A proof of concept phase I/II pilot trial of LSD1 inhibition by tranylcypromine combined with ATRA in refractory/relapsed AML patients not eligible for intensive therapy.

Adult Aged Antidepressive Agents / therapeutic use Antineoplastic Agents / therapeutic use Arabidopsis Proteins DNA-Binding Proteins Drug Resistance, Neoplasm / drug effects Drug Therapy, Combination Female Follow-Up Studies Humans Leukemia, Myeloid, Acute / drug therapy Male Middle Aged Neoplasm Recurrence, Local / drug therapy Prognosis Proof of Concept Study Prospective Studies Salvage Therapy Survival Rate Transcription Factors Tranylcypromine / therapeutic use Tretinoin / therapeutic use Young Adult

Journal

Leukemia

ISSN: 1476-5551

Titre abrégé: Leukemia

Pays: England

ID NLM: 8704895

Informations de publication

Date de publication:
03 2021

Historique:

received: 29 08 2019

accepted: 26 05 2020

revised: 16 04 2020

pubmed: 21 6 2020

medline: 23 3 2021

entrez: 21 6 2020

Statut: ppublish

Résumé

All-trans-retinoic acid (ATRA) is highly active in acute promyelocytic leukemia but not in other types of acute myeloid leukemia (AML). Previously, we showed that ATRA in combination with Lysine-specific demethylase 1 (LSD1) inhibition by tranylcypromine (TCP) can induce myeloid differentiation in AML blasts. This phase I/II clinical trial investigated the safety and efficacy of TCP/ATRA treatment as salvage therapy for relapsed/refractory (r/r) AML. The combination was evaluated in 18 patients, ineligible for intensive treatment. The overall response rate was 20%, including two complete remissions without hematological recovery and one partial response. We also observed myeloid differentiation upon TCP/ATRA treatment in patients who did not reach clinical remission. Median overall survival (OS) was 3.3 months, and one-year OS 22%. One patient developed an ATRA-induced differentiation syndrome. The most frequently reported adverse events were vertigo and hypotension. TCP plasma levels correlated with intracellular TCP concentration. Increased H3K4me1 and H3k4me2 levels were observed in AML blasts and white blood cells from some TCP/ATRA treated patients. Combined TCP/ATRA treatment can induce differentiation of AML blasts and lead to clinical response in heavily pretreated patients with r/r AML with acceptable toxicity. These findings emphasize the potential of LSD1 inhibition combined with ATRA for AML treatment.

Identifiants

DOI: 10.1038/s41375-020-0892-z PMID: 32561840 PMC: PMC7303943

pubmed: 32561840

doi: 10.1038/s41375-020-0892-z

pii: 10.1038/s41375-020-0892-z

pmc: PMC7303943

doi:

Substances chimiques

Antidepressive Agents 0

Antineoplastic Agents 0

Arabidopsis Proteins 0

DNA-Binding Proteins 0

LSD1 protein, Arabidopsis 0

Transcription Factors 0

Tranylcypromine 3E3V44J4Z9

Tretinoin 5688UTC01R

Types de publication

Clinical Trial, Phase I Clinical Trial, Phase II Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

701-711

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