Intensified Mycophenolate Mofetil (MMF) Dosing Is Safe from the Standpoint of Engraftment and Reduces Severe Acute Graft-Versus-Host Disease (aGVHD) after Double-Unit Cord Blood Transplantation (DCBT): An Analysis of 173 Patients

Background: Calcineurin-inhibitor/MMF based prophylaxis in DCBT is frequently associated with aGVHD. MMF dosing in CBT has traditionally been every 12 hours (q12). We increased MMF dosing to 1 gm every 8 hours (q8) to potentially ameliorate severe aGVHD. However, the toxicity and efficacy of intensified dosing is not established. Methods: We evaluated 173 4-6/6 HLA-matched DCBT recipients (median age 39 years) transplanted for hematologic malignancies 10/2005-5/2013. Patients received calcineurin-inhibitor/MMF from day -3 without ATG. Before 9/2009, 83 patients (48%) received 1 gm MMF IV q12 (if ≤12 years 15 mg/kg/dose). From 9/2009, 90 patients (52%) received 1 gm MMF IV q8 (15 mg/kg/dose if >12 years and <50 kg, or 20 mg/kg/dose if ≤12 years). Results: The median infused CD34+ cell doses of the dominant CB unit were similar in the groups. There were no differences in the speed or success of engraftment, day 180 TRM, or 1-year PFS (Table). Day 100 grade II-IV aGVHD were similar in the groups (46% vs 53%), and decreased day 100 grade III-IV aGVHD in the q8 group was suggested. As all patients >50 kg received 1 gm/dose, we then analyzed the effect of the total daily MMF dose/kg (regardless of dosing interval) in all 173 patients. A total daily dose/kg above the median was associated with a significant reduction in severe aGVHD [(23% (95%CI: 15-31) vs 10% (95%CI: 4-18), p=0.033, Figure]. Conclusions: Intensified q8 MMF dosing is safe from the standpoint of engraftment, TRM and relapse. While the reduction in severe aGVHD incidence in q8 MMF DCBT recipients did not reach significance, a total daily MMF dose/kg above the median significantly reduced severe aGVHD risk. Further investigation of intensified MMF dosing adjusted for body weight with trough level monitoring for the prevention of aGVHD in CBT recipients is strongly indicated. 

Outcome	MMF q12 Hour (n = 83)	MMF q8 Hour (n = 90)	P value
Neutrophil Engraftment:
Myeloablative	93% (95%CI: 82-98) Median 23 days (range 12-43)	96% (95%CI: 87-99) Median 24 days (range 12-40)	0.692
Non-myeloablative	96% (95%CI: 38-99) Median 9 days (range 7-36)	93% (95%CI: 17-99) Median 12.5 days (range 8-46)	0.343
+180 Platelet Engraftment:
Myeloablative	82% (95%CI: 69-90) Median 50 days (range 29-162)	88% (95%CI: 77-94) Median 45 days (range 29-137)	0.137
Non-myeloablative	87% (95%CI: 62-96) Median 34 days (range 9-59)	73% (95%CI: 40-90) Median 34 days (range 26-77)	0.229
+100 Grade II-IV aGVHD	46% (95%CI: 35-56)	53% (95%CI: 42-63)	0.505
+100 Grade III-IV aGVHD	22% (95%CI: 14-31)	13% (95%CI: 7-21)	0.166
+180 TRM	19% (95%CI: 12-28)	20% (95%CI: 13-29)	0.332
1-year PFS	63% (95%CI: 51-72)	61% (95%CI: 50-70)	0.760