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.

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.

Prolonged fluconazole prophylaxis is associated with persistent protection against candidiasis-related death in allogeneic marrow transplant recipients: long-term follow-up of a randomized, placebo-controlled trial.

Two randomized, placebo-controlled trials previously showed that fluconazole (400 mg/d) administered prophylactically decreases the incidence of candidiasis in blood and marrow transplant (BMT) recipients. However, there exists conflicting data regarding the optimal duration of fluconazole administration, specifically whether prophylaxis through acute graft-versus-host disease (GVHD) results in improved survival in allograft recipients. Reported here are the results of long-term follow-up and a detailed analysis of invasive candidiasis and candidiasis-related death in 300 patients who received fluconazole (400 mg/d) or placebo for 75 days after BMT at the Fred Hutchinson Cancer Research Center. Patients in both treatment arms were compared for survival, causes of death, and the incidence of invasive fungal infections early (less than 110 days) and late (more than 110 days) after BMT. After 8 years of follow-up, survival is significantly better in fluconazole recipients compared with placebo recipients (68 of 152 vs 41 of 148, P =.0001). The overall incidence of invasive candidiasis was increased in patients who received placebo compared with fluconazole (30 of 148 vs 4 of 152, P <.001). More patients who received placebo died with candidiasis early (13 of 148 vs 1 of 152, P =.001) and late (8 of 96 vs 1 of 121, P =.0068) after BMT. The incidence of severe GVHD involving the gut was higher in patients who did not receive fluconazole (20 of 143 vs 8 of 145, P =.02), and fewer patients who received fluconazole died with this complication. Thus, administration of fluconazole (400 mg/d) for 75 days after BMT appears to be associated with decreased gut GVHD, a persistent protection against disseminated candidal infections and candidiasis-related death, resulting in an overall survival benefit in allogeneic BMT recipients.

Hepatitis C virus infection and bone marrow transplantation: a cohort study with 10-year follow-up.

Before the introduction of routine blood donor screening in 1991, marrow transplant recipients were at significant transfusion-associated risk for infection with hepatitis C virus (HCV). We followed a cohort of 355 patients undergoing transplant in Seattle during 1987 to 1988 to determine (1) the impact of pretransplant HCV infection on the occurrence and severity of venocclusive disease (VOD); (2) the impact of HCV infection on liver dysfunction, other than VOD, occurring between 21 and 60 days after transplantation; and (3) the natural history of post-transplant HCV liver disease with a 10-year follow-up. HCV-RNA status was determined on serum stored before transplant and at day 100 post-transplant. Sixty-two (17%) patients were HCV-RNA positive before transplant, and 113 (32%) were HCV-RNA positive by day 100 post-transplant (or before death). Severe VOD developed in 22 of 46 (48%) evaluable patients with pretransplant HCV infection and in 150 of 229 (14%) evaluable patients without HCV (P <.0001). In multivariable analysis of risk factors for developing VOD, pretransplant HCV infection associated with elevated serum aspartate transaminase (AST) levels predicted the development of severe VOD (relative risk, 9.6; P =.0001). The presence of HCV with normal AST levels before transplant was not a risk factor for severe VOD. Between 21 and 60 days after transplant, HCV-RNA positive-patients had higher AST levels (median 101 U/L), but similar alkaline phosphatase and total bilirubin levels compared with HCV-negative patients, suggesting that cholestatic liver disease (particularly graft-versus-host disease [GVHD]) was not related to HCV infection. An acute flare of hepatitis (AST >10 times the upper limit of normal) developed at a mean of 136 +/- 58 days in 31% of HCV-positive patients; no patients developed fulminant hepatitis. Between 5 and 10 years after transplant, 57% of HCV-positive and 6% of HCV-negative patients had mild to moderate elevations of AST (P <. 0001), but HCV infection was not associated with excess mortality between 3 and 10 years after bone marrow transplantation. In summary, HCV infection with elevated AST levels is a significant risk factor for severe VOD after marrow transplant. However, the decision to proceed to transplantation in HCV-positive patients must balance the absolute risk of death from VOD against the risks of the underlying disease. In long-term survivors, HCV infection is not associated with excess mortality over 10 years of follow-up.

Cirrhosis of the liver in long-term marrow transplant survivors.

Patients who survive hematopoietic cell transplantation (HCT) have multiple risk factors for chronic liver disease, including hepatitis virus infection, iron overload, and chronic graft-versus-host disease (GVHD). We studied 3,721 patients who had survived 1 or more years after HCT at a single center and identified patients with histologic or clinical evidence of cirrhosis. Risk factors for the development of cirrhosis were evaluated and compared with a group of matched control subjects. Cirrhosis was identified in 31 of 3,721 patients surviving 1 or more years after HCT, 23 of 1,850 patients surviving 5 or more years, and in 19 of 860 patients surviving 10 or more years. Cumulative incidence after 10 years was estimated to be 0.6% and after 20 years was 3.8%. The median time from HCT to the diagnosis of cirrhosis was 10.1 years (range, 1.2 to 24.9 years). Twenty-three patients presented with complications of portal hypertension, and 1 presented with hepatocellular carcinoma. Thirteen patients have died from complications of liver disease, and 2 died of other causes. Three patients have undergone orthotopic liver transplantation. Hepatitis C virus infection was present in 25 of 31 (81%) of patients with cirrhosis and in 14 of 31 (45%) of controls (P =.01). Cirrhosis was attibutable to hepatitis C infection in 15 of 16 patients presenting more than 10 years after HCT. There was no difference in the prevalence of acute or chronic GVHD, duration of posttransplant immunosuppression, or posttransplant marrow iron stores between cases and controls. Cirrhosis is an important late complication of hematopoietic cell transplantation and in most cases is due to chronic hepatitis C. Long-term survivors should be evaluated for the presence of abnormal liver function and hepatitis virus infection.

Association of pulmonary function testing abnormalities and severe veno-occlusive disease of the liver after marrow transplantation.

We investigated an association between pulmonary function testing (PFT) before bone marrow transplantation and the development of severe veno-occlusive disease (VOD) of the liver. We previously noted that reductions in diffusing capacity of the lung for carbon monoxide (corrected for hemoglobin) (D(L)COc) were associated with mortality after transplantation, but this was not caused by respiratory failure. We performed a case-series review of prospectively collected data from 307 marrow recipients who underwent PFT within 2 weeks of transplantation. Of these, 170 (56%) developed VOD; 39 (13%) mild, 81 (26%) moderate, and 50 (16%) severe or fatal. Both total lung capacity (TLC) and D(L)COc were associated with severe VOD in univariate analysis (P = 0.006 for each). However, D(L)COc entered logistic regression models that contained variables for all known risk factors for severe VOD, while TLC did not contribute additional predictive information. The odds ratio (OR) associated with a D(L)COc below the lower limits of normal (70% of predicted) was 2.4 (95 % CI, 1.0 to 5.4; P = 0.04). We conclude that reduced diffusion capacity of the lung measured before marrow transplantation is an independent risk for severe hepatic VOD. We speculate that the decreased D(l)COc indicates pre-existing systemic endothelial cell damage and a susceptibility to severe hepatic injury from chemotherapy.

Acute pancreatitis in marrow transplant patients: prevalence at autopsy and risk factor analysis.

Pancreatitis has been described as an infrequent complication of marrow transplantation. This study investigated the prevalence of pancreatitis at autopsy in marrow transplant patients and determined risk factors for its development. We reviewed consecutive autopsy reports from 1991 to 1993. Medical records and laboratory reports were reviewed for analysis of clinical variables. Autopsy findings and clinical variables were correlated with the autopsy diagnosis of pancreatitis. Pancreatitis was found in 51 of 184 (28%) patients at autopsy. Of those with pancreatitis, 35% had abdominal pain, 10% had measurements of serum pancreatic enzymes, and 20% had abdominal imaging studies in the week prior to death. By univariable analysis, risk factors associated with development of pancreatitis included clinical grades 3 and 4 GVHD, GVHD at autopsy, liver GVHD at autopsy, major infection at autopsy, and increasing days of survival. By multivariable analysis, independent risk factors for its development included any GVHD at autopsy, increasing length of survival after transplantation, and major infection at autopsy. We conclude that pancreatitis is a common but often subclinical complication of marrow transplantation. Its development may be associated with a high prevalence of biliary sludge and prolonged treatment of GVHD with cyclosporine and prednisone.

Efficacy and safety of fluconazole prophylaxis for fungal infections after marrow transplantation--a prospective, randomized, double-blind study.

A randomized, double-blind, placebo-controlled trial assessed the efficacy and toxicity of 400 mg/day fluconazole in preventing fungal infections during the first 75 days after marrow transplantation. During prophylaxis, systemic fungal infections occurred in 10 (7%) of 152 fluconazole-treated patients compared with 26 (18%) of 148 placebo-treated patients (P = .004). There were no Candida albicans infections in fluconazole recipients compared with 18 in placebo recipients (P < .001) and no significant increase in Candida infections other than C. albicans. Fluconazole also significantly reduced the incidence of superficial fungal infections (P < .001), fungal colonization (P = .037), and empiric amphotericin B use (P = .005). The probability of survival was improved in fluconazole recipients, in whom 31 deaths occurred up to day 110 after transplantation compared with 52 deaths in placebo recipients (P = .004). No clinically significant toxicity was detected with fluconazole use. Prophylactic fluconazole was safe and significantly reduced systemic fungal infections with other benefits, including improved survival at day 110 after marrow transplantation.

Fungal liver infection in marrow transplant recipients: prevalence at autopsy, predisposing factors, and clinical features.

To determine the prevalence of fungal liver infection at autopsy in marrow transplant recipients, we reviewed autopsy results for the period 1980-1989. Cases were compared to randomly chosen autopsied controls without fungal infection. Fungal liver infection was found in 67 (9%) of 731 patients. Fungal cultures of liver lesions were positive for 34 of 67 patients, most of whom had been culture-positive for the same fungal species (largely Candida) during life. Multivariate analysis revealed that independent predictors of fungal liver infection were deep fungal infection after transplantation (RR, 35), colonization or superficial infection after transplantation (RR, 13), and severe liver dysfunction caused by veno-occlusive disease of the liver and/or graft-versus-host disease (RR, 7). Clinical and laboratory findings during the last month of life revealed no differences between cases and controls. Liver imaging studies performed during the last 15 days of life had a sensitivity of only 18% for detecting fungal liver lesions.

Veno-occlusive disease of the liver after marrow transplantation: histological correlates of clinical signs and symptoms.

We evaluated the relationship between the signs and symptoms of the clinical syndrome called veno-occlusive disease of the liver after bone marrow transplantation and the histological findings in 76 patients who later came to autopsy. Coded necropsy liver was scored for individual histological features that were correlated with prospectively assessed clinical features that the patients had exhibited during life. Patients were stratified into two groups: those with severe clinical veno-occlusive disease (n = 32) and those without. Clinically severe veno-occlusive disease was statistically correlated with several zone 3 acinar changes: occluded hepatic venules, the frequency of occluded hepatic venules x degree of occlusion, eccentric luminal narrowing/phlebosclerosis, zone 3 sinusoidal fibrosis and zone 3 hepatocyte necrosis (all p < or = 0.03). There was a significant relationship between the number of these histological abnormalities in zone 3 of the liver acinus and a clinical diagnosis of severe veno-occlusive disease (p = 0.003). The presence of ascites was significantly correlated with occluded venules, zone 3 sinusoidal fibrosis and zone 3 hepatocyte necrosis (p = 0.001). Maximum serum bilirubin in the first 20 days after transplant was significantly correlated with sinusoidal fibrosis, hepatocyte necrosis and eccentric luminal sclerosis/phlebosclerosis (p < 0.01) but not with venular occlusion. The clinical syndrome of liver toxicity (commonly called veno-occlusive disease) that results from cytoreductive therapy before bone marrow transplant is strongly correlated with a constellation of histological lesions involving structures in zone 3 of the liver acinus and the hepatic venules into which sinusoidal blood flows. This study suggests that there is no single diagnostic histological feature. The severity of clinical veno-occlusive disease appears to be proportional to the number of such histological changes and is not due solely to occlusion of small hepatic venules.

Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients.

OBJECTIVE: To determine the incidence and clinical course of veno-occlusive disease of the liver (VOD) after bone marrow transplantation and to analyze risk factors for severe VOD. DESIGN: Cohort study of 355 consecutive patients. SETTING: A bone marrow transplantation center. MEASUREMENTS: Each patient was prospectively evaluated for VOD, and many risk factors for severe VOD were analyzed using logistic regression models. The relation of VOD to renal and cardiopulmonary failure was analyzed using time-dependent proportional hazards models. RESULTS: Veno-occlusive disease developed in 190 of 355 patients (54%; 95% CI, 48% to 59%): Fifty-four patients had severe VOD and 136 had mild or moderate VOD. Independent variables derived from a multivariate model for predicting severe VOD included elevated transaminase values before transplantation (relative risk, 4.6; P < 0.0001); vancomycin therapy during cytoreductive therapy (relative risk, 2.9; P = 0.003); cytoreductive therapy with a high-dose regimen (relative risk, 2.8; P = 0.01); acyclovir therapy before transplantation (relative risk, 4.8; P = 0.02); mismatched or unrelated donor marrow (relative risk, 2.4; P = 0.02); and previous radiation therapy to the abdomen (relative risk, 2.2; P = 0.04). Vancomycin therapy was a marker for persistent fever. Multiorgan failure was more frequent among patients with VOD and usually followed the onset of liver disease. CONCLUSIONS: Veno-occlusive disease, which developed in 54% of bone marrow transplant recipients, is frequently associated with renal and cardiopulmonary failure. Pretransplant transaminase elevations, use of high-dose cytoreductive therapy, and persistent fever during cytoreductive therapy are independent predictors of severe VOD.

Quantification of cytomegalovirus in bronchoalveolar lavage fluid after allogeneic marrow transplantation by centrifugation culture.

A technique to quantify cytomegalovirus (CMV) by centrifugation culture of bronchoalveolar lavage fluid from marrow transplant recipients was developed. This technique was used to assess the CMV response to antiviral treatment and the relationship between viral load, asymptomatic excretion versus symptomatic infection, and prognosis. Relative to tube cell culture, centrifugation culture of bronchoalveolar lavage fluid was more sensitive than direct fluorescent-antibody staining. It was also a rapid, replicable method for detecting and measuring the amount of CMV. There was no significant difference between viral load at diagnosis and after 9 days of treatment with ganciclovir and intravenous immunoglobulin. Viral load was not predictive of outcome, and there was no difference in amount of virus between patients with asymptomatic CMV excretion and those with CMV pneumonia. The amount of CMV may not be as important as other factors (e.g., host immune response) in the pathogenesis of CMV pneumonia.

Mixed leukocyte culture reactivity and graft-versus-host disease in HLA-identical marrow transplantation for leukemia.

The results of pretransplant mixed leukocyte culture (MLC) assays were compared to subsequent risk of graft-versus-host disease (GVHD) in 783 patients receiving marrow transplants from HLA genotypically identical sibling donors. The mean MLC response observed between 1303 normal HLA identical sibling pairs was 0.0 +/- 4.2% RR. The donor anti-recipient MLC reaction, an in vitro response that presumably might be relevant to GVHD, was significantly increased (greater than mean + 2 sd) in 83 (10.6%) of the cases, most often in patients in relapse at the time of testing. No association was found, however, between this increased donor anti-recipient MLC reactivity pretransplant and the incidence or severity of subsequent acute or chronic GVHD. These data suggest that the increased MLC responses sometimes observed between leukemia patients and their HLA identical sibling donors prior to marrow transplantation do not represent genetic differences capable of causing GVHD.

Regimen-related toxicity and early posttransplant survival in patients undergoing marrow transplantation for lymphoma.

Ninety-five patients transplanted for malignant lymphoma were retrospectively evaluated for regimen-related toxicity (RRT) and early posttransplant survival. Nineteen patients developed life-threatening (grade 3) or fatal (grade 4) RRT in one or more organs. Grade 3 or 4 RRT was more common in patients with advanced disease versus those transplanted earlier in their course (P = .008), and was more common in patients with advanced disease conditioned with cytarabine (Ara-C)/total body irradiation (TBI) versus those prepared with cyclophosphamide (CY)/TBI (P = .033). There was no significant difference in the incidence of grade 3 or 4 toxicity in autologous, histocompatibility locus antigen (HLA)-identical, or HLA-mismatched marrow recipients. Grade 3 or 4 RRT tended to be more common and 100-day survival worse in patients with a Karnofsky performance status of less than 90 (P = .063 and .0002, respectively). Patients receiving 20 Gy or more of mediastinal irradiation before coming to transplant had more idiopathic or cytomegalovirus (CMV) interstitial pneumonitis than those who received less than 20 Gy (30% v 9%, P = .027). The probability of survival decreased with the number of organs in which toxicity was observed (P = .0001). Severe or fatal toxicities directly related to the preparative regimen are a significant problem in the treatment of patients with advanced malignant lymphoma and can be reduced by carrying out transplantation earlier in the course of the disease.