Abstract: Among the various aspects of the present disclosure is the provision of methods of detecting and treating immunotherapy-resistant B cell malignancies. Methods of detection include detecting a glycosylation state of CD19 or detecting expression or activity of SPPL3 in malignant B cells, comparing to a reference state or value, and determining that the B cell malignancy is resistant to immunotherapy if the glycosylation state of CD19 or expression or activity of SPPL3 is substantially increased or decreased relative to corresponding reference levels. Also provided are therapeutic agents capable of modulating CD19 glycosylation or SPPL3 expression or activity for treatment of B cell malignancies in combination with CD19-targeted immunotherapies.