Zanubrutinib

CLL/SLL: A Recent Addition to the Treatment Armamentarium

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) originate from abnormal B-cell lymphocytes and are different manifestations of the same disease (depending on where the abnormal lymphocytes are found). CLL is the most prevalent adult leukemia in Western countries.¹ In 2023, an estimated 18,740 people will be diagnosed with CLL in the United States, and an estimated 4,490 people will die of it.² The traditional treatment paradigm for CLL/SLL has recently changed dramatically, with increasing use of novel targeted therapies instead of chemoimmunotherapy regimens. Currently, some of the targeted agents used for the treatment of CLL/SLL include Bruton’s tyrosine kinase (BTK) inhibitors ibrutinib,³ acalabrutinib,⁴ and recently the approved second-generation BTK inhibitor zanubrutinib,⁵ as well as the B-cell lymphoma 2 (BCL2) inhibitor venetoclax.⁶

Pivotal Trials: SEQUOIA and ALPINE

Previously approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with relapsed or refractory mantle cell lymphoma (MCL) or marginal zone lymphoma (MZL), and Waldenström macroglobulinemia (WM), zanubrutinib was approved in early 2023 for treatment of patients with CLL/SLL.⁷ This approval was based on data from a multicenter, open-label phase III trial in treatment-naive patients (SEQUOIA; ClinicalTrials.gov identifier NCT0333633)⁸ and a randomized, multicenter, open-label phase III trial in patients with relapsed or refractory disease after at least one systemic therapy (ALPINE; NCT03734016).⁹

The SEQUOIA trial enrolled patients who were not candidates for treatment with a chemoimmunotherapy combination of fludarabine, cyclophosphamide, and rituximab (FCR; eg, age ≥ 65 years or younger patients with a total Cumulative Illness Rating Scale [CIRS] > 6, creatinine clearance 30 to 69 mL/min, or history of serious or recurrent infection). Patients without 17p deletion (del17p) were randomly assigned to receive either zanubrutinib at 160 mg twice daily until disease progression or intolerance (n = 241) or bendamustine plus rituximab (BR) for six cycles (n = 238).^5,8 The primary endpoint was progression-free survival (PFS) as determined by independent review committee (IRC) in the intention-to-treat population.

Zanubrutinib significantly improved PFS vs BR (hazard ratio [HR] = 0.42 [95% confidence interval (CI) = 0.28–0.63; two-sided P <.0001]), the overall response rate (ORR) was 93% versus 85% with BR, with an acceptable safety profile. Additionally, in a nonrandomized cohort of 110 patients with del17p and previously untreated disease, the estimated 24-month PFS rate was 89%, and the estimated 24-month overall survival (OS) rate was 94%.⁸

Most common all-grade adverse events in this cohort included contusion (20.2%), upper respiratory tract infection (19.3%), neutropenia/neutrophil count decrease (17.4%), and diarrhea (16.5%). Grade ≥ 3 adverse events were reported in 53 patients (48.6%), most commonly neutropenia (12.9%) and pneumonia (3.7%). Additionally, atrial fibrillation was reported in three patients (2.8%).¹⁰

In the ALPINE trial, 652 patients with relapsed or refractory CLL/SLL after at least one systemic therapy were randomly assigned in a 1:1 ratio, stratified by age, geographic region, refractoriness to last therapy, and del17p/TP53 mutation status, to receive either zanubrutinib at 160 mg orally twice daily (n = 327) or ibrutinib at 420 mg orally once daily (n = 325).^5,9 At a median follow-up of 29.6 months, zanubrutinib demonstrated superiority over ibrutinib with respect to investigator-assessed PFS (HR for disease progression or death = 0.65; 95% CI = 0.49–0.86; P = .002), which was similar to IRC-assessed PFS.⁹ At 24 months, the investigator-assessed PFS rates were 78.4% (zanubrutinib) and 65.9% (ibrutinib). Among patients with a del17p/TP53 mutation, treatment with zanubrutinib resulted in longer PFS compared with ibrutinib (HR for disease progression or death = 0.53; 95% CI = 0.31–0.88). Moreover, treatment with zanubrutinib consistently resulted in higher PFS rates across other major subgroups.⁹

The ORR was also higher in the zanubrutinib group than in the ibrutinib group (83.5% vs. 74.2%, as assessed by the investigators; and 86.2% vs. 75.7%, as assessed by the IRC). Also, the ORR (assessed by both the investigators and the IRC) favored zanubrutinib over ibrutinib across prespecified subgroups, including the high-risk population with del17p/TP53 mutation. Although median OS had not been reached in either treatment group as of the data cutoff in the final analysis, fewer deaths had been reported in the zanubrutinib group than in the ibrutinib group (48 and 60; HR for death = 0.76, 95% CI = 0.51–1.11).

Zanubrutinib demonstrated a better safety profile than ibrutinib, with fewer adverse events leading to treatment discontinuation and fewer cardiac events, including those leading to treatment discontinuation or death. Six deaths from cardiac disorders were reported, all in patients randomly assigned to the ibrutinib group. As for the adverse events of special interest, the incidence of atrial fibrillation or flutter (a key secondary outcome) of any grade was lower with zanubrutinib than ibrutinib (5.2% vs. 13.3%), and the incidence of grade ≥ 3 atrial fibrillation or flutter was also lower with zanubrutinib (2.5% vs. 4.0%).

Treatment Considerations for Various Regimens

Jennifer R. Brown, MD, PhD, told JNCCN 360 that “in general, before considering various treatment options for any given patient, I think it is important to get a good sense of their overall condition, including not only disease-related factors and previous therapy, if any, but their age, fitness/frailty, comorbidities, concomitant medications, lifestyle, and family/caregiver situation. We review efficacy, safety, as well as mode and duration of administration of various treatment options—and their likely effect on convenience, adherence, and cost. Then, while discussing the pros and cons of each option, I like to get a sense of the patient’s preferences, goals, and expectations.¹¹ Ultimately, the goal is to have individualized therapy selection.” Dr. Brown is Director of the CLL Center in the Division of Hematologic Malignancies at the Dana-Farber Cancer Institute and the Worthington and Margaret Collette Professor of Medicine in the Field of Hematologic Oncology at Harvard Medical School in Boston. Dr. Brown noted that targeted therapy is currently preferred over chemoimmunotherapy, such as FCR and BR, for most patients with CLL/SLL, including older patients with comorbidities and unfavorable prognostic markers.¹¹

If a patient has del17p/p53 mutation, I tend go with a BTK inhibitor such as acalabrutinib or zanubrutinib.

The current standard of care can be divided into two distinct approaches: continuous therapy with a BTK inhibitor with or without an anti-CD20 monoclonal antibody, such as obinutuzumab or rituximab, or the fixed-duration therapy (ie, for 1 year) with venetoclax plus obinutuzumab (VO). Dr. Brown continued: “Some of the factors to consider while weighing various pros and cons of each of these approaches include the following: convenience (eg, no need for infusions and tumor-lysis syndrome monitoring), long-term efficacy data including phase III data comparisons with FCR and BR, and more efficacy data for venetoclax at the time of disease progression while on ibrutinib—all favoring BTK inhibition.^12,13 On the other hand, some of the factors favoring venetoclax-based combinations such as VO include 1 year time-limited therapy, no known cardiac or bleeding risks, less concern for long-term adherence, and potential for cost-saving, assuming 1-year therapy results in durable responses,” she told JNCCN 360. “Higher rates of undetectable measurable residual disease, which is an independent predictor of improved survival, at least with fixed-duration regimens, may also favor VO.¹⁴

Typically,” Dr. Brown added, “if a patient has del17p/p53 mutation, I tend go with a BTK inhibitor such as acalabrutinib or zanubrutinib. Also, many older patients choose a BTK inhibitor, as there are fewer hospital visits needed; lately, about 75% of my patients get zanubrutinib and about 25% get acalabrutinib. For patients with favorable cytogenetics and, especially, those who are younger and active, I tend to go with VO. I want to point out, however, that most of my patients enroll in clinical trials.”

Amy L. Goodrich, RN, BSN, MSN, CRNP-AC, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, added that, when it comes to the treatment decision process, at her institution “within the multidisciplinary team, pharmacists play one of the key roles, as they are the ones who are invaluable in assessing the potential for drug-drug interactions and their implications. Also, when it comes to choosing an optimal BTK inhibitor, decisions are frequently made based on the team’s comfort with an agent and the availability of long-term data.”

We are using zanubrutinib more frequently than ever, particularly in patients with preexisting cardiac issues, as the rates of cardiac complications appear to be the lowest with zanubrutinib.

Ms. Goodrich continued: “In other words, providers tend to go with what they are familiar with. Currently, that means we have many patients on ibrutinib and acalabrutinib, as they are agents with which the team is familiar, have long term follow-up data and at this time, are more likely to be used over zanubrutinib. With longer follow-up and more mature safety data, however, that is likely to change,” she told JNCCN 360. “We are using zanubrutinib more frequently than ever, particularly in patients with preexisting cardiac issues, as the rates of cardiac complications appear to be the lowest with zanubrutinib. Longer follow-up is needed to see if that trend continues.”

Management of Adverse Events

Overall, zanubrutinib has a favorable safety profile, with a low incidence of major bleeding and cardiovascular toxicity in patients with CLL/SLL.¹⁵ The National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for CLL/SLL include zanubrutinib as one of the preferred regimens for in the first line or second and subsequent lines of therapy, regardless of the presence or absence of del(17p)/TP53 mutations.¹⁶ When it comes to the management of adverse events with zanubrutinib in patients with CLL/SLL, Ms. Goodrich pointed out that “unlike with other zanubrutinib indications, I don’t have much experience with it in this newest CLL/SLL indication. However, so far, I am not noticing any significant differences between those other indications and CLL/SLL and feel confident I can safely draw some parallels between my experiences with MCL, WM, or relapsed or refractory MZL. My experience so far is that, overall, zanubrutinib is better tolerated than acalabrutinib and especially ibrutinib.”

Some of the adverse events that may require special vigilance are hemorrhage, infections, cytopenia, second primary malignancies, cardiac arrhythmia, and embryofetal toxicity. According to Ms. Goodrich, it is necessary to monitor for signs and symptoms of bleeding and discontinue zanubrutinib if intracranial hemorrhage of any grade occurs. She adds, consider the benefit-risk of withholding zanubrutinib for 3 to 7 days before and after surgery, depending upon the type of surgery and the risk of bleeding.

For infections, Ms. Goodrich recommends considering prophylaxis for herpes simplex virus, Pneumocystis jirovecii pneumonia, and other infections, according to the standard of care in patients who are at increased risk for infections; as well as monitoring and evaluating patients for fever or other signs and symptoms of infection and treating appropriately. As for cytopenia, she suggests monitoring complete blood cell counts regularly during treatment and interrupting treatment, reducing the dose, or discontinuing treatment as warranted; in addition, treat with growth factor or transfusions, as needed.

Furthermore, Ms. Goodrich advises patients to use sun protection, and clinicians should monitor them for the development of second primary malignancies. Patients should also be monitored for signs and symptoms of cardiac arrhythmia, such as palpitations, dizziness, syncope, dyspnea, and chest discomfort and consider the risks and benefits of continued zanubrutinib treatment.

Finally, given the risk for embryofetal toxicity, women should be advised to avoid becoming pregnant while taking zanubrutinib and for 1 week after the last dose; men should be advised to avoid fathering a child during treatment and for 1 week after the last dose. If zanubrutinib is used during pregnancy, or if the patient becomes pregnant while taking zanubrutinib, the patient should be apprised of the potential hazard to a fetus.⁵

Key Takeaways

In closing, Dr. Brown pointed out that “targeted therapies have profoundly transformed treatment of patients with CLL/SLL in the past decade and relegated the usage of chemoimmunotherapy to a very narrow patient population (ie, for patients aged < 65 years with mutated IGHV region without significant comorbidities). Because of the superior efficacy and tolerability of targeted therapies compared with chemoimmunotherapy, today’s treatment selection is primarily driven by patients’ comorbidities and personal preferences and not so much by age and fitness status."

Targeted therapies have profoundly transformed treatment of patients with CLL/SLL in the past decade and relegated the usage of chemoimmunotherapy to a very narrow patient population.

For example, a history of cardiac disease may favor venetoclax-based regimens or more selective second-generation BTK inhibitors such as acalabrutinib or zanubrutinib. For patients with preexisting renal dysfunction, or those unable or reluctant to have more frequent hospital visits, a BTK inhibitor is a preferred option. For patients who do not want or have to be exposed to indefinite treatment (eg, those without del17p/p53 mutation), venetoclax-based therapy may be a preferred option, according to Dr. Brown.

Ms. Goodrich emphasized that “it is important to keep in mind that concurrent medications can affect the optimal dosing of the BTK inhibitor. Therefore, it is imperative that patients maintain an up-to-date list of their current medications, so possible drug interactions can be identified, and patients’ providers and teams can plan accordingly. One of the convenient and unique features of zanubrutinib, in addition to its favorable safety profile, is that it can be dosed either once or twice daily without an apparent effect on efficacy, which provides extra flexibility for patients.” 

Disclosures

Jennifer R. Brown, MD, PhD, has served as a consultant to AbbVie, Acerta/AstraZeneca, BeiGene, Genentech/Roche, Grifols Worldwide Operations, Hutchmed, iOnctura, Janssen, Kite, Loxo/Lilly, MEI Pharma, Numab Therapeutics, Pfizer, and Pharmacyclics; and has received research funding from BeiGene, Gilead Sciences, iOnctura, Loxo/Lilly, MEI Pharma, and TG Therapeutics.

Amy L. Goodrich, RN, BSN, MSN, CRNP-AC, reported no conflicts of interest. 

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