George B. McDonald

National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report.

The 2005 National Institutes of Health (NIH) Consensus Conference proposed new criteria for diagnosing and scoring the severity of chronic graft-versus-host disease (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 and more accurately measures the global burden of disease attributed to GVHD, and it will facilitate biomarker association studies.

Gastrointestinal graft-versus-host disease in man. A clinicopathologic study of the rectal biopsy.

Evaluation of the diagnostic utility of the rectal biopsy in graft-versus-host disease (GVHD), using the crypt abscess as a major diagnostic criterion, was based on 52 patients who had received marrow allografts for leukemia or aplastic anemia. Thirty-six of these patients had acute GVHD by skin biopsy criteria. These 36 patients demonstrated a strong association of the rectal crypt abscess with severity of clinical GVHD. High stool volume also correlated strongly with the crypt abscess. Patients without clear evidence of GVHD usually had normal rectal histology. Serial studies showed a good correlation of rectal biopsy results with the clinical course of acute GVHD. Patients with chronic GVHD had rectal muosal damage only during the acute phase. Rectal histology at autopsy reflected ileal and cecal disease accurately. The rectal biopsy is a useful adjunct to serial skin biopsies in the diagnosis of GVHD in man.

Defibrotide for the treatment of severe hepatic veno-occlusive disease and multiorgan failure after stem cell transplantation: a multicenter, randomized, dose-finding trial.

Therapeutic options for severe hepatic veno-occlusive disease (VOD) are limited and outcomes are dismal, but early phase I/II studies have suggested promising activity and acceptable toxicity using the novel polydisperse oligonucleotide defibrotide. This randomized phase II dose-finding trial determined the efficacy of defibrotide in patients with severe VOD following hematopoietic stem cell transplantation (HSCT) and identified an appropriate dose for future trials. Adult and pediatric patients received either lower-dose (arm A: 25 mg/kg/day; n = 75) or higher-dose (arm B: 40 mg/kg/day; n = 74) i.v. defibrotide administered in divided doses every 6 hours for > or =14 days or until complete response, VOD progression, or any unacceptable toxicity occurred. Overall complete response and day +100 post-HSCT survival rates were 46% and 42%, respectively, with no significant difference between treatment arms. The incidence of treatment-related adverse events was low (8% overall; 7% in arm A, 10% in arm B); there was no significant difference in the overall rate of adverse events between treatment arms. Early stabilization or decreased bilirubin was associated with better response and day +100 survival, and decreased plasminogen activator inhibitor type 1 (PAI-1) during treatment was associated with better outcome; changes were similar in both treatment arms. Defibrotide 25 or 40 mg/kg/day also appears effective in treating severe VOD following HSCT. In the absence of any differences in activity, toxicity or changes in PAI-1 level, defibrotide 25 mg/kg/day was selected for ongoing phase III trials in VOD.

Veno-occlusive disease of the liver after busulfan, melphalan, and thiotepa conditioning therapy: incidence, risk factors, and outcome.

The purpose of this study was to determine the incidence of veno-occlusive disease (VOD) after a high-dose regimen of busulfan, melphalan, and thiotepa and the risk factors for a more severe outcome. We followed 253 consecutive patients with malignant disorders who received autologous transplants after stem cell harvest followed by 12 mg/kg busulfan, 100 mg/m2 melphalan, and 500 mg/m2 thiotepa. Diagnosis of VOD was based on weight gain, hepatomegaly, and jaundice. Risk factors for moderate or severe VOD were identified using logistic regression models. VOD occurred in 70 of 253 patients (28%), of whom 31 (12%) had moderate and 11 (4%) severe VOD. The median day of onset of hyperbilirubinemia was day 9, significantly later than the onset of jaundice after our cyclophosphamide-based regimens (p < 0.001). Resolution of weight gain and jaundice, followed by their reappearance several weeks later, occurred in 23 of 70 patients with VOD and was an adverse prognostic sign. Risk factors for moderate or severe VOD were a diagnosis of lymphoma or myeloma (odds ratio [OR] 2.65 compared with breast cancer), tumor involvement in the liver (OR 3.95), fever in the month before transplant (OR 3.32), and prior radiation therapy (OR 2.70). We conclude that VOD after busulfan, melphalan, and thiotepa was less frequent and less severe and developed later than VOD after our historical cyclophosphamide-based regimens. Significant risk factors included a diagnosis other than breast cancer, hepatic metastases, persistent fever, and prior radiation therapy. This study suggests that alkylating agents of comparable overall toxicity differ in their liver toxicity.

Ganciclovir for the Treatment of Cytomegalovirus Gastroenteritis in Bone Marrow Transplant Patients: A Randomized, Placebo-Controlled Trial

STUDY OBJECTIVE To determine the efficacy of ganciclovir for the treatment of cytomegalovirus enteritis after bone marrow transplant. DESIGN A randomized, double-blind, placebo-controlled trial. SETTING Inpatient units of a cancer center. PATIENTS Consecutive patients with biopsy-documented cytomegalovirus infection of the gastrointestinal tract. Cytomegalovirus was identified by culture or by immunohistologic or standard histologic analysis. INTERVENTIONS Ganciclovir, 2.5 mg/kg body weight every 8 hours for 14 days, or placebo, with dosage adjusted for decreases in renal function. Therapy was discontinued if the neutrophil count or creatinine clearance fell below preset criteria. MEASUREMENTS AND MAIN RESULTS Virus cultures of throat, urine, and blood specimens were done before, 3 times weekly during, and weekly for 3 weeks after therapy. Endoscopy was repeated after treatment. Patients were examined, and blood counts, electrolytes, and renal and hepatic function were monitored during therapy. Ganciclovir recipients had cessation of oropharyngeal (P = 0.001) and urinary (P = 0.004) cytomegalovirus excretion and negative cultures of repeat esophageal specimens (P = 0.002) more often than placebo recipients. No difference existed in either clinical symptoms or endoscopic appearance between the groups after treatment. Cytomegalovirus pneumonia occurred in four patients who received ganciclovir and in six who received placebo. One ganciclovir recipient and four placebo recipients were withdrawn from treatment because of neutropenia, but there was no overall difference in the proportional decrease in leukocyte counts between groups. CONCLUSIONS Although ganciclovir suppressed cytomegalovirus replication, 2 weeks of treatment was not associated with clinical or endoscopic improvement when compared with supportive care.

Renal Thrombotic Microangiopathy after Hematopoietic Cell Transplant: Role of GVHD in Pathogenesis

BACKGROUND AND OBJECTIVES Thrombotic microangiopathy (TMA) is a known complication of hematopoietic cell transplantation (HCT). The etiology and diagnosis of TMA in this patient population is often difficult because thrombocytopenia, microangiopathic hemolytic anemia, and kidney injury occur frequently in HCT recipients, and are the result of a variety of insults. DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS The authors reviewed renal pathology and clinical data from HCT patients to determine the prevalence of TMA and to identify correlative factors for developing TMA in the kidney. Kidney tissue was evaluated from 314 consecutive autopsies on patients who died after their first HCT (received between 1992 and 1999). Renal pathology was classified into three groups: (1) no renal thrombus (65%), (2) TMA (20%), and (3) isolated thrombosis (15%). Logistic regression models estimated the associations between each histologic category and clinical parameters: donor and recipient gender, patient age, human leukocyte antigen (HLA) matching of the donor and recipient, total body irradiation (TBI), acute graft versus host disease (GVHD), acute kidney injury, medications, and viral infections. RESULTS In a multivariate analysis, TMA correlated with acute GVHD grades II to IV, followed by female recipient/male donor, TBI > 1200 cGy, and adenovirus infection. Grades II to IV acute GVHD and female gender were associated with isolated renal thrombus. CONCLUSIONS TMA in HCT recipients is associated with acute GVHD grades II to IV, recipient/donor mismatch, TBI > 1200 cGy, and adenovirus infection.

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/m2 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.

A prospective study of unexplained nausea and vomiting after marrow transplantation.

We prospectively studied patients with enigmatic nausea and vomiting after allogeneic marrow transplantation to define the causes of this syndrome. Fifty consecutive episodes of persistent vomiting were investigated using physical examination and laboratory tests, endoscopic biopsies and brushings, and clinical follow-up for four weeks. Potential causes of vomiting were identified in 39 of the 50 cases (78%). Fifteen cases had gastrointestinal infections (mainly herpesviruses), 13 had unsuspected acute intestinal graft-versus-host disease (GVHD), 8 had intestinal infection plus acute GVHD, and 3 had other causes (subdural hematomas, bacteremia, and encephalitis). In the remaining 11 cases, no cause of vomiting was found. Endoscopy was necessary for diagnosis in 36 cases and required a combination of methods: routine histology, cytology, viral culture, and immunohistology using monoclonal antibodies to cytomegalovirus (CMV) and herpes simplex virus type 1. Patients with unexplained vomiting or intestinal GVHD had significant improvement of nausea and vomiting over the four-week observation period, but those with CMV did not (P = .01). We conclude that most allogeneic marrow transplant patients with enigmatic nausea and vomiting have gastrointestinal herpesvirus infections, acute GVHD, or both. Untreated CMV infections and persistent GVHD are associated with protracted vomiting in these patients.

Pharmacokinetics of cyclophosphamide and its metabolites in bone marrow transplantation patients

To characterize the pharmacokinetics of cyclophosphamide and 5 of its metabolites in bone marrow transplant patients and to identify the mechanism of the increase in 4‐hydroxycyclophosphamide area under the plasma concentration‐time curve (AUC) from day 1 to day 2 of cyclophosphamide administration.

Persistent nausea and anorexia after marrow transplantation: a prospective study of 78 patients.

BACKGROUND Persistent nausea, vomiting, anorexia, and poor oral intake are common after hematopoietic cell transplantation. In the past, herpesvirus infections and acute intestinal graft-versus-host disease (GVHD) were the most common causes. METHODS We studied 76 patients with 78 episodes of these symptoms to discern the causes. Diagnoses were based on histology of skin and intestinal biopsy specimens, viral cultures, and responses to therapy. RESULTS The mean day of study entry was day 57+/-31.3 posttransplant. Acute GVHD was the most common cause of symptoms, affecting 63 patients (81%) as the sole cause of symptoms and an additional 4 patients (5%) who had other concurrent causes. Patients with GVHD had marrow donors who were unrelated or HLA-mismatched in 27/63 cases. Gastric edema, erythema, and apoptotic epithelial cells were the most useful findings for the diagnosis of GVHD. Prednisone therapy (1-2 mg/kg/day) was effective in 58 of 63 patients (92%). Infection by herpes simplex virus, cytomegalovirus, or Candida was found in six patients, three of whom had concurrent GVHD. Other causes of symptoms were medications (one patients), parenteral nutrition (one patient), and sagittal sinus thrombosis (one patient). CONCLUSIONS Acute GVHD is now the dominant cause of persistent nausea and anorexia in marrow transplant patients who are beyond day 20 posttransplant. The diagnosis can be made clinically in most cases and confirmed by endoscopic biopsy of gastric mucosa. Infections, medications, and rare cases of central nervous system disease are much less common.