Mycophenolate mofetil prophylaxis and treatment in pediatric patients with graft-versus-host disease

Approximately 20–50% of transplanted pediatric patients develop graft-versus-host disease (GvHD), which is the main cause of morbidity and mortality after allogeneic stem cell transplantation (allo-HSCT). Second-line therapeutic options are limited for patients who are resistant to corticosteroid treatment. The use of mycophenolate mofetil (MMF) as prophylaxis and therapy for children undergoing allo-HSCT requires further investigation.¹ In the International Journal of Hematology, Nozomu Kawashima et al. published their study evaluating the safety and efficacy of MMF in the prevention and treatment of pediatric GvHD, using a nationwide retrospective survey in Japanese children undergoing allo-HSCT between 1995 and 2011.²

Patients and methods

• N = 141 children
• Median age: 8 years (range 0–15)
• 89 males and 52 females
• MMF was administered orally
• Donors: primarily unrelated and mismatched related
• Diagnosis
  • AML: n = 39  
  • ALL: n = 23  
  • CML: n = 5  
  • MDS/MPN: n = 11  
  • Immunodeficiency: n = 13  
  • IBMFS: n = 11  
  • AA: n = 10  
  • CAEBV: n = 6  
  • Metabolic disease: n = 6  
  • Solid tumor: n = 5  
  • Others: n = 12
• This study included 3 groups:
  • GvHD prophylaxis: n = 35 children (25%) received MMF
  • Acute GvHD treatment: n = 62 (44%) received MMF
  • Chronic GvHD treatment: n = 44 (31%) received MMF

Key findings

1. Efficacy

GvHD prophylaxis group

• Thirty-five patients (25%) received MMF prophylaxis for GvHD
• All patients were engrafted in this cohort: neutrophil engraftment was achieved within the median of 17 days for BM recipients and 21 days for CB recipients
• Ten patients (29%) developed grade II–IV acute GvHD
• Three patients (8.6%) developed grade III–IV acute GvHD
• Affected organs: mainly skin and gastrointestinal
• 100-day cumulative incidence of developing grade II–IV aGvHD post-transplant: 28%
• There was no significant difference in MMF dose between children with grade ≤I and grade II–IV acute GvHD, respectively: median 532 mg/m² versus 546 mg/m², P = 0.76
• Five children experienced chronic GvHD: 4 children (13%) developed limited chronic GvHD, one child (3.1%) developed extensive chronic GvHD
• Two children developed grade II acute GvHD before the onset of chronic GvHD

Acute GvHD treatment group

• MMF was administered in 62 children (44%) for acute GvHD treatment
• Fourteen patients received MMF for both acute and chronic GvHD
• Fourty-eight patients had grade II–IV acute GvHD
• Twenty-eight children had grade III–IV acute GvHD
• The first-line therapy for acute GvHD:
  • Tacrolimus plus steroids (n = 51)
  • Steroids only (n = 8)
  • Other (n = 3; tacrolimus only; cyclosporin A plus steroid; and a combination of tacrolimus, cyclosporin A, and steroid)
• After MMF administration: decreased GvHD grade was observed in 38 children (61%)
  • Improvement in skin involvement: 40 children (65%)
  • Improvement in gastrointestinal involvement: 17 children (27%)
  • Improvement in liver involvement: 8 children (13%)
• Symptoms worsened in two patients (3.2%)
• Dose reduction in combined immunosuppressive therapy: 35 patients (57%)
• Discontinuation of combined immunosuppressive therapy: 11 patients (18%)

Chronic GvHD treatment group

• Fourty-four children (31%) received MMF for the treatment of chronic GvHD
• The first line of therapy for chronic GvHD:
  • Tacrolimus plus steroid (n = 20)
  • Steroid only (n = 16)
  • Tacrolimus (n = 5)
  • Other (n = 3; cyclosporin A plus steroid, cyclosporine A, and no other immunosuppressants)
• After MMF administration:
  • Improved subjective symptoms were observed: 16 patients (36%)
  • Limited chronic GvHD improved: 6/14 patients (43%)
  • Extensive chronic GvHD improved: 10/30 patients (33%)
  • Concomitant immunosuppressants were reduced: 17 patients (41%)
  • Concomitant immunosuppressants were discontinued: 10 patients (24%)

2. Safety

• Major adverse events (AEs)
  • Neutropenia (4.3%)
  • Infection (3.5%)
  • Thrombocytopenia (2.1%)
  • Myelosuppression (2.1%)
  • Diarrhea (1.4%)
• MMF dosage was reduced in two children due to grade ≥3 AEs
• Two children died from infection

In summary, this Japanese nationwide retrospective analysis showed that MMF is safe and effective as prophylaxis and treatment of pediatric GvHD. The authors added that “further prospective randomized studies including the pharmacokinetics are necessary to determine the optimal MMF dose and combination therapy for GvHD in children.”