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| Leukemia. 2020 Jan 3. doi: 10.1038/s41375-019-0693-4. pii: 10.1038/s41375-019-0693-4 |
| Immunomodulation with pomalidomide at early lymphocyte recovery after induction chemotherapy in newly diagnosed AML and high-risk MDS. |
| Zeidner JF1, Knaus HA2, Zeidan AM3, Blackford AL4, Montiel-Esparza R5, Hackl H6, Prince GT7, Gondek LP8, Ghiaur G9, Showel MM10, DeZern AE11, Pratz KW12, Douglas Smith B13, Levis MJ14, Gore S15, Coombs CC16, Foster MC17, Streicher H18, Karp JE19, Luznik L20, Gojo I21 |
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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/m/day IV continuous infusion days 1-3, daunorubicin 45 mg/m IV days 1-3, etoposide 400 mg/m 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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Publikations ID: 31900407 Quelle: öffnen |
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