Fitting Second Generation BTK Inhibitors into the R/R CLL Setting

CASE SUMMARY

History and Presentation:​

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

• Initially monitored​
• Two years later, developed anemia, night sweats, and splenomegaly​.
• Treated with venetoclax (Venclexta) plus obinutuzumab​ (Gazyva)
• Patient experienced undetectable minimal residual disease (MRD) 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​

6 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: 9.5 g/dL​
• Platelet Count: 80 x 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 x 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 is the current status of BTK inhibitors for patients with chronic lymphocytic leukemia (CLL)?

WILLIAM G. WIERDA, MD, PhD: Four BTK inhibitors are available, 3 of which are covalent [inhibitors]. Pirtobrutinib [Jaypirca] is available for patients with mantle cell lymphoma, but it's now in the National Comprehensive Cancer Network [NCCN] guidelines for patients with CLL and is being reviewed by the FDA for approval.¹ In the frontline and relapsed/refractory settings, the covalent inhibitors are all approved. Acalabrutinib [Calquence] is given twice a day, ibrutinib [Imbruvica] is recommended as once a day, and zanubrutinib [Brukinsa] can be given twice a day or once a day.

William G. Wierda, MD, PhD

Professor

Center Medical Director​

Department of Leukemia, Division of Cancer Medicine

Section Chief - Chronic Lymphocytic Leukemia

The University of Texas MD Anderson Cancer Center

Houston, TX​

[In terms of dosing these drugs], my preference is a split dose because these drugs all have a short serum half-life. They do what they need to do, which is covalently bind to BTK, but they wash away and then the cell remakes new BTK that is functional. So, I think you get better target coverage with twice a day dosing with these agents. [Therefore], for all of them my preference [is to give them] twice a day.

How do you manage a patient’s frontline treatment before moving to a BTK inhibitor?

Sometimes I'll give [the patient] a treatment break and watch them, then when the disease starts to grow again, I'll restart it. It's uncommon to see this explosive disease in patients who have remission, and their disease continues to be controlled with treatment. But if you stopped for intolerance, I think the median time to retreat [them] is about a year and a half to 2 years, because most of them are not rapidly progressing.

That's in contrast to patients who are on a covalent BTK inhibitor, and their disease is growing, whether they're on it, so their white blood cell counts are going up and the disease is increasing. If you stop [the BTK] abruptly, sometimes the disease will [rapidly increase] and you'll lose control of their disease. That's a big problem.

What was the design of the ALPINE study (NCT03734016)?

This was a randomized phase 3 trial in the relapsed setting, so [the patients on the study] were all previously treated patients and they were randomly assigned to receive treatment with either ibrutinib at 420 mg once a day or zanubrutinib at 160 mg twice a day.² Then, the enrolled patients were followed for toxicities and progression of disease. [The patients] were then stratified, but they allowed for the inclusion of patients with 17p deletion [del(17p)].

There wasn't much notable about this group of relapsed patients in terms of patient characteristics, but in contrast to [the phase 3 ELEVATE-RR trial (NCT02477696)], those in ALPINE weren't selected for any feature. For the ELEVATE-RR trial, those patients had to have either a 11q deletion or del(17p),³ but patients [in the ALPINE study] were not selected for any characteristic other than they had been previously treated.

Was there a notable number of patients given a prior BCL-2 inhibitor before moving to a BTK inhibitor?

There are a little more than 300 patients in each arm and the median number of prior treatments was 1.... Seven patients in the zanubrutinib arm had a prior BCL2 inhibitor [compared with] 8 patients in the ibrutinib arm.² There's not a lot of experience with [using a] BCL2 inhibitor followed by a BTK inhibitor. Most of these patients in the relapse setting are also going to have unmutated IGHV, so three fourths had unmutated IGHV, which one would expect from a trial of relapse patients.²

^References:

^{1. NCCN. Clinical Practice Guidelines in Oncology. Chronic lymphocytic leukemia/small lymphocytic lymphoma; version 3, 2023. https://tinyurl.com/2p9dvm2v}

^{2. Brown JR, Eichhorst B, Hilmen 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}

^{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}