Superior Outcome in Elderly AML Patients Receiving Adjuvant Serotonin-Reuptake-Inhibitors during Induction
Authors: Talukder Rafee , Mims Martha P. , Rivero Gustavo A. 
Published: November 2019

Background: Acute myelogenous leukemia [AML] in elderly patients has a poor prognosis. Age is a unique adverse predictor. However, the higher incidence of complex karyotype, secondary AML, and other unfavorable European-Leukemia-Network -2017 [ELN-2017] features are common. Induction failure is frequent and associated with chemotherapy resistance. These factors highlight an urgent need for "novel" therapy development. In recent years, in vitro, anti-tumor activity of Selective Serotonin Reuptake Inhibitors [SSRIs], such as Sertraline, have been demonstrated. Increased apoptosis, autophagy activation, and favorable modulation of P-glycoprotein and multidrug-resistance-associated-proteins are proposed mechanisms of anti-tumor effect. In this study, our primary aim was to detect "early [day 14] blast reduction" among patients [pt] receiving adjuvant SSRIs in combination with induction therapy as compared to patients who do not receive SSRIs. Additionally, we evaluated overall survival [OS] and relapse free survival [RFS] patients with and without exposure to SSRIs. Methods: With prior IRB approval, 176 pt diagnosed with AML from 1995 to 2017 at Baylor College of Medicine institutions [Michael E. DeBakey VA Medical Center and Baylor St. Luke's Medical Center] were analyzed. We identified older (age&gt;65) pts who received or did not receive SSRI for at least 6 months prior to induction therapy. "Early blast reduction" was evaluated by bone marrow (BM) exam on day 14. OS and RFS were evaluated by the Kaplan Meier method using PRISM 5. Independent variables with potential effect on OS and RFS [Mann-Whitney P=&lt;0.05] were incorporated into a Cox proportional regression model to estimate the independent predictive SSRI exposure's effect on both time to event variables. Statistical analysis was performed with SAS software, NC, USA and GraphPad Prism 5. Results: Among our AML cohort, 93/177 (52.8%) AML pt were older than 65 y. Median age was 72.1 y (67-82). 78/93 (83.8 %) pts had available data for response, survival and relapse evaluation after induction therapy. 12/78 pt (15.4%) and 66/78 pt (84.6%) received or not received SSRIs, respectively. Baseline characteristics were balanced among AML pt exposed or not to SSRI and are depicted in table 1. Post-induction, day 14 residual blast among those SSRI pos vs SSRI neg was 1.17% vs 19.9%, p=0.005. Median OS and RFS among AML pt older than 65 y exposed or not exposed to SSRIs were 368 d vs 90 d, p=0.005 [HR=2.2; 95% CI 1.2-3.9] and 515 d vs 83 d, p=0.01 [HR= 1.2;95% CI 1.4-29.09] [Fig.1Aand B]. A cox multivariate model adjusting for potential confounders that included ELN-2017 classification, absolute monocyte count at diagnosis, body mass index demonstrated that SSRI therapy [p=0.007, HR=0.78; 95% CI 0.65- 0.93] and ELN-2017 classification [p=0.005, HR= 1.16; 95% CI 1.04-1.29] were the only independent predictors for survival. A similar analysis was performed to evaluate the independent effect of SSRI exposure on RFS after adjusting for potential bias. This showed that SSRI therapy [p= 0.02, HR=0.72; 95% CI 0.55-0.95] and ELN-2017 [p=0.03, HR=1.18; 95% CI 1.01-1.38] retained prediction for relapse risk. Conclusions: Our study demonstrates improved OS and RFS among AML pt older than 65 y who were exposed to SSRIs. This is the first demonstration of the activity of SSRI in AML. At day 14, a lower number of blasts in pt exposed to SSRIs suggests that these drugs facilitate blast eradication when combined with induction therapy. We observed a 22% lower risk of death and 28% lower probability of relapse among AML pt &gt;65 y receiving induction who were exposed to SSRI. Our preliminary data supports the feasibility of combining adjuvant SSRIs with induction therapy for the treatment of elderly AML pt.

Disclosures
No relevant conflicts of interest to declare.