Hoffmann Discusses Deciding Factors for Treating Patients With CLL

CASE SUMMARY

History and presentation:​

A 70-year-old White man with asymptomatic lymphocytosis, identified 4 years ago​.

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

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 ​

Status:​

• ECOG performance status: 1​

Six months later​:

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

Diagnostic workup:​

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

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

Targeted Oncology: What are the main therapies to consider for a patient case like this?

MARC S. HOFFMANN, MD​: While chemotherapy is theoretically an option...there are [few times where] you're giving it for a patient like this, so what we've ended up with [in this space] is targeted therapy with either BTK inhibitors, BCL2 inhibitors, or monoclonal antibody therapy. All of these tend to be well tolerated treatments and are extraordinarily effective in the treatment of patients with chronic lymphocytic leukemia [CLL].¹ How you choose these [therapies usually] boils down to what patients prefer, and these regimens are a little bit different. Some of them are given indefinitely while some of them are given in a time limited fashion, and the toxicity profile of each of these drugs is distinct.

Marc S. Hoffmann, MD​

Assistant Professor,

Medical Director of Lymphoma and Myeloma

Hematologic Malignancies and Cellular Therapeutics

Medical Director of Lean and Quality Improvement

University of Kansas Cancer Center​

Leawood, KS

What biomarkers do you look for when considering treatment in CLL?

There are a lot of biological risk factors that you need to take into consideration for these patients, del(17p)​ and TP53​ mutations being the most prominent disease markers that still confer a negative prognosis.² Complex karyotypes are often accompanied by TP53​ mutations, but it is also an independent risk factor. So, if you do find a patient with a complex karyotype that is an individual that is at higher risk, and you may want to think about [how you treat that] patient a bit differently. You don't need to do a bone marrow biopsy; you should be able to get a simple karyotype on the peripheral blood test, and...that'll be more than adequate. Then for those patients with an IGHV mutation, which I would say is still under checked, I think it's quite beneficial [to help with] treatment selection and is often not checked in patients prior to therapy.²

Please describe the therapies available to these patients.

Acalabrutinib [Calquence] has an indication in treatment naive and relapsed/refractory patients with CLL, as well as for patients with mantle cell lymphoma [MCL], but it does not have approvals for patients with Waldenström's macroglobulinemia [WM] or marginal zone lymphoma [MZL].³ Ibrutinib [Imbruvica], which was the first initial in class [BTK inhibitor], had its indications for patients with MCL and MZL pulled,but has retained indications for patients with WM and CLL.⁴ Now, zanubrutinib [Brukinsa] is the new kid on the block and has approvals in all 4 different diseases.⁵ So you can use zanubrutinib across a wide variety of different treatment types.

How do you dose zanubrutinib for patients?

Zanubrutinib can be given either twice daily or [once] daily.⁵ Most of the clinical data with zanubrutinib is with the twice-daily dosing, but there are a lot of emerging clinical data with daily dosing. In general, my instinct is if I have a...[patient who has been on treatment] for the last 7 years prior to initiating zanubrutinib, and I'm pretty sure this patient is going to be able to take the medication twice a day, I'll often use the twice-daily dosing simply based upon the fact that's where the majority of the data lies. But pharmacokinetically, the daily dosing should be more than adequate, and if I have a patient that is likely to miss a significant number of doses, I'm far more likely to use the daily dosing. You do have a little bit of flexibility [with this therapy] and I think there will be emerging daily dosing clinical data.

^References:

^{1. Ghia P, Pluta A, Wach M, et al. ASCEND: phase III, randomized trial of acalabrutinib versus idelalisib plus rituximab or bendamustine plus rituximab in relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2020;38(25):2849-2861. doi:10.1200/JCO.19.03355}

^{2. Hallek M, Al-Sawaf O. Chronic lymphocytic leukemia: 2022 update on diagnostic and therapeutic procedures. Am J Hematol. 2021;96(12):1679-1705. doi:10.1002/ajh.26367}

^{3. Calquence. Prescribing information. AstraZeneca. Accessed March 19, 2024. https://tinyurl.com/wenj66kt}

^{4. Imbruvica. Prescribing information. Janssen Biotech, Inc. Accessed March 19, 2024. https://tinyurl.com/2tex83cw}

^{5. Brukinsa. Prescribing information. BeiGene, Ltd. Accessed March 19, 2024. https://tinyurl.com/48kzusz8}