Phase I Dose Escalation Study of ATRA Combined with the LSD1 inhibitor Tranylcypromine in AML and MDS
Preclinical studies have shown that combining the LSD1 inhibitor tranylcypromine (TCP) with all-trans retinoic acid (ATRA) induces differentiation and impairs survival in non-APL acute myeloid leukemia (AML). We conducted a Phase 1 clinical trial (NCT02273102) to evaluate the safety and preliminary activity of ATRA in combination with TCP in patients with relapsed/refractory AML and myelodysplasia (MDS). Seventeen patients (11 AML and 6 MDS) received ATRA-TCP therapy with ATRA (45 mg/m2 daily in divided doses) and TCP (3 dose levels: 10 mg twice-daily [BID], 20 mg BID, and 30 mg BID). ATRA-TCP had an acceptable safety profile. The maximum tolerated dose of TCP was 20 mg BID. There were 3 DLTs: dizziness (20 mg BID), asthenia (30 mg BID), and nausea/vomiting (30 mg BID). Best evaluable responses included 1 morphologic leukemia-free state (MLFS), 1 marrow complete remission (CR) with hematologic improvement, 2 stable disease with hematologic improvement, and 2 stable disease. In 13 response-evaluable patients, the overall response rate was 30.8% and clinical benefit rate 46.2%. Gene expression profiling of patient blasts showed that responding patients had a more dormant phenotype compared to non-responders at baseline. In human AML cell lines, we showed that treatment with ATRA-TCP increases differentiation capacity and/or cell death, and that ATRA-TCP regulates the in vitro expression of genes that segregate primary patients by their clinical response. These data indicate that LSD1 inhibition sensitizes AML cells to ATRA-induced differentiation and cell death and may restore clinical responsiveness in subsets of MDS and AML patients. Overall design: Total RNA-seq of purified CD34+ cell isolated from bone marrow of Relapsed/refractory AML and MDS patients before/after treatment with ATRA-TCP (phase-I clinical trial, NCT02273102). Total RNA-seq of  ATRA-treated, TCP-treated, and ATRA-TCP treated or vehicle control in U-937 and SKNO-1 cell lines in duplicates.