Ipilimumab is a humanized antibody to CTLA4 and is used to treat cancers refractory to conventional treatment. We treated 21 patients with refractory melanoma or prostate cancer with anti-CTLA4 ...antibody (ipilimumab), with subsequent development of significant colitis in nine cases. Two of these nine did not respond rapidly to high-dose (2 mg kg⁻¹ day⁻¹) glucocorticoids or infliximab. They required additional immunosuppression, and one ultimately died of opportunistic infection, representing a more refractory course than has previously been described complicating ipilimumab therapy. Both patients had received radiation to the pelvis for prostate cancer less than 1 year prior to receiving ipilimumab. We performed immunohistochemical analysis of colon biopsies from ipilimumab recipients to determine if colitis correlates with depletion of intramucosal FOXP3⁺ regulatory T cells (Tregs), which normally express CTLA4. However, we found no evidence of FOXP3⁺ T cell depletion in any of the nine patients who developed colitis.
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.
The purpose of the current study was to examine how head coach–player racial dissimilarity was associated with negative treatment from the head coach. Data were collected from 212 National Collegiate ...Athletic Association (NCAA) Division I women’s basketball players (124 Whites, 88 African Americans). Results indicate that racial dissimilarity was associated with greater incivility when the head coach was White, but not when the head coach was African American. In addition, incivility was negatively associated with players’ commitment to the team. The authors discuss theoretical contributions and practical implications.
We hypothesized that initial treatment of acute graft-versus-host disease (GVHD) with low-dose glucocorticoids (prednisone-equivalent dose of 1 mg/kg per day) instead of standard-dose glucocorticoids ...(prednisone-equivalent dose of 2 mg/kg per day) does not compromise major transplantation outcomes. We retrospectively analyzed outcomes among 733 patients who received transplants between 2000 and 2005 according to initial treatment with low-dose (n = 347) versus standard-dose (n = 386) systemic glucocorticoids. The mean cumulative prednisone-equivalent doses at day 100 after starting treatment were 44 and 87 mg/kg for patients given low-dose and standard-dose glucocorticoids, respectively. Adjusted outcomes between the groups given low-dose versus standard-dose glucocorticoids were not statistically significantly different: overall mortality (hazard ratio HR, 1.10; 95% confidence interval CI, 0.9-1.4), relapse (HR, 1.22; 95% CI, 0.9-1.7), nonrelapse mortality (HR, 1.06; 95% CI, 0.8-1.5). The small number of patients with grades III/IV acute GVHD at onset precluded definitive conclusions for this subgroup. In multivariate analysis, the risks of invasive fungal infections (HR, 0.59; 95% CI, 0.3-1.0) and the duration of hospitalization (odds ratio, 0.62; 95% CI, 0.4-0.9) were reduced in the low-dose prednisone group. We conclude that initial treatment with low-dose glucocorticoids for patients with grades I-II GVHD did not compromise disease control or mortality and was associated with decreased toxicity.
Acute renal failure after myeloablative hematopoietic cell transplant: Incidence and risk factors.
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.
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.
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 0.1mg/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.
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.
Busulfan is a commonly used chemotherapeutic agent in myeloablative conditioning regimens for allogeneic hematopoietic cell transplantation (allo-HCT). It has been associated with ...sinusoidal-obstructive syndrome (SOS) as a life-threatening complication of myeloablative allo-HCT, yet it has not been found to cause severe hepatocellular injury, even in cases of significant accidental overdose. We report the case of a 31-year-old male with a history of high-risk myelodysplastic syndrome transitioning to acute myeloid leukemia, who in complete remission underwent allo-HCT using myeloablative busulfan–fludarabine conditioning, and who developed hepatic failure. While he met clinical criteria for SOS and was treated with defibrotide, liver biopsy demonstrated severe subacute hepatic necrosis and lacked characteristics of SOS. Further evaluation revealed that the patient was homozygous for the HFE H63D gene mutation, associated with hereditary hemochromatosis. Both Busulfan and iron overload related to HFE H63D homozygosity can cause oxidative stress resulting in cellular injury, and the cumulative effects of these risk factors are possibly responsible for the severe hepatocellular injury in this case, making our patient the first-known case of subacute hepatic necrosis related to busulfan administration.
Veno-occlusive disease (VOD) is the most common regimen-related toxicity accompanying stem cell transplantation (SCT). Severe VOD complicated by multisystem organ failure (MOF) remains almost ...uniformly fatal. Preliminary experience with defibrotide (DF), a single-stranded polydeoxyribonucleotide with fibrinolytic, antithrombotic, and anti-ischemic properties, in the treatment for severe VOD has suggested safety and activity. Eighty-eight patients who developed severe VOD after SCT were treated with DF under a defined treatment plan. At diagnosis, median bilirubin was 76.95 μM (4.5 mg/dL), median weight gain was 7%, ascites was present in 84%, and abnormal hepatic portal venous flow was present in 35%. At DF initiation, median bilirubin had increased to 215.46 μM (12.6 mg/dL), and MOF was present in 97%. DF was administered intravenously in doses ranging from 5 to 60 mg/kg per day for a median of 15 days. No severe hemorrhage or other serious toxicity related to DF was reported. Complete resolution of VOD was seen in 36%, with 35% survival at day +100. Predictors of survival included younger age, autologous SCT, and abnormal portal flow, whereas busulfan-based conditioning and encephalopathy predicted worse outcome. Decreases in mean creatinine and plasminogen activator inhibitor 1(PAI-1) levels during DF therapy predicted better survival. The complete response rate, survival to day +100, and absence of significant DF-associated toxicity in this largest patient cohort reported to date confirm the results of earlier studies. Certain features associated with successful outcome may correlate with DF-related treatment effects, and prospective evaluation of DF therapy for severe VOD should allow better definition of predictors of response or failure.
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.
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.
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