Chronic lymphocytic leukemia (CLL) is the most common leukemia affecting adults, comprising approximately one-fourth of new leukemia diagnoses in the United States. For 2021, estimates by the American Cancer Society indicate 21,250 new CLL cases and 4320 deaths due to CLL.1

Rapid advances in CLL therapies over the past decade have transformed the landscape of treatment for this disease, with substantial improvements in patient outcomes.2 However, the increasing range of options and their potential challenges presents greater complexity in clinical decision-making, requiring consideration of numerous factors specific to each patient.

“We now have very good therapies for the frontline management of CLL with the new targeted agents, but there are cases in which patients may lose their response to these therapies,” said Brian T. Hill, MD, PhD, director of the Lymphoid Malignancies Program and staff physician in the Cleveland Clinic Taussig Cancer Institute, and associate professor of medicine at the Cleveland Clinic Lerner College of Medicine in Cleveland, OH.

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Despite the impressive efficacy of venetoclax-based regimens, for example, factors such as heavily pretreated disease, TP53 abnormalities, and unmutated IGHV, are associated with a high risk of developing resistance to these therapies.3 In addition, an estimated 3%-25% of CLL patients will develop Richter’s transformation in the course of the disease.4 “Disease progression in either refractory CLL or Richter’s transformation represents an unmet need even in the current era,” Dr Hill recently told Hematology Advisor.  

For patients with resistance to covalent BTK inhibitors, the new class of noncovalent BTK inhibitors such as pirtobrutinib (formerly known as LOXO-305) represent a promising alternative. Based on results of the first-in-human, open-label phase 1/2 BRUIN trial of pirtobrutinib published in The Lancet in March 2021, these agents “seem to have fewer serious side effects such as bleeding and atrial fibrillation,” Dr Hill noted.5

In 121 patients with CLL or small lymphocytic lymphoma (SLL) who had previously been treated with a covalent BTK inhibitor, pirtobrutinib was associated with an overall response rate (ORR) of 62% (95% CI, 53-71), with similar ORRs for CLL patients with previous resistance or intolerance to BTK inhibitors, BTK C481-mutant disease, and BTK wild-type disease.5

The phase 1/2 BRUIN trial is ongoing, and a phase 3 trial comparing pirtobrutinib to idelalisib plus rituximab or bendamustine plus rituximab in CLL/SLL patients is now underway.6 Additional phase 3 trials of pirtobrutinib in CLL are also slated to begin in the near future, according to a statement by Loxo Oncology at Lilly.7

“Also on the horizon, we are still exploring cell therapies with CAR-T cells, which preliminary data have shown to be effective in younger, fitter patients with CLL,” Dr Hill said. Although these agents are not yet approved by the US Food and Drug Administration, several registrational trials are underway to explore such approvals.8,2

To further discuss treatment strategies and challenges in CLL, we interviewed Jacqueline C. Barrientos, MD, MS, researcher and associate professor in the division of hematology and medical oncology at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell in New Hyde Park, NY.