Intensified Mycophenolate Mofetil (MMF) Dosing Every 8 Hours Is Safe From The Standpoint Of Engraftment and May Ameliorate Severe Acute Graft-Versus-Host Disease (GVHD) After Double-Unit Cord Blood Transplantation (CBT)
Authors: Ponce Doris M , Harnicar Stephen J. , Devlin Sean , Hilden Patrick , Evans Katherine L , Lubin Marissa N , Giralt Sergio A , Goldberg Jenna D , Perales Miguel-Angel , Kernan Nancy A. , Prockop Susan E. , Scaradavou Andromachi , Barker Juliet N 
Published: October 2019

Background
Acute graft-versus-host disease (aGVHD) is common after double-unit cord blood transplantation (CBT) with an incidence of grade II-IV aGVHD as high as 55% by day 180 in patients transplanted without ATG. aGVHD is associated with increased morbidity and transplant-related mortality (TRM). Mycophenolate mofetil (MMF) combined with a calcineurin-inhibitor is commonly used to prevent GVHD after CBT. However, unlike the 1 gram (gm) every 8 hours dosing that is now standard in adult donor allografts, MMF dosing in CBT has traditionally been every 12 hours. Our center has increased MMF dose from 1 gm every 12 (q12) to 1 gm every 8 (q8) hours in an effort to reduce severe aGVHD after double-unit CBT. However, the efficacy of this intervention is not established and a theoretical concern is that intensified MMF dosing could result in an increased risk of delayed engraftment or graft failure.

Methods
We evaluated 171 double-unit CBT recipients (median age 39 years, range 0.9-71) transplanted with either myeloablative (MA, n = 133) or non-myeloablative (NMA, n = 38) conditioning for high-risk hematologic malignancies between 10/2005 and 4/2013. CB units were 4-6/6 HLA-A, -B antigen, -DRB1 allele matched to the recipient (16 6/6, 171 5/6, 155 4/6). All patients received GVHD prophylaxis with intravenous calcineurin-inhibitor (predominantly CSA) and MMF from day -3 without ATG. Prior to 9/2009, 80 patients (47%) received MMF 1 gm IV q12 (and those <12 years received 15 mg/kg/dose). From 9/2009, 91 patients (53%) received MMF at 1 gm IV q8 for patients both >12 years and ≥50 kg (or 15 mg/kg/dose if >12 years but <50 kg, or 20 mg/kg/dose if <12 years). The Gray's test compared the incidence of GVHD across the q12 and q8 dosing while the log-rank test was used to compare progression-free survival (PFS).

Results
Patient characteristics and infused viable CD34+ cell doses were similar in the q12 and q8 MMF groups. A comparison of transplant outcomes by MMF dosing is shown (Table). There were no differences in the time to neutrophil or platelet engraftment and the median time to count recovery was also similar. The incidences of grade II-IV aGVHD at day 100 were similar in the groups (46% vs 52%). However, there was a suggestion of decreased grade III-IV aGVHD at day 100 in the q8 MMF group (12%) versus the q12 group (21%), although this comparison did not reach significance. With a median follow-up of 41 months (range 3-94), the PFS in each dosing group was not significantly different.

Conclusions
We demonstrated that intensified q8 MMF dosing is safe from the standpoint of engraftment and toxicity. There was a suggestion of decreased severe grade III-IV aGVHD in recipients of 1 gm IV every 8 hours. While a larger analysis is needed to further investigate these findings, the results are encouraging. They suggest that, as with adult donor allografts, intensified q8 hour MMF dosing should be the dose investigated for the prevention of aGVHD in CBT recipients transplanted with CSA/ MMF prophylaxis without ATG. Finally, aGVHD prophylaxis could be further optimized in CSA/ MMF-based CBT by mycophenolic acid trough level drug monitoring, early post-transplant biomarker measurements such as ST2, and delayed taper post-transplant.

Disclosures:
No relevant conflicts of interest to declare.