MRD Practical Guidance, BTK Degraders, and Resistance Mechanisms in CLL

The panel emphasizes MRD testing is not a current standard of care requirement, advising community oncologists not to feel obligated to order it outside clinical trials or high-risk treatment extension decisions. MRD currently functions primarily as a prognostic tool and quality-of-response assessment, analogous to historical use of bone marrow biopsies and scans after chemoimmunotherapy, rather than a reliable treatment decision driver. The MAGIC trial and CLL18 MRD-guided randomized study will provide more definitive guidance.

Practical MRD guidance includes that either flow cytometry or clonoSEQ (FDA-approved) are acceptable testing platforms, with the current IWCLL threshold of 1 × 10⁻⁴ as the undetectable MRD definition, which may evolve as technology improves.

Dr. Parikh introduces BTK degraders: proteolysis-targeting chimera compounds that eliminate the entire BTK protein rather than inhibiting enzymatic function, theoretically circumventing resistance mutations at the binding site. Two compounds are furthest in clinical development: one from Nurix Therapeutics and one from BeiGene. Phase 1-2 data in heavily pretreated patients (median 4-5 prior lines) show approximately 80% response rates as single agents, demonstrating proof-of-concept for this mechanism after both covalent and non-covalent BTK inhibitor exposure.

Dr. Lipsky and Dr. Shadman discuss BTK resistance mutation testing, noting that although they send testing to build knowledge, clinical actionability remains limited. Unlike the well-established CML mutation-to-drug tables, CLL resistance is more complex with many progressions occurring without identifiable resistance mutations, suggesting epigenetic and microenvironmental mechanisms remain incompletely understood.

Dr. Coombs raises the important sequencing consideration that covalent BTK inhibitor after non-covalent inhibitor lacks evidence and likely doesn't work, whereas degraders could theoretically work after pirtobrutinib based on resistance pathway differences. Whether optimizing degraders before or after pirtobrutinib yields better cumulative outcomes remains unknown pending phase 3 data.