Page 52 - Haematologica August 2018

Correspondence:
raj.muthusamy@osumc.edu
Received: January 10, 2018. Accepted: May 15, 2018. Pre-published: May 17, 2018.
doi:10.3324/haematol.2018.188193
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/8/1288
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Myelodysplastic Syndrome
The interleukin-3 receptor CD123 targeted SL-401 mediates potent cytotoxic activity against CD34+CD123+ cells from acute myeloid leukemia/myelodysplastic syndrome patients and healthy donors
Haematologica 2018 Volume 103(8):1288-1297
Rajeswaran Mani,1 Swagata Goswami,1 Bhavani Gopalakrishnan,1 Rahul Ramaswamy,1 Ronni Wasmuth,1 Minh Tran,1 Xiaokui Mo,2 Amber Gordon,1 Donna Bucci,1 David M. Lucas,1,3 Alice Mims,3
4 1,3 Christopher Brooks, Adrienne Dorrance,
1,3 1,3 William Blum,
Alison Walker, John C. Byrd,1,3 Gerard Lozanski,1,5 Sumithira Vasu1,3,*
and Natarajan Muthusamy1,3,*
1Comprehensive Cancer Center, The Ohio State University, Columbus, OH; 2Center for Biostatistics, The Ohio State University, Columbus, OH; 3Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH; 4Stemline Therapeutics, Inc., New York, NY and 5Department of Pathology, College of Medicine, The Ohio State University, Columbus, OH, USA
ABSTRACT
Diseases with clonal hematopoiesis such as myelodysplastic syn- drome and acute myeloid leukemia have high rates of relapse. Only a small subset of acute myeloid leukemia patients are cured with chemotherapy alone. Relapse in these diseases occurs at least in part due to the failure to eradicate leukemic stem cells or hematopoietic stem cells in myelodysplastic syndrome. CD123, the alpha chain of the interleukin-3 receptor heterodimer, is expressed on the majority of leukemic stem cells and myelodysplastic syndrome hematopoietic stem cells and in 80% of acute myeloid leukemia. Here, we report indiscrim- inate killing of CD123+ normal and acute myeloid leukemia / myelodys- plastic syndrome cells by SL-401, a diphtheria toxin interleukin-3 fusion protein. SL-401 induced cytotoxicity of CD123+ primary cells/blasts from acute myeloid leukemia and myelodysplastic syndrome patients but not CD123– lymphoid cells. Importantly, SL-401 was highly active even in cells expressing low levels of CD123, with minimal effect on modulation of the CD123 target in acute myeloid leukemia. SL-401 sig- nificantly prolonged survival of leukemic mice in acute myeloid leukemia patient-derived xenograft mouse models. In addition to pri- mary samples, studies on normal cord blood and healthy marrow show that SL-401 has activity against normal hematopoietic progenitors. These findings indicate potential use of SL-401 as a “bridge-to-trans- plant” before allogeneic hematopoietic cell transplantation in acute myeloid leukemia / myelodysplastic syndrome patients.
Introduction
Acute myeloid leukemia (AML) incidence increases with age, and about 21,000 new cases are expected in 2017.1,2 Significant heterogeneity exists in AML as shown by diversity of karyotype, genetic mutations and epigenetic aberrations. Standard chemotherapies and immunotherapies have only limited efficacy, and most AML patients relapse partly due to failure to eradicate AML leukemic stem cells (LSC) which undergo clonal evolution and serve as a reservoir for relapse.3 Up to 47% of patients older than 60 years who undergo allogeneic transplantation for AML will relapse.4 Myelodysplastic syndrome (MDS) incidence also increases with age with an expected incidence of 15,000 cases annually.5 Upon transformation to AML, MDS patients have a poor prognosis as compared to AML cases that occur de novo.6
*SV and NM contributed equally as senior authors
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