Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Case Reports
. 2016 May 19;127(20):2406-10.
doi: 10.1182/blood-2015-08-665547. Epub 2016 Feb 23.

Acquisition of a CD19-negative Myeloid Phenotype Allows Immune Escape of MLL-rearranged B-ALL From CD19 CAR-T-cell Therapy

Affiliations
Free PMC article
Case Reports

Acquisition of a CD19-negative Myeloid Phenotype Allows Immune Escape of MLL-rearranged B-ALL From CD19 CAR-T-cell Therapy

Rebecca Gardner et al. Blood. .
Free PMC article

Abstract

Administration of lymphodepletion chemotherapy followed by CD19-specific chimeric antigen receptor (CAR)-modified T cells is a remarkably effective approach to treating patients with relapsed and refractory CD19(+) B-cell malignancies. We treated 7 patients with B-cell acute lymphoblastic leukemia (B-ALL) harboring rearrangement of the mixed lineage leukemia (MLL) gene with CD19 CAR-T cells. All patients achieved complete remission (CR) in the bone marrow by flow cytometry after CD19 CAR-T-cell therapy; however, within 1 month of CAR-T-cell infusion, 2 of the patients developed acute myeloid leukemia (AML) that was clonally related to their B-ALL, a novel mechanism of CD19-negative immune escape. These reports have implications for the management of patients with relapsed and refractory MLL-B-ALL who receive CD19 CAR-T-cell therapy.

Trial registration: ClinicalTrials.gov NCT02028455.

Figures

Figure 1
Figure 1
Emergence of CD19myeloid phenotype blasts after effective CD19 CAR-T-cell therapy for CD19+ MLL-rearranged B-ALL. (A-E) Data from the patient in case 1. (F-H) Data from the patient in case 2. (A) The percentage of CD19-specific CAR-T cells in CD3+ T cells (open circles) and the absolute CAR-T-cell count (squares) in blood on the indicated days after CAR-T cell infusion are shown for patient 1. CAR-T cells were identified as viable CD45+/CD3+/epidermal growth factor receptor-positive events in a lymphoid forward scatter/side scatter gate by flow cytometry, and the absolute count was determined by multiplying the absolute lymphocyte count by the percentage of CAR-T cells in a lymphoid gate. (B) Flow cytometry of peripheral blood demonstrating CD19+ lymphoblasts (red) before CAR-T-cell therapy. The blasts expressed a low level of CD33 and were largely CD64, CD14, and CD4 (not shown). Flow plots are gated on mononuclear cells. (C) The abnormal blasts (*) before CAR-T-cell therapy were morphologically distinct from the abnormal blasts after CAR-T-cell therapy. (D) Flow cytometry of peripheral blood obtained on day 35 after CAR-T-cell infusion showing abnormal blasts (orange) without expression of CD19, CD20, CD22, CD24, or cytoplasmic CD79a (not shown). The abnormal blasts were CD33hi, CD64+, and CD4+ (not shown), and CD14 and CD34 (not shown), consistent with AML with monocytic differentiation. (E) CGAT identified multiple genomic aberrations in the monoblasts isolated after CAR-T-cell infusion, which were not present in the CD19+ lymphoblasts isolated before CAR-T-cell infusion. (F) The percentage of CD19-specific CAR-T cells in CD3+ T cells (open circles) and the absolute CAR-T-cell count (squares) in blood on the indicated days after CAR-T-cell infusion are shown for patient 2. (G) All plots show mononuclear cells. Flow cytometry of bone marrow before CAR-T-cell therapy demonstrating CD19+ abnormal lymphoblasts (red). At diagnosis, the patient’s abnormal blasts also expressed CD34, CD22 (not shown) without CD4, CD10 (not shown), CD13, significant CD33, CD56, CD64, or CD117. (H) Flow cytometry of bone marrow on day 30 after CAR-T-cell infusion, showing no abnormal CD19+ blasts or normal B-cell precursors, but abnormal myeloblasts (orange) that express CD34 with CD4, CD13, bright CD33, CD64 (intermediate), and CD117 (subset), with aberrant expression of CD56 on a major subset.

Comment in

Similar articles

See all similar articles

Cited by 120 articles

See all "Cited by" articles

Publication types

MeSH terms

Substances

Associated data

LinkOut - more resources

Feedback