Recognizing BTKi Resistance in CLL—Incorporating Pirtobrutinib in Relapsed/Refractory Disease

Recognizing BTKi Resistance in CLL—Incorporating Pirtobrutinib in Relapsed/Refractory Disease

BTK resistance mutation testing has become an important diagnostic tool in managing patients with progressive disease on BTK inhibitor (BTKi) therapy, although its clinical utility remains limited by current treatment options and data availability. Although many clinicians routinely perform resistance testing, the results do not significantly alter treatment decisions given that pirtobrutinib, the primary next-generation BTKi option, demonstrates comparable efficacy regardless of mutation status according to BRUIN trial data. Current practice involves offering pirtobrutinib to all patients with BTKi progression, irrespective of resistance mutation findings, particularly given the limited alternative options available for heavily pretreated patients outside of clinical trials. However, specific scenarios may warrant different approaches, such as patients with high-level mutations who might benefit from BCL2 inhibitor therapy if not previously exposed.

The decision-making process around resistance testing varies significantly among practitioners, with approaches ranging from universal testing to selective patient discussions about testing benefits and limitations. Some clinicians routinely test all progressing patients, whereas others engage in shared decision-making conversations about testing utility, given that results rarely change immediate treatment plans. Insurance coverage considerations and patient understanding of test limitations factor into these discussions. The low frequency of certain resistance mutations and unclear clinical significance of many detected variants contribute to uncertainty about acting on test results, making it crucial to set appropriate patient expectations about why testing is performed and what results may or may not indicate about treatment options.

An important clinical consideration involves managing patient expectations when resistance mutations are absent despite clear disease progression. Approximately one-third of patients experiencing BTK inhibitor progression will not have detectable BTK or PLCγ2 resistance mutations, yet they still demonstrate objective disease progression through lymphocytosis or lymph node enlargement. Patients often question the need for treatment changes when no mutations are detected, requiring careful explanation that clinical progression, rather than molecular findings, drives treatment decisions. This scenario highlights the complexity of resistance mechanisms beyond detectable mutations and reinforces that treatment switching should be based on clinical evidence of progression rather than solely on molecular findings. The future role of resistance testing may expand as more targeted treatment options become available for specific mutation patterns.