Prospective Evaluation of A ‘Two-Pronged' Strategy of Atorvastatin Administration As Acute Graft-Versus-Host Disease (aGVHD) Prophylaxis, to Both Donors and Recipients of Matched Related Donor (MRD) Allogeneic Hematopoietic Cell Transplantation (alloHCT)

Atorvastatin (ATOR) is a potent immunomodulatory agent that holds promise as a novel and safe agent for aGVHD prophylaxis. In murine models ATOR administration to both donor and recipient mice, prevented aGVHD by inhibiting donor T-cell proliferation, inducing TH-2 polarization, and by inhibiting recipient antigen presenting cell function. 

We conducted a phase II study (NCT01175148) to evaluate the safety and efficacy of ATOR administration for aGVHD prophylaxis, to both adult donors and recipients of MRD alloHCT. As aGVHD prophylaxis, ATOR (40mg/day PO) was administered to sibling donors, starting 14-28 days before the anticipated 1^st day of stem cell collection. In alloHCT recipients aGVHD prophylaxis consisted of tacrolimus, micro-dose methotrexate and ATOR (40mg/day) administered from day -14 to day +180. Ex vivo or in vivo T-cell depletion was not permitted. Primary outcomes were rate of grade (Gr) II-IV aGVHD at day 100 and safety of ATOR administration to alloHCT donors/recipients. We tested the null hypothesis H₀: p≥35%, vs. the alternate H₁: p≤15%; where p is the probability of Gr II-IV aGVHD at day 100.

Between Sep 2010 and Oct 2012, target enrollment of 30 donor/recipient pairs was completed. Median donor age was 52.5 yrs (range 24-75). ATOR prophylaxis in healthy donors (median duration 14 days [range 7-24]), was not associated with any Gr 3-4 adverse events (AEs). Table 1 shows baseline patient (pt) characteristics. No ATOR related Gr 2-4 AEs were seen. 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 80.5% for T-cells and 100% for myeloid cells. Respective numbers at day 180 are 100% and 100%. Among 29 evaluable pts (1 pt waiting to engraft), the cumulative incidence (CI) of Gr II-IV and III–IV aGVHD at day 100 are 3.7 ±3.7% and 0% respectively. Respective, rates at day 180 are 13 ±7.3% and 9.1 ±7.3%. CI of mild/moderate and severe chronic GVHD at 1 year are 26 ±11.5% and 23.5 ± 10.7%, respectively. Only 2 pts had CMV reactivation. Non-relapse mortality was 0% at day 100 and 5% at day 180. CI of relapse at day 180 was 19.7%. 1-year progression-free and overall survival estimates are 68% and 69%, respectively. 

A two-pronged strategy of ATOR administration to both donors and recipients of MRD alloHCT appears to be a feasible, safe and effective method for aGVHD prophylaxis.

Table 1.

	Patients N=30 (range)
Male pts	20
Median age, yrs	55  (22 – 72)
Median days on statin	190  (60 – 199)
Median KPS	85 (70-100)
Median HCT-CI	1.5 (0-5)
CIBMTR Disease Risk       Low       Intermediate       High	_ 10 9 11
Diagnosis      AML      CML/CMML      MDS/MPD      CLL/SLL      NHL/Hodgkin      Others	_ 8 2 5 2 11 2
Chemorefractory	11
Prior autograft	5
10/10 HLA match	30
Conditioning      RIC      Myeloablative	_ 16 14
Peripheral blood graft	30
ABO mismatched	10
Female donor to male patient	10
Median infused CD34 cells/kg	4.1  x 106
Median infused CD3 cells/kg	33.2  x 107
Median Follow-up of survivors, days	222 (11-717)