Mycophenolate mofetil is used increasingly to provide immunosuppression after nonmyeloablative allogeneic hematopoietic cell transplantation. There is wide variability in the pharmacokinetics of mycophenolic acid (MPA), the active metabolite, and low concentrations are associated with rejection after organ transplantation. We hypothesized that low MPA was associated with poorer engraftment and a higher incidence of acute graft versus host disease. We evaluated the pharmacokinetics in 87 adult subjects undergoing nonmyeloablative-related and nonmyeloablative-unrelated hematopoietic cell transplantation who were receiving 1 g mycophenolate mofetil orally or intravenously every 12 hours plus cyclosporine (INN, ciclosporin). Subjects with an unbound MPA area under the curve (AUC) from 0 to 6 hours of less than 150 ng . h/mL had a higher cumulative incidence of grade II-IV acute graft versus host disease than subjects with a greater AUC (68% versus 40%, P = .02). An unbound AUC from 0 to 12 hours of less than 300 ng . h/mL was also associated with more frequent acute graft versus host disease (58% versus 35%, P = .05). There was no association between graft versus host disease and trough concentrations (P < or = .62). A higher cumulative incidence of engraftment was associated with total MPA trough concentrations greater than 1 microg/mL (P < .01). All engraftment failures occurred in the cord blood recipients. About one half of subjects were below the unbound AUC target after oral dosing with nearly a 5-fold variability in AUC. Intravenous dosing achieved unbound targets better than oral dosing. The current practice of dosing with 1 g twice daily provides inadequate plasma concentrations in many patients, and doses of at least 3 g/d are likely necessary. Therapeutic monitoring of MPA concentrations with dose adjustment into the therapeutic target appears to be necessary for the most effective use of mycophenolate mofetil.

Summary:Painful oral mucositis is a common complication after bone marrow transplantation (BMT). Glutamine is a nutrient for rapidly dividing cells and the major energy source for intestinal epithelium. This study tested whether an oral glutamine preparation could decrease the severity of oral mucositis in patients undergoing BMT. Glutamine or a placebo (glycine) were administered from admission until day +28 in 193 BMT patients in a randomized, double-blind, placebo-controlled study at a dose of 1.0 g amino acid/m 2 /dose swish and swallow four times a day. In autologous BMT patients (n = 87) glutamine was associated with significantly less mouth pain by self report and by opiate use (5.0 ؎ 6.2 days of morphine for glutamine vs 10.3 ؎ 9.8 days for placebo; P = 0.005). Matched sibling BMT patients had no effect by self report and an increased duration of opiate use (23.2 ؎ 5.7 days for glutamine vs 16.3 ؎ 8.3 days for placebo) (P = 0.002). However, day 28 survival of allogeneic patients was improved by glutamine. No significant differences in TPN use, rate of relapse or progression of malignancy, parenteral antibiotic use, acute or chronic GVHD, or days of hospitalization were observed in either autologous or allogeneic recipients. No toxicity of glutamine was observed. We conclude that oral glutamine can decrease the severity and duration of oropharyngeal mucositis in autologous BMT patients but not in allogeneic BMT patients, possibly due to interaction with methotrexate. Keywords: mucositis; stomatitis; supportive care; nutrition; epithelium; chemotherapy Many of the major adverse effects of BMT are related to disruption of mucosal integrity from high-dose chemotherapy and/or radiation-induced damage of oral and intestinal epithelium. Preclinical studies have demonstrated less damage to rat intestinal epithelium if high doses of enteral glutamine were included in the diet during and after 1000 cGy of whole abdominal radiation. [1][2][3] Glutamine is the most abundant amino acid in the blood, but is generally absent Correspondence: Dr P Anderson, Pediatrics-East 9, Mayo Clinic, Rochester, MN 55905, USA Received 7 November 1997; accepted 16 March 1998 from total parenteral nutrition (TPN) for solubility and stability reasons. [4][5][6][7] The intestine utilizes glutamine as its primary energy source, and glutamine has been shown to be an essential dietary component for support and maintenance of intestinal growth and function. 8-10 Supplementation of TPN with glutamine has been shown to decrease villous atrophy associated with exclusive feeding via TPN. 11,12 Nutritionally depleted patients have been shown to have decreased plasma glutamine and mucosal glutamine. 13 Recent studies have also demonstrated a survival advantage of TPN supplementation with glutamine in critically ill patients. 14 Since no information was available concerning the effect of oral glutamine on the squamous epithelium of the oropharynx after chemotherapy and/or radiation, we conducted an earlier pilot study using oral glutamine 4 g/m 2 t...

Although hemorrhagic cystitis (HC) is a common complication of allogeneic hematopoietic cell transplantation (alloHCT), its risk factors and effects on survival are not well-known. We evaluated HC in a large cohort (n=1321, 2003 – 2012) receiving alloHCT from all graft sources, including umbilical cord blood (UCB). We compared HC patients with non-HC (control) patients and examined clinical variables at HC onset and resolution. Of these 1321 patients, 219 (16.6%) developed HC at a median of 22 days after alloHCT. BK viruria was detected in 90% of 109 tested HC patients. Median duration of HC was 27 days. At the time of HC diagnosis, acute graft-versus-host disease (GVHD), fever, severe thrombocytopenia, and steroid use were more frequent than at the time of HC resolution. In univariate analysis, male sex, age <20 years, myeloablative conditioning with cyclophosphamide and acute GVHD were associated with HC. In multivariate analysis, HC was significantly more common in males and HLA-mismatched UCB graft recipients. Severe grade HC (grade III–IV) was associated with increased treatment-related mortality (TRM) but not with overall survival at 1 year. HC remains hazardous and therefore better prophylaxis and early interventions to limit its severity are still needed.

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Despite its common use in nonmyeloablative preparative regimens, the pharmacokinetics of fludarabine are poorly characterized in hematopoietic cell transplantation (HCT) recipients and exposure-response relationships remain undefined. Our objective of this study was to evaluate the association between plasma F-ara-A exposure, the systemically circulating moiety of fludarabine, and engraftment, acute graft vs host disease (GVHD), treatment-related mortality (TRM) and survival after HCT. The preparative regimen consisted of cyclophosphamide 50 mg/kg/day i.v. day −6; plus fludarabine 30-40 mg/m2/day i.v. on days −6 to −2 and TBI 200 cGy on day −1. F-ara-A pharmacokinetics were performed with the first dose of fludarabine in 87 adult patients. Median (range) F-ara-A AUC (0-∞) was 5.0 ug*hr/mL (2.0-11.0), clearance 15.3 L/hour (6.2-36.6), Cmin 55 ng/mL (17-166), and concentration on dayzero 16.0 ng/mL (0.1-144.1). Despite dose reductions, patients with renal insufficiency had higher F-ara-A exposures. There was strong association between high plasma concentrations of F-ara-A and increased risk of TRM and reduced overall survival. Patients with an AUC(0-∞) greater than 6.5 ug*hr/mL had 4.56 greater risk of TRM and significantly lower survival. These data suggest that clinical strategies are needed to optimize dosing of fludarabine to prevent overexposure and toxicity in HCT.

We studied whether early cyclosporine A (CsA) trough levels were associated with the risk of acute graft-vs.-host disease (GVHD) in 337 patients after either sibling peripheral blood stem cell or double umbilical cord blood transplantation. All patients, regardless of donor type, started CsA at a dose of 5 mg/kg IV divided twice daily, targeting trough concentrations 200–400 ng/ml. The CsA level was studied by a weighted average method calculated by giving 70% of the weight to the level that was measured just prior to the onset of the event or day +30. We found that higher weighted average CsA trough levels early post-transplantation contributed to lower risk of acute GVHD, and lower non-relapse and overall mortality. Thus, our data support close monitoring with active adjustments of CsA dosing to maintain therapeutic CsA levels in the first weeks of allo-HCT. In patients who are near or even modestly above the CsA target trough level, in the absence of CsA related toxicity, dose reduction should be cautious in order to avoid subtherapeutic drug levels resulting in higher risks for acute GVHD.

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Mycophenolate mofetil (MMF) is frequently used in hematopoietic cell transplantation (HCT) for graft-versus-host disease (GVHD) prophylaxis and to facilitate engraftment. We previously reported that a higher level of mycophenolic acid can be achieved with an MMF dose of 3 g/day as compared to 2g/day. Here, we retrospectively compared clinical outcomes of reduced intensity conditioning (RIC) double umbilical cord blood (dUCB) HCT recipients receiving cyclosporine A with MMF 2g (n=93) vs. 3g (n=175) daily. Multiple regression analysis adjusted for ATG in the conditioning revealed that MMF 3g/day led to a 49% relative risk reduction in grade II–IV acute GVHD rate (RR=0.51, 95%CI 0.36–0.72; p<0.01). However, the higher MMF dose was not protective for chronic GVHD. Additionally, MMF dose was not an independent predictor of neutrophil engraftment, treatment-related mortality at 6 months, or 2-year post-transplant disease relapse, disease-free survival, or overall survival. Higher MMF dose did not increase risk of infectious complications and infection-related mortality was similar for both MMF doses. Our data indicate that MMF 3g/day reduces the risk of acute GVHD without affecting other clinical outcomes and should be used for GVHD prophylaxis after RIC dUCBT.