Biomedical subjects

George B McDonald

Publications and source records attributed to George B McDonald.

At least 19 recordsLinked to original sources

PubMed2006

Mutations in the gene encoding the PML nuclear body protein Sp110 are associated with immunodeficiency and hepatic veno-occlusive disease.

We describe mutations in the PML nuclear body protein Sp110 in the syndrome veno-occlusive disease with immunodeficiency, an autosomal recessive disorder of severe hypogammaglobulinemia, combined T and B cell immunodeficiency, absent lymph node germinal centers, absent tissue plasma cells and hepatic veno-occlusive disease. This is the first report of the involvement of a nuclear body protein in a human primary immunodeficiency and of high-penetrance genetic mutations in hepatic veno-occlusive disease.

Female↗

PubMed2006

An acute graft-versus-host disease activity index to predict survival after hematopoietic cell transplantation with myeloablative conditioning regimens.

Algorithms for grading acute graft-versus-host disease (GVHD) are inaccurate in assessing mortality risk. We developed a method to predict mortality by using data from 386 patients with acute GVHD. From the onset of GVHD to day 100, GVHD manifestations were scored for the skin, liver, and upper and lower gastrointestinal tract, and data were recorded for immunosuppressive treatment, performance, and fever. Logistic regression models predicting nonrelapse mortality (NRM) at day 200 were developed with data from 193 randomly selected patients and then validated in the remaining 193 patients. Clinical parameters were grouped to optimize predictive accuracy measured as the area under a receiver-operator characteristic (ROC) curve. The optimal model included the total serum bilirubin concentration, oral intake, need for treatment with prednisone, and performance score. When the overall burden of GVHD was measured by using average Acute GVHD Activity Index (aGVHDAI) scores for each patient in training and validation data sets, areas under ROC curves were 0.87 and 0.85, respectively. Contour lines were generated to reflect the predicted NRM at day 200 as a function of current aGVHDAI scores. These results demonstrate that clinical manifestations of GVHD severity can be used to accurately predict the risk of NRM in real time.

Acute Disease↗

PubMed2006

Gastrointestinal graft-versus-host disease in recipients of autologous hematopoietic stem cells: incidence, risk factors, and outcome.

Graft-versus-host disease (GVHD) is seen in skin, intestinal mucosa, and liver after autologous stem cell transplantation. We reviewed 681 consecutive patients to estimate the probability of gastrointestinal (GI) GVHD, response to treatment, risk factors for development, and effect on survival. GI GVHD was defined by persistent symptoms, mucosal abnormalities at endoscopy, and histology showing apoptotic crypt cells with or without lymphoid infiltrates. The proportion of patients with GI GVHD was 90/681 (13%). Nausea and vomiting occurred in 90% and diarrhea in 40%. The mean time to developing symptoms was day +15, that to histologically proven diagnosis was day +42, and that to starting prednisone treatment was day +45 after stem cell infusion. Treatment with a short course of prednisone effected durable responses in 79% of patients, and an additional 18% responded to a second course of prednisone. A multivariable logistic regression model demonstrated that the combined factor of a diagnosis of breast cancer or hematologic malignancy and female sex was statistically significantly associated with the probability of GI GVHD (P = .003). Survival in patients with GI GVHD was not statistically different than that in those without GVHD. We conclude that women with breast cancer or hematologic malignancy are more likely to develop GI GVHD after autologous transplantation, and that treatment with prednisone was effective.

Adult↗

PubMed2006

Advances in prevention and treatment of hepatic disorders following hematopoietic cell transplantation.

Development of jaundice is an ominous prognostic sign, whether it occurs early or late in the months following hematopoietic cell transplant. In the first weeks after transplant, the dominant causes of liver injury are Sinusoidal Obstruction Syndrome (toxic damage resulting from myeloablative conditioning regimens) and cholangitis lenta (cholestasis of sepsis). Later after transplant, cholestasis is more commonly caused by acute graft-vs.-host disease and drugs. Hepatic infections have become uncommon because of the use of prophylactic anti-fungal and anti-viral drugs. Treatment of severe liver dysfunction is often futile in this setting, but prevention of liver injury is feasible. Hepatic sinusoidal injury can be prevented by avoiding sinusoidal toxins as part of conditioning therapy in patients at high-risk. Cholestatic liver damage can be minimized by prophylactic use of ursodiol and by careful drug monitoring. Anti-microbial drugs will prevent most fungal liver infections and viral hepatitis caused by herpesviruses and hepatitis B virus.

Drug Monitoring↗

PubMed2005

The effects of atorvastatin (10 mg) on systemic inflammation in heart failure.

In observational studies, statins are associated with lower mortality in patients with heart failure (HF), including those with nonischemic HF. Such benefits could be related to anti-inflammatory effects; however, the effects of statins on systemic inflammation in HF are not well-established. We conducted a 16-week, single-center, randomized, double-blind, placebo-controlled, crossover clinical trial of the effects of atorvastatin 10 mg/day on concentrations of systemic inflammatory markers in 22 patients with HF (including 20 with nonischemic HF) with New York Heart Association class II or III symptoms and left ventricular ejection fraction of <40%. The absolute and percentage of changes in inflammatory marker levels were evaluated using analysis of variance. Statin treatment reduced the concentrations of soluble tumor necrosis factor receptor-1 by 132 pg/ml (p = 0.04) and 8% (p = 0.056), C-reactive protein by 1.6 mg/L (p = 0.006) and 37% (p = 0.0002), and, after adjustment for treatment order, endothelin-1 by 0.21 pg/ml (p = 0.007) and 17% (p = 0.01). In post hoc analyses, the reduction in tumor necrosis factor receptor-1 levels was highest among patients with elevated levels at baseline (at or higher than the median of 1,055 pg/ml, p interaction = 0.001), among whom statin therapy reduced the levels by 306 pg/ml (p <0.001) and 22% (p <0.001). Statin treatment did not significantly affect the levels of other inflammatory markers, including interleukin-6 and brain natriuretic peptide. In conclusion, short-term atorvastatin therapy reduced the levels of several important inflammatory markers in patients with HF.

Adult↗

PubMed2005

Usefulness of relative lymphocyte count as an independent predictor of death/urgent transplant in heart failure.

The usefulness of low relative lymphocyte count as an independent predictor of death/urgent transplant in patients with heart failure (HF) and the association between low relative lymphocyte count and neurohormone and cytokine activation were investigated. Relative lymphocyte count, clinical variables, neurohormones, and cytokines were measured in 129 outpatients with HF. Follow-up extended to a mean of 3.0 +/- 1.2 years for death/urgent transplant. Low relative lymphocyte count was independently associated with a 3.4-fold increased risk of death/urgent transplant. Relative lymphocyte count was positively associated with hemoglobin and inversely associated with age, jugular venous pressure, creatinine, leukocyte count, and soluble tumor necrosis factor receptor-1. There was only a borderline inverse association with cortisol levels during evening hours.

Biomarkers↗

PubMed2005

Serum bilirubin levels and mortality after myeloablative allogeneic hematopoietic cell transplantation.

Many patients who undergo hematopoietic cell transplantation experience liver injury. We examined the association of serum bilirubin levels with nonrelapse mortality by day +200, testing the hypothesis that the duration of jaundice up to a given point in time provides more prognostic information than either the maximum bilirubin value or the value at that point in time. We studied 1,419 consecutive patients transplanted from allogeneic donors. Total serum bilirubin values up to day +100, death, or relapse were retrieved-along with nonrelapse mortality by day +200 as an outcome measure--using Cox regression models with each bilirubin measure modeled as a time-dependent covariate. The bilirubin value at a particular point in time provided the best fit to the model for mortality. With bilirubin at a point in time modeled as an 8th-degree polynomial, an increase in bilirubin from 1 to 3 mg/dL is associated with a mortality hazard ratio of 6.42. An increase from 4 to 6 mg/dL yields a hazard ratio of 2.05, and an increase from 10 to 12 mg/dL yields a hazard ratio of 1.17. Among patients who were deeply jaundiced, survival was related to the absence of multiorgan failure and to higher platelet counts. In conclusion, the value of total serum bilirubin at a particular point in time after transplant carries more informative prognostic information than does the maximum or average value up to that point in time. The increase in mortality for a given increase in bilirubin value is larger when the starting value is lower.

Adolescent↗

PubMed2005

Metabolism-based cyclophosphamide dosing for hematopoietic cell transplant.

When cyclophosphamide (120 mg/kg) is used for hematopoietic cell transplant, the increased area under the curve of carboxyethylphosphoramide mustard (AUC(CEPM)) is related to liver toxicity and death. We determined the feasibility of dose-adjusting cyclophosphamide to a preset metabolic endpoint (AUC(CEPM), 325 +/- 25 micromol/L.h). In 20 patients blood sampling was done over a 16-hour period after administration of 45 mg/kg cyclophosphamide; AUC(CEPM) from 0 to 16 hours was calculated by noncompartmental analysis. The expected AUC(CEPM) for 0 to 48 hours was estimated, and the second cyclophosphamide dose was determined. The mean second cyclophosphamide dose was 42 mg/kg, and the mean total cyclophosphamide dose was 86 mg/kg (range, 54-120 mg/kg). The mean AUC(CEPM) for the time from 0 to 48 hours was 296 micromol/L.h (95% confidence interval, 275-317 micromol/L.h). A retrospective analysis indicated that AUC(CEPM) could be more accurately predicted by use of a population pharmacokinetic model. We conclude that metabolism-based dosing of cyclophosphamide is feasible and that a lower cyclophosphamide dose does not affect engraftment.

Adolescent↗

PubMed2005

Acute renal failure after myeloablative hematopoietic cell transplant: incidence and risk factors.

BACKGROUND: Survival after myeloablative therapy followed by hematopoietic cell transplant (HCT) is limited by substantial treatment-related toxicities. Acute renal failure (ARF) develops in 25% to 50% of patients after HCT. METHODS: One hundred forty-seven patients were followed prospectively from time of transplant. ARF was defined as a doubling of baseline serum creatinine at any time during the first 100 days post-transplant. We conducted a nested case-control study to identify precipitants of ARF. For each person who developed ARF, 2 controls were selected at random from patients who had not developed ARF as of that time. An exposure period was defined for each case as the 2 weeks prior to the day on which the matched case met the criteria for ARF. The risk of ARF in relation to demographic and anthropometric characteristics, and to types of treatment and comorbidity, was examined using univariable and multivariable conditional logistic regression models. Odds ratios for the associations with ARF were estimated, taking into account the matching. RESULTS: Fifty-three patients (36%) developed ARF at a median of 33 days after transplant (range 1 to 97). Elevated risks were observed in patients who received liposomal amphotericin (OR 6.58; 95%CI 1.45-29.95) and conventional (OR 3.60; 95%CI 0.79-16.55), and in those patients with sinusoidal obstruction syndrome (SOS) (previously termed veno-occlusive disease) (OR 9.37; 95%CI 2.29-38.38). For every 0.1 mg/dL increase in baseline serum Cr, the risk of ARF decreased by 30%. Neither total body irradiation (TBI) dose, levels of metabolites of cyclophosphamide, sepsis, acute graft versus host disease (GVHD), nor cyclosporine (CSA) levels was associated with an increased risk of ARF. CONCLUSION: The cumulative incidence of ARF after HCT remains high. Amphotericin use during the 2-week exposure period and presence of hepatic sinuosoidal injury increased the risk of ARF within the first 100 days after HCT. Higher levels of serum creatinine at baseline were associated with a lower risk of ARF.

Acute Kidney Injury↗

PubMed2004

Risk factors for syngeneic graft-versus-host disease after adult hematopoietic cell transplantation.

Syngeneic graft-versus-host disease (sGVHD) has been described after hematopoietic cell transplantation (HCT) but remains poorly defined. We retrospectively reviewed adult syngeneic HCTs at our center (1980-2002) for sGVHD to investigate incidence, morbidity, and risk factors with a primary focus on parity. Among 119 transplantations, there were 21 cases of biopsy-proven sGVHD. The cumulative incidence was 18%, with multiorgan involvement in 6 cases and 1 death. sGVHD was more frequent when the donor was parous (32%) than nulliparous (9%) or male (13%; P =.03) and when the recipient was parous (31%) than nulliparous (7%) or male (13%; P =.02). Other univariable risk factors included older age (P <.01), busulfan/melphalan/thiotepa conditioning (P <.01), interleukin-2 (P =.02), HLA-A26 (P =.03), and more recent transplantation year (P <.01). Overall, risk factors were similar to those described in GVHD. Although an independent effect of parity could not be completely separated from other factors, donor and recipient pregnancy history merits further investigation.

Adolescent↗

PubMed2004

Increasingly frequent diagnosis of acute gastrointestinal graft-versus-host disease after allogeneic hematopoietic cell transplantation.

The reported incidence of grades II to IV acute graft-versus-host disease (GVHD) after hematopoietic cell transplantation with HLA-identical sibling donors has increased considerably during the past 15 to 20 years at our center. The purpose of this study was to evaluate the potential reasons for this change. We reviewed organ stages and overall grades of GVHD for 2220 patients who received a first marrow or peripheral blood cell transplant from an HLA-identical sibling or an HLA-allele-matched unrelated donor with the use of a posttransplantation immunosuppressive regimen that included both methotrexate and cyclosporine between 1985 and 2001. The most striking change was an increased incidence of stage 1 gut involvement from 10% to 20% before 1992 to 50% to 60% since 1992, both with related and unrelated donors. This change increased the incidence of grade II GVHD with sibling donors, such that the overall incidence of grade II to IV GVHD is now 60% to 70%. Among patients with chronic myeloid leukemia in chronic phase, the increasingly frequent diagnosis of acute GVHD since 1992 has not been associated with decreased survival. A high diagnostic sensitivity and increased awareness that gut GVHD can occur without skin involvement account for the increased incidence of acute GVHD at our center.

Acute Disease↗

PubMed2004

Diminishing the risk of nonrelapse mortality in hematopoietic stem cell transplantation: Prediction of exposure to the cyclophosphamide metabolite carboxyethylphosphoramide mustard.

OBJECTIVES: Our objectives were (1) to develop a population pharmacokinetic model for cyclophosphamide, 4-hydroxycyclophosphamide, and carboxyethylphosphoramide mustard (a reporter for nonrelapse mortality) in hematopoietic stem cell transplantation patients and (2) to validate a Bayesian approach to dosing. METHODS: In this study 147 patients received intravenous infusions of 60 mg. kg -1. d -1 cyclophosphamide for 2 days, followed by 12 to 14.4 Gy total body irradiation. A population model was developed to fit concentration-time data of cyclophosphamide and metabolites. Bayesian prediction of the area under the curve (AUC) was validated by dividing the data set into an index set (98 patients) and validation set (49 patients). Parameters from the index data set were used as priors. RESULTS: Cyclophosphamide elimination was best described by noninducible and inducible routes producing 4-hydroxycyclophosphamide. Induction was described by a zero-order maximum fold of induction-type increase in enzyme level. The prediction of the AUC of carboxyethylphosphoramide mustard was clinically accurate and precise (mean prediction error = -3.5% and root mean squared prediction error = 12.2%) with data limited to 5 to 6 points obtained in the first 16 hours. However, the AUC of 4-hydroxycyclophosphamide was overestimated (mean prediction error = 16.9%-23.6%). Several alternative models did not improve the result. CONCLUSION: The integrated mechanism-based model describes the pharmacokinetics of cyclophosphamide and carboxyethylphosphoramide mustard. Accurate modeling of 4-hydroxycyclophosphamide is limited by its chemical instability. Exposure to carboxyethylphosphoramide mustard could be accurately and precisely predicted with minimal data obtained over a 16-hour period after the first dose, offering the potential of pharmacokinetically guided dosing to reduce the nonrelapse mortality rate.

Adolescent↗

PubMed2004

trans fatty acids and systemic inflammation in heart failure.

BACKGROUND: trans fatty acid (TFA) intake increases systemic inflammation in healthy persons. However, the effect in patients with established heart disease is unknown. OBJECTIVE: Our aim was to determine whether TFAs are associated with systemic inflammation in patients with established heart disease. DESIGN: Red blood cell membrane TFAs, a biomarker of dietary intake, and inflammatory marker concentrations were ascertained in 86 ambulatory patients with established heart failure. Associations between TFA levels and inflammatory markers were evaluated by linear regression. RESULTS: Mean (+/-SD) TFA levels were 1.8 +/- 0.4% of membrane fatty acids (range: 0.7-2.9%). For each inflammatory marker, associations are presented as the absolute difference and percentage difference from the mean for each 1% higher membrane TFA level. After adjustment for age, sex, body mass index, diabetes, smoking, ejection fraction, New York Heart Association class, ischemic etiology, statin use, and serum glucose, TFA levels were positively associated with interleukin (IL) 1beta (difference from mean: 0.38 pg/mL; percentage difference from mean: 66%; P=0.04), IL-1 receptor antagonist (4033 pg/mL; 297%; P=0.006), IL-6 (9.5 pg/mL; 123%; P=0.006), IL-10 (241 pg/mL; 183%; P=0.02), tumor necrosis factor (TNF) alpha (256 pg/mL; 249%; P=0.02), TNF receptor 1 (537 pg/mL; 41%; P=0.03), TNF receptor 2 (39 242 pg/mL; 247%; P=0.001), monocyte chemoattractant protein 1 (117 pg/mL; 119%; P=0.004), and brain natriuretic peptide (40 pg/mL; 57%; P=0.04). Further adjustments for other patient characteristics did not significantly alter the results. CONCLUSION: TFAs are strongly associated with systemic inflammation in patients with heart disease, which suggests that attention to TFA intake may be important for secondary prevention efforts.

Biomarkers↗

PubMed2004

Supportive care.

To optimize treatment outcomes for hematologic malignancies, minimizing the consequences of treatment complications requires as much skill as the choice of the treatment itself. Myelosuppression and immunosuppression are frequent complications and have potentially serious infectious consequences. Invasive fungal infections and infections from respiratory viruses are increasing in frequency and have life-threatening potential. Damage to vital organs, especially the liver, is another important concern. In this chapter, the scope of invasive fungal and respiratory viral infections, recent insights into the pathogenesis of hepatic sinusoidal injury, and recent developments that impact prevention and treatment approaches for these complications are described. In Section I, Dr. John Wingard describes the advantages and disadvantages of various treatment options for invasive infections by the two chief fungal pathogens, Candida and Aspergillus. Adjunctive therapies and practical considerations that clinicians should weigh in choosing one or another of the various agents are discussed. The studies that have evaluated antifungal prophylaxis and empirical treatment strategies are reviewed. Finally, new approaches such as combination therapy, new diagnostics, and efforts to bolster host immunity are considered. In Section II, Dr. W. Garrett Nichols describes the epidemiology of community-acquired respiratory viruses (CRV) in patients with hematologic malignancies. Risk factors, clinical syndromes, and possible indirect effects of CRV infections are discussed. Treatment and prevention options are reviewed. In Section III, Dr. George McDonald describes sinusoidal obstruction syndrome (once known as hepatic veno-occlusive disease). Recent insights into pathogenesis are described. Diagnostic criteria and the advantages and disadvantages of various diagnostic methods are reviewed and prognosis is considered. Prevention and treatment options are discussed.

Aspergillosis↗

PubMed2003

Cyclophosphamide metabolism is affected by azole antifungals.

We performed a randomized trial to compare the safety and efficacy of itraconazole with fluconazole in preventing fungal infections in patients undergoing allogeneic stem cell transplantation (SCT). Itraconazole (intravenous 200 mg daily, or oral solution 2.5 mg/kg 3 times daily) and fluconazole (intravenous or oral, 400 mg daily) were administered with the start of conditioning therapy, until at least 120 days after SCT. After enrollment of the first 197 patients, a data and safety monitoring board reviewed potential drug-related toxicities. Patients who received itraconazole developed higher serum bilirubin and creatinine values in the first 20 days after SCT, with highest values in patients who received itraconazole concurrent with cyclophosphamide (CY) conditioning. Analysis of CY metabolism in a subset of patients demonstrated higher exposure to toxic metabolites among recipients of itraconazole compared with fluconazole. These data suggest that azole antifungals, through differential inhibition of hepatic cytochrome P-450 isoenzymes, affect CY metabolism and conditioning-related toxicities.

Adolescent↗

PubMed2003

Hepatic injury after nonmyeloablative conditioning followed by allogeneic hematopoietic cell transplantation: a study of 193 patients.

Liver injury is a frequent, serious complication of allogeneic hematopoietic cell transplantation (HCT) following myeloablative preparative regimens. We sought to determine the frequency and severity of hepatic injury after nonmyeloablative conditioning and its relationship to outcomes. One hundred ninety-three consecutive patients who received 2 Gy total body irradiation with or without fludarabine were evaluated for end points related to liver injury. Patients with diseases treatable by HCT who were ineligible for conventional myeloablative allogeneic HCT because of advanced age and/or comorbid conditions were included. Fifty-one patients (26%) developed hyperbilirubinemia of 68.4 microM (4 mg/dL) or greater, most commonly resulting from cholestasis due to graft-versus-host disease (GVHD) or sepsis. Pretransplantation factors associated with liver dysfunction were a diagnosis of aggressive malignancy (hazard ratio [HR] 1.9; P =.04) and the inclusion of fludarabine in the conditioning regimen (HR 1.8; P =.07). Overall survival at 1 year was superior for patients who had maximal serum bilirubin levels in the normal (78%) or minimally elevated (22.23-66.69 microM [1.3-3.9 mg/dL]) ranges (69%) compared with those in the 68.4 to 117.99 microM (4-6.9 mg/dL; 20%), 119.7 to 169.29 microM (7.0-9.9 mg/dL; 17%), and 171.0 microM (10 mg/dL; 19%) or greater groups. In summary, significant jaundice occurred in 26% of patients and was predominantly due to cholestasis resulting from GVHD and/or sepsis. Aggressive malignancies (mainly advanced disease) and later development of jaundice after transplantation predicted inferior survival.

Adolescent↗

PubMed2003

Conditioning with fludarabine and targeted busulfan for transplantation of allogeneic hematopoietic stem cells.

A regimen of busulfan and cyclophosphamide is standard therapy before transplantation of allogeneic hematopoietic stem cells in patients with chronic myelogenous leukemia (CML) or myelodysplastic syndrome (MDS). The clinical trial reported here was undertaken to test the hypothesis that fludarabine can replace cyclophosphamide in this regimen and facilitate donor engraftment with reduced toxicity. The conditioning regimen consisted of 30 mg/m2 intravenous fludarabine daily from day -9 to day -6, and oral busulfan given at 1 mg/kg 4 times a day every 6 hours from day -5 to day -2, with doses adjusted to target plasma levels of 900 +/- 100 ng/mL at steady state. Cyclosporine and methotrexate were used for prophylaxis for graft-versus-host disease. Enrolled were 42 patients with high-risk CML (n = 4) or MDS (n = 38). The median patient age was 52 years (range, 12-65 years). Mobilized blood stem cells were obtained from HLA-compatible siblings (n = 16) or unrelated donors (n = 26). Engraftment was achieved in all patients, and the day-100 regimen-related mortality was 7%. With a median follow-up of 18 months (range, 13-27 months), the probabilities of overall survival, disease-free survival, and nonrelapse mortality were 42.4%, 34.9%, and 24%, respectively. These data indicate that the combination of fludarabine and targeted busulfan is sufficiently immunosuppressive to facilitate engraftment of blood stem cells from HLA-matched siblings and unrelated donors. Based on these encouraging results, further studies of fludarabine and targeted busulfan are warranted in standard-risk patients.

Adolescent↗

PubMed2002

Cyclophosphamide metabolism, liver toxicity, and mortality following hematopoietic stem cell transplantation.

Liver toxicity caused by high-dose myeloablative therapy leads to significant morbidity after hematopoietic cell transplantation. We examined the hypothesis that liver toxicity after cyclophosphamide and total body irradiation is related to cyclophosphamide through its metabolism to toxins. Cyclophosphamide was infused at 60 mg/kg over 1 to 2 hours on each of 2 consecutive days, followed by total body irradiation. Plasma was analyzed for cyclophosphamide and its major metabolites. Liver toxicity was scored by the development of sinusoidal obstruction syndrome (veno-occlusive disease) and by total serum bilirubin levels. The hazards of liver toxicity, nonrelapse mortality, tumor relapse, and survival were calculated using regression analysis that included exposure to cyclophosphamide metabolites (as the area under the curve). Of 147 patients, 23 (16%) developed moderate or severe sinusoidal obstruction syndrome. The median peak serum bilirubin level through day 20 was 2.6 mg/dL (range, 0.5-41.1 mg/dL). Metabolism of cyclophosphamide was highly variable, particularly for the metabolite o-carboxyethyl-phosphoramide mustard, whose area under the curve varied 16-fold. Exposure to this metabolite was statistically significantly related to sinusoidal obstruction syndrome, bilirubin elevation, nonrelapse mortality, and survival, after adjusting for age and irradiation dose. Patients in the highest quartile of o-carboxyethyl-phosphoramide mustard exposure had a 5.9-fold higher risk for nonrelapse mortality than did patients in the lowest quartile. Engraftment and tumor relapse were not statistically significantly related to cyclophosphamide metabolite exposure. Increased exposure to toxic metabolites of cyclophosphamide leads to increased liver toxicity and nonrelapse mortality and lower overall survival after hematopoietic cell transplantation.

Adolescent↗