How I treat acute graft-versus-host disease of the gastrointestinal tract and the liver

McDonald, George B.

doi:10.1182/blood-2015-10-612747

Cited by 70 publications

(53 citation statements)

References 57 publications

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“…Nonetheless, it is likely that this approach may be more feasible to implement across providers, multicenter institutions, and larger clinical populations, which could prove useful in guiding therapy for patients with clinical features in between "low" and "very high" risk for mortality. 29 Alternatively, another potential approach is to include biomarkers in risk-stratification models. 24,30,31 For example, a recent study developed a biomarker-based algorithm to predict NRM within 6 months of diagnosis of acute GVHD.…”

Section: Discussionmentioning

confidence: 99%

Plasma biomarkers of risk for death in a multicenter phase 3 trial with uniform transplant characteristics post–allogeneic HCT

Zaid

et al. 2017

Blood

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Key Points• High ST2 and TIM3 at day 28 after allogeneic HCT were associated with nonrelapse mortality and overall survival at 2 years.• Low day 28 L-Ficolin was associated with VOD/SOS and high CXCL9 correlated with chronic GVHD.A phase 3 clinical trial (BMT CTN 0402) comparing tacrolimus/sirolimus (Tac/Sir) vs tacrolimus/methotrexate (Tac/Mtx) as graft-versus-host disease (GVHD) prophylaxis after matched-related allogeneic hematopoietic cell transplantation (HCT) recently showed no difference between study arms in acute GVHD-free survival. Within this setting of a prospective, multicenter study with uniform GVHD prophylaxis, conditioning regimen, and donor source, we explored the correlation of 10 previously identified biomarkers with clinical outcomes after allogeneic HCT. We measured biomarkers from plasma samples collected in 211 patients using enzyme-linked immunosorbent assay (Tac/Sir 5 104, Tac/ Mtx 5 107). High suppression of tumorigenicity-2 (ST2) and T-cell immunoglobulin mucin-3 (TIM3) at day 28 correlated with 2-year nonrelapse mortality in multivariate analysis (P 5 .0050, P 5 .0075, respectively) and in a proportional hazards model with time-dependent covariates (adjusted hazard ratio: 2.43 [1.49-3.95], P 5 .0038 and 4.87 [2.53-9.34], P < .0001, respectively). High ST2 and TIM3 correlated with overall survival. Chemokine (C-X-C motif) ligand 9 (CXCL9) levels above the median were associated with chronic GVHD compared with levels below the median in a time-dependent proportional hazard analysis (P 5 .0069). Low L-Ficolin was associated with hepatic veno-occlusive disease (P 5 .0053, AUC 5 0.80). We confirmed the correlation of plasma-derived proteins, previously assessed in single-center cohorts, with clinical outcomes after allogeneic HCT within this prospective, multicenter study. (Blood. 2017;129(2):162-170)

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Section: Discussionmentioning

confidence: 99%

Plasma biomarkers of risk for death in a multicenter phase 3 trial with uniform transplant characteristics post–allogeneic HCT

Zaid

et al. 2017

Blood

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“…The pain is attributed to inflammation, oedema, increased mucosal friability and ileus 161 . The use of NSAIDs and paracetamol might be limited by bleeding and hepatotoxicity risks, respectively.…”

Section: Managementmentioning

confidence: 99%

Acute graft-versus-host disease of the gut: considerations for the gastroenterologist

Naymagon

Wong

et al. 2017

Nat Rev Gastroenterol Hepatol

126

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Haematopoietic stem cell transplantation (HSCT) is central to the management of many haematological disorders. A frequent complication of HSCT is acute graft-versus-host disease (GVHD), a condition in which immune cells from the donor attack healthy recipient tissues. The gastrointestinal system is among the most common sites affected by acute GVHD, and severe manifestations of acute GVHD of the gut portends a poor prognosis in patients after HSCT. Acute GVHD of the gastrointestinal tract presents both diagnostic and therapeutic challenges. Although the clinical manifestations are nonspecific and overlap with those of infection and drug toxicity, diagnosis is ultimately based on clinical criteria. As reliable serum biomarkers have not yet been validated outside of clinical trials, endoscopic and histopathological evaluation continue to be utilized in diagnosis. Once a diagnosis of gastrointestinal acute GVHD is established, therapy with systemic corticosteroids is typically initiated, and non-responders can be treated with a wide range of second-line therapies. In addition to treating the underlying disease, the management of complications including profuse diarrhoea, severe malnutrition and gastrointestinal bleeding is paramount. In this Review, we discuss strategies for the diagnosis and management of acute GVHD of the gastrointestinal tract as they pertain to the practising gastroenterologist.

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“…1,2 The overall severity of GVHD has recently shifted toward less severe organ involvement and improved survival. 1,3 Newer methods of GVHD prophylaxis such as post-transplant cyclophosphamide, depletion of naïve T-cells from the graft and better HLA matching of unrelated donors and recipients have improved outcomes.…”

Section: Introductionmentioning

confidence: 99%

“…2,11 Ideally, GVHD management could be improved by adopting a personalized treatment strategy where patients predicted to have treatment-responsive GVHD could be effectively treated with lower doses of prednisone or shorter-duration systemic therapy in conjunction with oral topical glucocorticoid. 12–14 This approach to treatment is inappropriate for patients who have findings at disease onset that are associated with more severe GVHD and a greater risk of non-relapse mortality.…”

Section: Introductionmentioning

confidence: 99%

“…12–14 This approach to treatment is inappropriate for patients who have findings at disease onset that are associated with more severe GVHD and a greater risk of non-relapse mortality. 2,12 Several studies have tested the hypothesis that plasma biomarkers measured at GVHD onset or at a set time after transplant can predict whether GVHD is likely to respond to initial treatment or not. 3,15–19 We recently reported a study of plasma biomarkers measured before the clinical onset of acute GVHD.…”

Section: Introductionmentioning

confidence: 99%

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Predictive Value of Clinical Findings and Plasma Biomarkers after Fourteen Days of Prednisone Treatment for Acute Graft-versus-host Disease

McDonald

Tabellini

Storer

et al. 2017

Biology of Blood and Marrow Transplantation

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We examined the hypothesis that plasma biomarkers and concomitant clinical findings after initial glucocorticoid therapy can accurately predict failure of graft-versus-host-disease treatment and mortality. We analyzed plasma samples and clinical data in 165 patients after 14 days of glucocorticoid therapy and used logistic regression and areas under receiver-operating characteristic curves (AUC) to evaluate associations with treatment failure and non-relapse mortality (NRM). Initial treatment of GVHD was unsuccessful in 49 patients (30%). For predicting GVHD treatment failure, the best clinical combination (total serum bilirubin and skin GVHD stage, AUC 0.70) was competitive with the best biomarker combination (TIM3 and ST2, AUC 0.73). The combination of clinical features and biomarker results offered only a slight improvement (AUC 0.75). For predicting NRM at 1 year, the best clinical predictor (total serum bilirubin, AUC 0.81) was competitive with the best biomarker combination (TIM3 and sTNFR1, AUC 0.85). The combination offered no improvement (AUC 0.85). Infection was the proximate cause of death in virtually all patients. We conclude that after 14 days of glucocorticoid therapy, clinical findings (serum bilirubin, skin GVHD) and plasma biomarkers (TIM3, ST2, sTNFR1) can predict failure of GVHD treatment and non-relapse mortality. These biomarkers reflect counter-regulatory mechanisms and provide insight into the pathophysiology of GVHD reactions following glucocorticoid treatment. The best predictive models, however, exhibit inadequate positive predictive values for identifying high-risk GVHD cohorts for investigational trials, as only a minority of patients with high-risk GVHD would be identified, and most patients would be falsely predicted to have adverse outcomes.

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How I treat acute graft-versus-host disease of the gastrointestinal tract and the liver

Cited by 70 publications

References 57 publications

Plasma biomarkers of risk for death in a multicenter phase 3 trial with uniform transplant characteristics post–allogeneic HCT

Plasma biomarkers of risk for death in a multicenter phase 3 trial with uniform transplant characteristics post–allogeneic HCT

Acute graft-versus-host disease of the gut: considerations for the gastroenterologist

Predictive Value of Clinical Findings and Plasma Biomarkers after Fourteen Days of Prednisone Treatment for Acute Graft-versus-host Disease

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