Entinostat Plus Clofarabine Demonstrates Promising Safety, Efficacy for Philadelphia Chromosome-Negative ALL

The histone deacetylase inhibitor entinostat plus clofarabine is active and tolerable in older, newly-diagnosed patients with Philadelphia chromosome-negative acute lymphoblastic leukemia (ALL) and acute biphenotypic leukemia (ABL).

“The benzamide derivative entinostat inhibits histone deacetylase and induces histone hyperacetylation. The purine nucleoside analogue clofarabine is FDA-approved for (relapsed/refractory) R/R ALL in children 1−21 years of age. Low doses of clofarabine have been reported to induce DNA hypomethylation,” wrote lead author Hetty Carraway, MD, Cleveland Clinic, and colleagues.

In the phase 1 study, 28 patients with leukemia were treated with entinostat.

The first arm included newly diagnosed patients aged 60 and older, as well as those 21 and younger with R/R disease. Patients were treated every 3 weeks at 3 entinostat dose levels (4 mg, 6 mg or 8 mg orally days 1 and 8) and also received clofarabine (10 mg/m2/day IV for 5 days, days 3–7).

The second arm consisted of adults between 40 and 59 years old with newly diagnosed ALL/ABL, as well as those aged 21 and younger in their first relapse. Patients received entinostat and clofarabine prior to traditional chemotherapy on day 11.

The OR rate was 32%, but 50% for newly diagnosed patients. Two patients died (1 from sepsis, 1 from intracranial bleed), but there were no severe hyperglycemia or peripheral neuropathy cases.

Changes in DNA damage, global protein lysine acetylation, myeloid-derived suppressor cells and monocytes were measured before and during therapy.

“Entinostat increased global protein acetylation and inhibited immunosuppressive monocyte subpopulations, while clofarabine induced DNA damage in all cell subsets examined. Entinostat plus clofarabine appears to be tolerable and active in older adults with ND ALL/ABL, but less active in R/R patients,” the authors wrote.

Source:

Carraway H, Sawalha Y, Gojo I, et al. Phase 1 study of the histone deacetylase inhibitor entinostat plus clofarabine for poor-risk Philadelphia chromosome-negative (newly diagnosed older adults or adults with relapsed refractory disease) acute lymphoblastic leukemia or biphenotypic leukemia. Leuk Res. Published online September 10, 2021. doi:10.1016/j.leukres.2021.106707