Pharmacokinetics-based Mycophenolate Mofetil Dosing for GVHD Prevention
Condition: Allogeneic Blood and Marrow Transplantation (BMT); Graft Versus Host Disease
MeSH terms: Graft vs Host Disease
Study type: Interventional
Phase: Phase 2

Summary: 
      Bone marrow transplantation (BMT) is used to successfully treat high-risk forms of leukemia,
      lymphoma, and other childhood cancers that were once considered incurable. A major barrier to
      the application of this life-saving treatment is acute graft-versus-host disease (GVHD) which
      develops in approximately 30-80% of patients and is a leading cause of death from transplant
      complications. Current GVHD prevention methods are not very efficacious and lead to
      unacceptable side effects. Mycophenolate mofetil (MMF), an anti-rejection medication used in
      solid organ transplants, has shown great promise in BMT recipients. The effectiveness of MMF
      depends on blood levels of mycophenolic acid (MPA, the active form of MMF). Different
      patients have been found to have different blood levels of MPA when they are given the same
      dose of MMF. The purpose of this study is to study a novel method of giving MMF based on its
      metabolism (pharmacokinetics) to achieve desired blood levels of MPA for prevention of GVHD.
      Non-invasive ways of monitoring the drug exposure will also be studied. The ultimate goal of
      this study is to improve approaches to GVHD prevention and improve outcomes of BMT in
      children.
    

Detailed description: 
      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
      dosing.

      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.
    

Intervention name(s): Mycophenolate mofetil
Intervention type(s): Drug
Intervention description(s): Based on individual pharmacokinetics data, mycophenolate mofetil will be administered by continuous infusion to target a desired AUC exposure
Other intervention name(s): Cellcept; MMF
Intervention MeSH terms: Mycophenolic Acid
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Allogeneic blood and marrow transplantation (BMT); Graft versus host disease; Mycophenolate mofetil; Pharmacokinetics