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

Leuk Res. 2016 Oct:49:90-7. doi: 10.1016/j.leukres.2016.09.003. Epub 2016 Sep 3.

Abstract

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) 125μg/m(2)/day plus 1) bexarotene (BEX) 300mg/m(2)/day or 2) entinostat (ENT) 4-8mg/m(2)/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/mm(3), p=0.096; ENT: 578 to 1 137 cells/mm(3), 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.

Keywords: Acute myeloid leukemia; Bexarotene; Differentiation; Entinostat; Myelodysplastic syndrome.

Publication types

  • Clinical Trial, Phase II

MeSH terms

  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / therapeutic use*
  • Benzamides / administration & dosage
  • Benzamides / adverse effects
  • Bexarotene
  • Female
  • Granulocyte-Macrophage Colony-Stimulating Factor / administration & dosage
  • Granulocyte-Macrophage Colony-Stimulating Factor / adverse effects
  • HL-60 Cells
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy*
  • Male
  • Middle Aged
  • Myelodysplastic Syndromes / drug therapy*
  • Neutrophils / cytology
  • Pyridines / administration & dosage
  • Pyridines / adverse effects
  • Recombinant Proteins / administration & dosage
  • Recombinant Proteins / adverse effects
  • Remission Induction
  • Salvage Therapy / methods*
  • Tetrahydronaphthalenes / administration & dosage
  • Tetrahydronaphthalenes / adverse effects
  • Treatment Outcome
  • U937 Cells

Substances

  • Antineoplastic Agents
  • Benzamides
  • Pyridines
  • Recombinant Proteins
  • Tetrahydronaphthalenes
  • entinostat
  • sargramostim
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Bexarotene