Treatment Considerations for CLL and Adverse Event Management

Chronic lymphocytic leukemia (CLL) is a long-term, slowly developing disease that begins in the bone marrow and extends into the blood. The treatment paradigm has evolved for CLL, starting with chemotherapy and more recently moving into small molecule therapies used both alone and in combination with immunotherapy. New therapeutic approaches have demonstrated significant efficacy with chemo-immunotherapy over chemotherapy alone.

During a presentation at the Asembia 2020 Summit, Alison Duffy, PharmD, BCOP, associate professor in the Department of Pharmacy Practice and Science and oncology clinical pharmacy specialist at the Greenebaum Comprehensive Cancer Center at the University of Maryland, and Kirollos S. Hanna, PharmD, BCPS, BCOP, oncology pharmacy manager at M Health Fairview and assistant professor of pharmacy at the Mayo Clinic College of Medicine in Rochester, MN, discussed treatment options for CLL, including novel approaches.

Dr. Duffy noted that this is primarily a disease of older individuals (median age of diagnosis, 70 years), so age must be considered for its impact on treatment-related factors and decisions; particularly, patients’ functional status should be considered. Patient preference, as well as financial and treatment location considerations, should guide treatment decisions.

She discussed therapies for treatment-naïve CLL, including ibrutinib, acalabrutinib, and BCL-2 inhibitors, as well as relapsed/refractory disease, including BCL-2 and phosphoinositide 3-kinase (PI3K) inhibitors. Dr. Duffy also presented novel treatments and future options. Zanubrutinib is a potent, specific, irreversible Bruton’s tyrosine kinase (BTK) inhibitor that was approved by the U.S. Food and Drug Administration in 2019 to treat relapsed/refractory mantle cell lymphoma. Several clinical trials are either in progress, recruiting, or soon starting to assess this agent in CLL. Some other drugs in the pipeline include BTK inhibitors tirabrutinib and spebrutinib, selective spleen tyrosine kinase inhibitor entospletinib, second-generation PI3K inhibitor umbralisib, chimeric antigen receptor T-cell therapy lisocabtagene maraleucel, and more.

Next, Dr. Hanna talked about how multidisciplinary care is necessary for this patient population, including supportive care and laboratory monitoring, pharmacy-led oral chemotherapy management programs, and identification of clinically significant issues—most commonly drug reactions. “Pharmacists play a critical role,” he said.

Dr. Hanna then discussed adverse event (AE) management for CLL treatments. A 2016 study published in Blood assessed data from 10 academic centers and the Connect CLL Registry to identify patients who discontinued therapy between 2013 and 2015. For ibrutinib and idelalisib, the most common reason for discontinuation was toxicity. A multicenter, retrospective study published in 2018 in Blood assessed patients with CLL treated with ibrutinib and found that after a median follow-up of 17 months, the discontinuation rate was 42%. In the frontline setting, the most common AEs related to discontinuation were arthralgias, atrial fibrillation (AF), and rash. In the relapsed/refractory setting, the most common AEs leading to discontinuation were AF, infection, pneumonitis, bleeding, and diarrhea.

For AF (which occurs in 9% of ibrutinib-, 4.1% of acalabrutinib-, and 2% of zanubrutinib-treated patients), monitor for signs and symptoms like palpitations, lightheadedness, dizziness, fainting, shortness of breath, and chest discomfort. Consider non-warfarin anticoagulation, and monitor patients carefully. If AF continues to be uncontrolled, consider switching to an alternative therapy. For bleeding (occurring in 4% of ibrutinib-, 3% of acalabrutinib-, and 2% of zanubrutinib-treated patients), the impact of platelet aggregation is reversible within one week of discontinuation. Consider the risks and benefits with antiplatelet and anticoagulation therapy. Monitor for signs of bleeding, and evaluate the risks and benefits of surgery. Treatment-related lymphocytosis is another AE that occurs with many therapies used to treat B-cell malignancies. This is not indicative of progressive disease and often resolves within eight months from treatment initiation, he said.

Pharmacists provide clinical considerations and operational best practices to optimize oral chemotherapy dispensing and management. Pharmacists play a role in the initiation, coordination, and maintenance of treatment. But barriers to treatment persist, and the first year of treatment is critical, he said. Within four months, severe AEs and treatment intolerance can lead to treatment cessation. “We have to ensure that these patients are adhering to therapy, because if they are not, their disease can progress and they can develop mutations that render select therapies ineffective, and we have to switch to a different mechanism of action with potentially less effective therapies,” Dr. Hanna said.

The pharmacist can provide clinical and operational services to engage the patients in treatment and improve adherence. Offering education and counseling, providing a comprehensive medication review, monitoring efficacy and AEs, and assisting patients with benefits and refills and renewals can be important. Patient education checklists can also be used to improve medication adherence. “Engaging the patients throughout this process is really important,” said Dr. Hanna.

Finally, Dr. Hanna discussed financial barriers to CLL treatment. The annual cost of CLL management has increased by 590%, and the per-patient lifetime cost of therapy is increasing by 310%, “which is a huge barrier for our patients,” Dr. Hanna said. He discussed findings from a 2019 Journal of Managed Care & Specialty Pharmacy study that addressed payer perceptions of CLL cost management strategies, some of which include the use of provider-developed pathways, excluding agents from formulary, and use of management tools such as split fills. When patients face the financial burden of treatment, it can decrease adherence and delay treatment, as well as decrease quality of life and lead to suboptimal disease outcomes. Pharmacists can offer support with early benefits investigations, provide patient counseling, engage in copay assistance programs and free drug programs, and integrate a financial team within the practice.

Presentation: The Dynamic Landscape of CLL and Its Effect on Specialty Pharmacy Practice. Asembia 2020 Specialty Pharmacy Summit Virtual Experience, May 6, 2020.