Exploring BTK Inhibitors for Patients With CLL and Del(17p) Mutations
During a live event, Danielle M. Brander, MD, discussed use of zanubrutinib in high-risk chronic lymphocytic leukemia.
Danielle M. Brander, MD
High-risk chronic lymphocytic leukemia (CLL), characterized by genetic aberrations like deletion 17p (del[17p]) and TP53 mutations, poses significant treatment challenges. Danielle M. Brander, MD, an associate professor of medicine and hematologic oncologist at Duke Health, provided expert insights into modern therapeutic approaches for these patients at a virtual Case-Based Roundtable event. She discussed preferred regimens such as continuous Bruton tyrosine kinase (BTK) inhibitors or fixed-duration treatments, emphasizing the importance of clinical trials for high-risk cases. She also highlighted key findings from the SEQUOIA trial (NCT03336333).
CASE SUMMARY
History and presentation:
- A 66-year-old White woman presented with fatigue and unintentional weight loss.
- ECOG performance status: 1
Comorbidities:
- Hyperlipidemia
- Chronic kidney disease (stage III)
Medications:
- Atorvastatin
- Omeprazole
Imaging studies
- CT scan: largest lymph node: 3.2 × 1.9 cm
- PET scan: standardized uptake value (SUV): 3
- Splenomegaly: 17 cm along the long axis
Laboratory profile results
- White blood cells (WBCs): 66.8 × 109 cells/μL
- Absolute lymphocyte count (ANC): 55.1 × 109 cells/μL
- Hemoglobin: 9.7 g/dL
- Platelet count: 175 × 103/μL
- Lactate dehydrogenase: 240 U/L
Molecular testing results
- Karyotype: not complex
- Fluorescence in situ hybridization: del(17p)
- IGHV: unmutated (VH1-69)
- Mutations of interest: mutated TP53
The patient is in the unfavorable risk category.
Targeted OncologyTM: What are the available regimens for this patient with high-risk CLL?
Danielle M. Brander, MD: This patient had high-risk aberrations of del(17p) and TP53 mutation. In the most recent posted NCCN guidelines in regards to treatment for patients, the highest risk group still [should] consider clinical trials if available.1 Nowadays, with the preferred regimens, honestly, most of this is very similar with or without del(17p) but these patients are still highest risk, and considering clinical trials is important. But there are decision points around either the continuous BTK inhibition plus or minus anti-CD20, or the fixed-duration venetoclax [Venclexta] and obinutuzumab [Gazyva]. In terms of the BTK, both acalabrutinib [Calquence] and zanubrutinib [Brukinsa] are the preferred regimens in terms of BTK, and then venetoclax plus obinutuzumab.
Can you discuss the design of the trial investigating zanubrutinib?
With the SEQUOIA study, there was one cohort without del(17p).2 Those were the patients randomly assigned either to standard of care at the time, bendamustine/rituximab [Rituxan; BR] or continuous zanubrutinib. There was also a second cohort for patients with del(17p). Of course, those patients could not be randomly assigned to chemoimmunotherapy, given what was known at the time. But that'll be a very interesting cohort as well, I think, in terms of follow up, because that's over 100 patients in the frontline with del(17p) aberrations.
What was the efficacy seen in the SEQUOIA trial for the CLL population and the subgroups?
The primary end point was looking at progression-free survival [PFS], and we have 6-year follow-up that was presented at American Society of Hematology Annual Meeting.3 Now with the follow-up past 5 years, there is still a significant difference between the patients who got BR vs zanubrutinib. Now going out 5 years, close to 80% of patients are still without progression on zanubrutinib.
In terms of looking at PFS and breaking it down by IGHV, with mutated IGHV being considered the favorable risk factor, we can see with the chemoimmunotherapy a marked difference between the unmutated [patients] post chemotherapy, the worse PFS vs mutated. There is some separation, certainly not nearly as much, so I think that is the takeaway for patients treated with continuous BTK.
Overall survival was very similar and not surprising. A median was not reached for these patients.
What points are relevant about the adverse events (AEs) seen in this trial?
An important point... for all BTK inhibitors, we think of the standard AEs across therapies in terms of infections and cytopenias. For zanubrutinib, one of the differences, or in general, for BTK, we consider the duration of exposure for patients vs fixed-duration chemotherapy. But for example, for neutropenia, still more common with chemotherapy, whereas some of the infections are same or higher with the targeted inhibitors.
The AEs of special interest for BTK inhibitors are certainly well recognized and likely what helps differentiate in your own practice when thinking about some of the AEs that are seen specifically with BTK inhibitors, for example, the bleeding risk thought tied to the anti-platelet action of BTK inhibitor, which is much more common in zanubrutinib vs the chemotherapy.4 Hypertension, another AE for BTK inhibitors of special interest, higher in the zanubrutinib vs the chemotherapy. Some of the other cytopenias are still present, but less than with the chemotherapy. But then lastly, in terms of AE of special interest, [I am] drawing attention to the atrial fibrillation and flutter. There is not a direct comparison here. I think in long-term follow-up, for example, with first-generation ibrutinib [Imbruvica], many of those atrial fibrillation or flutter incidence rates were closer to 12% or 15% in real-world follow-up studies, so [we are] seeing less of that in the second generation.
DISCLOSURES: Brander previously reported honoraria from Pharmacyclics and BeiGene, and a consulting or advisory role with Genentech/AbbVie and Pharmacyclics.
