Case report: Circulating tumor DNA technology displays temporal and spatial heterogeneity in Waldenström macroglobulinemia during treatment with BTK inhibitors.

Background: Waldenström macroglobulinemia (WM) is a rare subtype of B-cell lymphoma. Rituximab-based combination therapy and Bruton's tyrosine kinase (BTK) inhibitors have greatly improved the prognosis of WM. Despite the high response rate and good tolerance of BTK inhibitors in treatment of WM, a proportion of patients still experience disease progression. Case presentation: We report a 55-year-old man with relapsed WM. The patient achieved partial remission after six courses of CHOP chemotherapy and multiple plasma exchanges in initial treatment. He was admitted to the hospital with abdominal distension, and was diagnosed with relapsed WM and subsequently started on zanubrutinib. Disease progression and histological transformation occurred during treatment. We performed liquid biopsies on transformed plasma, tumor tissue and ascites at the same time and found high consistency between ascites and tissues. Moreover, we detected resistance mutations of BTK inhibitors (BTK, PLCG2) in ascites that were not detected in plasma or tissue. Eventually, the patient died during the 15-month follow-up after relapse. Conclusion: We describe a rare case of WM transformation to DLCBCL treated with chemoimmunotherapy and BTK inhibition. We analyzed tumor DNA obtained at different anatomic sites and circulating tumor DNA (ctDNA) derived from plasma and ascites specimens, with apparent significant temporal and spatial heterogeneity. The case specifically highlights the clinical value of ctDNA of ascites supernatant from WM patients, which is a more convenient and relatively noninvasive method compared with traditional invasive tissue biopsy.