CD19-directed chimeric antigen receptor T cell therapy in Waldenström macroglobulinemia: a preclinical model and initial clinical experience

J Immunother Cancer. 2022 Feb;10(2):e004128. doi: 10.1136/jitc-2021-004128.


Background: Waldenström macroglobulinemia (WM) is an incurable disease and, while treatable, can develop resistance to available therapies and be fatal. Chimeric antigen receptor (CAR) T cell therapy directed against the CD19 antigen has demonstrated efficacy in relapsed or refractory B lymphoid malignancies, and is now approved for B cell acute lymphoblastic leukemia and certain B cell lymphomas. However, CAR T therapy has not been evaluated for use in WM.

Methods and results: We performed preclinical studies demonstrating CAR T cell activity against WM cells in vitro, and developed an in vivo murine model of WM which demonstrated prolonged survival with use of CAR T therapy. We then report the first three patients with multiply relapsed and refractory WM treated for their disease with CD19-directed CAR T cells on clinical trials. Treatment was well tolerated, and observed toxicities were consistent with those seen in CAR T treatment for other diseases, and no grade 3 or higher cytokine release syndrome or neurotoxicity events occurred. All three patients attained at least a clinical response to treatment, including one minimal residual disease-negative complete response, though all three eventually developed recurrent disease between 3 and 26 months after initial treatment.

Conclusions: This report summarizes preclinical and clinical activity of CD19-directed CAR T therapy in WM, demonstrating early tolerability and efficacy in patients with WM, and representing a possible treatment option in patients with heavily pretreated and relapsed or refractory WM. Larger studies evaluating CAR T therapy in WM are warranted, along with further evaluation into mechanisms of resistance to CAR T therapy.

Keywords: cell engineering; chimeric antigen; hematologic neoplasms; receptors; t-lymphocytes; translational medical research.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Antigens, CD19 / immunology*
  • Cell- and Tissue-Based Therapy / methods*
  • Female
  • Humans
  • Male
  • Mice
  • Middle Aged
  • Receptors, Chimeric Antigen / therapeutic use*
  • Translational Research, Biomedical / methods*
  • Waldenstrom Macroglobulinemia / drug therapy*
  • Waldenstrom Macroglobulinemia / pathology


  • Antigens, CD19
  • Receptors, Chimeric Antigen