TY - JOUR
T1 - Immunomodulation with pomalidomide at early lymphocyte recovery after induction chemotherapy in newly diagnosed AML and high-risk MDS
AU - Zeidner, Joshua F.
AU - Knaus, Hanna A.
AU - Zeidan, Amer M.
AU - Blackford, Amanda L.
AU - Montiel-Esparza, Raul
AU - Hackl, Hubert
AU - Prince, Gabrielle T.
AU - Gondek, Lukasz P.
AU - Ghiaur, Gabriel
AU - Showel, Margaret M.
AU - DeZern, Amy E.
AU - Pratz, Keith
AU - Douglas Smith, B.
AU - Levis, Mark J.
AU - Gore, Steven
AU - Coombs, Catherine C.
AU - Foster, Matthew C.
AU - Streicher, Howard
AU - Karp, Judith E.
AU - Luznik, Leo
AU - Gojo, Ivana
N1 - Funding Information:
Acknowledgements This data was presented at the annual American Society of Hematology conference in 2015 in Orlando, FL (poster), 2016 in San Diego, CA (poster), and 2018 in San Diego, CA (oral presentation). This study was supported in part by research funding from UM1-CA186691 and P30 CA006973 (Johns Hopkins), 5-UM1-CA186704 (University of North Carolina), and P30CA016359/5-UM1-CA186689-5 (Yale). JFZ was supported and funded by Leukemia and Lymphoma Society Special Fellow in Clinical Research Award. HAK was supported by ASBMT New Investigator Award/ Gabrielle’s Angel Foundation and by the Vienna Fund for Innovative Cancer Research. AMZ is a Leukemia and Lymphoma Society Scholar in Clinical Research and is also supported by a NCI’s Cancer Clinical Investigator Team Leadership Award (CCITLA). The authors would like to thank the research support staff at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, University of North Carolina, Lineberger Comprehensive Cancer Center, and Yale Cancer Center. We would also like to thank all of the patients and their families who trusted us for their care. Without these partnerships, this trial could not have been performed.
Funding Information:
Funding This study was supported in part by research funding from UM1-CA186691 and P30 CA006973 (Johns Hopkins), 5-UM1-CA186704 (University of North Carolina), and P30CA016359/5-UM1-CA186689-5 (Yale). JFZ was supported and funded by Leukemia and Lymphoma Society Special Fellow in Clinical Research Award. HAK was supported by ASBMT New Investigator Award/ Gabrielle’s Angel Foundation and by the Vienna Fund for Innovative Cancer Research. AMZ is a Leukemia and Lymphoma Society Scholar in Clinical Research and is also supported by a NCI’s Cancer Clinical Leadership Award (CCITLA).
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2020/6/1
Y1 - 2020/6/1
N2 - An immunosuppressive microenvironment promoting leukemia cell immune escape plays an important role in the pathogenesis of AML. Through its interaction with cereblon, a substrate receptor for the E3 ubiquitin ligase complex, pomalidomide leads to selective ubiquitination of transcription factors Aiolos and Ikaros thereby promoting immune modulation. In this phase I trial, 51 newly diagnosed non-favorable risk AML and high-risk MDS patients were enrolled and treated with AcDVP16 (cytarabine 667 mg/m2/day IV continuous infusion days 1–3, daunorubicin 45 mg/m2 IV days 1–3, etoposide 400 mg/m2 IV days 8–10) induction therapy followed by dose- and duration-escalation pomalidomide beginning at early lymphocyte recovery. Forty-three patients (AML: n = 39, MDS: n = 4) received pomalidomide. The maximum tolerated dose of pomalidomide was 4 mg for 21 consecutive days. The overall complete remission (CR + CRi) rate, median overall survival, and disease-free survival were 75%, 27.1 and 20.6 months, respectively. Subset analyses revealed 86% CR/CRi rate in AML patients with unfavorable-risk karyotype treated with pomalidomide. Pomalidomide significantly decreased Aiolos expression in both CD4+ and CD8+ peripheral blood and bone marrow T cells, promoted T cell differentiation, proliferation, and heightened their cytokine production. Finally, pomalidomide induced distinct gene expression changes in immune function-related ontologies in CD4+ and CD8+ T cells.
AB - An immunosuppressive microenvironment promoting leukemia cell immune escape plays an important role in the pathogenesis of AML. Through its interaction with cereblon, a substrate receptor for the E3 ubiquitin ligase complex, pomalidomide leads to selective ubiquitination of transcription factors Aiolos and Ikaros thereby promoting immune modulation. In this phase I trial, 51 newly diagnosed non-favorable risk AML and high-risk MDS patients were enrolled and treated with AcDVP16 (cytarabine 667 mg/m2/day IV continuous infusion days 1–3, daunorubicin 45 mg/m2 IV days 1–3, etoposide 400 mg/m2 IV days 8–10) induction therapy followed by dose- and duration-escalation pomalidomide beginning at early lymphocyte recovery. Forty-three patients (AML: n = 39, MDS: n = 4) received pomalidomide. The maximum tolerated dose of pomalidomide was 4 mg for 21 consecutive days. The overall complete remission (CR + CRi) rate, median overall survival, and disease-free survival were 75%, 27.1 and 20.6 months, respectively. Subset analyses revealed 86% CR/CRi rate in AML patients with unfavorable-risk karyotype treated with pomalidomide. Pomalidomide significantly decreased Aiolos expression in both CD4+ and CD8+ peripheral blood and bone marrow T cells, promoted T cell differentiation, proliferation, and heightened their cytokine production. Finally, pomalidomide induced distinct gene expression changes in immune function-related ontologies in CD4+ and CD8+ T cells.
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UR - http://www.scopus.com/inward/citedby.url?scp=85077463057&partnerID=8YFLogxK
U2 - 10.1038/s41375-019-0693-4
DO - 10.1038/s41375-019-0693-4
M3 - Article
C2 - 31900407
AN - SCOPUS:85077463057
VL - 34
SP - 1563
EP - 1576
JO - Leukemia
JF - Leukemia
SN - 0887-6924
IS - 6
ER -