Considering the Durability of Zanubrutinib in Relapsed/Refractory 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: In patients with relapsed del(17p) chronic lymphocytic leukemia (CLL) initially given venetoclax, would you continue this therapy indefinitely?

MARC S. HOFFMANN, MD: My take on it, is that there is no good high-quality data for the long-term administration of venetoclax. The initial study looking at [patients with] del(17p) CLL that led to the monotherapy indication is all we have, and that data is now older.¹ It's not reflective of current practice patterns. Most of those patients have not had a BTK inhibitor, for instance, as it's not given in conjunction with anti-CD20 therapy.

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 is the reasoning behind your decision?

In the modern era, all the data we have is either 1 year or 2 years of treatment if you're giving venetoclax plus anti-CD20 therapy on-label. There are data that giving it continuously does allow for the emergence of resistance mutations.² Now, if you look at the response kinetics of venetoclax and if you look at a BTK inhibitor, when you start ibrutinib [Imbruvica], or zanubrutinib [Brukinsa], or acalabrutinib [Calquence], it doesn't matter which [BTK inhibitor], you get slow debulking over years...and a long-term response. Until they develop a resistance mutation [while on the BTK inhibitor], or that patient starts to progress, every day that they're on therapy, they're getting into a deeper remission.... When you look at venetoclax, in the first couple months…the disease rapidly debulks and then [the patient gets] extra benefit while they stay on the drug. But it's not one of these drugs where they can stay on long term and get a continuous response.

Please describe the bassline characteristics of patients on the phase 3 ALPINE trial (NCT03734016).

There were a good number of patients who had a del(17p)...and it comprised around 20% of the population [in each arm of the study].³ In the zanubrutinib arm, 22.9% had either a TP53 mutation, del(17p), or both [compared with 23.1% in the ibrutinib arm]. The mutated status was less common because it was a relapsed/refractory patient population. However, patients with a complex karyotype were reasonably well represented, but data were missing for over 30% in either arm.

Most of these patients [in either arm] had 1 line of treatment, although there were some patients who were more heavily pretreated. A lot of these patients were BTK naive and the majority of them had had an anti-CD20 therapy [83.8%], while [79.5%] had prior chemoimmunotherapy and a minority of patients had previous BCL2 inhibitors [2.1%] or P13K inhibitors [3.4%].³

What was the long-term progression-free survival (PFS) observed in this study?

We have long-term data going out to 3 years that now indicates a sustained PFS benefit with zanubrutinib over the ibrutinib....⁴ At a median follow up of 36.3 months, the PFS benefit was sustained [in 65.8% of patients on zanubrutinib compared with 54.3% on ibrutinib (HR, 0.67; 95% CI, 0.52-0.86; P = .0016)].⁴ In patients who were positive for del(17)p, a TP53 mutation, or both, the effect is particularly pronounced. There was significantly greater PFS benefit at 2-years with zanubrutinib compared with ibrutinib among this subset of patients [at 72.6% vs 54.6% (HR, 0.53; 95% CI, 0.31-0.88].³ Numbers were relatively small here, as there were only 60 patients represented, but these data were compelling for the sustained benefit [of zanubrutinib] in this higher risk group of patients.

What safety data are important to highlight from this study?

There were both fewer progression events in the zanubrutinib arm and fewer adverse events that lead to toxicity….³ In terms of the safety, most of these patients did not require any significant treatment discontinuation. The discontinuations were seen in 15.4% in the zanubrutinib arm and 22.2% in the ibrutinib arm, while the dose interruptions were more common with ibrutinib [at 56.8% compared with 50.0% of patients on zanubrutinib]. The rate of dose reductions was also more common with ibrutinib compared with zanubrutinib at 17.0% vs 12.3%, respectively.³

REFERENCES:

1. FDA approves venetoclax for CLL or SLL, with or without 17 p deletion, after one prior therapy. FDA. June 8, 2018. Accessed April 11, 2024. https://tinyurl.com/44mhaazr

2. Skånland SS, Mato AR. Overcoming resistance to targeted therapies in chronic lymphocytic leukemia. Blood Adv. 2021;5(1):334-343. doi:10.1182/bloodadvances.2020003423

3. Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia. N Engl J Med. 2023;388(4):319-332. doi:10.1056/NEJMoa2211582

4. Brown JR, Eichhorst B, Hillmen P, et al. Extended Follow-up of ALPINE Randomized Phase 3 Study Confirms Sustained Superior Progression-Free Survival of Zanubrutinib Versus Ibrutinib for Treatment of Relapsed/Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma (R/R CLL/SLL). Blood. 2023;142(1):202. doi:10.1182/blood-2023-174289