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A Pilot Study of Pharmacokinetics-based Mycophenolate Mofetil Dosing for Graft-Versus-Host-Disease Prophylaxis in Pediatric Blood and Marrow Transplantation

Phase 2
6 Months
21 Years
Open (Enrolling)
Allogeneic Blood and Marrow Transplantation (BMT), Graft Versus Host Disease

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Trial Information

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.

Inclusion Criteria:

- Patients must be between 6 months and 21 years of age.

- Recipients of an allogeneic blood and marrow transplant (BMT).

- Stem cell sources should be bone marrow or umbilical cord blood.

- Bone marrow or cord blood unit: Sibling should be HLA matched at A, B and DRB1 loci.
Unrelated cord blood unit should be at a minimum 4/6 matched at allele level on HLA
A, B and DRB1 loci. Unrelated donor should be HLA allele level matched at A, B, C and
DRB1 loci.

- Minimum prefreezing nucleated cell dose for cord blood units: 3x10^7/kg for malignant
diseases and 5x10^7/kg for nonmalignant diseases.

- Conditioning regimen must be myeloablative in intensity. Examples include but are
not limited to Cy/TBI, BuCy 200, etc.

- Patients ≥ 16 years old must have a Karnofsky score ≥ 70%, and patients < 16 years
old must have a Lansky score ≥ 70%.

- Renal: Creatinine clearance or radioisotope GFR ≥ 70 mL/min/1.73 m2.

- Hepatic: Total bilirubin ≤ 2.5 mg/dL unless the increase in bilirubin is attributable
to Gilbert's syndrome; and SGOT (AST), SGPT (ALT), and Alkaline Phosphatase < 5 x
upper limit of normal (ULN) for age.

- Cardiac: Left ventricular ejection fraction at rest > 40%, or shortening fraction >
26%, by echocardiogram or radionuclide scan.

- Pulmonary: FEV1, FVC, and DLCO (diffusion capacity) > 50% of predicted (corrected
for hemoglobin); if unable to perform pulmonary function tests, then O2 saturation >
92% of room air.

Exclusion Criteria:

- Patients with a known hypersensitivity to MMF.

- Prior autologous or allogeneic BMT < 12 months prior to enrollment.

- Mismatched related donor.

- Mismatched unrelated marrow donor.

- Peripheral blood stem cell source.

- Reduced intensity conditioning.

- Uncontrolled bacterial, viral, fungal or other infection.

- Evidence of HIV infection or HIV positive serology.

- Requirement of supplemental oxygen.

- Patients who are pregnant (B-hCG positive) or breastfeeding. All females of 11 years
of age or older and/or who have begun menstruating will be screened for hCG by either
urinalysis or a blood sample in order to screen for pregnancy status, as per
institutional BMT policy.

Type of Study:


Study Design:

Endpoint Classification: Pharmacokinetics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Regimen-related Toxicity - Grade ≥3 toxicities scored according to the CTCAE Version 4.0.

Outcome Time Frame:

100 days

Safety Issue:


Principal Investigator

Randy M Windreich, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Children's Hospital of Pittsburgh of UPMC


United States: Institutional Review Board

Study ID:




Start Date:

June 2010

Completion Date:

February 2015

Related Keywords:

  • Allogeneic Blood and Marrow Transplantation (BMT)
  • Graft Versus Host Disease
  • Allogeneic blood and marrow transplantation (BMT)
  • Graft versus host disease
  • Mycophenolate mofetil
  • Pharmacokinetics
  • Graft vs Host Disease



Children's Hospital of Pittsburgh of UPMC Pittsburgh, Pennsylvania  15213