Tumor-intrinsic and -extrinsic determinants of response to blinatumomab in adults with B-ALL. Blood 2021 Jan 28;137(4):471-484
Date
09/04/2020Pubmed ID
32881995Pubmed Central ID
PMC7845009DOI
10.1182/blood.2020006287Scopus ID
2-s2.0-85099973176 (requires institutional sign-in at Scopus site) 84 CitationsAbstract
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.
Author List
Zhao Y, Aldoss I, Qu C, Crawford JC, Gu Z, Allen EK, Zamora AE, Alexander TB, Wang J, Goto H, Imamura T, Akahane K, Marcucci G, Stein AS, Bhatia R, Thomas PG, Forman SJ, Mullighan CG, Roberts KGAuthor
Anthony E. Zamora PhD Assistant Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdolescentAdult
Aged
Amino Acid Sequence
Aneuploidy
Antibodies, Bispecific
Antigens, CD19
Antigens, Neoplasm
Antineoplastic Agents, Immunological
B-Lymphocytes
Cytotoxicity, Immunologic
Drug Resistance, Neoplasm
Female
Gene Expression Profiling
Humans
Male
Middle Aged
Mutation
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
Protein Isoforms
RNA, Messenger
RNA, Neoplasm
Recurrence
Retrospective Studies
Salvage Therapy
Sequence Alignment
Sequence Homology, Amino Acid
Single-Cell Analysis
T-Lymphocyte Subsets
Young Adult
