Low Incidence of Grade II-IV Acute Gvhd Following Tacrolimus and q8h Mycophenolate Mofetil (MMF) Prophylaxis in Pediatric and Young Adult Recipients of Allogeneic Stem Cell Transplantion (AlloSCT)

Background:

Optimal dosing and monitoring of MMF and its metabolites has been a subject of extensive debate/investigations in the stem cell transplant literature. Due to a shorter half-life and lack of enterohepatic recycling, more frequent and higher dosing of MMF may be required in the early post-AlloSCT period, particularly in children. [Bhatia/Cairo et al. BBMT 2010;16(3):333-43.]

 

Objective:

To determine efficacy of MMF administered q8h in combination with tacrolimus for acute GVHD prophylaxis in 39 children and young adult AlloSCT recipients.

 

Methods:

GVHD prophylaxis consisted of tacrolimus 0.03-0.04 mg/kg/day IVCI on Day -1 or 1st day of conditioning (target range 10-20 ng/mL) and MMF 900 mg/m2 (max 1.5 g/dose) or 15 mg/kg (age ≥ 18 y or weight ≥ 70 kg, max 1.5 g/dose) IV/PO q8h starting on Day +1. Patients were changed to PO tacrolimus (1:4 dose conversion IV:PO) as clinically appropriate post-AlloSCT. GVHD prophylaxis was continued until Day +180 followed by a taper in patients with non-malignant disorders. In patients with malignant disorders, MMF was discontinued on Day +30 or Day +60, followed by a slow tacrolimus taper starting on Day +60. Mycophenolic acid (MPA) trough concentrations were obtained if MMF-induced toxicity was suspected. AGVHD, chronic GVHD (cGVHD) and overall survival (OS) were determined by Kaplan-Meier (K-M) method.

 

Results:

39 patients (mean age 12 years [range 0.1-23.5 years]; 27 male vs 12 female) received myeloablative (n=20) and non-myeloablative (n=19) conditioning for malignant (n=28) and non-malignant disorders (n=11).  Donor sources were: 6/6 MSD (n=12), 4/6-6/6 UCB (n=16), and 9/10 or 10/10 MUD (n=11). Sixteen/28 patients with malignant disease were poor risk. Median time to myeloid and platelet engraftment was 16 and 32 days, respectively. Probability of Grade II-IV aGVHD and grade III-IV aGVHD was 16.6% (CI₉₅: 1.8-44.7) and 2.9% (CI₉₅: 0-60.6), respectively (n=37 evaluable patients).[Figure 1]  Only one patient experienced grade III (liver +gut) aGVHD, with no patients developing grade IV aGVHD. Probability of limited + extensive cGVHD (n=34 evaluable patients) was 23.6% (CI₉₅: 8.0-50.5).

Nine patients died at a median 198 days post-SCT (range 109-549).  Causes of death included chronic GVHD (n=2), acute GVHD (n=1), TMA (n=1), viral or fungal infection (n=2), relapse (n=2), and EBV PTLD (n=1). K-M probability of 1 year overall survival was 72.5% (CI₉₅: 53.3-84.9).

 

Conclusion:

Tacrolimus in combination with MMF given q8h as described above are highly effective for aGVHD prophylaxis in this heterogeneous group of pediatric and young adult AlloSCT recipients. The incidence of grade II-IV aGVHD in the current study appears to be substantially lower then reported in our previous trial with MMF dosed at 900 mg/m2 q6h in a similar group of pediatric and adolescent AlloSCT recipients (16.6% vs 54.4%).[Bhatia/Cairo et al. BBMT 2010;16(3):333-343]