Tumor-intrinsic and -extrinsic determinants of response to blinatumomab in adults with B-ALL

Blood. 2021 Jan 28;137(4):471-484. doi: 10.1182/blood.2020006287.


Blinatumomab, a bispecific antibody that directs CD3+ T cells to CD19+ tumor cells, shows variable efficacy in B-progenitor acute lymphoblastic leukemia (B-ALL). To determine tumor-intrinsic and -extrinsic determinants of response, we studied 44 adults with relapsed or refractory B-ALL (including 2 minimal residual disease positive) treated with blinatumomab using bulk tumor and single-cell sequencing. The overall response rate in patients with hematological disease was 55%, with a high response rate in those with CRLF2-rearranged Philadelphia chromosome-like ALL (12 [75%] of 16). Pretreatment samples of responders exhibited a tumor-intrinsic transcriptomic signature of heightened immune response. Multiple mechanisms resulted in loss of CD19 expression, including CD19 mutations, CD19-mutant allele-specific expression, low CD19 RNA expression, and mutations in CD19 signaling complex member CD81. Patients with low hypodiploid ALL were prone to CD19- relapse resulting from aneuploidy-mediated loss of the nonmutated CD19 allele. Increased expression of a CD19 isoform with intraexonic splicing of exon 2, CD19 ex2part, at baseline or during therapy was associated with treatment failure. These analyses demonstrate both tumor-intrinsic and -extrinsic factors influence blinatumomab response. We show that CD19 mutations are commonly detected in CD19- relapse during blinatumomab treatment. Identification of the CD19 ex2part splice variant represents a new biomarker predictive of blinatumomab therapy failure.

Publication types

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

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Amino Acid Sequence
  • Aneuploidy
  • Antibodies, Bispecific / immunology
  • Antibodies, Bispecific / pharmacology
  • Antibodies, Bispecific / therapeutic use*
  • Antigens, CD19 / biosynthesis
  • Antigens, CD19 / genetics*
  • Antigens, CD19 / immunology
  • Antigens, Neoplasm / biosynthesis
  • Antigens, Neoplasm / genetics*
  • Antigens, Neoplasm / immunology
  • Antineoplastic Agents, Immunological / immunology
  • Antineoplastic Agents, Immunological / pharmacology
  • Antineoplastic Agents, Immunological / therapeutic use*
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / immunology
  • Cytotoxicity, Immunologic / drug effects
  • Drug Resistance, Neoplasm / physiology
  • Female
  • Gene Expression Profiling
  • Humans
  • Male
  • Middle Aged
  • Mutation
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / genetics
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / genetics
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • RNA, Neoplasm / biosynthesis
  • RNA, Neoplasm / genetics
  • Recurrence
  • Retrospective Studies
  • Salvage Therapy*
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Single-Cell Analysis
  • T-Lymphocyte Subsets / drug effects*
  • T-Lymphocyte Subsets / immunology
  • Young Adult


  • Antibodies, Bispecific
  • Antigens, CD19
  • Antigens, Neoplasm
  • Antineoplastic Agents, Immunological
  • CD19 molecule, human
  • Protein Isoforms
  • RNA, Messenger
  • RNA, Neoplasm
  • blinatumomab