Immunomodulation with pomalidomide at early lymphocyte recovery after induction chemotherapy in newly diagnosed AML and high-risk MDS

Joshua F. Zeidner, Hanna A. Knaus, Amer M. Zeidan, Amanda L. Blackford, Raul Montiel-Esparza, Hubert Hackl, Gabrielle T. Prince, Lukasz P. Gondek, Gabriel Ghiaur, Margaret M. Showel, Amy E. DeZern, Keith W. Pratz, B. Douglas Smith, Mark J. Levis, Steven Gore, Catherine C. Coombs, Matthew C. Foster, Howard Streicher, Judith E. Karp, Leo LuznikIvana Gojo

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1563-1576
Number of pages14
JournalLeukemia
Volume34
Issue number6
DOIs
StatePublished - Jun 1 2020

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Immunomodulation with pomalidomide at early lymphocyte recovery after induction chemotherapy in newly diagnosed AML and high-risk MDS'. Together they form a unique fingerprint.

Cite this