Markers of coagulation activation and acute kidney injury in patients after hematopoietic cell transplantation.

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.

Prognostic factors and outcomes of severe gastrointestinal GVHD after allogeneic hematopoietic cell transplantation.

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.

Prospective qualitative and quantitative non-invasive evaluation of intestinal acute GVHD by contrast-enhanced ultrasound sonography.

Intestinal acute GVHD (I-aGVHD) is a life-threatening complication after allografting. Non-invasive bed-side procedures to evaluate extension and treatment response are still lacking. We hypothesized that, during I-aGVHD, contrast-enhanced ultrasound sonography (CEUS) could detect microcirculation changes (MVC) of the bowel wall (BW) and help to monitor treatment response. We prospectively employed CEUS in 83 consecutive patients. Of these, 14 patients with biopsy-proven intestinal GVHD (I-GVHD) were defined as the study group, whereas 16 patients with biopsy-proven stomach GVHD (U-GVHD) without intestinal symptoms, 6 normal volunteers and 4 patients with neutropenic enterocolitis were defined as the control group. All patients were evaluated with both standard ultrasonography (US) and CEUS at the onset of intestinal symptoms, during clinical follow-up and at flare of symptoms. Standard US revealed BW thickening of multiple intestinal segments, useful to determine the extension of GVHD. CEUS showed MVC, which correlated with GVHD activity, treatment response, and predicted flare of intestinal symptoms. US and CEUS findings were superimposable at diagnosis and in remission. CEUS was, however, more sensitive and specific to identify subclinical activity in patients with clinical relevant improvement. These findings were not observed in the control groups. CEUS is a non-invasive, easily reproducible bed-side tool useful to monitor I-aGVHD.

[Treatment algorithm for gastrointestinal graft-versus-host disease]. / Eich gastrointestinal aguda: algoritmo de tratamiento inicial basado en datos científicos.

Over the last decade, there has been a dramatic decline in the frequency of organ failure, infection, and severe acute CVHD as causes of non-relapse mortality after allogeneic hematopoietic cell transplantation. Gastrointestinal CVHD, however, remains a significant obstacle to survival. Patients who present with non-progressive symptoms of the upper gut phenotype of GVHD seldom progress to severe CVHD, but may have a prolonged course, they can be successfully treated with prednisone 1 mg/kg/day for a limited time, along with topical and oral glucocorticoid. Patients who present with the mid-gut phenotype of GVHD can be recognized soon after presentation by secretory protein-losing enteropathy and falling serum albumin; their treatment requires prednisone 2 mg/kg/day and probably an additional drug such as mycophenolic acid. Failure to improve identifies a cohort with a poor prognosis; secondary therapy should be started while gut mucosa is still intact, but no secondary therapies have been proven in randomized trials to improve survival. Patients whose initial presentation (large volume diarrhea, low serum albumin, jaundice, mucosal necrosis and sloughing at initial endoscopy) presages a fatal outcome have not been studied prospectively.

Influence of oral beclomethasone dipropionate on early non-infectious pulmonary outcomes after allogeneic hematopoietic cell transplantation: results from two randomized trials.

Early non-infectious pulmonary complications represent a significant cause of mortality after hematopoietic cell transplantation (HCT). We tested the hypothesis that oral beclomethasone dipropionate (BDP) is effective for preventing early non-infectious pulmonary complications after allogeneic HCT. We retrospectively reviewed the medical records of 120 patients, 60 in each treatment arm, to identify non-infectious and infectious pulmonary events and pulmonary function test results from all patients who participated in two randomized trials of oral BDP for treatment of acute gastrointestinal GVHD. 17-Beclomethasone monopropionate (17-BMP), the active metabolite of BDP, was evaluated in blood from the right atrium in four patients. Thirty-three of 42 (79%) placebo-treated patients experienced a decrease of the DL(CO) from pretransplant to day 80 after transplant, compared with 27 of 49 (55%) BDP-treated patients (P=0.02). In the first 200 days after randomization, there were no cases of non-infectious pulmonary complications in BDP-treated patients, vs four cases among placebo-treated patients (P=0.04). Levels of 17-BMP were detected in atrial blood at steady state. Delivery of a potent glucocorticoid such as 17-BMP to the pulmonary artery after oral dosing of BDP may be useful in modulating pulmonary inflammation and preventing the development of non-infectious pulmonary complications after allogeneic HCT.

Personalized dosing of cyclophosphamide in the total body irradiation-cyclophosphamide conditioning regimen: a phase II trial in patients with hematologic malignancy.

This study investigates the efficacy and safety of personalized cyclophosphamide (CY) dosing in 50 patients receiving CY along with total body irradiation (TBI). Participants received CY 45 mg/kg with subsequent therapeutic drug monitoring using Bayesian parameter estimation to personalize the second CY dose to a target area under the curve (AUC) for carboxyethylphosphoramide mustard (CEPM) (a reporter molecule for CY-derived toxins) and for hydroxycyclophosphamide (to ensure engraftment). The mean second CY dose was 66 mg/kg; the total dose ranged from 45 to 145 mg/kg. After completion of this phase II study, we compared participants' clinical outcomes with those of concurrent controls (n = 100) who received TBI along with standard CY doses of 120 mg/kg. Patients receiving personalized CY dosing had significantly lower postconditioning peak total serum bilirubin (P = 0.03); a 38% reduction in the hazard of acute kidney injury (AKI) (P = 0.03); and nonrelapse and overall survival rates similar to those in the controls (P = 0.70 and 0.63, respectively) despite the lower doses of CY administered to most of the patients in the personalized dosage group.

Severe hepatocellular injury after hematopoietic cell transplant: incidence, etiology and outcome.

Hepatic complications of transplant are a common cause of mortality. Although mild elevations of serum aminotransferase enzymes (aspartate and alanine (AST, ALT)) do not carry an adverse prognosis, this is not the case with severe hepatocellular injury. We reviewed 6225 consecutive recipients to determine the incidence and outcomes of severe hepatocellular injury (AST >1500 U/l) before day 100, which occurred in 88 patients. Causes were sinusoidal obstruction syndrome (SOS) (n = 46), hypoxic hepatitis (n = 33), varicella zoster virus (VZV) hepatitis (n = 4), drug-liver injury (n = 2) and unknown (n = 3). The incidence declined from 1.9% in the 1990s to 1.1% recently (owing to a fivefold decline in SOS and disappearance of VZV hepatitis). In hypoxic hepatitis, peak serum AST was 3545 U/l (range, 1380-25 246) within days of shock or prolonged hypoxemia; case fatality rate was 88%. In SOS, AST increases occurred 2-6 weeks after diagnosis; peak AST was 2252 U/l (range, 1437-8281); case fatality rate was 76%, with only serum bilirubin able to distinguish survivors (2.7 vs 11.3 mg/100 ml, P=0.0009). We conclude that circulatory insults (sinusoidal injury, hypotension and hypoxemia), and not infection, are the most common cause of severe hepatocellular injury, the frequency of which has declined because of a falling incidence of SOS and VZV hepatitis.

Pharmacogenomic associations in ABCB1 and CYP3A5 with acute kidney injury and chronic kidney disease after myeloablative hematopoietic cell transplantation.

Renal disease is a major complication in patients following myeloablative allogeneic hematopoietic cell transplantation (HCT). Post-HCT patients receive immunosuppressive regimens containing calcineurin inhibitor (CNIs), cyclosporine or tacrolimus, for graft-versus-host disease prophylaxis. In this retrospective trial, we investigated pharmacogenomic associations in the multidrug resistance (ABCB1) and cytochrome P450 3A5 (CYP3A5) genes and acute kidney injury (AKI) and chronic kidney disease (CKD) in a cohort of 121 patients. ABCB1 and CYP3A5 are responsible for the renal disposition of CNIs, which are known to be nephrotoxic. AKI was defined as doubling of baseline serum creatinine during the first 100 days post-HCT, and CKD as at least one glomerular filtration rate <60 ml/min/m2 between 6 and 18 months post-HCT. Patients were genotyped for CYP3A5*1>*3 and ABCB1 single nucleotide polymorphisms (SNPs) (1199G>A, 1236C>T, 2677G>T/A and 3435C>T). Odds ratios were calculated using logistic regression. Haplotype estimation and univariate association analyses were performed because of strong ABCB1 linkage disequilibrium (LD). AKI occurred in 48 of 121 patients (39.7%) and CKD in 16 of 66 patients (24.2%). No pharmacogenomic associations were found between ABCB1 and CYP3A5 SNPs and the incidences of AKI or CKD. The degree of LD(r2) between ABCB1 SNPs was estimated as follows: 2677G>T/3435C>T (0.44), 1236C>T/3435C>T (0.42) and 1236C>T/2677G>T (0.72). ABCB1 1199G>A showed no LD to other SNPs (<0.05). No associations were found between the most common ABCB1 haplotypes and AKI or CKD. Since no significant pharmacogenomic associations were observed, tailoring CNIs dosing based on these genotypes is unlikely to lower significantly the risk of renal injury following myeloablative HCT.

Prolonged anorexia and elevated plasma cytokine levels following myeloablative allogeneic hematopoietic cell transplant.

Myeloablative conditioning regimens commonly lead to prolonged anorexia and poor oral intake. In a prospective study of 147 patients receiving CY, total body irradiation and allogeneic hematopoietic cells, we determined the extent of decline in oral intake and assessed plasma cytokine levels and development of acute GVHD as explanations for protracted anorexia. For each patient, daily oral caloric intake was expressed as a percent of estimated basal requirements, calculated as basal energy expenditure, through day 20. Oral caloric intake was significantly reduced in 92% of patients and remained low. The nadir in oral intake occurred at days 10-12, when median oral caloric intake was 3% of basal energy requirements. Plasma cytokines known to affect appetite (IL2, IL6, tumor necrosis factor-alpha) were significantly elevated above normal following conditioning therapy (P<0.001 for each cytokine). Acute GVHD did not appear to affect oral intake to transplant day 20 in this cohort of patients; however, plasma levels of IL6 rose steeply before the clinical onset of GVHD. Persistent fever occurred with the greatest frequency in patients with most profound reduction in oral intake. We conclude that prolonged alterations in oral intake following this myeloablative regimen may be related to circulating cytokines known to alter eating behavior.

Chronic kidney disease in long-term survivors of hematopoietic cell transplant.

We conducted a cohort study to identify risk factors of chronic kidney disease (CKD) among long-term survivors of hematopoietic cell transplant (HCT). We studied 1635 patients transplanted at the Fred Hutchinson Cancer Research Center (FHCRC) between 1991 and 2002, who survived to day +131 after transplant and had serum creatinine measured on at least two occasions after day +131. CKD was defined as a glomerular filtration rate < 60 ml/min/m(2) on two occasions separated by at least 30 days between days 100 and 540 post transplant. Cox regression models estimated hazard ratios (HRs) describing associations between demographic data, clinical variables and the risk of developing CKD. A total of 376 patients (23%) developed CKD at a median of 191 days post transplant (range 131-516 days). An increased risk of CKD was associated with acute renal failure (ARF) (HR=1.7, 95% confidence interval (CI) 1.3-2.1), acute graft-vs-host disease (aGVHD) grade II (HR=2.0, 95% CI 1.4-2.9) and grades III/IV (HR=3.1, 95% CI 2.1-4.6) and chronic GVHD (HR=1.8, 95% CI 1.4-2.2). Total body irradiation (TBI) (HR=1.0, 95% CI 0.8-1.3) was not associated with an increased risk of CKD. CKD is relatively common among survivors of HCT. The presence of ARF and GVHD, but not receipt of TBI, appears to be associated with the occurrence of CKD.

Review article: management of hepatic disease following haematopoietic cell transplant.

Hepatic diseases are common complications of haematopoietic cell transplant. The causes are multiple: myeloablative conditioning regimens may cause sinusoidal injury; acute and chronic graft-versus-host disease lead to damaged hepatocytes and small bile ducts; microcrystalline deposits in the gall bladder can cause biliary symptoms; drug-induced liver injury is common; and the liver may be infected by viruses and fungi during the period of severe immune suppression that follows transplant. Pre-transplant evaluation and prevention of liver injury are often more useful than treatment of deeply jaundiced patients in improving transplant outcomes. This review covers pre-transplant evaluation, common hepatobiliary problems in the six months following transplant, and hepatic problems in long-term survivors.

Efficacy of neodymium:YAG laser therapy for gastric antral vascular ectasia (GAVE) following hematopoietic cell transplant.

We determined the incidence of severe bleeding from gastric antral vascular ectasia (GAVE) after myeloablative hematopoietic cell transplant and the outcomes after treatment with endoscopic neodymium:YAG laser photocoagulation. From 1992 to 2005, the incidence of severe bleeding from GAVE was 6/4491 (0.13%). All patients had received oral busulfan and four had sinusoidal obstruction syndrome. Gastrointestinal bleeding began a median of 53 days after transplant (range 15-2952). After GAVE was diagnosed by endoscopic and histologic findings, a median of three (range 2-7) sessions of laser therapy were required to control the bleeding with a median of 2737 J (range 1117-6160 J) per session. A median of 16 units (range 4-44) had been transfused prior to laser therapy and a median of four additional units (range 0-113) were transfused until bleeding was controlled. All patients were followed for at least 70 days after the last laser therapy session, with no further episodes of bleeding. Complications were mild and included abdominal pain and asymptomatic ulceration; however, one patient required gastrectomy due to gastric necrosis following transarterial embolizations. In summary, severe bleeding from GAVE is rare following hematopoietic cell transplant. Treatment with endoscopic therapy using the Nd:YAG laser is safe and effective.

Lack of cytoprotective effect of amifostine following HLA-identical sibling transplantation for advanced myelodysplastic syndrome (MDS): a pilot study.

The objective of this prospective study was to determine whether amifostine (Ethyol) reduced conditioning-related toxicity following a regimen of busulfan (7 mg/kg) and fractionated total body irradiation (6 x 200 cGy). In all, 12 patients with advanced myelodysplastic syndrome transplanted from HLA-identical siblings were enrolled. Patients received 340 mg/m(2) amifostine i.v. twice daily during conditioning (days -7 through -1). All patients developed oropharyngeal mucositis. Six patients had evidence of sinusoidal obstruction syndrome of the liver. Six patients experienced pulmonary toxicity of grades II-III. A total of 11 patients died, one with relapse and 10 with infectious complications or regimen-related toxicity. Nonrelapse causes of death included invasive aspergillosis in three, multiorgan failure in three, and idiopathic interstitial pneumonitis in two patients. One patient each died of organizing pneumonia and CMV pneumonia. One patient is alive in complete remission 31 months after transplantation. These results were not superior to those in patients conditioned with busulfan plus fractionated total body irradiation and not given amifostine, and suggest that amifostine, as administered here, has no protective effect against toxicity from this myeloablative regimen.

Portal vein thrombosis after hematopoietic cell transplantation: frequency, treatment and outcome.

Patients who develop veno-occlusive disease (VOD) of the liver may have low plasma levels of the natural anticoagulants protein C and antithrombin III, but large vessel thromboses are not commonly reported in these patients. We reviewed the records of 1847 consecutive patients for evidence of portal vein thrombosis. Eight patients (0.4%) developed portal vein thrombosis (PVT) at a median of day +28 (range 3-58). All patients had clinical evidence of VOD with ascites, a median total serum bilirubin 11.9 mg/dl, and median weight gain from baseline of 7.9%. Median plasma levels of antithrombin III and protein C were low (36% and 21%, respectively). Four patients with PVT died of severe VOD and multi-organ failure, but PVT did not contribute to death. We conclude that PVT is a rare complication of hematopoietic cell transplant and is associated with hepatic VOD. We speculate that PVT resulted from diminished portal venous flow (related to hepatic sinusoidal obstruction to blood flow) and a hypercoagulable state (related to low circulating antithrombin III and protein C levels). Prognosis depended on the severity of the underlying VOD and not PVT per se, suggesting that treatments directed solely toward dissolution of portal vein thrombi should be used with caution in this setting.