MRD Testing Across CLL Treatment Strategies

Dr. Lipsky outlines MRD testing utility across the three major treatment approaches. For continuous BTKi monotherapy, there is no clinical reason to check MRD status; only a very small proportion of patients on long-term therapy eventually achieve MRD negativity, and this is not actionable in current practice.

For venetoclax-obinutuzumab, approximately three-quarters of patients achieve MRD negativity around end of treatment based on CLL14 data, though nearly all patients eventually lose that negativity, with only approximately 8% remaining truly MRD-negative years later. MRD results bifurcate significantly by IGHV mutational status, with mutated patients achieving higher undetectable MRD rates and substantially better clinical outcomes.

For oral BTKi-venetoclax doublets, MRD data currently serves as a surrogate efficacy endpoint given the absence of long-term follow-up from studies like AMPLIFY. Importantly, for patients with unmutated IGHV or TP53 aberrations receiving zanubrutinib-venetoclax (SEQUOIA ARMD), extending therapy beyond one year improves undetectable MRD rates from year 1 to year 2. Dr. Shadman extends this approach to acalabrutinib-venetoclax based on extrapolation, offering an additional year of combination therapy to high-risk patients who haven't achieved undetectable MRD.

Dr. Shadman notes he would also consider extending therapy in mutated IGHV patients who haven't achieved undetectable MRD, treating them as functionally high risk regardless of favorable baseline markers, anticipating that ongoing studies including the MAGIC trial and CLL18 MRD-guided randomized trial will provide more definitive answers.

Both panelists agree that neither MRD testing nor treatment modification based on MRD status is currently standard practice in the continuous BTKi setting, and MRD-guided treatment decisions for fixed-duration therapy remain investigational outside of clinical trials.