Evolution of tumor subclones and T-cell dynamics underlie variable ibrutinib responses in Waldenström macroglobulinemia
Abstract
Abstract To elucidate the molecular basis underlying differential responses and resistance to ibrutinib in Waldenström macroglobulinemia (WM), we conducted a prospective phase 2 trial of ibrutinib monotherapy in treatment-naïve patients. A total of 74 sequential bone marrow (BM) aspirates from 17 patients, collected from baseline through 48 treatment cycles, were profiled using single-cell multiomics. BM cells were segregated primarily into B-cell/plasma cell and T-cell compartments. Longitudinal clonal tracking of malignant B cells/plasma cells identified 3 distinct evolutionary patterns: evolution (early clone contraction with late clone expansion and increasing genomic complexity), devolution (early clone expansion with late clone contraction and genomic simplification), and no evolution (stable clonal architecture). The evolution pattern was strongly associated with disease progression, whereas devolution correlated with durable clinical response. Transcriptomic profiling of resistant clones enabled development and validation of the Waldenström ibrutinib prediction (WIP) score, which predicted treatment response at baseline. Within the WIP signature, LYN emerged as a key regulator; LYN knockdown or inhibition significantly increased WM cell sensitivity to ibrutinib, suggesting a rational combination strategy. In parallel, GZMB+ CD8+ effector-memory T cells expanded after treatment in patients with progressive disease and coexisted with tumor evolution. These cells exhibited persistently impaired cytotoxic programs (eg, GNLY), a dedifferentiated memory-like state, elevated PDCD1 expression, and reduced T-cell receptor diversity. Together, this study provides, to our knowledge, the first single-cell framework of tumor clonal evolution and T-cell dysfunction under ibrutinib in WM, introduces the WIP score as a predictive biomarker for treatment response, and identifies actionable tumor-intrinsic and immune mechanisms driving resistance. This trial was registered at www.ClinicalTrials.gov as NCT02604511.
Article Details
Authors (33)
Hao Sun
Romanos Sklavenitis-Pistofidis
Shirong Liu
Xia Liu
Nicholas Tsakmaklis
John M. Hatcher
1Bing Center for Waldenström’s Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA
Maria Luisa Guerrera
1Bing Center for Waldenström’s Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA
Amanda Kofides
1Bing Center for Waldenström’s Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA
Andres Ramirez-Gamero
1Bing Center for Waldenström’s Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA
Abigail L. Peachey
1Bing Center for Waldenström’s Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA
Shuqiang Li
Derin B. Keskin
Vipheaviny Chea
Nawoo Kim
2Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
Haoxiang Lyu
2Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
Wesley Lu
2Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
Kenneth J. Livak
Kirsten Meid
1Bing Center for Waldenström’s Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA
Alberto Guijosa
1Bing Center for Waldenström’s Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA
Catherine A. Flynn
1Bing Center for Waldenström’s Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA
Dominic Pizzarella
1Bing Center for Waldenström’s Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA
Christopher J. Patterson
1Bing Center for Waldenström’s Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA
Mu Hao
4State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
Shuhua Yi
4State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
Weiping Yuan
Beijing National Laboratory for Condensed Matter Physics, Institute of Physics, Chinese Academy of Sciences 1 , Beijing 100190,
Andrew R. Branagan
Department of Medicine, Massachusetts General Hospital, Boston
Catherine J. Wu
Irene M. Ghobrial
Lugui Qiu
Shayna R. Sarosiek
1Bing Center for Waldenström’s Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA
Jorge J. Castillo
1Bing Center for Waldenström’s Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA
Zachary R. Hunter
Steven P. Treon