Second Generation BTK Inhibitors Improve Survival in 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, he 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 segment-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 was the efficacy outcomes with zanubrutinib (Brukinsa) on the ALPINE trial (NCT03734016)?

WILLIAM G. WIERDA, MD, PhD: There was a significant difference in progression-free survival (PFS) with the follow-up that they had on this trial favoring patients with chronic lymphocytic leukemia [CLL] who had had treatment with zanubrutinib.¹ [In the zanubrutinib arm], 78.4% had a PFS at 2 years vs 66.0% [in the ibrutinib (Imbruvica) arm], with the end result of treatment at 2 years. Now….this trial’s follow-up, on a scale of things, for BTK inhibitor maintenance-type treatment is a relatively short follow-up [at 29.6 months].¹

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​

Comparatively, you'll see that the follow up [for the ELEVATE-RR (NCT02477696) trial] as a longer follow-up at 40.9 months.² If you look at the patients with 17p deletion [del(17p)], TP53 mutation, or both, you'll see a similar pattern of improved PFS for patients who have received the zanubrutinib, [at 72.6% vs 54.6% on ibrutinib (HR, 0.53; 95% CI, 0.31-0.88)].¹ Most of these patients get partial response [with treatment] at 76%...and 7% had a complete remission with zanubrutinib vs 4.9%.¹

What was notable about the safety profile of this therapy for patients with CLL?

I think the one feature to highlight is the safety profile and the difference in events that we've seen between zanubrutinib and ibrutinib…. [Compared with zanubrutinib], ibrutinib was associated with higher incidences of some of the more serious and concerning adverse events [AEs] that we see, particularly, atrial fibrillation [at 1.9% vs 3.7%, respectively]. Serious AEs were seen in 42% with zanubrutinib over 50% with ibrutinib.¹

What are some of the AEs to watch out for on this therapy?

In these patients [with relapsed CLL], we see a reasonable frequency of cytopenias, anemia, neutropenia, etc, which is somewhat expected. There has been some discussion about the neutropenia associated with zanubrutinib groups, and [in this trial] it's a little bit higher than it was for ibrutinib at grade 3 or greater, [with 16.0% vs 13.9%, respectively].¹ The cumulative incidence [of cardiac disorders and atrial fibrillation or flutter] were greater for both cardiac disorders and atrial fibrillation for the patients who received ibrutinib vs zanubrutinib. [Further], the cumulative risk long-term [of these cardiac disorders] runs around 10% to 15%.¹

^References

^{1. 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}

^{2. 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}