Managing Cardiac Toxicities with Zanubrutinib in Relapsed CLL

CASE SUMMARY

History and Presentation:​

A 70-year-old White man with asymptomatic lymphocytosis identified 4 years previously​

• Initially monitored​
• Two years later, he developed anemia, night sweats, and splenomegaly​.
• Treated with venetoclax (Venclexta) plus obinutuzumab​ (Gazyva)
• The patient experienced undetectable minimal residual disease at end of year 1 of treatment​.
• Twenty-four months later, his disease progressed​.

Comorbidities:​

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

Medications:​

• Simvastatin​
• Amlodipine​
• Clopidogrel, aspirin ​

Current Status:​

• ECOG performance status: 1​

Six Months Later​:

• On physical examination: palpable splenomegaly​
• CT scan: largest node, 4.2 × 2.8 cm​
• All others < 3 cm​

Diagnostic Workup:​

• White blood cell count: 35.0 × 109 cells/μL​
• Absolute lymphocyte count: 22.0 × 109 cells/μL​
• Hemoglobin: 9.5 g/dL​
• Platelet Count: 80 × 103/μL​
• Lactate dehydrogenase: 255 U/L​
• Karyotype: complex, 4 abnormalities​
• Fluorescence in situ hybridization: del(11q); without del(17p)​
• IGHV: unmutated​
• Mutations of interest: wild type TP53​
• Largest node on imaging: 4.2 × 2.8 cm​

Due to progression of disease after BCL2 inhibitor, the decision was made to initiate therapy with a Bruton tyrosine kinase (BTK) inhibitor.

Targeted Oncology: What toxicities associated with zanubrutinib (Brukinsa) should other physicians know about? How do these compare with those associated with ibrutinib (Imbruvica)?

SAMEER A. PARIKH, MBBS: The risk of high blood pressure [on zanubrutinib] was lower than with ibrutinib, but the risk of neutropenia was higher with zanubrutinib than ibrutinib.¹ However, cough, pneumonia and other infection-related complications were lower [with zanubrutinib]. In general, if you look at the cardiac safety data, the risk was significantly lower with zanubrutinib compared with ibrutnib, which, in my opinion, is why we gravitated toward... zanubrutinib compared with the traditional ibrutinib.

Sameer A. Parikh, MBBS

Assistant Professor of Medicine and Oncology

Division of Hematology

Mayo Clinic

Rochester, MN

The one thing that wasn’t very different was the risk of hypertension and again, it’s unclear to me why that is the case. I always thought that with atrial fibrillation the risk is based on many other risk factors including hypertension, but apparently, at least in the ALPINE trial [NCT03734016], the risk of hypertension wasn’t lower. The risk of infection was lower in zanubrutinib, despite having a higher risk of neutropenia. That suggests that maybe there are other reasons for these infections.¹

How do you address atrial fibrillation (AFib) for patients on a BTK inhibitor?

AFib is usually an early event [when a patient is on a BTK inhibitor therapy], so if you look at the risk of AFib [on zanubrutinib] it happens in the first 12 to 18 months and then [the risk slowly goes down].1 I think if someone does develop AFib beyond that time period, then I would question if I need to do anything different because by that time a lot of patients have had a very good response to the treatment already. I might not change anything if their disease is decently controlled.

Does the risk of hypertension impact your treatment decision?

I’m not going to stop prescribing them anything because I’m worried about hypertension. [When you] look at BTK inhibitors vs non-BTK inhibitors there’s always a high risk of hypertension.² So, this will induce hypertension, but the question is, is that going to matter to the patient? Because if their hypertension is defined as 140 over 90 [mm Hg], but you’re going to continuously give the BTK inhibitor for 5 to 7 years, [ultimately, the risk is limited over time].

REFERENCES:

1. Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2023; 388:319-332. doi:10.1056/NEJMoa2211582

2. Sestier M, Hillis C, Fraser G, Leong D. Bruton’s tyrosine kinase inhibitors and cardiotoxicity: more than just atrial fibrillation. Curr Oncol Rep. 2021;23(10):113. doi:10.1007/s11912-021-01102-1