responded well to covalent BTK but then has to come off due to toxicity, most specialists will tell you if they’ve been on for a bit and had adequate disease control, you don’t necessarily have to jump right into another treatment. You can give them a break for a while and give them a reason to [start] another treatment.

I understand the reticence for sending an 88-year-old patient to get venetoclax and obinutuzumab [Gazyva]. I have, in certain circumstances, gotten pirtobrutinib as a second-line option when maybe venetoclax with anti-CD20 hasn’t been realistic.

There is a trial that had positive [findings called the] BRUIN CLL-321 study [NCT04666038], and it looked at pirtobrutinib’s use in the second-line setting.2 The control arm on that study was either idelalisib [Zydelig] or bendamustine and rituximab. Not surprising there, pirtobrutinib was reported as showing superiority.… It might be easier to get pirtobrutinib as a second-line treatment option. If pirtobrutinib was available in the second-line setting, would you use that instead of venetoclax in a patient who has experienced progression on zanubrutinib?

DANDAMUDI: I try to change the mechanism of action in that situation, so I would try to treat with venetoclax and then try pirtobrutinib at that time.

_REFERENCES

_{1. Mato AR, Shah NN, Jurczak W, et al. Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study. Lancet. 2021;397(10277):892-901. doi:10.1016/S0140-6736(21)00224-5}

_{2. Sharman JP, Munir T, Grosicki S, et al. BRUIN CLL-321: randomized phase III trial of pirtobrutinib versus idelalisib plus rituximab (IdelaR) or bendamustine plus rituximab (BR) in BTK inhibitor pretreated chronic lymphocytic leukemia/small lymphocytic lymphoma. Blood. 2024;144(suppl 1):886. doi:10.1182/blood-2024-198147}