Intensified Mycophenolate Mofetil Dosing and Higher Mycophenolic Acid Trough Levels Reduce Severe Acute Graft-versus-Host Disease after Double-Unit Cord Blood Transplantation

Abstract

While mycophenolate mofetil (MMF) has replaced corticosteroids as immunosuppression in cord blood transplantation (CBT), optimal MMF dosing has yet to be established. We intensified MMF dosing from every 12 to 8 hours to augment graft-versus-host disease (GVHD) prophylaxis in double-unit CBT (dCBT) and evaluated outcomes according to the total daily MMF dose/kg in 174 double-unit CBT recipients (median age 39 years, range 1–71) transplanted for hematologic malignancies. Recipients of a MMF dose ≤ the median (36 mg/kg/day) had an increased day 100 grade III-IV acute GVHD (aGVHD) incidence compared with patients who received > 36 mg/kg/day (24% versus 8%, p = 0.008). Recipients of ≤ the median dose who had highly HLA-allele (1-3/6) mismatched dominant units had the highest day 100 grade III-IV aGVHD incidence of 37% (p = 0.009). This finding was confirmed in multivariate analysis (p = 0.053). In 83 patients evaluated for mycophenolic acid (MPA) troughs, those with a mean week 1-2 trough < 0.5 mcg/mL had an increased day 100 grade III-IV aGVHD of 26% versus 9% (p = 0.063), and those who received a low total daily MMF dose and had a low week 1-2 MPA trough had a 40% incidence (p = 0.008). Higher MMF dosing or MPA troughs had no impact on engraftment after myeloablation. This analysis supports intensified MMF dosing in mg/kg/day and MPA trough level monitoring early post-transplant in dCBT recipients.

High Disease-Free Survival with Enhanced Protection against Relapse after Double-Unit Cord Blood Transplantation When Compared with T Cell–Depleted Unrelated Donor Transplantation in Patients with Acute Leukemia and Chronic Myelogenous Leukemia

“…In contrast, DCBT recipients are most compromised by early TRM due to delayed engraftment, organ toxicity, and acute GVHD. Numerous strategies to mitigate these complications such as improved CB graft selection with consideration of CD34+ cell dose 7,8 and high resolution HLA-match 22,39,40 , augmentation of engraftment (improved homing, ex vivo expansion or co-infusion of third-party progenitors) 41–47 , reduced toxicity preparative regimens 21,31,48–50 , augmented GVHD prophylaxis 35,36,51 , and intensive supportive care 52–54 are being investigated, and will be assisted by an increase in the size of the global CB inventory.…”

Autoimmune hemolysis and immune thrombocytopenic purpura after cord blood transplantation may be life-threatening and warrants early therapy with rituximab

“…A calcineurin-inhibitor (CNI) and mycophenolate mofetil (MMF) were used for graft-versus-host disease (GVHD) prophylaxis. (REF 12, 13, 14, 15) All patients received double unit grafts comprised of 2 units that were 4–6/6 HLA-A, -B antigen, -DRB1 allele matched to the recipient. No patients during the study period received single unit grafts per MSKCC policy.…”

Pharmacokinetics, Pharmacodynamics, and Pharmacogenomics of Immunosuppressants in Allogeneic Hematopoietic Cell Transplantation: Part II

“…The Memorial Sloan-Kettering group intensified oral MMF dosing, in combination with cyclosporine or tacrolimus, from every 12 h to every 8 h in 174 double cord blood transplant (dCBT) recipients. 72 A subset analysis of 83 patients evaluated the mean week 1 and 2 total MPA trough concentrations; patients with a trough concentration < 0.5 μg/mL had an increased incidence of day +100 grades III and IV acute GVHD compared to patients with trough concentrations ≥ 0.5 μg/mL (26% versus 9%, p = 0.063). Patients whose MMF dose was below the group median (≤ 43 mg/kg/day) and had low mean week 1 and 2 MPA trough concentrations (0.05 μg/mL) had a 40% incidence of grades III–IV acute GVHD at day +100 (p =0.008), compared to a 10% incidence in patients with other dose and trough concentration combinations (i.e., high MMF dose regardless of trough concentration or trough > 0.5 μg/mL regardless of MMF dose).…”

“…This analysis supports every 8 h oral MMF dosing and total MPA trough concentration monitoring early after alloHCT in dCBT recipients. 72 …”

“…77 If TCI is desired in UCB alloHCT recipients, then either total MPA trough concentrations or unbound MPA AUC should be monitored based on pharmacodynamic findings. However, given that only the association of total MPA AUC with acute GVHD in alloHCT recipients of UCB grafts has been replicated, 11,72 further pharmacodynamic findings are needed in homogenous populations with similar conditioning regimens, graft sources, and postgraft immunosuppression.…”