Impact of Atorvastatin on Cellular Immunome of Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation (AHSCT)
Authors: Efebera Yvonne A , Geyer Susan , Bingman Anissa , Kitzler Rhonda , Elder Patrick , Andritsos Leslie A. , Jaglowski Samantha M. , Vasu Sumithira , Blum William , Klisovic Rebecca B. , Penza Sam , Coombes Kevin , Hofmeister Craig C , Benson Don , Devine Steven M. , Lozanski Gerard 
Published: October 2019

Abstract
Introduction: Donor T cells have been known to be the most powerful effectors for acute graft-versus-host-disease(aGVHD). The HMG-CoA reductase inhibitors, statins, have been shown to inhibit T-helper 1(Th-1) driven responses, reduce pro-inflammatory cytokines while increasing the migration of anti-inflammatory cytokines T-regs and T-helper-2 cells(Th-2), with a potential to reduce aGVHD. We analyzed the effect of atorvastatin on the immune reconstitution pattern on patients enrolled in a phase II study evaluating the efficacy of atorvastatin as GVHD prophylaxis in patients undergoing HLA-matched-related donor AHSCT in which donors and patients were exposed to atorvastatin. The results of this study were compared to historical matched controls at Ohio State where neither related donor nor patients were exposed to any cholesterol lowering medications. Methods: Forty patients (statin gp) were enrolled (NCT01491958) between March 2012 and January 2014. Atorvastatin at 40mg/day orally was administered to sibling donors, starting 14-28 days before the anticipated 1st day of stem cell collection. In AHSCT recipients, atorvastatin (40mg/day) was administered from day -14 to day +180 (or until stopping immunosuppression, toxicity, development of grade [Gr] II-IV aGVHD, or severe chronic GVHD (cGVHD). In addition all recipients received standard GVHD prophylaxis with tacrolimus and methotrexate. Historic matched controls were 25 patients (and related donors) not on any cholesterol lowering medications (non-statin gp) and had mobilized peripheral blood (PB) allograft samples (day 0) and PB samples on days 30 and 100 post AHSCT collected. We analyzed the absolute numbers of T, NK, NKT, B cells and immunophenotypic characterization of their activation status. Results: Median duration of atorvastatin prophylaxis in statin donors was 14 days (range 13-26) and in statin patients 132 days (32-400). Baseline patient’s characteristics were well matched between the groups with respect to age, sex, donor/recipient sex, intensity of regimen, disease and disease status at transplant and number of stem cells infused. The clinical results of this study are presented in a separate abstract in which we found no statistically significant difference in clinical outcomes including aGVHD and cGVHD between the two gps. While there were no differences in the B and total T cells reconstitution in all time points, the statin gp allografts contained less NK and T-regulatory cells (T-regs) than the non-statin gp (Table 1). This reduction of the NK and T-regs, appeared to affect the reconstitution of these subsets post-transplant as reflected by their continued decrease on days 30 and 100 post-transplant compared to the non-statin gp (Table 1). Conclusion: while we found no differences in clinical outcome with the addition of atorvastatin, it did result in a statistically significant decrease in NK and T-reg cells for the statin gp in the graft when administered to donors, and on days 30 and 100 post HSCT in the recipients. We are yet to determine the significance of this.
Table Statin gp vs. non-statin gp allograft for % markers Median (range)Statin N=40 Median (range)Non-statin N=25 Wilcoxon test p-value CD3-/CD5616+ 8.00 (2.30-26.90) 10.75 (4.7-20.0) 0.0374 CD3+/CD134+ 1.40 (0.30-8.70) 3.1 (0.5-11.2) 0.0367 CD3+ / CD86+ 0.20 (0.05-0.56) 0.3 (0.1-0.5) 0.0148 CD4+/CD25+/CD127- 0.10 (0-1.60) 1.0 (0-4.7) <0.0001 CD4+/CD25+/CD127-ALT 0.25 (0-1.20) 0.6 (0.2-1.5) 0.0072 CD3-/CD5616+/CD158b+ 1.70 (0.30-5.40) 2.7 (0.4-9.7) 0.0225 CD3-/CD5616+/CD159a+ 1.60 (0.20-5.30) 3.4 (0.8-8.3) 0.0003 Statin gp D 30 vs. non-statin D 30 CD19+ 1.20 (0-21.10) 0.7 (0-5.8) 0.0194 CD3+/CD134+ 0.60 (0-9.60) 3.4 (0.2-7.3) 0.0010 CD4+/CD25+/CD127- 0.20 (0-2.30) 0.9 (0-3.6) 0.0010 CD3-/CD5616+/CD69+ 0.30 (0-2.10) 0.8 (0-18.9) 0.0010 CD3-/CD5616+/CD159a+ 13.80 (0.50-28.10) 20.9 (1.3-48.3) 0.0220 CD3-/CD5616+/CD314+ 5.90 (0.60-28.60) 15.1 (2.1-39.3) 0.0021 CD3-/CD5616+/CD63+/CD314+ 0.30 (0-3.40) 2.7 (0.3-17.6) <0.0001 CD16+/CD56+/CD3-/CD117- 9.90 (0.70-38.20) 21.6 (3.9-47.8) 0.0009 Statin gp D 100 vs. non-statin D 100 CD3+ / CD86+ 0.2 (0-1.3) 0.5 (0.1-1.3) 0.0158 CD4+/CD25+/CD127- 0.1 (0-0.9) 0.8 (0.1-1.8) 0.0002 CD3-/CD5616+/CD63+/CD314+ 0.3 (0-6.3) 1.9 (0.2-14.8) 0.0003 CD16+/CD56+/CD3-/CD117- 8.6 (0-28.8) 11.5 (6.6-51.3) 0.0660

Disclosures
Blum: Celgene: Consultancy.