Version July 2025
This algorithm presents our general approach to the selection of second-line therapy for CLL. We always encourage patients to enroll in a well-conducted clinical trial. This applies particularly to the third-line setting, when BCL2 and BTK inhibition treatment paradigms are exhausted, as highly effective innovative options are available for such patients in trials (eg, BTK degraders, bispecific antibodies, CAR-T cell therapy).
Patients who discontinue a therapy due to intolerance may be candidates for treatment with a different agent from the same class as long as mechanism of action interfering mutations are not present. BTK inhibitors and venetoclax-based treatment are used prior to other agents. When choosing between regimens that include BTK inhibitors and venetoclax, we consider patient characteristics as shown in the inset. After attaining a response for treatment of progressive disease, younger patients with a matched donor (related or unrelated) should be evaluated for allogeneic HCT. HCT may be especially attractive in those with higher-risk CLL (eg, del17p, TP53 mutation) and/or progression within 5 to 6 years of initial therapy.
BTK: Bruton tyrosine kinase; CAR: chimeric antigen receptor; CLL: chronic lymphocytic leukemia; CYP: cytochrome P450; HCT: hematopoietic cell transplantation; PI3K: phosphoinositide 3'-kinase.
* Most patients with progression after initial chemoimmunotherapy should be treated with a BTK inhibitor or venetoclax-based therapy. Targeted therapies are well-established in this setting, as this population corresponds with that used in the trials, demonstrating the efficacy of these agents.
¶ We loosely define early relapse as progression within 2 to 3 years of initial treatment with time-limited therapy, although we do not know what duration of prior remission will allow for meaningful benefit upon retreatment. If the patient has limited alternatives, a remission duration of 1 to 2 years may be clinically meaningful and a clear rationale for retreatment.
Δ Those with mutations in BCL2 are unlikely to achieve a durable response following venetoclax-based therapy and may be candidates for a single-agent BTK inhibitor. Those with mutations in BTK or PLCg2 are unlikely to respond to a covalent BTK inhibitor and may be candidates for venetoclax plus obinutuzumab. Those with mutations in BCL2 and either BTK and/or PLCg2 may be candidates for treatment with a noncovalent BTK inhibitor or PI3K inhibitor.
◊ The noncovalent BTK inhibitor pirtobrutinib has demonstrated activity in CLL with BTK C481 mutation. Other mutations in BTK (eg, those in positions 528, 474, or 428) may also be acquired with covalent BTK inhibitor treatment and may confer resistance to pirtobrutinib as well. However, the presence of mutations at a small allelic frequency does not preclude successful treatment with pirtobrutinib for a short period of time.
§ A BTK inhibitor may be preferred over venetoclax in patients with impaired creatine clearance and in those on strong CYP3A inhibitors due to an increased risk of tumor lysis syndrome; however, BTK inhibitors are also CYP3A substrates, and dose adjustment or avoidance may be warranted, depending on the agent. Refer to drug interactions program.
