Persistence Pays Off With Zanubrutinib: A Challenging CLL Case With a Prior BTK Inhibitor Failure

A recent case report highlights the success of the Bruton tyrosine kinase (BTK) inhibitor zanubrutinib (Brukinsa; BeiGene) in treating the relapsed disease of a 77-year-old woman with a long history of chronic lymphocytic leukemia (CLL)—after she had received another BTK inhibitor earlier in her treatment course. According to the physicians who presented the case of this patient—who had no resistance mutations—in Leukemia Research Reports, this treatment scenario seems to be the first of its kind to be published.¹

CLL is the most common type of leukemia in the US, according to this case report. | Image Credit: © momius - stock.adobe.com

Zanubrutinib ultimately brought the patient’s white blood cell count (WBC) down to 7.5 × 10³/μL. The agents she had previously received, to greater or lesser degrees of success, included acalabrutinib as well as rituximab, idelalisib, and venetoclax.

Patient history. Now aged 77 years, this patient was initially diagnosed with CLL in 2011. At that time, she achieved clinical remission with rituximab (Rituxan; Genentech; a monoclonal antibody) and 2 chemotherapy agents: fludarabine and cyclophosphamide (Cytoxan; Baxter).

Five years later, in 2016, her WBC count reached 212 (4.2-9.1) × 10³/μL, with predominant lymphocytosis, transfusion-independent anemia, and thrombocytopenia, described the authors. Idelalisib (Zydelig; Gilead Sciences; a PI3 kinase inhibitor) eventually improved the WBC count to 53.5 × 10³/μL.

The BTK inhibitor ibrutinib, they noted, was not recommended due to her history of severe sulfa allergy.

The patient’s WBC count stayed in the 50-to-80 × 10³/μL range until October 2020 when, despite still being on idelalisib, her WBC count reached 238 × 10³/μL. “Peripheral blood flow cytometry showed lambda light chain-restricted B cells consistent with involvement,” they noted.

Fluorescent in situ hybridization testing found a deletion 13q14.3 and no TP53 mutation, they continued. With a switch to obinutuzumab (Gazyva; Genentech; a monoclonal antibody) and acalabrutinib (Calquence; AstraZeneca; a BTK inhibitor), the patient’s WBC count normalized.

A year later, in November 2021, while still on acalabrutinib, her WBC count increased again, peaking at 47.3 × 10³/μL in May 2022.

Treatment changed to the BCL2 inhibitor venetoclax, the authors said, but severe hyponatremia and seizure followed 1 week later, and she was hospitalized. Brain imaging findings were negative for acute abnormalities, and venetoclax was discontinued.

A bone marrow examination confirmed that the patient’s CLL had relapsed, and leukocytosis persisted after her hospital discharge. A combination treatment strategy of rituximab and the chemotherapy bendamustine lasted just 3 cycles after she developed severe transfusion-dependent anemia and thrombocytopenia. She continued supportive transfusions because, the authors noted, such options as “chemotherapy and transplant evaluation were deemed unfeasible due to severe anemia, thrombocytopenia, and the patient’s performance status.”

In February 2023, her WBC count rose to 110 × 10³/μL; her hemoglobin was 4.6 (13.7-17.5 g/dL) and her platelet count was 23 (163-337 × 10³/μL). At this point, her chance of 5-year survival was less than 25%, the team declared.

“Peripheral blood next-generation mutational analysis showed TP53 and SF3B1 mutations and no mutations in BTK and PLCG2 genes,” they wrote. So, although “there [had been] no [prior] reports of treatment with a second BTK inhibitor” in this scenario, the patient’s doctors began her on zanubrutinib. She tolerated it well, and by 16 weeks post treatment, her WBC count had improved to 7.5 × 10³/μL.

Possibilities for others. “We hypothesize that patients with CLL can be treated with zanubrutinib after progression with other BTK inhibitors,” the authors concluded. “Zanubrutinib’s high BTK specificity, fewer off-target effects, and longer half-life are likely reasons for its efficacy.” Their patient, they again noted, had no evidence of resistance mutations.

The uptake of zanubrutinib has also been increasing for first-line CLL, Jennifer Brown, MD, PhD, director of the Chronic Lymphocytic Leukemia Center and an institute physician at Dana-Farber Cancer Institute, told The American Journal of Managed Care® last year.² “There has been less experience with zanubrutinib to date compared to acalabrutinib, and so many people are still using acalabrutinib and starting to dabble in zanubrutinib and moving over gradually,” she said.

References

1. Nwankwo N, Reddy A, Kumar S, Zafar M. Treatment of relapsed/refractory chronic lymphocytic leukemia with zanubrutinib after progressing on other BTK inhibitors. Leuk Res Rep. 2024;21:100459. doi:10.1016/j.lrr.2024.100459

2. Jeremias S, McNulty R. Dr Jennifer Brown discusses zanubrutinib uptake in CLL, SLL. AJMC. August 23, 2023. Accessed May 9, 2024. https://www.ajmc.com/view/dr-jennifer-brown-discusses-zanubrutinib-uptake-in-cll-sll