Immunomodulation of Both Donors and Recipients with Atorvastatin As a Strategy for the Prevention of Acute Graft-Versus-Host Disease (aGVHD): Results of Two Parallel Prospective Trials in Recipients of Matched Sibling Allogeneic Hematopoietic Cell Transplantation (alloHCT)

Acute GVHD is a leading cause of morbidity and mortality following alloHCT. Atorvastatin (a statin drug) is a potent immunomodulatory agent capable of suppressing T cell–dependent immune responses that holds promise as a novel and safe agent for the prophylaxis of aGVHD. In murine models atorvastatin administration to both donor and recipient mice (compared to prophylaxis in either donors or recipients alone), prevented aGVHD by inhibiting donor T-cell proliferation, inducing T-helper 2 polarization, and by inhibiting recipient antigen presenting cell function (Zeiser et al. Blood, 2007). Several retrospective studies also suggest statins as potential prophylactic agents for aGVHD.

We report here the results of two parallel, ongoing, prospective, phase II trials (NCT01175148 & NCT01491958) evaluating the safety and efficacy of a ‘two-pronged’ strategy of atorvastatin administration as aGVHD prophylaxis, to both adult (age ≥18yrs) donors and recipients of matched sibling alloHCT. The approach was identical in both protocols. Subjects with a history of atorvastatin allergy/intolerance were not eligible. As GVHD prophylaxis, atorvastatin at 40mg/day orally was administered to sibling donors, starting 14–28 days before the anticipated 1^st day of stem cell collection. In alloHCT recipients GVHD prophylaxis consisted of atorvastatin (40mg/day) 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. Ex vivo CD34+ cell selection or in vivo T-cell depletion was not permitted. Primary outcomes were rate of Gr II-IV aGVHD at day +100 and safety of atorvastatin administration to alloHCT donor/recipient pairs. Both trials tested the null hypothesis H₀: p≥35%, vs. the alternate H₁: p≤15%, where p is probability of Gr II-IV aGVHD at day 100. Secondary outcomes included rates of late-onset aGVHD, cGVHD, relapse, progression-free survival (PFS), and overall survival (OS).

Between September 2010 and June 2012, 34 donor/recipient pairs were enrolled at WVU (n=24) and OSU (n=10). Median donor age was 50.5 yrs (range 24–69). Median duration of atorvastatin prophylaxis in donors was 15 days (range 7–26). No atorvastatin related Gr 3–4 toxicities were seen in the healthy donors. Table 1 shows baseline patient (pt) characteristics. At transplantation 16 pts (47%) had high-risk disease, 12 (35%) were chemorefractory, 11 (32%) had HCT-CI of ≥3, 14 (41%) were female to male allografts, and 12 (35%) pts had ABO mismatched transplants. Median follow up of survivors is 158 days (range 31 – 658). Atorvastatin was well tolerated with no Gr 2–4 adverse events. All pts engrafted. The median time to ANC ≥500/μL was 18 days (range 5–25) and to platelets ≥20k/μL was 15 days (range 11–51). The median day 100 chimerism was 85.5% (55–100%) for T-cells and 100% (26–100%) for myeloid cells. Respective numbers at day 180 are 99.5% and 100%. Among 34 evaluable pts, the cumulative incidences (CI) of Gr II-IV and Gr III–IV aGVHD at day 100 were 6.0 ± 4.2% and 0% respectively. Respective CI rates at day 180 are 16.7 ± 8.3% and 10.2 ± 7%. CI of mild/moderate and severe cGVHD at 1 year are 15.8 ± 8.9% and 18.3 ± 10.2%, respectively. Infectious complications were infrequent, with no fungal infections or EBV reactivations and few CMV reactivations (n=3). Non-relapse mortality was 0% at day 100 and 4.5% at day 180. CI of relapse at day 180 was 27.6 ± 9.2%. One year PFS and OS estimates are 54% and 66%, respectively.

A two-pronged immunomodulatory strategy of atorvastatin administration to alloHCT donors/recipients appears to be a feasible, safe and potentially effective modality for aGVHD prophylaxis. Final results of NCT01175148 & updated results of NCT01491958 will be presented at the meeting.

Hamadani:Celgene Corp: Speakers Bureau; American Cancer Society 116837-IRG-09-061-01: Research Funding; ASBMT & Millennium New Investigator Award: Research Funding; Conquer Cancer Foundation of ASCO: Research Funding. Off Label Use: Off Label use of atorvastatin for GVHD prophylaxis. Efebera:(NIA) K12 CA1333250: Research Funding; Leukemia and Lymphoma Society: Research Funding.