Deciding on Therapy for a Patient With High-Risk Relapsed CLL

Nakhle Saba, MD

Associate Professor of Clinical Medicine

Tulane Cancer Center Member - Translational Oncology Research Program

New Orleans, LA

CASE SUMMARY

• History and presentation:​
• 70-year-old man with asymptomatic lymphocytosis identified 4 years previously​
• Initially monitored; after 2 years, developed anemia, night sweats, and splenomegaly​
• Treated with venetoclax (Venclexta) plus obinutuzumab​ (Gazyva)
• Relapsed 24 months later
• ECOG performance status of 1​
• Palpable splenomegaly​
• CT of chest, abdomen, pelvis: largest node: 4.2 x 2.8 cm; all others less than 3 cm ​

Comorbidities:​

• Coronary artery disease
• High cardiovascular risk due to history of non-ST-elevation myocardial infarction status post 2 stents​

Medications:​

• Simvastatin; amlodipine; clopidogrel, aspirin​

Workup:​

• Laboratory values:​
• White blood cells – 35.0 x 10³ cells/μL​
• Absolute lymphocyte count – 22.0 x 10³ cells/μL​
• Hemoglobin – 9.5 g/dL​
• Platelets - 80 x 10³/μL​
• Lactate dehydrogenase – 255 U/L​
• Karyotype: complex; 4 abnormalities​
• Fluorescence in situ hybridization: del(11q); w/o del(17p)​
• IGHV status: unmutated​
• Mutations of interest: unmutated TP53​
• Largest node on imaging: 4.2 x 2.8 cm​

DISCUSSION QUESTION

• What are your next steps for treatment of this patient with chronic lymphocytic leukemia (CLL)?​

Nakhle Saba, MD: If you look at the NCCN guidelines in the frontline setting, the recommended therapies are either a single-agent BTKI [Bruton tyrosine kinase inhibitor] continuously, or you can combine with an anti-CD20 [antibody] in the setting of acalabrutinib [Calquence], or venetoclax plus obinutuzumab, which is a fixed-duration treatment.¹

If you start with venetoclax plus obinutuzumab in the front line, it's a 1-year treatment. After the patient relapses, you can go to a BTKI, or you can repeat the venetoclax plus obinutuzumab [treatment]. You have both options. What is the duration of remission that would trigger you to re-treat with a venetoclax-based therapy? That’s subjective. There's no real guidance on what the minimum duration of remission is after you finish venetoclax plus obinutuzumab, but you have both options, venetoclax plus obinutuzumab or BTKI.

Would you re-treat with venetoclax plus obinutuzumab or venetoclax plus rituximab [Rituxan]? I use venetoclax plus obinutuzumab even in the relapse, because I think obinutuzumab is a better anti-CD20 than rituximab. What's the minimum duration of remission that triggers you to retreat?

Vrushali Dabak, MD: Probably a year or more is what I have been using in this patient. Although with high risk, he has a couple years out of venetoclax plus obinutuzumab. He has some underlying cardiac issues. It may be better to consider venetoclax plus obinutuzumab again over BTKI, because of those toxicities.

Saba: Because you're worried about the risk of atrial fibrillation that comes with BTKI with this risk status. So, 1 year after [the end of] treatment, you would re-treat. There is no right or wrong. Two years might be good for somebody and might not be good enough for somebody else.

Mohammad Muhsin Chisti, MD: If it is already apparent that this was not a successful regimen, I would rather go to BTKI. It's continuous, and chances of relapse would be lower. I know it's not time bound, but I would probably go to zanubrutinib [Brukinsa], or pirtobrutinib [Jaypirca], or something like that.

Saba: Are you worried about the risk of bleeding with the dual anti-platelet [therapy]? Would you maybe talk to the cardiologist to see if you can take 1 off, and then monitor closely?

Chisti: With acalabrutinib, it has been much lower, so we have successfully used it with cardiac patients. I have many patients like that. They are doing well.

Saba: Would you worry about atrial fibrillation in this patient, or just [the] bleeding, or both?

Chisti: I would. But like I said, with venetoclax you could potentially rechallenge, but the patient has already shown that [CLL] has relapsed on the venetoclax-based regimen. I would try to do something else.

Saba: So the 2-year treatment-free remission is not sufficient for you, and that's totally fair. I've seen [physicians who like] 2 years. I've seen [those who] would like to see 3 years. I've seen people like to see 4 years, or the whole median progression-free survival of 5 or 6 years.

Tim Cox, MD: Does a deletion 11q have anything to do with this? Don't they do better with BTKIs?

Saba: For a 11q, for some reason, if you give a BTKI to a patient with 11q, they seem to do somewhat better than the non-11q. I would say 11q is not a big player with BTKI. The 17p and complex karyotype might be a player in the relapsed setting. In the front line, none of this matters. Even if you have a 17p, they seem to do well in the long run, as if they don't have a 17p, as opposed to venetoclax plus obinutuzumab, where the high risk continues to play a role, particularly TP53 alteration, or 17p deletion, or TP53 mutation and complex karyotype, and then unmutated IGHV as well.

Robert Bloom, MD: If the patient got a year or 2 out of that regime, I probably would put them on a BTKI. That doesn't mean that I'm done with venetoclax. Just because we don't use it now doesn't mean we may not use it down the road. He didn't relapse on it, and he had some degree of remission. I would not put him back on it immediately within 2 years, but I would keep it in reserve for the future when he needs another treatment switch.

Saba: These are 3 different strategies, and all 3 are being used, and none of them are wrong. It's a preference; it's experience. I agree, and you still have pirtobrutinib down the line if you progress on both.

DISCUSSION QUESTIONS

• If you choose to use a BTKI in the second line:​
• How do you characterize the efficacy of acalabrutinib vs ibrutinib?​

• How do you characterize the efficacy of zanubrutinib vs ibrutinib?​

Let's say you decide to go with a BTKI, which one do you go with? We’re going with covalent BTKI. We're keeping pirtobrutinib for later, at least for now. Are you doing ibrutinib [Imbruvica], acalabrutinib, or zanubrutinib?

Samer Ballouz: I use acalabrutinib or zanubrutinib. I can tell you I use more acalabrutinib, maybe [this is] just a matter of habit, but that's what I will use for this patient. I know it is a preferred treatment by NCCN; ibrutinib is not a preferred treatment anymore. I think it is [as] effective as ibrutinib. It's probably less toxic there. It's a very reasonable option.

Saba: Between acalabrutinib and ibrutinib, which is superior in terms of efficacy?

Ballouz: I think they are the same.

Saba: What about zanubrutinib vs ibrutinib in terms of efficacy?

Dabak: I think the ALPINE trial [NCT03734016] showed in the relapsed setting that zanubrutinib was better compared with ibrutinib.²

Saba: You're on spot with that and both acalabrutinib and zanubrutinib were safer than ibrutinib.2,3

_References:

_{1. NCCN. Clinical Practice Guidelines in Oncology. Chronic lymphocytic leukemia/small lymphocytic leukemia, version 1.2025. Accessed January 20, 2025. https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf}

_{2. Brown JR, Eichhorst B, Lamanna N, et al. Sustained benefit of zanubrutinib vs ibrutinib in patients with R/R CLL/SLL: final comparative analysis of ALPINE. Blood. 2024;144(26):2706-2717. doi:10.1182/blood.2024024667}

_{3. Byrd JC, Hillmen P, Ghia P, et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized phase III trial. J Clin Oncol. 2021;39(31):3441-3452. doi:10.1200/JCO.21.01210}