Sensitization of non-M3 acute myeloid leukemia blasts to all-trans retinoic acid by the LSD1 inhibitor tranylcypromine: TRANSATRA phase I study
Elderly, non-fit AML/MDS patients relapsed/refractory (R/R) after HMA-based treatment represent a highly unmet clinical need, necessitating the development of age-appropriate therapies with an acceptable safety profile, e.g. with all-trans retinoic acid (ATRA). As histone demethylase LSD1 (KDM1A) is a rational therapeutic target in AML, we conducted a phase I trial with the LSD1 inhibitor tranylcypromine (TCP, dose levels [DL] 20, 40, 60, 80mg p.o. d1-28) combined with fixed-dose ATRA (45mg/m2 p.o. d10-28) and low-dose cytarabine (LDAC, 40mg s.c. d1-10). The primary endpoint was dose limiting toxicity (DLT) in the first 28 days of treatment. The aim was the determination of the maximum tolerated dose (MTD). Enrollment into DLs was performed using the rolling six design. Twenty-three patients with R/R AML and 2 with relapsed MDS were accrued, with a median age 75 years (range 62-84), after a median of two prior treatment lines (range, 1-5). Three, 6, 6 and 10 patients were allocated to DL 20, 40, 60, and 80 mg TCP, respectively, with 3, 12, 6 , 4 patients achieving the respective dose of 20, 40, 60, and 80 mg, and 3 patients on each DL being fully evaluable for MTD. TCP was administered for a median of 39.5 days (range 11-228), for >60 days in 30% of patients. No dose-limiting toxicities (DLTs) were observed at any DL, MTD could not be established. Most common adverse events > grade 3 occurring in >10% of patients were:  pneumonia (16%) and febrile neutropenia (12%). No differentiation syndrome occurred. Two patients attained a partial remission; stable disease was achieved in 10 of 22 evaluable patients. Median overall survival was 62 days (range 14-325). Accompanying studies included pharmacokinetics, serial determinations of fetal hemoglobin and genes known to be regulated by LSD1 or ATRA, such as CD86, CD38 and GFI1B. Patients' quality of life, anxiety and depression were determined before and after treatment. In conclusion, the combination of TCP with ATRA and LDAC was well feasible, even at the highest DL. Almost half of the patients attained stable disease, indicating limited cross-resistance with prior HMA treatment. Hence, studies with more potent LSD1 inhibitors appear warranted. Overall design: Sampling of peripheral blood was perforemd during the trial to investigate changes in gene expression in peripheral blood blasts. Smapling was performed at screening, d10, d20, d28 (end of cycle one), and at the end of every following cycle as well as at EOT.