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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.
- Source :
-
Leukemia research [Leuk Res] 2021 Nov; Vol. 110, pp. 106707. Date of Electronic Publication: 2021 Sep 10. - Publication Year :
- 2021
-
Abstract
- Purpose: Despite advances in immunotherapies, the prognosis for adults with Philadelphia chromosome-negative, newly diagnosed (ND) or relapsed/refractory (R/R) acute lymphoblastic leukemia/acute biphenotypic leukemia (ALL/ABL) remains poor. The benzamide derivative entinostat inhibits histone deacetylase and induces histone hyperacetylation. The purine nucleoside analogue clofarabine is FDA-approved for R/R ALL in children 1-21 years of age. Low doses of clofarabine have been reported to induce DNA hypomethylation. We conducted a phase 1 study of low dose clofarabine with escalating doses of entinostat in adults with ND or R/R ALL/ABL.<br />Experimental Design: Adults ≥60 years with ND ALL/ABL or ≥21 years with R/R ALL/ABL received repeated cycles every 3 weeks of entinostat (4 mg, 6 mg or 8 mg orally days 1 and 8) and clofarabine (10 mg/m <superscript>2</superscript> /day IV for 5 days, days 3-7) (Arm A). Adults aged 40-59 years with ND ALL/ABL or age ≥21 years in first relapse received entinostat and clofarabine prior to traditional chemotherapy on day 11 (Arm B). Changes in DNA damage, global protein lysine acetylation, myeloid-derived suppressor cells and monocytes were measured in PBMCs before and during therapy.<br />Results: Twenty-eight patients were treated at three entinostat dose levels with the maximum administered dose being entinostat 8 mg. The regimen was well tolerated with infectious and metabolic derangements more common in the older population versus the younger cohort. There was no severe hyperglycemia and no peripheral neuropathy in this small study. There were 2 deaths (1 sepsis, 1 intracranial bleed). Overall response rate was 32 %; it was 50 % for ND ALL/ABL. Entinostat increased global protein acetylation and inhibited immunosuppressive monocyte subpopulations, while clofarabine induced DNA damage in all cell subsets examined.<br />Conclusion: Entinostat plus clofarabine appears to be tolerable and active in older adults with ND ALL/ABL, but less active in R/R patients. Further evaluation of this regimen in ND ALL/ABL appears warranted.<br /> (Copyright © 2021. Published by Elsevier Ltd.)
- Subjects :
- Adult
Aged
Benzamides administration & dosage
Clofarabine administration & dosage
Female
Follow-Up Studies
Histone Deacetylase Inhibitors therapeutic use
Humans
Male
Maximum Tolerated Dose
Middle Aged
Neoplasm Recurrence, Local pathology
Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology
Prognosis
Pyridines administration & dosage
Salvage Therapy
Young Adult
Antineoplastic Combined Chemotherapy Protocols therapeutic use
Cell Lineage
Drug Resistance, Neoplasm
Neoplasm Recurrence, Local drug therapy
Philadelphia Chromosome
Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1873-5835
- Volume :
- 110
- Database :
- MEDLINE
- Journal :
- Leukemia research
- Publication Type :
- Academic Journal
- Accession number :
- 34563945
- Full Text :
- https://doi.org/10.1016/j.leukres.2021.106707