A Pilot Study of Pharmacokinetics-based Mycophenolate Mofetil Dosing for Graft-Versus-Host-Disease Prophylaxis in Pediatric Blood and Marrow Transplantation
Graft-versus-host disease (GVHD) remains a major barrier to the success of allogeneic blood
and marrow transplant (BMT) therapy. Acute GVHD is seen in 30-80% of patients and once
established, often responds poorly to therapy and is associated with chronic disease and
increased risk of death. Although combination of methotrexate (MTX) and a calcineurin
inhibitor has been the "standard of care" for more than a quarter of a century, there is
little consensus on the most effective and least toxic approach to GVHD prevention. MTX use
is associated with painful mucositis, delay in engraftment and potential pulmonary toxicity.
For cord blood transplants, commonly, a calcineurin inhibitor is used with corticosteroids
and antithymocyte globulin. Steroid therapy is frequently complicated by high rates of
infection, hyperglycemia and hypertension.
Mycophenolate mofetil (MMF), whose metabolite mycophenolic acid (MPA) inhibits proliferation
of lymphocytes, is approved for prevention of organ transplant rejection. MMF in combination
with CsA is widely used for GVHD prevention in patients receiving reduced-intensity
conditioning BMT. It has also been successfully used in primary and salvage therapy of acute
GVHD. In myeloablative transplants, while the GVHD outcomes appear comparable, this regimen
appears to have superior toxicity profile in comparison to CsA and MTX with faster
hematopoietic engraftment and reduced severity and duration of mucositis.
One challenge with MMF use in BMT recipients is a significantly lower MPA exposure in the
immediate post-conditioning period when compared to organ transplant recipients. This has
been shown in a number of pharmacokinetics studies including our preliminary data on
pediatric myeloablative transplants. Low total and unbound MPA trough concentrations are
associated with higher rates of acute GVHD and graft rejection, and lower response rates in
treatment of acute GVHD. There is also poor correlation between MPA trough concentration and
area under the concentration curve (AUC). While most previous studies have used fixed MMF
dosing, one recent study in adults has shown feasibility of AUC-based individualized MMF
This protocol is based on the premise that optimization of MPA exposure in the immediate
post-transplant phase will lead to better acute GVHD prevention. It will study an AUC-based
targeting of MMF in pediatric patients undergoing myeloablative allogeneic BMT. We propose a
novel continuous infusion method for MMF administration to achieve total MPA steady state
concentration. Salient findings emerging from this study will be examined and in replicate
cohorts of pediatric and adult patients undergoing allo-BMT.
Endpoint Classification: Pharmacokinetics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Regimen-related Toxicity - Grade ≥3 toxicities scored according to the CTCAE Version 4.0.
Randy M Windreich, MD
Children's Hospital of Pittsburgh of UPMC
United States: Institutional Review Board
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