With a better understanding of the underlying pathophysiology of chronic lymphocytic leukemia and the introduction of novel targeted agents, such as Bruton kinase Inhibitors, the prognosis of high-risk patients has changed dramatically.
BG is a 76-year-old female presenting to the oncologist’s office for follow up of chronic lymphocytic leukemia (CLL). BG is also followed for stage IIB triple-positive breast cancer, initially treated with chemoradiation followed by infusions of cyclophosphamide and doxorubicin.
She then received weekly paclitaxel with trastuzumab infusions; however, she experienced cardiotoxicity with trastuzumab resulting in therapy discontinuation. She has completed 10 years of endocrine therapy with anastrozole, and her past medical history is consistent for hyperlipidemia and cataracts.
CLL is positive for 17p ATM mutation. She was originally managed on venetoclax and obinutuzumab and then transitioned to acalabrutinib. BG was on acalabrutinib capsules and tolerated them well for over a year with no adverse events of concern.
In December 2022, the manufacturer discontinued the distribution of the capsule formulation of acalabrutinib. BG was then switched to the tablet formation.
She soon developed a bilateral rash of the upper extremities and stopped taking the acalabrutinib tablets at the direction of her oncologist. The pharmacy still had the capsules in stock and after consulting with the oncologist, the decision was made to switch the patient back to the original capsule formulation.
At the time of subsequent fulfilment of acalabrutinib capsules, the pharmacy was completely out of stock of the capsule formulation with no supply available from the manufacturer.
What are potential alternatives that the pharmacist may suggest to the oncologist?
CLL is marked by the accumulation of functionally incompetent lymphocytes in the blood, lymph nodes, and spleen. Both CLL and small lymphocytic leukemia (SLL) affect the lymphocytes, however, the location of the cancer cells differs between the 2 diseases. SLL manifests primarily in the lymph nodes with CLL manifesting primarily in the bloodstream and bone marrow. Treatment is similar due to the affected cells exhibiting similar immunophenotype and morphology.1
CLL typically affects older populations with an average age of 70 years at diagnosis. Younger patients may also be affected, but occurrence in a pediatric patient is extremely rare. As is the case with most malignancies, genetics play a role and first-degree relatives of patients with CLL have double the risk of developing the disease.2
Approximately one-third of patients with CLL will never require treatment and about 70%-80 % of patients are asymptomatic at initial diagnosis. Oncologists use the Rai or the Binet staging system for classifying patients into the low- and high-risk categories.3
Both of these staging methods are used in contemporary practice, though Rai staging is often used in the United States and Binet staging in Europe. Rai staging focuses more on stratifying disease based on risk and Binet staging categorizes disease based on the number of affected lymphoid tissue groups.
In patients with more indolent disease, with lower risk based on Rai or Binet staging, a “watch and wait” approach may be taken. In this scenario, patients are monitored for disease progression rather than initiating therapy.
An estimated 95% of patients with CLL have at least 1 medical comorbidity with the median age at diagnosis and there are often other comorbidities at play that may have a greater influence on survival. Studies have shown that patients with lower risk may exhibit similar survival rates without treatment versus the control population.
According to the International Workshop of CLL, patients with symptomatic disease (significant fatigue, unintentional weight loss, fever without infection, or drenching night sweats), progressive anemia or thrombocytopenia, or steroid refractory autoimmune cytopenias meet the criteria for treatment initiation.
The National Comprehensive Cancer Network (NCCN) cites Bruton’s kinase inhibitors with or without an anti-CD20 monoclonal antibody as a preferred regimen for CLL or SLL. The other preferred agent is the BCL-2 inhibitor venetoclax in combination with an anti-CD20 monoclonal antibody.
This marks a shift from infusion-based chemotherapy to oral chemotherapy-based regimens as the preferred treatment for this disease state. However, the guidelines also recommend numerous alterative regimens for cases in which the disease is refractory or relapsed after treatment with a preferred agent.4 Many of which are infusion-based regimens, such as bendamustine with rituximab or obinutuzumab.
Bruton’s tyrosine kinases (BTK) are involved in the B-cell receptor signaling pathway modulating the survival of both normal and malignant B cells. Covalent BTK inhibitors, such as first generation ibrutinib, and second-generation agents acalabrutinib and zanubrutinib, irreversibly inhibit the BTK enzymes, leading to an antiproliferative effect.5 However, though the members of this class could control the progression of disease, they cannot eradicateit.
Common toxicities from BTK inhibitors include gastrointestinal adverse effects (AEs), such as nausea, vomiting, and diarrhea, though some patients report constipation and appetite suppression. Many patients report fatigue, arthralgias or myalgias, and headaches.6
More serious AEs include worsening or new onset hypertension, atrial fibrillation, and increased risk of bleeding due to inhibition of platelet aggregation. Although major bleeding is uncommon, this may be compounded by concurrent use of anticoagulants, which is relatively common in patients with CLL or SLL.
Neutropenia is also known to occur in patients taking BTK inhibitors, therefore monitoring of ANC is imperative in this population. Opportunistic infections, such as invasive aspergillosis and pneumocystis jirovecii, among others are not common but have been reported.7
The first-generation agent ibrutinib is very potent against BTK, but also has greater off-target affinity for other kinases, leading to toxicities, including increased rates of bleeding and arrhythmia. Second-generation BTK inhibitors are more selective for BTK and, therefore, better tolerated by patients.
Until recently, the only second generation BTK inhibitor approved by the FDA for CLL and SLL was acalabrutinib. On January 19, 2023, the FDA approved zanubrutinib as another option for patients with CLL and SLL.8
This was based on the result of the SEQUOIA trial, which was a large, open-label, multicenter, phase 3 study that compared zanubrutinib to bendamustine and rituximab, with the primary endpoint being progression-free survival.9 SEQUOIA supported the use of zanubrutinib as a treatment option based on the improved progression-free survival (PFS) versus bendamustine-rituximab; however, it is worth noting that bleeding events, atrial fibrillation, and neutropenia were more common in the zanubrutinib group.10
Other recent studies have also supported the use of zanubrutinib in CLL and SLL. The ALPINE trial was a large, international, multicentered study that compared zanubrutinib to ibrutinib with a primary endpoint being the investigator assessed overall response in the setting of relapsed or refractory CLL or SLL. Secondary endpoints for this trial included PFS and the incidence of AEs, such as atrial fibrillation or flutter.11
ALPINE suggested zanubrutinib had better efficacy than ibrutinib in this specific setting. The results showed improved PFS and overall response in the zanubrutinib group; however, this did not correlate with improved overall survival.12
It is worth noting, that the zanubrutinib group had lower rates of discontinuation versus the ibrutinib group and there were also fewer cardiac events and deaths in patients taking zanubrutinib.13 Therefore, zanubrutinib may have similar or even superior efficacy compared to older BTK inhibitors as well as potentially better safety and patient tolerability.
In the case of BG, there are a variety of agents that are approved for CLL other than acalabrutinib, such as ibrutinib, zanubrutinib, ventoclax with obinutuzumab, and infusion-based regimens. Because BG tolerated acalabrutinib capsules well and was without disease progression, the oncologist preferred to keep her patient on a second-generation BTK inhibitor. Because zanabrutinib is the only other second-generation BTK inhibitor approved by the FDA, with a favorable AE profile compared to the first-generation agent—the pharmacist recommends it as a substitute.
It has now been months since BG was transitioned to zanubrutinib and she continues to tolerate the new medication without any complaints of AEs. Her follow up appointments with her oncologist show no evidence of disease progression and she continues this regimen.
About the Authors
Drew Gazetos, PharmD, is a specialty clinical pharmacist working in oncology at the Outpatient Pharmacy Services (OPS) within the Yale New Haven Health System.
Bisni Narayanan, PharmD, MS, is the pharmacy supervisor at OPS. OPS is a specialty pharmacy integrated within the Yale New Haven Health System.