TY - JOUR
T1 - CAR T-cell therapy is effective for CD19-dim B-lymphoblastic leukemia but is impacted by prior blinatumomab therapy
AU - Pillai, Vinodh
AU - Muralidharan, Kavitha
AU - Meng, Wenzhao
AU - Bagashev, Asen
AU - Oldridge, Derek A.
AU - Rosenthal, Jaclyn
AU - van Arnam, John
AU - Melenhorst, Jos J.
AU - Mohan, Diwakar
AU - DiNofia, Amanda M.
AU - Luo, Minjie
AU - Cherian, Sindhu
AU - Fromm, Jonathan R.
AU - Wertheim, Gerald
AU - Thomas-Tikhonenko, Andrei
AU - Paessler, Michele
AU - June, Carl H.
AU - Luning Prak, Eline T.
AU - Bhoj, Vijay G.
AU - Grupp, Stephan A.
AU - Maude, Shannon L.
AU - Rheingold, Susan R.
N1 - Funding Information:
This work was supported by a Cancer Research Institute Clinic and Laboratory Integration Program Grant (V.P.); a research grant from Alex’s Lemonade Stand Foundation and Love Your Melon (J.R. and K.M.); National Institutes of Health (NIH), National Cancer Institute Grant P30CA016520 (W.M.); a Young Investigator Award from Alex’s Lemonade Stand Foundation (A.B.); NIH,
Funding Information:
The authors thank the Children?s Hospital of Philadelphia (CHOP) flow cytometry laboratory, the CHOP hematology laboratory, the Human Immunology Core facility, the CAR T-cell therapy team, and the Division of Genomic Diagnostics for contributions to the study; Robert Doms and Stephen Hunger for critical reading of the manuscript; and Marybeth Helfrich and Joseph McMann for help with the study. This work was supported by a Cancer Research Institute Clinic and Laboratory Integration Program Grant (V.P.); a research grant from Alex?s Lemonade Stand Foundation and Love Your Melon (J.R. and K.M.); National Institutes of Health (NIH), National Cancer Institute Grant P30CA016520 (W.M.); a Young Investigator Award from Alex?s Lemonade Stand Foundation (A.B.); NIH, National Cancer Institute Grant U01CA232563, Stand Up To Cancer-St. Baldrick?s Pediatric Dream Team Grant SU2C-AACRDT1113, a 2016 research grant from William Lawrence and Blanche Hughes Foundation, and The V Foundation for Cancer Research Grant T2018-014 (A.T.-T.); and the St. Baldrick?s Foundation, the V Foundation, Stand Up To Cancer-St. Baldrick?s Pediatric Dream Team Grant SU2C-AACR-DT1113, and NIH, National Cancer Institute Grant 1P01CA214278-01 (S.L.M.).
Publisher Copyright:
© 2019 by The American Society of Hematology.
PY - 2019
Y1 - 2019
N2 - Tisagenlecleucel, a chimeric antigen receptor (CAR) T-cell product targeting CD19 is approved for relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, the impact of pretreatment variables, such as CD19 expression level, on leukemic blasts, the presence of CD19– subpopulations, and especially prior CD19-targeted therapy, on the response to CAR T-cell therapy has not been determined. We analyzed 166 patients treated with CAR T-cell therapy at our institution. Eleven patients did not achieve a minimal residual disease (MRD)– deep remission, whereas 67 patients had a recurrence after achieving a MRD– deep remission: 28 patients with CD19+ leukemia and 39 patients with CD19–leukemia. Return of CD19+ leukemia was associated with loss of CAR T-cell function, whereas CD19– leukemia was associated with continued CAR T-cell function. There were no significant differences in efficacy of CAR T cells in CD19-dim B-ALL, compared with CD19-normal or -bright B-ALL. Consistent with this, CAR T cells recognized and lysed cells with very low levels of CD19 expression in vitro. The presence of dim CD19 or rare CD19– events by flow cytometry did not predict nonresponse or recurrence after CAR T-cell therapy. However, prior therapy with the CD19-directed, bispecific T-cell engager blinatumomab was associated with a significantly higher rate of failure to achieve MRD–remission or subsequent loss of remission with antigen escape. Finally, immunophenotypic heterogeneity and lineage plasticity were independent of underlying clonotype and cytogenetic abnormalities.
AB - Tisagenlecleucel, a chimeric antigen receptor (CAR) T-cell product targeting CD19 is approved for relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, the impact of pretreatment variables, such as CD19 expression level, on leukemic blasts, the presence of CD19– subpopulations, and especially prior CD19-targeted therapy, on the response to CAR T-cell therapy has not been determined. We analyzed 166 patients treated with CAR T-cell therapy at our institution. Eleven patients did not achieve a minimal residual disease (MRD)– deep remission, whereas 67 patients had a recurrence after achieving a MRD– deep remission: 28 patients with CD19+ leukemia and 39 patients with CD19–leukemia. Return of CD19+ leukemia was associated with loss of CAR T-cell function, whereas CD19– leukemia was associated with continued CAR T-cell function. There were no significant differences in efficacy of CAR T cells in CD19-dim B-ALL, compared with CD19-normal or -bright B-ALL. Consistent with this, CAR T cells recognized and lysed cells with very low levels of CD19 expression in vitro. The presence of dim CD19 or rare CD19– events by flow cytometry did not predict nonresponse or recurrence after CAR T-cell therapy. However, prior therapy with the CD19-directed, bispecific T-cell engager blinatumomab was associated with a significantly higher rate of failure to achieve MRD–remission or subsequent loss of remission with antigen escape. Finally, immunophenotypic heterogeneity and lineage plasticity were independent of underlying clonotype and cytogenetic abnormalities.
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U2 - 10.1182/bloodadvances.2019000692
DO - 10.1182/bloodadvances.2019000692
M3 - Article
C2 - 31738832
AN - SCOPUS:85076344065
SN - 2473-9529
VL - 3
SP - 3539
EP - 3549
JO - Blood Advances
JF - Blood Advances
IS - 22
ER -