Managing Chronic Lymphocytic Leukemia in Older Adults: Clinical Perspectives on Sequoia Zanubrutinib

CLL is a disease that mainly affects older individuals. Therefore, in the treatment of patients with CLL, consideration must be given to the patients’ age, comorbid medical conditions, functional status, and ability to tolerate treatment. There have been significant changes in the treatment of patients with CLL in recent years with the introduction of several novel targeted agents that have advantages over traditional chemoimmunotherapy in certain patient populations.

In the SEQUOIA study, 1 previously untreated CLL/SLL patient was treated with Zanubrutinib. In the study’s randomized cohort, 50 treatment-naïve CLL/SLL patients without del(17p) were randomly assigned to receive either Zanubrutinib or BR. With a median follow-up of 61.2 months, PFS was significantly longer for patients who received Zanubrutinib (median PFS not reached) than for those who received BR (median PFS of 44.1 months; hazard ratio of 0.29). Estimated 60-month OS rates were 85.8% for Zanubrutinib and 85.0% for BR. For the 38 patients with both mutated and unmutated IGHV genes, PFS was significantly longer for patients who received Zanubrutinib than for those who received BR. No new safety signals for Zanubrutinib were identified. The rate of atrial fibrillation was 7.1%.

In addition to the reported PFS endpoint, the SEQUOIA study provides information for the management of older patients with CLL. Assessing whether Zanubrutinib or other approaches including chemoimmunotherapy are appropriate for the treatment of patients with CLL considers the patients’ overall health status, coexisting medical problems and concomitant medications. An assessment of the patients’ functional status and ability to take long-term oral medications is also considered.

Why Age Matters in CLL Management

Most of the older patients with CLL will have a wide range of physical and mental abilities. They will have many different co-morbid conditions. They will be on many different medications. They will have many different physical and mental limitations. We can call these limitations the patient’s “physical and mental fitness” or their “biological age” and this is usually different from the patient’s “chronological age”.

Two patients of the same age can have vastly different levels of functional status, comorbid disease, renal function, cardiovascular disease and on medications. So in addition to chronological age, the biological age or fitness of the patient and their clinical status need to be taken into consideration when deciding on treatment.

Comorbidities and concomitant medications are more common with advancing age in CLL patients. These factors must be taken into consideration when choosing a treatment for CLL patients as well as when monitoring CLL patients on treatment.

Historically, few studies have included adequate numbers of older patients with CLL to draw meaningful conclusions regarding their clinical course and the effects of treatment. More recently, there is little data regarding the treatment of patients with CLL and significant comorbidity. Therefore, most studies regarding the treatment of CLL have been conducted in relatively healthy younger patients. These studies must be interpreted in the context of the older patient with CLL.

What SEQUOIA Adds to the Evidence Base

Separate analysis in del(17p) patients receiving sequoia zanubrutinib, data cut-off of July 2023, median follow-up of 26.1 months, median PFS not reached. Patients were followed for a median of 26.2 months. With longer follow-up (61.2 months), the median PFS for patients treated with Zanubrutinib had not been reached (NR) in comparison with a PFS of 44.1 months for patients treated with BR (HR = 0.29; 95% CI = 0.22-0.37; estimated 60-month OS rates of 85.8% vs 85.0% for Zanubrutinib vs BR, respectively).

There was no new safety signals identified with longer follow-up. The incidence of reported atrial fibrillation (AF) was 7.1% in patients treated with Zanubrutinib and 9.4% in patients treated with BR.

While the SEQUOIA study provides data on the use of zanubrutinib in the study population, it is not appropriate or recommended for the treatment of all older patients with CLL.

Assessing Fitness Rather Than Age Alone

For an older patient to be considered for treatment, there are several factors that need to be assessed before choosing a treatment.

These can include:

●     Performance status

●     Activities of daily living

●     Frailty

●     Cardiovascular disease

●     Renal and hepatic function

●     Infection history

●     Cognitive status

●     Nutritional status

●     Polypharmacy

●     Previous treatment exposure

●     Patient preferences and treatment goals

This assessment allows us to differentiate between a fit older adult and a frail patient with many co-morbidities competing for attention. The example of a 70-year-old fit patient with very few co-morbidities would be managed very differently to an 85 year old frail patient with co-existing cardiovascular disease, renal impairment and on multiple medications.

Cardiovascular Considerations with Zanubrutinib

Cardiac arrhythmias, including serious and life-threatening cardiac arrhythmias, have been reported in patients with Zanubrutinib treatment. These events have occurred in patients with cardiac risk factors, including those with hypertension, and in patients experiencing an acute infection.

These individuals should have their concomitant cardiovascular medications identified by complete medication reconciliation and a bleeding risk assessment for patients on anticoagulants for conditions such as atrial fibrillation and other indications.

Review of cardiac history, blood pressure and cardiac rhythm as well as of concomitant antithrombotic treatment before as well as during Zanubrutinib treatment.

Bleeding and Concomitant Medications

There are cardiovascular medications that the older patient is likely to be on, including anticoagulants and antiplatelet agents. The potential interactions with the BTK inhibitor and their consequences need to be assessed and their impact on the overall treatment of the patient’s other medical problems considered.

Review of the patient’s prescription and non-prescription medicines and supplements, as well as any vitamins, are needed for a complete assessment of medicines to identify any possible drug interactions and determine if a patient’s current medicines are still needed. In old patients with many medicines (polypharmacy) the number of drug interactions increases. These interactions are difficult to detect.

Monitoring Blood Counts and Organ Function

Monitoring blood counts and organ function is needed for a long-term treatment with Zanubrutinib. It is necessary to regularly monitor blood counts to look for signs of developing cytopenia and organ function to search for early warning signs of emerging problems.

The aging process and underlying disease can lead to decreased renal function and/or decreased hepatic function with even minor changes having important clinical implications. Monitor the patient on Zanubrutinib individually based on the patient’s specific disease, treatment, co-morbidities and clinical situation.

Infection Risk and Supportive Care

Infections are important in the management of CLL patients. They are affected by the disease and by therapy. Zanubrutinib has been associated with infections, including serious ones. A pooled safety analysis of Zanubrutinib across B-cell malignancies reported pneumonia, sepsis, and other infections among serious adverse events.

Patients ≥75 years of age reported a higher rate of adverse events of Grade 3 or higher and serious adverse events compared to younger patients. Consider the patient’s past history of infections, assess their current vaccination status, determine the frequency of their infections and assess their overall immune competence.

Treatment Adherence and Practical Considerations

Although oral therapy is given outside of an infusion center, it can be given for a long period of time and therefore needs to be monitored. Older adults may have difficulty with the scheduling of their oral medication, due to factors such as cognitive impairment, inability to read the label, need for transportation to a pharmacy, and need for a caregiver.

Assess the ability of the older patient and their family/caregiver to manage oral drugs, with or without help from others. Medication reconciliation for all oral drugs, including those for CLL, should be performed for all patients every time they are seen in the clinic. Consideration of the practical burden of long-term treatment should be considered in the discussion of the treatment of CLL in the older patient.

Interpreting SEQUOIA for Individual Patients

SEQUOIA may be considered for individual patients in a similar fashion to the study population. There are, however, limitations to how one can apply the results of a single clinical trial to individual patients with CLL. The SEQUOIA study enrolled treatment-naïve patients with CLL/SLL without del(17p) and the resulting data assesses the safety and efficacy of Zanubrutinib in this subgroup of patients. There have been separate clinical trials assessing the safety and efficacy of Zanubrutinib in patients with del(17p) and, although there are encouraging results for certain endpoints (including OS), the results for PFS have not been as strong as in treatment-naïve patients without del(17p).

Even a clinical trial cannot include all a patient’s health problems, medicines, degree of frailness, preferences, and other health problems. Thus, the results of SEQUOIA have to be applied with a lot of common sense in individual cases.

A Multidisciplinary Approach Can Be Valuable

Older CLL patients with complex problems, such as CLL and multiple co-morbidities on multiple medications, need a multidisciplinary approach to their care. This team would consist of members from the disciplines of hematology, primary care, cardiology, pharmacy, and nursing, among others. This team of healthcare professionals may be able to manage the CLL in the older patient with complicated issues such as anticoagulation, renal impairment, recurrent infections, etc.

The key to managing older CLL patients in the multidisciplinary team setting is to take account of all their health problems. Managing the disease in older patients is not just a matter of discussing treatment with the patient and their family and drawing on the expertise of several different healthcare professionals including those from primary care, hematology, cardiology, pharmacy and nursing. Rather, all the patients’ health problems need to be considered, for example, their cardiovascular disease, requirement for anticoagulation, renal impairment, history of recurrent infections, and polypharmacy.

Final Thoughts

In SEQUOIA, Zanubrutinib demonstrated higher level of efficacy as compared with bendamustine plus rituximab (BEND + RIT) in treatment-naïve patients with CLL/SLL without del(17p) mutation. Follow-up of 5 years or longer from start of study treatment, where available, continues to show PFS advantage for ZANU with no new safety concerns.

Besides the chronological age of patients with CLL, their functional status and potential degree of frailty, the cardiovascular risk, the risk of bleeding as well as of infections need to be considered in the treatment decision. Furthermore, organ function, the concomitant medication, the possibility of treatment as well as the treatment goals of individual patients need to be considered. In summary, consideration of the SEQUOIA trial results as they relate to the management of older adults with CLL utilizing Zanubrutinib may be useful in the patient’s overall clinical care. The results of such trials can serve as very valuable information to aid in making clinical decisions as it relates to the management of individual patients.

Disclaimer: The information provided in this article is intended for educational purposes only and should not be interpreted as medical advice, a clinical guideline, or a recommendation for any specific treatment.