Page 121 - 2019_04-Haematologica-web
P. 121
Acute Lymphoblastic Leukemia
CD123 expression patterns and selective targeting with a CD123-targeted antibody-drug conjugate (IMGN632)
in acute lymphoblastic leukemia
Ferrata Storti Foundation
Haematologica 2019 Volume 104(4):749-755
Evgeniya Angelova,1 Charlene Audette2, Yelena Kovtun,2 Naval Daver,3 Sa A. Wang,1 Sherry Pierce,3 Sergej N. Konoplev,1 Haitham Khogeer,1 Jeffrey L. Jorgensen,1 Marina Konopleva,3 Patrick A. Zweidler-McKay,2 L. Jeffrey Medeiros,1 Hagop M. Kantarjian,3 Elias J. Jabbour3 and Joseph D. Khoury1
1Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX; 2ImmunoGen, Inc., Waltham, MA and 3Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
ABSTRACT
The potential of CD123-targeted therapies in acute lymphoblastic leukemia/lymphoma remains largely unexplored. We examined CD123 expression levels in a large cohort of patients with acute lymphoblastic leukemia/lymphoma and assessed the in vitro impact of IMGN632, a conjugate of CD123-binding antibody with a novel DNA- alkylating payload. CD123 expression on leukemic blasts was sur- veyed using multicolor/multiparameter flow cytometry. The in vitro effect of IMGN632 was evaluated on B acute lymphoblastic leukemia/lymphoma cell lines and primary B acute lymphoblastic leukemia/lymphoma blasts. The study cohort (n=213) included 183 patients with B acute lymphoblastic leukemia/lymphoma and 30 with T acute lymphoblastic leukemia/lymphoma. CD123 expression was more prevalent in B acute lymphoblastic leukemia/lymphoma than in T acute lymphoblastic leukemia/lymphoma (164/183, 89.6% versus 13/30, 43.3%; P<0.0001), and within B acute lymphoblastic leukemia/lymphoma CD123 expression was more prevalent in Philadelphia chromosome-positive patients than in Philadelphia chro- mosome-negative patients (96.6% versus 86.3%; P=0.033). In T acute lymphoblastic leukemia/lymphoma, 12/13 (92.3%) patients with CD123-positive blasts had either early T precursor (ETP) or early non- ETP immunophenotype. IMGN632 was highly cytotoxic to B acute lymphoblastic leukemia/lymphoma cell lines, with half maximal inhibitory concentrations (IC50) between 0.6 and 20 pM. In five of eight patients’ samples, low pico-molar concentrations of IMGN632 elimi- nated more than 90% of the B acute lymphoblastic leukemia/lym- phoma blast population, sparing normal lymphocytes. In conclusion, CD123 expression is prevalent across acute lymphoblastic leukemia/lymphoma subtypes, and the CD123-targeted antibody-drug conjugate IMGN632 demonstrates promising selective activity in pre- clinical models of B acute lymphoblastic leukemia/lymphoma.
Introduction
Acute lymphoblastic leukemia (ALL) is an aggressive hematologic neoplasm arising from immature lymphoid precursors. In adults, 75% of ALL cases devel- op from B-cell precursors (B-ALL) and the remainder from T-cell precursors (T- ALL). B-ALL has been long known for its genetic heterogeneity and includes a subset of cases that harbors the BCR-ABL1 fusion located on the derivative chro- mosome 22 (Philadelphia chromosome) resulting from t(9;22)(q34.1;q11.2). Philadelphia chromosome (Ph)-positive (Ph+) B-ALL patients and patients with
Correspondence:
JOSEPH D. KHOURY
jkhoury@mdanderson.org
Received: August 23, 2018. Accepted: October 22, 2018. Pre-published: October 25, 2018.
doi:10.3324/haematol.2018.205252
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/4/749
©2019 Ferrata Storti Foundation
Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com- mercial purposes is not allowed without permission in writing from the publisher.
haematologica | 2019; 104(4)
749
ARTICLE
