Efficacy of the Addition of RGI-2001 to Tacrolimus and Methotrexate for Acute Gvhd Prevention in Myeloablative HSCT Using HLA-Matched Donors

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Conference Proceeding

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Transplantation and Cellular Therapy


Background: RGI-2001 is a liposomal glycolipid that binds the CD1d receptor of antigen-presenting cells (APC) resulting in activation of invariant natural killer (iNKT) cells. In the context of alloHCT, this interaction results in a cytokine-dependent Treg proliferation with potential modulation of the GvHD pathogenic cascade. Earlier dose-finding studies have shown that a single dose of RGI-2001 given on the day of alloHCT is safe and potentially contributed to prevention of acute GVHD (aGVHD).

Methods: RGI-2001-003 is an open-label, multi-center phase 2b study evaluating the efficacy and safety of RGI-2001 when added to a calcineurin inhibitor with methotrexate or mycophenolate mofetil (without T-cell depletion) for the prevention of aGvHD in subjects following myeloablative alloHCT. RGI-2001 was administered in a 30-minute infusion at a dose of 100 ug/kg IV weekly ×6 doses, starting on the day of transplant (Days 0, 7, 14, 21, 28, 35). The primary endpoint of the study is incidence of grades II-IV aGvHD by day 100.

Results: 49 subjects treated at 7 U.S. transplant centers were enrolled. Median age was 52 (range 21-65); 27 were male. Donors were 8/8 HLA-matched unrelated (n=32, 65%) 8/8 HLA-matched related (n=16, 33%), or 7/8 HLA-matched unrelated (n=1, 2%). The most common underlying diseases were AML (n=26, 53%), ALL (n=11, 22%), and MDS (n=8, 16%). Graft sources were PBSC (n=40) or BM (n=9). Common conditioning regimens were Bu/Flu (83%) and TBI/Cy (12.2%). All subjects received standard tacrolimus/methotrexate for GvHD prophylaxis. One infusion reaction (Grade 2) was reported. Treatment-emergent adverse events (TEAE >5%) related to RGI-2001 were stomatitis 14%, diarrhea 12%, nausea 12%, abdominal pain 8%, increased bilirubin 8%, ALT enzyme elevation 6%, ALP elevation 6%, and rash 6%. Grade 3 or 4 related TEAE >2% were stomatitis (6%), anemia (4%), and leukopenia (4%). Per protocol, patients were followed for a maximum of 1 year. The median follow-up of 46 survivors was 363 days (range, 164-365), and 46 of 49 patients had complete follow-up to day 180. Through day 100, there were 10 cases of grades II-IV aGvHD [20.4% (95% CI 10.2-34.3%)], two of which were grades III-IV [(4.1% (0.5-14.0%)]. One subject died at day 102 from aGvHD due to GI bleeding, 2 subjects died without aGvHD (at days 100 and 127). Figure 1 shows outcomes involving aGVHD by donor. Day-180 estimates of overall survival (OS) and grades II-IV aGvHD-free survival (aGFS) were 93.9% (82.2-98.0%) and 75.5% (60.9-85.3%), respectively. Figure 2 summarizes the probability of OS and aGFS as a function of time.

Conclusions: RGI-2001 added to the standard-of-care tacrolimus / methotrexate GvHD prophylaxis shows promising efficacy in the prevention of aGvHD for HLA-matched donors (related or unrelated) with an acceptable safety profile. A phase III study is planned.





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