Cell morphology change renders tolerance to therapies in MCL preclinical models. (A) Enlarged tumor cells were detected in PDX samples from patient 4 (PT4) treated with BTKis (pirtobrutinib and IBN), or anti–ROR1 (receptor tyrosine kinase–like orphan receptor 1) monoclonal antibody zilovertamab. Yellow arrows, regular-sized tumor cells; red arrows, enlarged tumor cells. Scale bar, 100 μm. (B) The enlarged cells from the PDX tumor (PT4) were cultured as PDOs treated with acalabrutinib (10 μM) or pirtobrutinib (10 μM) for 2 weeks. They reproliferated as regular-sized tumor cells upon drug removal. Representative brightfield images are shown at different time points. Active proliferating/expanding cells are highlighted by squares. Scale bar, 100 μm. (C) Representative images of enlarged cells generated in the ex vivo PDO model using apheresis from PT6. The PDOs were treated with acalabrutinib and pirtobrutinib at 10 μM for over 2 weeks. Scale bar, 100 μm. DMSO, dimethyl sulfoxide.