John Rogosheske

Effect of low-dose oral glutamine on painful stomatitis during bone marrow transplantation

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/m2/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.

Relationship of mycophenolic acid exposure to clinical outcome after hematopoietic cell transplantation

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 ≤ .62). A higher cumulative incidence of engraftment was associated with total MPA trough concentrations greater than 1 μg/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.

A prospective randomized trial of the anti-emetic efficacy of ondansetron and granisetron during bone marrow transplantation

To determine the comparative anti-emetic efficacy of ondansetron and granisetron in patients undergoing bone marrow transplantation, we performed a double-blind, randomized trial in pediatric and adult patients receiving transplants at the University of Minnesota. The results in 187 patients stratified by age (<18 years, n = 51; > or =18 years, n = 136) were analyzed. The average number of emetic episodes in the entire group from day -7 to 2 was 0.86/day for patients receiving ondansetron and 0.73/day for those receiving granisetron (p = 0.32). No differences were noted between the two drugs in total days of complete or major control of emesis or in the number of requests for additional drugs to alleviate symptoms of nausea. The use of total-body irradiation-containing conditioning regimens was associated with a decreased number of emetic episodes compared with regimens of chemotherapy alone. Perceived nausea was evaluated using a nausea scoring system, and no differences were apparent between the granisetron and ondansetron groups; however, reported nausea was significantly higher in females (p<0.01) and in the adult population (p = 0.05). We conclude that both ondansetron and granisetron provide good control of nausea and vomiting experienced with conditioning regimens for bone marrow transplantation. The relative cost of the drugs within an institution must be considered in developing standard anti-emetic regimens for bone marrow transplantation.

Use of a somatostatin analogue, octreotide acetate, in the management of acute gastrointestinal graft-versus-host disease

PURPOSE Because the secretory diarrhea of acute graft-versus-host disease (GvHD) of the gut induces serious metabolic and nutritional disturbances, this study was initiated to assess the use of a somatostatin analogue, octreotide acetate, as adjunctive therapy for severe GvHD of the gut with massive diarrhea. PATIENTS AND METHODS In a pilot study, six patients with biopsy-confirmed acute gut GvHD after allogeneic bone marrow transplantation received octreotide 50 to 250 micrograms three times a day subcutaneously. RESULTS Three of the six treated patients had a prompt and dramatic reduction in stool volume within 1 to 3 days of initiation of octreotide therapy. CONCLUSIONS Somatostatin and its analogues have been used successfully in diarrheal states by antagonism of neuropeptide overproduction, although other potential therapeutic mechanisms include inhibition of fluid secretion, enhanced salt absorption, and inhibition of gut motility. Somatostatin and its analogues may be promising adjunctive agents in the treatment of gastrointestinal GvHD, although assessment in a controlled trial will be required to confirm their therapeutic efficacy.

Higher Dose of Mycophenolate Mofetil Reduces Acute Graft-versus-Host Disease in Reduced-Intensity Conditioning Double Umbilical Cord Blood Transplantation

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 than with 2 g/day. Here, we retrospectively compared clinical outcomes of reduced-intensity conditioning (RIC) double umbilical cord blood (dUCB) HCT recipients receiving cyclosporine A with MMF 2 g (n = 93) versus 3 g (n = 175) daily. Multiple regression analysis adjusted for antithymocyte globulin in the conditioning revealed that MMF 3 g/day led to a 49% relative risk (RR) reduction in grade II to IV acute GVHD rate (RR, .51; 95% confidence interval, .36 to .72; P < .01). However, the higher MMF dose was not protective for chronic GVHD. Additionally, MMF dose was not an independent predictor of neutrophil engraftment or treatment-related mortality at 6 months or 2-year post-transplantation 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 3 g/day reduces the risk of acute GVHD without affecting other clinical outcomes and should be used for GVHD prophylaxis after RIC dUCB transplantation.

High fludarabine exposure and relationship with treatment-related mortality after nonmyeloablative hematopoietic cell transplantation.

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. The objective of this study was to evaluate the association between plasma F-ara-A exposure, the systemically circulating moiety of fludarabine, and engraftment, acute GVHD, TRM and OS after HCT. The preparative regimen consisted of CY 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 carried out with the first dose of fludarabine in 87 adult patients. Median (range) F-ara-A area-under-the-curve (AUC(0−∞)) was 5.0 μg h/mL (2.0–11.0), clearance 15.3 L/h (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 OS. Patients with an AUC(0−∞) greater than 6.5 μg h/mL had 4.56 greater risk of TRM and significantly lower OS. These data suggest that clinical strategies are needed to optimize dosing of fludarabine to prevent overexposure and toxicity in HCT.

Comparison of two mycophenolate mofetil dosing regimens after hematopoietic cell transplantation.

Mycophenolic acid (MPA) is the active component of mycophenolate mofetil (MMF). Low MPA exposure is associated with a higher incidence of acute GVHD and possibly worse engraftment. Therapeutic plasma targets have been proposed in hematopoietic cell transplantation (HCT), however, are difficult to achieve in adult patients with MMF doses of 2 g/day. Mycophenolate pharmacokinetics was prospectively studied in adults undergoing nonmyeloablative HCT who received MMF 3 g/day with CYA. The first 15 individuals received 1.5 g every 12 h and the second 15 received 1 g every 8 h. Sampling was performed in each patient with i.v. and oral administration. There were no differences in total or unbound MPA 24-h cumulative area under the curves (AUCs), concentrations at steady state (Css) or troughs between the two dosing regimens (all P>0.01). The previously proposed total MPA Css target of 3 μg/ml and trough ⩾1 μ/ml were achieved in only 13–27% and 20–53% of patients, respectively, on 3 g/day. However, the 3 g/day regimens readily achieved satisfactory unbound 24-h cumulative AUC targets of 0.600 μg*h/ml in 87–100% of subjects. There appears to be no significant difference in daily MPA exposure when MMF of 3 g/day is divided into two or three equal doses.

A limited sampling model for estimation of total and unbound mycophenolic acid (MPA) area under the curve (AUC) in hematopoietic cell transplantation (HCT)

Objectives Renal transplant patients with suboptimal mycophenolic acid (MPA) areas under the curves (AUCs) are at greater risk of acute rejection. In hematopoietic cell transplantation, a low MPA AUC is also associated with a higher incidence of acute graft versus host disease. Therefore, a limited sampling model was developed and validated to simultaneously estimate total and unbound MPA AUC0−12 in hematopoietic cell transplantation patients. Methods Intensive pharmacokinetic sampling was performed at steady state between days 3 to 7 posttransplant in 73 adult subjects while receiving prophylactic mycophenolate mofetil 1 g per 12 hours orally or intravenously plus cyclosporine. Total and unbound MPA plasma concentrations were measured, and total and unbound AUC0−12 was determined using noncompartmental analysis. Regression analysis was then performed to build IV and PO, total and unbound AUC0−12 models from the first 34 subjects. The predictive performance of these models was tested in the next 39 subjects. Results Trough concentrations poorly estimate observed total and unbound AUC0−12 (r2<0.48). A model with 3 concentrations (2-, 4-, and 6-hour post start of infusion) best estimated observed total and unbound AUC0−12 after IV dosing (r2>0.99). Oral total and unbound AUC0−12 was more difficult to estimate and required at least 4 concentrations (0-, 1-, 2-, and 6-hour post dose) in the model (r2>0.85). The predictive performance of the final models was good. Eighty-three percent of IV and 70% of PO AUC0−12 predictions fell within ±20% of the observed values without significant bias. Conclusion Trough MPA concentrations do not accurately describe MPA AUC0−12. Three intravenous (2-, 4-, 6-hour post start of infusion) or 4 oral (0-, 1-, 2-, and 6-hour post dose) MPA plasma concentrations measured over a 12-hour dosing interval will estimate the total and unbound AUC0−12 nearly as well as intensive pharmacokinetic sampling with good precision and low bias. This approach simplifies AUC0−12 targeting of MPA post hematopoietic cell transplantation.

Highly Variable Mycophenolate Mofetil Bioavailability Following Nonmyeloablative Hematopoietic Cell Transplantation

This study determined the oral bioavailability of mycophenolic acid, the active metabolite of mycophenolate mofetil, in patients undergoing nonmyeloablative hematopoietic cell transplantation. Eighteen adults receiving a preparative regimen containing fludarabine, cyclophosphamide, and total body irradiation were studied. Immune suppression consisted of cyclosporine and mycophenolate 1 g twice daily. Pharmacokinetic variability was high after intravenous and oral dosing. Intravenous dosing resulted in a median area under the curve (AUC) of 28.3 μg•h/mL (range, 9.96–70.4) and an oral AUC of 16.7 μg•h/mL (range, 9.38–35.3). C max after intravenous and oral dosing was 12.18 and 5.29 μg/mL, respectively. The median oral bioavailability was 72.3% (20.5%–172%), with 8‐fold variability. Five patients (28%) had an oral bioavailability ≤50%. At time of oral pharmacokinetics, 15 patients (83%) had an AUC0–12 <30 μg•h/mL. The initial oral dose should be at least 25% greater than the intravenous dose with follow‐up assessment of plasma concentrations.

Posttransplant day significantly influences pharmacokinetics of cyclosporine after hematopoietic stem cell transplantation.

Cyclosporine-based immunosuppression is common after allogeneic hematopoietic stem cell transplantation (HSCT). Elevated cyclosporine concentrations are associated with significant toxicity and often result in the temporary cessation or discontinuation of cyclosporine. Low blood concentrations also result in significant immunologic risks, primarily graft-versus-host disease and loss of stem cell graft. The pharmacokinetics of cyclosporine are highly complex, and maintaining therapeutic and safe cyclosporine concentrations are challenging. Several clinical factors are known to independently influence in vivo cyclosporine pharmacokinetic behavior. However, in the critically ill patient, several of these clinical factors are generally present simultaneously. Unfortunately, there are no studies that have evaluated the combined effects of these clinical factors on cyclosporine disposition in HSCT. The objective of our study is to determine the population pharmacokinetic parameters of intravenous and oral cyclosporine, evaluate the effects of clinical covariates on cyclosporine pharmacokinetics, and develop a model that estimates clearance (Cl) and dose requirements for an individual HSCT patient with these clinical covariates. The authors analyzed 740 cyclosporine steady-state whole blood concentrations in 129 adult patients obtained between day 0 and discharge or 60 days posttransplant, whichever came first. Patients received intravenous cyclosporine at 2.5 mg/kg every 12 hours if body weight was greater than 50 kg, 2.5 mg/kg every 8 hours if less than 50 kg, or 5 to 7.5 mg/kg/d given as a continuous infusion, beginning on day-3. Patients were converted to oral therapy as tolerated. The influence of clinical covariates on the Cl of cyclosporine was tested with a nonlinear mixed effects model (NONMEM). The tested clinical covariates were age, height, body weight on admission, body surface area, sex, type of hematologic malignancy, transplant type, preparative regimen, baseline serum creatinine, T-cell depletion of graft, number of methotrexate doses, day of onset, and maximum grade of acute graft-versus-host disease. The route and frequency of cyclosporine administration, day posttransplant, total bilirubin level, serum creatinine level, actual body weight, presence of concurrent CYP450 enzyme inhibitors and inducers, or nephrotoxins on the day of the cyclosporine blood measurement were also evaluated. Cyclosporine Cl significantly decreased each week posttransplant. The authors found no significant effect of any of the other tested covariates including total bilirubin on Cl. The final regression model for the estimation of Cl is: Cl (L/hr) = ([body weight in kg - 70] * 0.183 + 22.3) * (day posttransplant factor). The corresponding day posttransplant factor estimates are 1.46, 1.32, 1.20, and 1.0 during days 0 to 7, 8 to 14, 15 to 21 and greater than 21 posttransplant, respectively. The interindividual variability in Cl was 27.7%. The dose of intravenous or oral cyclosporine can be calculated using the estimated Cl. Understanding cyclosporine pharmacokinetics and the clinical events that lead to alterations in Cl and exposure is critical in optimizing immunosuppressive therapy. The authors found that cyclosporine Cl significantly decreased posttransplant until day 21. A pharmacokinetics model was developed that incorporates the day posttransplant to predict cyclosporine Cl. Cyclosporine dose requirements in an individual HSCT patient to achieve the desired therapeutic blood target can be estimated using this model.