Differentiation therapy in poor risk myeloid malignancies: Results of companion phase II studies

Kelly J. Norsworthy, Eunpi Cho, Jyoti Arora, Jeanne Kowalski, Hua Ling Tsai, Erica Warlick, Margaret Showel, Keith W. Pratz, Lesley A. Sutherland, Steven D. Gore, Anna Ferguson, Sarah Sakoian, Jackie Greer, Igor Espinoza-Delgado, Richard J. Jones, William H. Matsui, B. Douglas Smith

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Pre-clinical data in non-M3 AML supports the use of differentiation therapy, but clinical activity has been limited. Myeloid growth factors can enhance anti-leukemic activity of differentiating agents in vitro. We conducted companion phase II trials investigating sargramostim (GM-CSF) 125 μg/m2/day plus 1) bexarotene (BEX) 300 mg/m2/day or 2) entinostat (ENT) 4–8 mg/m2/week in patients with MDS or relapsed/refractory AML. Primary endpoints were response after at least two treatment cycles and toxicity. 26 patients enrolled on the BEX trial had a median of 2 prior treatments and 24 enrolled on the ENT trial had a median of 1. Of 13 response-evaluable patients treated with BEX, the best response noted was hematologic improvement in neutrophils (HI-N) seen in 4 (31%) patients; none achieved complete (CR) or partial remission (PR). Of 10 treated with ENT, there was 1 (10%) partial remission (PR) and 2 (20%) with HI-N. The secondary endpoint responses of HI-N with each combination were accompanied by a numerical increase in ANC (BEX: 524 to 931 cells/mm3, p = 0.096; ENT: 578 to 1 137 cells/mm3, p = 0.15) without increasing marrow blasts. Shared grade 3–4 non-hematologic toxicities included febrile neutropenia, bone pain, fatigue, and dyspnea. GM-CSF plus either BEX or ENT are well tolerated in resistant and refractory MDS and AML and showed modest clinical and biologic activity, most commonly HI-N.

Original languageEnglish (US)
Pages (from-to)90-97
Number of pages8
JournalLeukemia research
StatePublished - Oct 1 2016


  • Acute myeloid leukemia
  • Bexarotene
  • Differentiation
  • Entinostat
  • Myelodysplastic syndrome

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    Norsworthy, K. J., Cho, E., Arora, J., Kowalski, J., Tsai, H. L., Warlick, E., Showel, M., Pratz, K. W., Sutherland, L. A., Gore, S. D., Ferguson, A., Sakoian, S., Greer, J., Espinoza-Delgado, I., Jones, R. J., Matsui, W. H., & Smith, B. D. (2016). Differentiation therapy in poor risk myeloid malignancies: Results of companion phase II studies. Leukemia research, 49, 90-97. https://doi.org/10.1016/j.leukres.2016.09.003