Distinct immune and genomic signatures predict resistance to ibrutinib therapy in Waldenström macroglobulinemia

Despite recent advances in treatment strategies of Waldenström macroglobulinemia (WM) patients, the disease remains incurable. While several genomic features predict poor outcomes with ibrutinib, the contribution of immune dysfunction to tumor behavior remains unclear. Single-cell RNA sequencing on longitudinal bone marrows from 37 Waldenström macroglobulinemia patients before and after ibrutinib therapy profiled 348,000 cells and identified distinct immune phenotypes associated with ibrutinib progression. This was primarily characterized by the accumulation of T-effector cells, Tregs and pro-inflammatory M1-like monocytes, alongside a depletion of naïve T-cells. The tumor architecture in progressing patients, exhibited a unique transcriptomic signature, also validated in an external cohort of 47 WM patients, driven by genes including LTB, NFKBIA, DUSP2 , NR4A1 leading to shorter progression-free survival. Mutational profiling using whole-genome sequencing identified mutational signature SBS1/SBS5 being significantly associated with poorer outcome. Finally, we demonstrate that integrating tumor with immune cell compartments can significantly improve ibrutinib response prediction scoring.