G B McDonald

Fred Hutchinson Cancer Research Center, Seattle, Washington, United States

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Publications (188)1308.62 Total impact

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    ABSTRACT: We identified plasma biomarkers that presaged outcomes in patients with gastrointestinal GVHD by measuring 23 biomarkers in samples collected before initiation of treatment. Six analytes with the greatest accuracy in predicting grade 3-4 GVHD in the first cohort (74 patients) were then tested in a second cohort (76 patients). The same six analytes were also tested in samples collected at day 14±3 from 167 patients free of GVHD at the time. Logistic regression and calculation of an area under a receiver-operating characteristic (ROC) curve for each analyte were used to determine associations with outcome. Best models in the GVHD onset and landmark analyses were determined by forward selection. In samples from the second cohort, collected a median of 4 days before start of treatment, levels of TIM3, IL6, and sTNFR1 had utility in predicting development of peak grade 3-4 GVHD (area under ROC curve, 0.88). Plasma ST2 and sTNFR1 predicted non-relapse mortality within 1 year after transplantation (area under ROC curve, 0.90). In the landmark analysis, plasma TIM3 predicted subsequent grade 3-4 GVHD (area under ROC curve, 0.76). We conclude that plasma levels of TIM3, sTNFR1, ST2, and IL6 are informative in predicting more severe GVHD and non-relapse mortality. Copyright © 2015 American Society of Hematology.
    Blood 05/2015; 126(1). DOI:10.1182/blood-2015-03-636753 · 10.45 Impact Factor
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    ABSTRACT: The 2006 National Institute of Health (NIH) Consensus paper presented recommendations by the Ancillary Therapy and Supportive Care Working Group to support clinical research trials in chronic GVHD. Topics covered in that inaugural effort included the prevention and management of infections and common complications of chronic GVHD, as well as recommendations for patient education, and appropriate follow-up. Given the new literature that has emerged during the past 8 years we made further organ specific refinements to these guidelines. Minimum frequencies are suggested for monitoring key parameters relevant to chronic GVHD during systemic immunosuppressive therapy and, thereafter, referral to existing late effects consensus guidelines is advised. Using the framework of the prior consensus, the 2014 NIH recommendations are organized by organ or other relevant systems and graded according to the strength and quality of supporting evidence. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 03/2015; 21(7). DOI:10.1016/j.bbmt.2015.03.024 · 3.40 Impact Factor
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    ABSTRACT: We conducted a phase III study to test the hypothesis that initial therapy with lower-dose prednisone is effective and safe for patients with newly diagnosed acute graft-versus-host disease. We hypothesized that a 50% decrease in the initial dose of prednisone for treatment of acute graft-versus-host disease would suffice to control graft-versus-host disease without increasing the incidence of secondary treatment. Patients with Grade IIa-manifestations (upper gastrointestinal symptoms, stool volumes <1.0 L/day, rash involving <50% of the body surface, no hepatic dysfunction; n=102) were randomized to start treatment with prednisone at 1 mg/kg/day or 0.5 mg/kg/day. Those with ≥Grade IIb-manifestations (rash involving ≥50% of the body surface, stool volumes ≥1.0 L/day or hepatic involvement; n=62) were randomized to start treatment with prednisone at 2 mg/kg/day or 1 mg/kg/day. The primary study endpoint, a ≥33% relative reduction of the mean cumulative prednisone dose by day-42 after initial treatment with lower-dose prednisone, was not reached. With a median follow-up of 36 (7-53) months, initial treatment with lower-dose prednisone appeared to be effective for patients presenting with Grade IIa-manifestations since it did not increase the likelihood of requiring secondary immunosuppressive therapy. Further exploratory analyses suggested that for patients presenting with skin-predominant ≥IIb-manifestations, initial treatment with lower-dose prednisone was associated with an increased risk of requiring secondary immunosuppressive therapy (41% vs. 7%, p=0.001). In summary, initial treatment of newly diagnosed acute graft-versus-host disease with lower-dose prednisone is effective. Within the statistical limitations of the study, results showed no suggestion that use of lower-dose prednisone adversely affected survival. Copyright © 2015, Ferrata Storti Foundation.
    Haematologica 02/2015; 100(6). DOI:10.3324/haematol.2014.118471 · 5.81 Impact Factor
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    S R Hingorani · K Seidel · E Pao · R Lawler · G B McDonald
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    ABSTRACT: Acute kidney injury (AKI) is common after hematopoietic cell transplant (HCT). The etiology of AKI is unknown because biopsies are rarely performed. The pathophysiology of injury is inferred from clinical data. Thrombotic microangiopathy (TMA) is often invoked as the cause of renal injury. Patients >2 years old undergoing their first HCT at Fred Hutchinson Cancer Research Center participated in this study. We prospectively measured plasma markers of coagulation activation, (PAI-1 and tPA) and fibrinolyis (D-dimer) weekly in 149 patients during the first 100 days post transplant. Cox proportional hazards modeling was used to determine associations between these markers and AKI (doubling of baseline serum creatinine). Kruskal-Wallis test was used to determine the associations between day 100 urinary albumin to creatinine ratios and these markers. Thirty one percent of patients developed AKI. Though elevations in these markers occurred frequently, neither PAI-1 nor tPA were associated with the development of AKI. D-dimer was associated with a slightly increased risk of AKI (relative risk=1.76; P-value 0.04). None of these markers were associated with micro- or macroalbuminuria at day 100. The lack of an association with AKI suggests that endothelial injury in the form of TMA is not a common cause of AKI early after transplant.Bone Marrow Transplantation advance online publication, 9 February 2015; doi:10.1038/bmt.2015.2.
    Bone Marrow Transplantation 02/2015; 50(5). DOI:10.1038/bmt.2015.2 · 3.57 Impact Factor
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    ABSTRACT: The 2005 National Institutes of Health (NIH) Consensus Conference proposed new criteria for diagnosing and scoring the severity of chronic GVHD. The 2014 NIH consensus maintains the framework of the prior consensus with further refinement based on new evidence. Revisions have been made to address areas of controversy or confusion, such as the overlap chronic GVHD subcategory and the distinction between active disease and past tissue damage. Diagnostic criteria for involvement of mouth, eyes, genitalia, and lungs have been revised. Categories of chronic GVHD should be defined in ways that indicate prognosis, guide treatment, and define eligibility for clinical trials. Revisions have been made to focus attention on the causes of organ-specific abnormalities. Attribution of organ-specific abnormalities to chronic GVHD has been addressed. This paradigm shift provides greater specificity, more accurately measures the global burden of disease attributed to GVHD, and will facilitate biomarker association studies. Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 12/2014; 21(3). DOI:10.1016/j.bbmt.2014.12.001 · 3.40 Impact Factor
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    ABSTRACT: Development of liver disease after hematopoietic cell transplantation is common and the causes diverse. Infection by hepatitis C virus (HCV) can be seen in patients who are chronically infected before transplant or from passage of virus from an infected donor; the normal 10-year course of hepatitis C after transplant is one of waxing and waning of serum aminotransferase enzymes, with little morbidity. In the series of 3 patients reported here, the course of hepatitis C was rapidly fatal, with the onset of jaundice at day 60 to 80 after transplant and liver histology typical of fibrosing cholestatic hepatitis (marked bile ductular proliferation, ballooned hepatocytes, and associated collagenous fibrosis centered around ductules). The bile ductular reaction pattern varied from elongated structures without a recognizable lumen to a pattern of cuboidal cells with a clear lumen. There was significant cholestasis with bile within hepatocytes and canalicular bile plugs. In situ HCV RNA hybridization studies from 1 patient showed a robust infection with high levels of HCV-infected hepatocytes and active viral replication. All 3 patients were on immunosuppressive drugs after transplant, including mycophenolate mofetil (MMF), which irreversibly inhibits inosine monophosphate dehydrogenase, on which T and B lymphocytes are dependent. We speculate that fatal fibrosing cholestatic hepatitis C in these cases was related to the immunosuppressive effects of MMF, as we had not recognized this presentation of HCV infection before the introduction of MMF.
    American Journal of Surgical Pathology 12/2014; 39(2). DOI:10.1097/PAS.0000000000000345 · 5.15 Impact Factor
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    ABSTRACT: Background and objectivesGraft-versus-host disease (GVHD) is associated with kidney injury after hematopoietic cell transplantation (HCT). Because plasma elafin levels correlate with skin GVHD, this study examined urinary elafin as a potential marker of renal inflammation and injury.Design, setting, participants, & measurementsUrine was collected prospectively on 205 patients undergoing their first HCT from 2003 to 2010. Collections were done at baseline, weekly through day 100, and monthly through year 1 to measure elafin and urine albumin-to-creatinine ratio (ACR). Associations between urinary elafin levels and microalbuminuria, macroalbuminuria, AKI and CKD, and mortality were examined using Cox proportional hazards or linear regression models. Available kidney biopsy specimens were processed for immunohistochemistry.ResultsMean urinary elafin levels to day 100 were higher in patients with micro- or macroalbuminuria (adjusted mean difference, 529 pg/ml; P=0.03) at day 100 than in those with a normal ACR (adjusted mean difference, 1295 pg/ml; P<0.001). Mean urinary elafin levels were higher in patients with AKI compared with patients without AKI (adjusted mean difference, 558 pg/ml; P<0.01). The average urinary elafin levels within the first 100 days after HCT were higher in patients who developed CKD at 1 year than in patients without CKD (adjusted mean difference, 894 pg/ml; P=0.002). Among allogeneic recipients, a higher proportion of patients with micro- or macroalbuminuria at day 100 also had grade II-IV acute GVHD (80% and 86%, respectively) compared with patients with a normal ACR (58%; global P<0.01). Each increase in elafin of 500 pg/ml resulted in a 10% increase in risk of persistent macroalbuminuria (hazard ratio, 1.10; 95% confidence interval [95% CI], 1.06 to 1.13; P<0.001) and a 7% increase in the risk of overall mortality (95% CI, 1.02 to 1.13, P<0.01). Renal biopsy specimens from a separate cohort of HCT survivors demonstrated elafin staining in distal and collecting duct tubules.Conclusion Higher urinary elafin levels are associated with an increased risk of micro- and macroalbuminuria, AKI and CKD, and death after HCT.
    Clinical Journal of the American Society of Nephrology 11/2014; 10(1). DOI:10.2215/CJN.01840214 · 4.61 Impact Factor
  • Paul A Hoffmeister · Barry E Storer · George B McDonald · K Scott Baker
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    ABSTRACT: Purpose: To determine risk factors for the development of gallstones and the prevalence of related cholecystectomy in children following hematopoietic cell transplantation (HCT). Patients and methods: A retrospective chart review of 1343 patients aged below 18 years old who survived at least 1 year after HCT from 1969 to 2011 was performed. Multivariate Cox regression models were used to estimate the hazard ratio (HR) of risk factors associated with gallstones. Results: Gallstones developed in 91 patients, a median of 3.5 (range, 0.1 to 30.9) years after HCT at 16.3 (range, 0.8 to 44.2) years of age, with a 40-year cumulative incidence of 11%. At initial diagnosis, 61 (67%) patients were symptomatic and 30 (23%) had incidental gallstones. Risk factors associated with gallstones included autologous transplant (HR=2.7, P=0.02), unrelated donor (HR=2.0, P=0.05), grade 3 to 4 acute graft-versus-host disease (GVHD) (HR=2.2, P=0.03), chronic GVHD (HR=2.0, P=0.05), second transplant (HR=2.3, P=0.03), diabetes (HR=2.2, P=0.05), and estrogen therapy (HR=1.8, P=0.03). Fifty-six patients underwent cholecystectomy. The prevalence of cholecystectomy among 853 surviving patients was 5.2%. Conclusions: Childhood HCT patients have an increased risk of developing gallstones.
    Journal of Pediatric Hematology/Oncology 07/2014; 36(6). DOI:10.1097/MPH.0000000000000213 · 0.90 Impact Factor
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    ABSTRACT: We hypothesized that clinical risk factors could be identified within 2 weeks of onset of severe (stage 3 or 4) acute gut GVHD for identifying a patient population with a very poor outcome. Among 1462 patients who had allogeneic hematopoietic cell transplantation (HCT) between January 2000 and December 2005, 116 (7.9%) developed stage 3-4 gut GVHD. The median time for onset of stage 3-4 gut GVHD was 35 (4-135) days after allogeneic HCT. Eighty-five of the 116 patients (73%) had corticosteroid resistance before or within 2 weeks after the onset of stage 3-4 gut GVHD. Significant risk factors for mortality included corticosteroid resistance (hazards ratio (HR)=2.93; P=0.0005), age >18 years (HR=4.95; P=0.0004), increased serum bilirubin (HR 2.53; P=0.0001) and overt gastrointestinal bleeding (HR 2.88; P=0.0004). Among patients with stage 3-4 gut GVHD, the subgroup with 0, 1 or 2 risk factors had a favorable prognosis, whereas the subgroup with 3 or 4 risk factors had a dismal prognosis. This information should be considered in designing future studies of severe gut GVHD and in counseling patients about prognosis.Bone Marrow Transplantation advance online publication, 28 April 2014; doi:10.1038/bmt.2014.69.
    Bone marrow transplantation 04/2014; 49(7). DOI:10.1038/bmt.2014.69 · 3.57 Impact Factor
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    ABSTRACT: Cord colitis syndrome after umbilical cord blood transplantation (UCBT) is late-onset diarrhea, absence of infection or GVHD, chronic active colitis and granulomatous inflammation, responding to antibiotics. We tested the hypothesis that Seattle recipients of UCBT had late-occurring colitis distinct from GVHD and colitis in other allograft recipients. We conducted a blinded histologic review of 153 colon biopsies obtained between days 70-365 from 45 UCBT recipients and 45 matched allograft controls. Diarrhea was the primary indication for biopsy in 10 UCBT and 11 controls. No histological differences were seen between UCBT patients and controls with diarrhea or between the entire cohort of UCBT patients and their controls. Distorted mucosal architecture and apoptotic crypt cells typical of GVHD were common in both groups; Paneth cell metaplasia and granulomas were rare findings. Chronic active colitis was present in 58% of UCBT recipients and in 62% of controls. No UCBT recipient with diarrhea was treated with antibiotics and all responded to systemic corticosteroids. Allograft recipients with colitis after day 70 had acute GVHD as the explanation, independent of the source of donor cells. We could not identify a histologically distinct cord colitis syndrome in either UCBT or non-cord blood allograft recipients.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 04/2014; 20(7). DOI:10.1016/j.bbmt.2014.03.020 · 3.40 Impact Factor
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    S Hingorani · T Gooley · E Pao · B Sandmaier · G McDonald
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    ABSTRACT: We compared urinary levels of cytokines in patients with and without albuminuria, proteinuria and kidney disease (glomerular filtration rate<60 mL/min per 1.73 m(2)) after HCT. Plasma and urine were collected at baseline and weekly through day 100 and monthly through year 1, for measurement of IL-6, gp130, sIL6r, IL-10, IL15, MCP-1 and urine albumin-to-creatinine ratios (ACRs). Cox-proportional hazards modeling examined associations between urinary cytokine levels and development of these renal end points. The association of ACR with the hazard of overall mortality was assessed using Cox regression. Increasing urinary IL-6 and IL-15 were associated with an increased risk of developing proteinuria. Urinary MCP-1 during the first 100 days post HCT was associated with kidney disease at 1 year. The degree of albuminuria at any time point in the first 100 days post transplant was related to the subsequent risk of death (for ACR 30-299, hazard ratio (HR)=1.91; 95% confidence interval (CI): 1.27-2.87; for ACR >300, HR=2.82; 95% CI: 1.60-4.98). After HCT, elevated urinary levels of pro-inflammatory cytokines are associated with development of albuminuria and proteinuria, suggesting early intra-renal inflammation as an important pathogenetic mechanism. Albuminuria and proteinuria within the first 100 days post HCT are associated with decreased overall survival.Bone Marrow Transplantation advance online publication, 9 December 2013; doi:10.1038/bmt.2013.197.
    Bone marrow transplantation 12/2013; 49(3). DOI:10.1038/bmt.2013.197 · 3.57 Impact Factor
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    ABSTRACT: The Tim-3 receptor has been implicated as a negative regulator of adaptive immune responses. We have utilized a proteomic strategy to identify novel proteins associated with graft vs host disease (GVHD) following allogeneic hematopoietic cell transplantation (HCT). Mass spectrometry analysis of plasmas from subjects with mid-gut and upper-gut GVHD compared to those without GVHD identified increased levels of a protein identified with high confidence as Tim-3. A followup validation study using an immunoassay to measure Tim-3 levels in individual plasma samples from 127 patients demonstrated significantly higher plasma Tim-3 concentrations in patients with the more severe mid-gut, compared to those with upper gut GVHD (p=0.005), patients without GVHD (p=0.002), and normal controls (p<0.0001). Surface expression of Tim-3 was increased on CD8(+) T cells from patients with grade II-IV acute GVHD (p=0.01). Mass spectrometry based profiling of plasmas from multiple subjects diagnosed with common diseases provided evidence for restricted release of soluble Tim-3 in the context of GVHD. These findings have mechanistic implications for the development of novel strategies for targeting the Tim-3 immune regulatory pathway as an approach to improving control of GVHD.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 06/2013; 19(9). DOI:10.1016/j.bbmt.2013.06.011 · 3.40 Impact Factor
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    ABSTRACT: Targeted busulfan/cyclophosphamide ((T)BU/CY) for allogeneic hematopoietic cell transplantation (HCT) carries a high risk of sinusoidal obstruction syndrome (SOS) in patients transplanted for myelofibrosis. We tested the hypothesis that reversing the sequence of administration (from (T)BU/CY to CY/(T)BU) will reduce SOS and day +100 non-relapse mortality (NRM). We enrolled 51 patients with myelofibrosis (n=20), acute myeloid leukemia (AML, n=20), or myelodysplastic syndrome (MDS, n=11) in a prospective trial of CY/(T)BU conditioning for HCT. Cyclophosphamide 60 mg/kg/day IV for two days was followed by daily IV BU for four days, targeted to a concentration at steady state (Css) of 800-900 ng/mL. CY/(T)BU-conditioned patients had higher exposure to CY (p<0.0001) and lower exposure to 4-hydroxyCY (p<0.0001) compared to (T)BU/CY-conditioned patients. Clinical outcomes were compared with controls (n=271) conditioned with (T)BU/CY for the same indications. In patients with myelofibrosis, CY/(T)BU conditioning was associated with a significantly reduced incidence of SOS (0% vs. 30% after (T)BU/CY, p=0.006), while SOS incidence was low in both cohorts with AML/MDS. Day +100 mortality was significantly lower in the CY/(T)BU cohort (2% vs. 13%, p=0.01). CY/(T)BU conditioning markedly impacted CY pharmacokinetics and was associated with significantly lower incidences of SOS and day +100 mortality, suggesting that CY/(T)BU is superior to (T)BU/CY as conditioning for patients with myelofibrosis.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 04/2013; 19(7). DOI:10.1016/j.bbmt.2013.04.005 · 3.40 Impact Factor
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    ABSTRACT: The purpose of this prospective observational study was to determine the incidence of hepatic sinusoidal obstruction syndrome (SOS), following gemtuzumab ozogamicin (GO) therapy in routine clinical practice. Patients receiving GO for acute myeloid leukemia (AML) were eligible. Assessments were requested to be performed weekly for 6 weeks after the start of GO therapy or 4 weeks after the last dose (whichever was later), and after 6 months. The primary outcome variable was the incidence of SOS as judged by a panel of independent experts. A total of 512 patients were enrolled at 54 US centers and 482 were evaluable. The incidence of SOS in this study population was 9.1 % (44/482; 95 % confidence interval 6.9-12.0 %). Of the 44 patients classified as having SOS, 8 were mild, 17 moderate, and 19 severe; 33 died within 6 months (20 of disease progression and 13 of SOS and multiorgan failure). Most (68 %) patients in the study died within 6 months; most of these deaths (73 %) were due to progression of AML. Serious adverse events occurred in 85 % of patients, most (81 %) due to AML, febrile neutropenia, pyrexia, and sepsis. GO administered in routine clinical practice carries an overall 9.1 % risk of SOS and a 2.7 % risk of death from SOS and multiorgan failure. No risk factors were identified for the development of SOS.
    International journal of hematology 03/2013; 97(4). DOI:10.1007/s12185-013-1275-2 · 1.92 Impact Factor
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    Biology of Blood and Marrow Transplantation 02/2013; 19(2):S260-S261. DOI:10.1016/j.bbmt.2012.11.351 · 3.40 Impact Factor
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    ABSTRACT: Existing standards for screening and management of late effects occurring in children who have undergone hematopoietic cell transplantation (HCT) include recommendations from pediatric cancer networks and consensus guidelines from adult-oriented transplantation societies applicable to all HCT recipients. Although these approaches have significant merit, they are not pediatric HCT-focused, and they do not address post-HCT challenges faced by children with complex nonmalignant disorders. In this article we discuss the strengths and weaknesses of current published recommendations and conclude that pediatric-specific guidelines for post-HCT screening and management would be beneficial to the long-term health of these patients and would promote late effects research in this field. Our panel of late effects experts also provides recommendations for follow-up and therapy of selected post-HCT organ and endocrine complications in pediatric patients.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 03/2012; 18(3):334-47. DOI:10.1016/j.bbmt.2012.01.003 · 3.40 Impact Factor
  • Aiko Kida · George B McDonald
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    ABSTRACT: Gastrointestinal and hepatobiliary problems in the second year after allogeneic hematopoietic cell transplant (HCT) are usually a continuation of symptoms of protracted acute graft-versus-host disease (GVHD), chronic GVHD, medication side effects, and infection related to immune suppression. As time passes, as tolerance develops, and as immunity improves, the frequency and severity of these problems wane, but new problems involving the gut and liver may arise, sometimes insidiously and sometimes decades after the transplant. Examples are esophageal strictures related to chronic GVHD, gallstones, cirrhosis caused by chronic hepatitis C, secondary malignancy, and rare cases of pancreatic atrophy. One very common complication of transplantation, iron overload, is often associated with substantial iron accumulation in the liver; however, the most troublesome complications are not hepatic but cardiac and endocrine-related.
    Seminars in Hematology 01/2012; 49(1):43-58. DOI:10.1053/j.seminhematol.2011.10.006 · 3.27 Impact Factor
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    ABSTRACT: Long-term complications after hematopoietic cell transplantation (HCT) have been studied in detail. Although virtually every organ system can be adversely affected after HCT, the underlying pathophysiology of these late effects remain incompletely understood. This article describes our current understanding of the pathophysiology of late effects involving the gastrointestinal, renal, cardiac, and pulmonary systems, and discusses post-HCT metabolic syndrome studies. Underlying diseases, pretransplantation exposures, transplantation conditioning regimens, graft-versus-host disease, and other treatments contribute to these problems. Because organ systems are interdependent, long-term complications with similar pathophysiologic mechanisms often involve multiple organ systems. Current data suggest that post-HCT organ complications result from cellular damage that leads to a cascade of complex events. The interplay between inflammatory processes and dysregulated cellular repair likely contributes to end-organ fibrosis and dysfunction. Although many long-term problems cannot be prevented, appropriate monitoring can enable detection and organ-preserving medical management at earlier stages. Current management strategies are aimed at minimizing symptoms and optimizing function. There remain significant gaps in our knowledge of the pathophysiology of therapy-related organ toxicities disease after HCT. These gaps can be addressed by closely examining disease biology and identifying those patients at greatest risk for adverse outcomes. In addition, strategies are needed for targeted disease prevention and health promotion efforts for individuals deemed at high risk because of their genetic makeup or specific exposure profile.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 09/2011; 17(11):1573-84. DOI:10.1016/j.bbmt.2011.09.013 · 3.40 Impact Factor
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    ABSTRACT: Biomarkers capable of predicting the onset and severity of acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic cell transplantation (HCT) would enable preemptive and risk-stratified therapy. Severe aGVHD leads to gastrointestinal protein loss, resulting in hypoalbuminemia. We hypothesized that decreases in serum albumin at onset of aGVHD would predict the risk of progression to severe aGVHD. We identified 401 patients who developed aGVHD grades II-IV after reduced-intensity allogeneic HCT and reviewed all available serum albumin values from 30 days before HCT to 45 days after initiation of treatment for aGVHD. A ≥0.5 g/dL decrease in serum albumin concentration from pretransplantation baseline to the onset of treatment for aGVHD predicted the subsequent development of grade III/IV aGVHD (versus grade II aGVHD) with a sensitivity of 69% and a specificity of 73%. Overall mortality at 6 months after initiation of aGVHD treatment was 36% versus 17% for patients with and without ≥0.5 g/dL decreases in serum albumin, respectively (P = .0009). We conclude that change in serum albumin concentration from baseline to initiation of aGVHD treatment is an inexpensive, readily available, and predictive biomarker of GVHD severity and mortality after reduced-intensity allogeneic HCT.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 07/2011; 17(11):1594-601. DOI:10.1016/j.bbmt.2011.07.021 · 3.40 Impact Factor
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    ABSTRACT: Daily intravenous (i.v.) busulfan is increasingly being used in hematopoietic cell transplantation (HCT) conditioning regimens. Intravenous busulfan doses administered at the traditional frequency of every 6 hours can be targeted ((T)Bu) to a patient-specific concentration at steady state (C(ss)) using therapeutic drug monitoring (TDM). In this report, we describe our experiences with TDM of daily i.v. busulfan in an adult population, with the specific aims of (1) evaluating covariates associated with busulfan clearance, and (2) assessing the feasibility of TDM for outpatient administration of daily (T)Bu with pharmacokinetic sampling over 6 hours. A retrospective pharmacokinetic analysis was conducted in 87 adults receiving daily (T)Bu as part of cyclophosphamide followed by (T)BU (CY/(T)BU), fludarabine monophosphate (fludarabine) followed by (T)BU, or (T)BU concurrent with fludarabine conditioning. The desired C(ss) was achieved in 85% of patients receiving daily i.v. busulfan. Busulfan clearance was not associated with sex or age, but was associated with the day of dosing and conditioning regimen (P = .0016). In patients receiving CY/(T)BU, no differences in clearance were found between dosing days (P > .36); however, clearance decreased significantly in patients receiving fludarabine-based regimens (P = .0016). Busulfan clearance and C(ss) estimates from pharmacokinetic sampling over 8, 11, or 24 hours were comparable (P > .4). However, pharmacokinetic modeling of individual patient concentration-time data over 6 hours could not reliably estimate busulfan clearance or C(ss).
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 07/2011; 18(2):265-72. DOI:10.1016/j.bbmt.2011.06.013 · 3.40 Impact Factor

Publication Stats

12k Citations
1,308.62 Total Impact Points


  • 1980–2015
    • Fred Hutchinson Cancer Research Center
      • • Division of Clinical Research
      • • Division of Public Health Sciences
      Seattle, Washington, United States
  • 1980–2014
    • University of Washington Seattle
      • • Department of Pediatrics
      • • Department of Medicine
      • • Division of Gastroenterology
      • • Department of Pharmaceutics
      • • Fred Hutchinson Cancer Research Center
      • • Department of Radiology
      Seattle, Washington, United States
  • 2005
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2004–2005
    • Harvard Medical School
      • Department of Medicine
      Boston, MA, United States
    • University of Florida
      Gainesville, Florida, United States
  • 2001
    • Emory University
      Atlanta, Georgia, United States
  • 1998
    • VA Puget Sound Health Care System
      Washington, Washington, D.C., United States
    • Swedish Medical Center
      Englewood, Colorado, United States