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To the editor: In late December 2016, Seattle Genetics, Inc., announced that the US Food and Drug Administration (FDA) had placed a hold or partial hold on several early-stage clinical trials of vadastuximab talirine (SGN-CD33A) in acute myeloid leukemia (AML) to further evaluate the potential risk

We identified plasma biomarkers that presaged outcomes in patients with gastrointestinal graft-versus-host disease (GVHD) by measuring 23 biomarkers in samples collected before initiation of treatment. Six analytes with the greatest accuracy in predicting grade 3-4 GVHD in the first cohort (74 patients) were then tested in a second cohort (76 patients). The same 6 analytes were also tested in samples collected at day 14 ± 3 from 167 patients free of GVHD at the time. Logistic regression and calculation of an area under a receiver-operating characteristic (ROC) curve for each analyte were used to determine associations with outcome. Best models in the GVHD onset and landmark analyses were determined by forward selection. In samples from the second cohort, collected a median of 4 days before start of treatment, levels of TIM3, IL6, and sTNFR1 had utility in predicting development of peak grade 3-4 GVHD (area under ROC curve, 0.88). Plasma ST2 and sTNFR1 predicted nonrelapse mortality within 1 year after transplantation (area under ROC curve, 0.90). In the landmark analysis, plasma TIM3 predicted subsequent grade 3-4 GVHD (area under ROC curve, 0.76). We conclude that plasma levels of TIM3, sTNFR1, ST2, and IL6 are informative in predicting more severe GVHD and nonrelapse mortality.

Hepatitis C virus (HCV) infection is not uncommon in cancer patients. Over the past 5 years, treatment of chronic HCV infection in patients with hematologic malignancies has evolved rapidly as safe and effective direct-acting antivirals (DAAs) have become the standard-of-care treatment. Today, chronic HCV infection should not prevent a patient from receiving cancer therapy or participating in clinical trials of chemotherapy because most infected patients can achieve virologic cure. Elimination of HCV from infected cancer patients confers virologic, hepatic, and oncologic advantages. Similar to the optimal therapy for HCV-infected patients without cancer, the optimal therapy for HCV-infected patients with cancer is evolving rapidly. The choice of regimens with DAAs should be individualized after thorough assessment for potential hematologic toxic effects and drug-drug interactions. This study presents clinical scenarios of HCV-infected patients with hematologic malignancies, focusing on diagnosis, clinical and laboratory presentations, complications, and DAA therapy. An up-to-date treatment algorithm is presented.

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.

We tested the hypothesis that oral beclomethasone dipropionate (BDP) would control gastrointestinal graft-versus-host disease (GVHD) in patients with anorexia, vomiting, and diarrhea. Patients were randomized to prednisone for 10 days and either oral BDP 8 mg/d (n = 62) or placebo (n = 67) tablets for 50 days. At study day 10, prednisone was rapidly tapered while continuing study drug. On an intent-to-treat basis, the risk of GVHD-treatment failure was reduced for the BDP group at study day 50 (hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.35-1.13) and at 30 days follow-up (HR 0.55, 95% CI 0.32-0.93). Among patients eligible for prednisone taper at study day 10, the risk of GVHD-treatment failure was significantly reduced at both study days 50 and 80 (HR 0.39 and 0.38, respectively). By day 200 after transplantation, 5 patients randomized to BDP had died compared with 16 deaths on placebo, a 67% reduction in the hazard of mortality (HR 0.33, P = .03). In 47 recipients of unrelated and HLA-mismatched stem cells, mortality at transplantation day 200 was reduced by 91% in the BDP group compared with placebo (HR 0.09, P = .02). The survival benefit was durable to 1 year after randomization. Oral BDP prevents relapses of gastrointestinal GVHD following tapering of prednisone; survival is statistically significantly better among patients receiving BDP.

Treatment of acute graft-versus-host disease (GVHD) has evolved from a one-size-fits-all approach to a more nuanced strategy based on predicted outcomes. Lower and time-limited doses of immune suppression for patients predicted to have low-risk GVHD are safe and effective. In more severe GVHD, prolonged exposure to immunosuppressive therapies, failure to achieve tolerance, and inadequate clinical responses are the proximate causes of GVHD-related deaths. This article presents acute GVHD-related scenarios representing, respectively, certainty of diagnosis, multiple causes of symptoms, jaundice, an initial therapy algorithm, secondary therapy, and defining futility of treatment.

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.

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.

H EMATOPOIETIC CELL transplantation (HCT) is performed annually in over 30,000 patients worldwide for a range of underlying disorders including hematologic malignancy, severe aplastic anemia, solid tumors, and genetic diseases.[1][1] While the risk of acquiring hepatitis virus infection from

The purpose of this report is to review the Fred Hutchinson Cancer Research Center experience of treating patients with venocclusive disease of the liver (VOD) after marrow transplantation using recombinant human tissue plasminogen activator (rh-tPA) and heparin. The charts of 42 patients who had received rh-tPA and heparin for the treatment of VOD between February 1991 and December 1995 were reviewed. Response to rh-tPA and heparin was defined as a reduction in total serum bilirubin by 50% within 10 days of starting treatment. Total serum bilirubin, percent weight gain, and serum creatinine before, after, and at the start of rh-tPA and heparin were examined to determine whether these laboratory values distinguished patients who responded to treatment from those who did not. We also evaluated whether evidence of multiorgan failure (requirement for supplemental oxygen, requirement for hemodialysis, requirement for mechanical ventilation) or whether the calculated probability of a fatal outcome from VOD could discriminate responders from nonresponders. In addition, the incidence and outcome of bleeding as a major complication of thrombolytic therapy was examined. Twelve patients responded to rhtPA and heparin and 30 patients did not. There were no statistically significant differences between responders and nonresponders in the day treatment was started, dose of rh-tPA, total serum bilirubin, and percent weight gain before, after, or at the start of treatment, or the calculated probability of dying from VOD on the day treatment with rh-tPA and heparin was begun. More nonresponding patients required dialysis or mechanical ventilation (11 of 30) before or at the start of rh-tPA and heparin than responding patients (0 of 12), P = .0183. Serum creatinine was greater at the start of treatment in nonresponding patients (1.9 ± 1.3 mg/dL) than in responding patients (1.1 ± 0.4 mg/dL), P = .0794. Ten patients had severe bleeding episodes, which resulted in death in three patients and may have contributed to death in an additional three patients. Treatment for VOD using rh-tPA and heparin was successful in 29% of patients but was associated with a significant risk of life-threatening hemorrhage. Requirement for supplemental oxygen, dialysis, or mechanical ventilation before the start of treatment were prognostic indicators of no response to thrombolytic therapy. We do not recommend treatment using tPA and heparin in patients with severe VOD who have already developed multiorgan dysfunction.

Acute graft-versus-host disease (GVHD) is most often treated with high dose glucocorticoids, but less than half of patients have durable overall improvement. Previous phase I and phase II studies suggested that treatment with a CD5-specific immunotoxin (XomaZyme-CD5 Plus) could ameliorate symptoms of GVHD. In a randomized, double-blind trial, we compared XomaZyme-CD5 Plus and glucocorticoids versus placebo and glucocorticoids as initial therapy for 243 patients who developed acute GVHD after allogeneic marrow transplantation. The study drug (XomaZyme. CD5-Plus or an identical appearing placebo) was administered at a dose of 0.1 mg/kg body weight on each of 14 consecutive days. All patients were treated concomitantly with a standard regimen of methylprednisolone. At the time of entry on study, 94% of patients had a rash, 56% had hyperbilirubinemia, 61% had diarrhea, and 84% had nausea and vomiting. At 3, 4, and 5 weeks after starting treatment, symptom severity was less in the CD5 group than in the placebo group. At 4 weeks, 40% of patients assigned to the CD5 group had complete response compared with 25% of those assigned to the control group (P = .019). At 6 weeks, 44% of patients assigned to the CD5 group had complete response as compared with 38% in the placebo group (P = .36). Clinical extensive chronic GVHD developed in 65% of patients in the CD5 group compared with 72% in the control group (P = .35). Survival at 1 year after treatment was 49% in the CD5 group and 45% in the control group (P = .68). Side effects required close monitoring and appropriate adjustment of treatment. The combined administration of a CD5-specific immunotoxin and glucocorticoids controls GVHD manifestations more effectively than treatment with glucocorticoids alone during the first 5 weeks after starting treatment. Use of this immunotoxin does not result in any long-term clinical benefit for patients with acute GVHD.

We performed a randomized trial to compare the safety and efficacy of itraconazole with fluconazole in preventing fungal infections in patients undergoing allogeneic stem cell transplantation (SCT). Itraconazole (intravenous 200 mg daily, or oral solution 2.5 mg/kg 3 times daily) and fluconazole (intravenous or oral, 400 mg daily) were administered with the start of conditioning therapy, until at least 120 days after SCT. After enrollment of the first 197 patients, a data and safety monitoring board reviewed potential drug-related toxicities. Patients who received itraconazole developed higher serum bilirubin and creatinine values in the first 20 days after SCT, with highest values in patients who received itraconazole concurrent with cyclophosphamide (CY) conditioning. Analysis of CY metabolism in a subset of patients demonstrated higher exposure to toxic metabolites among recipients of itraconazole compared with fluconazole. These data suggest that azole antifungals, through differential inhibition of hepatic cytochrome P-450 isoenzymes, affect CY metabolism and conditioning-related toxicities.

This study evaluated the effect of pentoxifylline (PTX) on the incidence of regimen-related toxicity in patients receiving allogeneic marrow transplants from related donors. All patients received a regimen of methotrexate and cyclosporine as prophylaxis against acute graft- versus-host disease (GVHD). Patients were randomized to receive PTX or a placebo for 70 days and the outcome was examined in a blinded fashion. Forty-four patients were evaluate in each study arm. PTX had no significant effect on engraftment, the incidence of GVHD, venocclusive disease of the liver, infection, the need for oxygen, posttransplant survival, or the duration of hospitalization. Patients receiving PTX were significantly more likely to develop major elevations of serum creatinine levels. PTX was poorly tolerated and induced significantly more vomiting than the placebo. PTX as administered in this randomized study was associated with significant toxicity and offered no benefit in reducing transplant-related morbidity or mortality.

Seven patients were treated with recombinant human tissue plasminogen activator (tPA) for severe hepatic venocclusive disease (VOD) that developed after bone marrow transplantation for hematologic malignancy. Recombinant human tPA (10 mg/d x 2 days) and heparin (1,000 U bolus followed by continuous intravenous infusion of 150 U/kg/d x 10 days) were begun a median of 9 days (range, 4 to 18 days) posttransplant. The median total serum bilirubin and percent weight gain from baseline were 19.4 mg/dL (range, 14.6 to 34.9 mg/dL) and 9.1% (range, 1% to 18.5%), respectively, at the start of tPA administration. Five patients responded to therapy with prompt reduction in total serum bilirubin within 96 hours of starting tPA. Three patients are alive 178 to 379 days posttransplant without evidence of VOD. No patient had significant hemorrhagic complications with tPA. We conclude that recombinant human tPA can be administered to patients with severe VOD at the dosage described. Whereas preliminary data suggests that recombinant human tPA can alter the natural history of severe VOD, further study is necessary to determine its efficacy.

We have reviewed results of secondary therapy in 427 patients with acute graft-versus-host disease (GVHD) who did not have a durable satisfactory response after primary treatment. At the beginning of secondary treatment, 320 patients (75%) had rash, 252 (59%) had liver dysfunction, and 228 (53%) had gut dysfunction. Secondary treatment was with glucocorticoids (n = 249), cyclosporine (n = 80), antithymocyte globulin (n = 114), or monoclonal antibody (n = 19) either singly (n = 390) or in combination (n = 37). Parameters of GVHD severity were recorded weekly, and responses were determined according to values at the initiation of tertiary treatment or, for patients without such treatment, using values on day 29 of secondary treatment or the last recorded values before death, whichever occurred first. Minimal criteria for improvement or deterioration were defined for each organ, but no attempt was made to define liver or gut outcome if another complication such as venocclusive disease or infectious enteritis was present. Improvement or resolution of GVHD in the respective organ was seen in 45% of patients with skin disease, 25% of patients with evaluable liver disease, and in 35% of patients with evaluable gut disease. Overall complete or partial responses were seen in 40% of patients. The highest complete response rate with secondary therapy (23%) was seen when GVHD recurred during the taper phase of primary glucocorticoid treatment and was managed by increasing the dose of glucocorticoids. Multivariate analyses were performed to identify patient, disease, or treatment factors associated with likelihood of complete response or overall improvement. A similar analysis was performed to identify covariates associated with time to treatment failure (defined as initiation of tertiary therapy or death not due to relapse of malignancy). Severe dysfunction in the skin, liver, and gut at the beginning of treatment was associated both with a decreased likelihood of complete response and an increased treatment failure rate. The times to treatment failure and the proportions of patients in various response categories were similar for primary and secondary treatment, suggesting that the potential efficacy of new immunosuppressive agents for treatment of acute GVHD can be assessed meaningfully in patients who have not responded adequately to initial therapy.

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.

Syngeneic graft-versus-host disease (sGVHD) has been described after hematopoietic cell transplantation (HCT) but remains poorly defined. We retrospectively reviewed adult syngeneic HCTs at our center (1980-2002) for sGVHD to investigate incidence, morbidity, and risk factors with a primary focus on parity. Among 119 transplantations, there were 21 cases of biopsy-proven sGVHD. The cumulative incidence was 18%, with multiorgan involvement in 6 cases and 1 death. sGVHD was more frequent when the donor was parous (32%) than nulliparous (9%) or male (13%; P = .03) and when the recipient was parous (31%) than nulliparous (7%) or male (13%; P = .02). Other univariable risk factors included older age (P < .01), busulfan/melphalan/thiotepa conditioning (P < .01), interleukin-2 (P = .02), HLA-A26 (P = .03), and more recent transplantation year (P < .01). Overall, risk factors were similar to those described in GVHD. Although an independent effect of parity could not be completely separated from other factors, donor and recipient pregnancy history merits further investigation.

Liver injury is a frequent, serious complication of allogeneic hematopoietic cell transplantation (HCT) following myeloablative preparative regimens. We sought to determine the frequency and severity of hepatic injury after nonmyeloablative conditioning and its relationship to outcomes. One hundred ninety-three consecutive patients who received 2 Gy total body irradiation with or without fludarabine were evaluated for end points related to liver injury. Patients with diseases treatable by HCT who were ineligible for conventional myeloablative allogeneic HCT because of advanced age and/or comorbid conditions were included. Fifty-one patients (26%) developed hyperbilirubinemia of 68.4 μM (4 mg/dL) or greater, most commonly resulting from cholestasis due to graft-versus-host disease (GVHD) or sepsis. Pretransplantation factors associated with liver dysfunction were a diagnosis of aggressive malignancy (hazard ratio [HR] 1.9; P = .04) and the inclusion of fludarabine in the conditioning regimen (HR 1.8; P = .07). Overall survival at 1 year was superior for patients who had maximal serum bilirubin levels in the normal (78%) or minimally elevated (22.23-66.69 μM [1.3-3.9 mg/dL]) ranges (69%) compared with those in the 68.4 to 117.99 μM (4-6.9 mg/dL; 20%), 119.7 to 169.29 μM (7.0-9.9 mg/dL; 17%), and 171.0 μM (10 mg/dL; 19%) or greater groups. In summary, significant jaundice occurred in 26% of patients and was predominantly due to cholestasis resulting from GVHD and/or sepsis. Aggressive malignancies (mainly advanced disease) and later development of jaundice after transplantation predicted inferior survival.

Liver toxicity caused by high-dose myeloablative therapy leads to significant morbidity after hematopoietic cell transplantation. We examined the hypothesis that liver toxicity after cyclophosphamide and total body irradiation is related to cyclophosphamide through its metabolism to toxins. Cyclophosphamide was infused at 60 mg/kg over 1 to 2 hours on each of 2 consecutive days, followed by total body irradiation. Plasma was analyzed for cyclophosphamide and its major metabolites. Liver toxicity was scored by the development of sinusoidal obstruction syndrome (veno-occlusive disease) and by total serum bilirubin levels. The hazards of liver toxicity, nonrelapse mortality, tumor relapse, and survival were calculated using regression analysis that included exposure to cyclophosphamide metabolites (as the area under the curve). Of 147 patients, 23 (16%) developed moderate or severe sinusoidal obstruction syndrome. The median peak serum bilirubin level through day 20 was 2.6 mg/dL (range, 0.5-41.1 mg/dL). Metabolism of cyclophosphamide was highly variable, particularly for the metaboliteo-carboxyethyl-phosphoramide mustard, whose area under the curve varied 16-fold. Exposure to this metabolite was statistically significantly related to sinusoidal obstruction syndrome, bilirubin elevation, nonrelapse mortality, and survival, after adjusting for age and irradiation dose. Patients in the highest quartile ofo-carboxyethyl-phosphoramide mustard exposure had a 5.9-fold higher risk for nonrelapse mortality than did patients in the lowest quartile. Engraftment and tumor relapse were not statistically significantly related to cyclophosphamide metabolite exposure. Increased exposure to toxic metabolites of cyclophosphamide leads to increased liver toxicity and nonrelapse mortality and lower overall survival after hematopoietic cell transplantation.

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 microM (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 microM (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.

Gemtuzumab ozogamicin (Mylotarg) targets leukemia cells expressing the CD33 receptor by means of a monoclonal antibody conjugated to a cytotoxic agent, calicheamicin. Treatment of acute myeloid leukemia (AML) with gemtuzumab ozogamicin may result in liver injury. We reviewed the course of 23 patients who were given gemtuzumab ozogamicin for AML that had relapsed after hematopoietic cell transplantation. Liver toxicity was assessed through physical examination, serum tests, histologic examination, and hepatic venous pressure measurements. Liver injury developed in 11 patients after gemtuzumab ozogamicin administration; it was manifested as weight gain, ascites, and jaundice in 7 patients. Seven patients died with persistent liver dysfunction and either multiorgan failure or sepsis at a median of 40 days after gemtuzumab ozogamicin infusion. Portal pressure measurements were elevated in 2 patients. Results of liver histologic examination in 5 patients showed sinusoidal injury with extensive sinusoidal fibrosis, centrilobular congestion, and hepatocyte necrosis. Six patients experienced AML remission that was sustained for at least 60 days after gemtuzumab ozogamicin infusion. In summary, hepatic sinusoidal liver injury developed after gemtuzumab ozogamicin infusion. Histology showed striking deposition of sinusoidal collagen, suggesting that gemtuzumab ozogamicin targets CD33+ cells residing in hepatic sinusoids as the mechanism for its hepatic toxicity.

In this issue of Blood , Burt and colleagues demonstrate that patients with severe refractory Crohn disease achieved clinically meaningful improvement and substantially reduced their requirements for immunosuppressive therapy after high-dose cyclophosphamide and antithymocyte globulin followed by

The influence of busulfan (BU) plasma concentration on outcome of transplantation from HLA identical family members for the treatment of chronic myelogenous leukemia (CML) was examined in 45 patients transplanted in chronic phase (CP) (n = 39) or accelerated phase (AP) (n = 6). All patients received the same regimen of BU, 16 mg/kg orally and cyclophosphamide (CY), 120 mg/kg intravenously. Plasma concentrations of BU at steady state (CSSBU) during the dosing interval were measured for each patient. The mean CSSBU was 917 ng/mL (range, 642 to 1,749; median, 917; standard deviation, 213). Of patients with CSSBU below the median, seven (five of 18 in CP and two of four in AP) developed persistent cytogenetic relapse and three of these patients died. There were no relapses in patients with CSSBU above the median. The difference in the cumulative incidence of relapse between the two groups was statistically significant (P = .0003). CSSBU was the only statistically significant determinant of relapse in univariable or multivariable analysis. The 3-year survival estimates were 0.82 and 0.64 for patients with CSSBU above and below the median (P = .33). There was no statistically significant association of CSSBU with survival or nonrelapse mortality, although the power to detect a difference in survival between 0.82 and 0.64 was only 0.24, similarly CSSBU above the median was not associated with an increased risk of severe regimen-related toxicity. We conclude that low BU plasma levels are associated with an increased risk of relapse.

Background Although prospective randomized studies have identified no demonstrable benefit for treatment of acute GVHD with methylprednisolone at doses >2 mg/kg/day, the minimum effective dose of methylprednisolone has not been defined. In a previous retrospective comparison of patients who initiated acute GVHD-treatment with prednisone-equivalent doses of 1 mg/kg/day or 2 mg/kg/day, the cumulative prednisone doses at day-42 of treatment were 31 mg/kg and 58 mg/kg, respectively (Mielcarek et al., Blood 2009). We therefore conducted a prospective phase III study to test the hypothesis that initial treatment of acute GVHD with “lower-dose” prednisone (prednisone-equivalent doses ≤1 mg/kg/day) is effective and safe. Methods Patients with newly diagnosed acute GVHD (≥ Grade IIa) after allogeneic hematopoietic cell transplantation between 2009 and 2013 were eligible for the study. Patients were stratified according to severity of GVHD at symptom-onset. Patients with Grade IIa manifestations (upper gastrointestinal symptoms of anorexia, nausea, vomiting attributed to acute GVHD, with stool volumes 2 mg/dL) were randomized to start treatment with a prednisone-equivalent dose of either 2 or 1 mg/kg/day. Medications administered for GVHD-prophylaxis were continued as tolerated, and oral beclomethasone dipropionate and budesonide were typically used in combination with systemic glucocorticoids in patients with gastrointestinal GVHD. The rate of prednisone withdrawal was not prescribed by the protocol. The primary endpoint of the study was a ≥33% reduction of cumulative prednisone exposure by day-42 after initiation of treatment among patients given lower-dose prednisone compared to those given higher-dose prednisone. Measures of prednisone toxicity (infections, hyperglycemia) and possible harm (progression to Grade III/IV GVHD, secondary therapy for refractory GVHD, non-relapse mortality, recurrent malignancy) were secondary endpoints. Results One-hundred and fifty patients were enrolled on the study (Grade IIa manifestations, n=92; Grade IIb-IV manifestations, n=58). For patients with Grade IIa GVHD treated initially with either 1 or 0.5 mg/kg, the cumulative prednisone doses at day-42 of treatment were 27.1 vs 22.2 mg/kg, respectively (18% reduction; p=0.08). For patients with Grade IIb-IV GVHD treated initially with either 2 or 1 mg/kg, cumulative prednisone doses at day-42 were 41.3 vs 38.4 mg/kg, respectively (7% reduction; p=0.4) (Figure 1). With a median follow-up of 27 (1-48) months, there were no significant differences in the risks of non-relapse mortality, recurrent malignancy and overall survival among patients started on higher-dose compared to those started on lower-dose initial therapy (15% vs 15%; 17% vs 11%; 76% vs 77%, respectively). Patients with Grade IIb-IV GVHD who started treatment with lower-dose prednisone were more likely to require secondary systemic immunosuppressive therapy than those who started treatment with higher-dose prednisone (41% vs 7%, p=0.001), and a trend suggested an increase in the risk of progression to Grade III-IV acute GVHD (19% vs 7%, p=0.2). The risks of infection and measures of glycemic control were not affected by initially assigned prednisone dose. Conclusions The primary endpoint of the study (≥33% reduction of cumulative prednisone exposure by day-42) was not reached due to the evolving practice of rapid prednisone withdrawal in responding patients treated with the higher dose. For patients presenting with Grade IIa GVHD manifestations, initiating treatment with lower-dose prednisone (0.5 mg/kg/day) was safe and effective. For patients presenting with Grade IIb-IV manifestations, however, initial treatment with lower-dose prednisone (1 mg/kg/day) was associated with an increased likelihood of requiring secondary immunosuppressive therapy without adversely affecting survival. Disclosures: No relevant conflicts of interest to declare.

We have previously reviewed the risks for developing acute hepatitis B following hematopoietic cell transplantation (HCT).[1][1] When a transplant recipient is seronegative for all hepatitis B virus (HBV) screening tests and the donor is HBV DNA negative, the risk of HBV infection in the recipient

Abstract 1146 Poster Board I-168 BACKGROUND Acute graft-vs.-host disease (aGVHD) varies in its intensity and response to therapy. Biomarkers capable of differentiating treatment-responsive from severe aGVHD at symptom onset may enable risk-stratified therapy. With the advent of prophylactic ursodiol, liver aGVHD has become rare, and gut involvement is responsible for much of the morbidity and mortality associated with severe aGVHD. Protein loss through altered epithelial tight junctions, and ultimately through mucosal necrosis, results in hypoalbuminemia in severe aGVHD (Weisdorf et al., Gastroenterology 1983 85:1076-81). We hypothesized that intestinal protein loss correlated with severity of aGVHD and thus predicted outcome. To test this hypothesis, we retrospectively evaluated changes in serum albumin as a marker of protein loss at the onset of aGVHD symptoms. To reduce the confounding effect of regimen-related gut toxicity, we restricted our analysis to patients who received non-myeloablative conditioning. PATIENTS AND METHODS Among 708 recipients of a first non-myeloablative allogeneic HCT at our Center, 412 (58%) developed aGVHD grade II–IV. We retrospectively evaluated these 412 patients (336 grade II; 76 grade III/IV). Patients were conditioned with 2 Gy total body irradiation, with or without fludarabine 90 mg/m2. Post-grafting immunosuppression consisted of cyclosporine and mycophenolate mofetil, and corticosteroids were used as first-line treatment of aGVHD. Median patient age was 55 (range, 1–75) years. 170 patients (41%) had related donors. Among the 242 patients (59%) with unrelated donors, there were 31 HLA-allele-mismatched donors, 28 HLA-antigen-mismatched donors, and 6 allele and antigen mismatched donors. We reviewed all serum albumin values from 30 days before to 45 days after clinical onset of aGVHD. The lowest albumin value in the 30 days before HCT was considered a patient's baseline value. Trends in serum albumin before and after aGVHD onset were compared among patients with peak grade II vs. peak grade III/IV aGVHD. We also compared 6-month estimates of non-relapse mortality (NRM) associated with changes in serum albumin and the performance of falling serum albumin as a predictor of grade III/IV aGVHD. RESULTS Clinical onset of aGVHD in the study cohort occurred at a median of 35 days after HCT. Patients who went on to develop severe (grade III/IV) aGVHD showed sharp decreases from baseline serum albumin levels; these decreases were already apparent at the onset of clinical aGVHD (Fig. 1). In contrast, patients whose aGVHD never exceeded grade II showed no changes on average from baseline serum albumins at aGVHD onset. Receiver-operator characteristic (ROC) curves demonstrated that among patients with new-onset symptoms of aGVHD requiring treatment, a drop from baseline in serum albumin of 0.5 g/dL optimally discriminated between those who went on to develop severe aGVHD versus those whose aGVHD peaked at grade II (ROC area under curve, 0.75). A drop from baseline albumin of 0.5 g/dL at onset of aGVHD symptoms was also associated with an increased risk of NRM at 6 months after aGVHD onset (28% vs. 8%, HR 2.13 [1.3–3.4], p=0.002; Fig. 2). CONCLUSION A sharp decrease in serum albumin may precede and predict severe aGVHD as well as NRM. Serial measurement of serum albumin is an inexpensive and readily available potential prognostic biomarker in patients with new-onset symptoms of aGVHD after non-myeloablative allogeneic HCT. In combination with other biomarkers or clinical predictors of aGVHD severity, the kinetics of serum albumin may enable specific and risk-stratified targeting of therapies for aGVHD, reserving intensive and protracted immunosuppression for the small percentage of patients at highest risk of severe aGVHD. FIGURES: Disclosures No relevant conflicts of interest to declare.

Abstract 1175 Poster Board I-197 BACKGROUND: Regimen-related toxicity is a significant cause of morbidity and mortality after myeloablative allogeneic hematopoietic cell transplantation (HCT). The widely-used conditioning regimen of busulfan followed by cyclophosphamide (BU/CY) has been associated with mortality rates of 12–13% at 100 days after HCT (BBMT 2007 13:355–65, Blood 2002 100:1201–7). Additionally, regimen-related liver injury in the form of moderate or severe hepatic sinusoidal obstruction syndrome (SOS) occurs in 9% of allogeneic HCT recipients conditioned with targeted BU/CY. Preclinical evidence suggests that BU, when given first in order, may deplete hepatic glutathione and potentiate the toxicity of CY, and that reversing the sequence of conditioning agents might reduce toxicity (BBMT 2007 13:853–62). We report the preliminary clinical and pharmacokinetic findings of an ongoing prospective Phase I/II clinical trial designed to test this hypothesis by reversing the standard order of conditioning agents, using CY followed by targeted IV BU. PATIENTS AND METHODS: As of June 17, 2009, 25 patients with myelofibrosis (n=14) or acute myeloid leukemia (AML)/myelodysplasia (MDS) (n=11) were enrolled and observed through day +100 after HCT. Median age was 55 (range, 34–62) years. Twelve patients (48%) had related donors, while 13 had unrelated donors. Among the 13 unrelated donors, 12 were HLA-matched while 1 was mismatched at one HLA allele. Patients received IV CY 60 mg/kg/day on days -7 and -6 before HCT, followed by IV BU (Busulfex, Otsuka Pharmaceutical) 4 mg/kg/day on days -5 through -2. After the first BU dose, subsequent doses were adjusted based on pharmacokinetic monitoring to achieve plasma BU concentrations at steady state (Css) of 800–900 ng/mL. Prophylactic phenytoin was administered on days -6 through -1, and prophylactic ursodiol was administered starting 2 weeks before HCT and continuing through day +90. All patients received G-CSF-mobilized peripheral blood stem cell grafts. Graft-vs.-host disease (GVHD) prophylaxis consisted of tacrolimus combined with methotrexate 10 mg/m2 on days +1, +3, +6, and +11. Endpoints included engraftment, liver and renal toxicity, day +100 mortality, overall survival, and pharmacokinetics of CY and its metabolites 4-hydroxycyclophosphamide (HCY) and O-carboxyethyl-phosphoramide mustard (CEPM). RESULTS: All patients initially engrafted, with neutrophil engraftment at a median of 17 (range, 11–26) days after HCT. One patient (4%) with an HLA-allele-mismatched unrelated-donor allograft had late graft failure approximately 3 months after HCT. Bilirubin values in the first 20 days after HCT peaked at a median of 1.9 (range, 0.5–12.4) mg/dL. SOS occurred in 1 patient (4%), who had a 10 kg weight gain, peak bilirubin of 2.3, and tender hepatomegaly with eventual resolution. Median peak serum creatinine in the first 20 days after HCT was 1.0 (range, 0.6–3.7) mg/dL. One patient (4%) experienced acute renal insufficiency, defined as a doubling of serum creatinine from pre-transplant baseline, within the first 20 days after HCT in the setting of septic shock. Day +100 survival was 96%; one patient died of sepsis at day +42. Kaplan-Meier estimated survival at the median follow-up of 8 months was 91% (myelofibrosis, 100% and AML/MDS, 80%). In the 6 patients who had died at last follow-up, causes of death included graft-vs.-host disease (n=2), sepsis (n=2), relapsed AML (n=1), and metastatic prostate cancer (n=1). Peak plasma concentrations of CY, HCY, and CEPM were 365.3 ± 58.2 μM, 9.5 ± 5.0 μM, and 12.7 ± 5.9 μM respectively after dose 1 of CY. After dose 2 of CY, peak plasma concentrations of CY, HCY, and CEPM were 312.9 ± 54.7 μM, 21.7 ± 8.6 μM, and 27.7 ± 11.0 μM respectively. The areas under the curve from time 0 to 48 hours for CY, HCY, and CEPM were 4737.0 ± 1361.3 μM • h, 182.4 ± 51.3 μM • h, and 508.5 ± 185.6 μM • h respectively. CONCLUSIONS: Reversing the sequence of conditioning agents in allogeneic HCT, from BU/CY to CY/BU, produced engraftment with low rates of regimen-related toxicity and 96% survival at day +100 after HCT. Our preliminary findings lend clinical support to the hypothesis that reversing the sequence of these agents may lessen exposure to toxic CY metabolites and improve clinical outcomes. Disclosures: Rezvani: Otsuka: Research Funding. Off Label Use: Describes intravenous busulfan in combination with cyclophosphamide as conditioning for allogeneic hematopoietic cell transplantation in patients with acute myeloid leukemia, myelodysplasia, and myelofibrosis.. McCune:Otsuka: Consultancy, Research Funding. Deeg:Otsuka: Research Funding.

Introduction: Treatment of severe GI GVHD poses a challenge, as little progress has been made in developing better treatments and survival remains poor. One problem is that it is difficult to know the ultimate severity of GVHD and the outcome at the onset of symptoms. We analyzed patients with peak stage 3–4 GI GVHD to identify factors within 2 weeks of the onset of GVHD that predicted the eventual outcome. This information could be useful in initial patient management and to inform the design of clinical trials. Patients and methods: We reviewed the records of 117 consecutive patients transplanted between 2000–2005 who developed stages 3–4 GI GVHD. Data were collected for more than 20 parameters, including stool volume, abdominal pain, melena, upper GI symptoms, serum albumin, number of GVHD treatments, visual findings at endoscopy and histopathologic grade of GI biopsies. Clinical parameters were measured as the peak value during each 14 day period starting from 2 weeks before the diagnosis of GI GVHD to the resolution of symptoms, loss of follow-up or patient death. Patients had been treated with myeloablative or reduced intensity conditioning regimens and received either marrow or growth factor-mobilized blood cells from related or unrelated HLA-matched donors. All patients received prophylactic pharmacologic immunosuppression for GVHD. Results: Median onset of symptoms was day 28 (range 4 – 113); 11 (9.6%) patients presented after day 80. Mean daily stool volume at diagnosis was 1494 ±1450 mL/day. At onset of GI symptoms, 75% of patients had ≥ stage 1 skin GVHD and 65% had ≥ stage 1 liver GVHD. At onset, 78% had upper GI symptoms (nausea and vomiting); less than 50% of patients presented with severe abdominal pain. Within the first 2 weeks after the diagnosis of GI GVHD, 52 (44.8%), 45 (38.7%), 7 (6.2%) and 12 (10.3%) patients had a peak GI stage of 4, 3, 2 and 1 respectively. All patients received high dose prednisone/prednisolone as initial treatment; 67 received 2nd line therapy; and 32 received three or more lines of treatment. Steroid refractoriness was defined as worsening GI symptoms after 3 days of high-dose steroid therapy, or non-response after 7 days, or only partial response after 14 days of therapy. Patients who developed stage 3 or 4 GI GVHD while receiving high dose prednisone for skin or liver GVHD were also considered steroid refractory. Non-relapse mortality was 71% and 41% at 1 year after transplant in patients with steroid-refractory and steroid-responsive GVHD, respectively. Overall survival was 30% at 1 year after HCT and 26% at 2 years. Thirteen patients relapsed, and all but 1 died subsequently. Adult patients who had steroid-refractory GVHD within 2 weeks of onset had a 1-year survival of 16% compared to 88% among steroid refractory pediatric patients. During the 14 day periods immediately before or after the onset of GI symptoms, these risk factors for overall mortality were identified by multivariable analysis: All patients, no endoscopy result considered (N=117) Factor Hazard Ratio p-value Adult age 3.2 .007 Jaundice (bilirubin >3.1 mg/dL) 1.97 .006 Albumin ≤1.6 g/dL 1.91 .01 Steroid refractory 1.76 .02 In a subgroup of patients who underwent endoscopy (N=73), a finding of ulcerated mucosa was predictive of mortality (HR 2.52, p=0.02). Conclusions: Within 2 weeks of GI symptom onset, mortality in patients with GVHD can be predicted by age, jaundice, hypoalbuminemia, response to prednisone, and presence of ulcerated mucosa at endoscopy. More effective early treatment in GI GVHD patients at risk for mortality is likely to be more useful than salvage therapy for steroid-refractory patients.

Objectives: GO is a conjugate of calicheamicin and a monoclonal antibody that targets CD33+ myeloblasts in acute myeloid leukemia (AML). After GO administration, ascites, weight gain, elevated aminotransferase enzymes, and jaundice (Sinusoidal Obstruction Syndrome, SOS, formerly known as VOD) have been reported. After approval by the FDA for relapsed AML in 2000 and its introduction into routine clinical practice, the incidence of SOS after GO infusion has been the subject of debate. The objectives of this study were to estimate the incidence rate of SOS after GO infusion in routine clinical practice, identify risk factors associated with the development of SOS, describe the incidence rates of serious adverse events (SAEs) and nonserious adverse events of special interest (ESIs). Methods: This study was a prospective observational study that enrolled consenting patients who were to receive GO for AML, with assessments at baseline, weekly x6 after the 1st dose of GO or 4 weeks after the last dose (whichever was later), and at 6 months. There were no exclusion criteria. Two hepatologists (GBM, LDD) reviewed cases with liver abnormalities and classified patients as either SOS, liver disease unlikely to be SOS, or no SOS. A diagnosis of SOS was based on 2 of the following 3 criteria: elevated bilirubin (>34 mmol/L or 2 mg/dL), increase in liver size or right upper quadrant liver pain, weight gain (>2.5% after GO infusion), along with exclusion of other liver diseases with this presentation. The study was conducted according to the Declaration of Helsinki and its amendments. Results: 512 patients were enrolled at 54 U.S. centers and 482 were analyzed. The study population consisted predominantly of men (59%); the mean age was 61.5 years; 73% had an ECOG performance status of 0 or 1 at baseline. 18% had received prior hematopoietic cell transplant (HCT), 4% had prior graft versus host disease (GVHD), 11% prior irradiation, 40% reported alcohol intake, and 19% were smokers. Most patients had received prior chemotherapy (87%). AML in first relapse was the indication for GO in 44%. Most patients received chemotherapy concomitantly with GO, most common were cytarabine (16%) and hydroxycarbamide (14%). The mean number of GO infusions per patient was 1.5 and the mean dose of GO per infusion was 7.8 mg/m2. The incidence of SOS was 8.9% (43/482; 95% confidence interval [CI]: 6.5% to 11.8%), with 19 cases classified as severe, 15 moderate, and 9 mild. Of 43 patients with SOS, 33 died within 6 months; of these, 20 died of AML progression. By multivariate analysis, only prior HCT was significantly related to development of moderate/severe SOS (odds ratio 2.2, CI 1.01–4.99). There was no evidence to suggest that age, blast count, body weight, GO dosing, prior chemotherapy, concomitant chemotherapy, or use of acetaminophen were related to development of SOS. 68% of patients died within 6 months. Progression of AML was the primary cause of death (73% of deaths); 7% were due to cardiovascular causes, 7% were due to infection, 6% were due to multiorgan failure, and 7% were due to other causes. SAEs occurred in 85% of patients; most (81%) due to other reasons, including AML, febrile neutropenia, pyrexia, and sepsis. Of the special interest categories, most SAEs were due to hepatic events (10%). 73% of patients experienced ESIs (both serious and nonserious); most ESIs were infusion-related events (46%) and 44% were hepatic events. Conclusions: GO can be safely administered in routine clinical practice with an overall 8.9% risk of SOS and with most cases moderate to severe. The only risk factor identified was prior HCT. Development of SOS following GO cannot be predicted in the majority of cases. Most ESIs were infusion-related events and most SAEs of the special interest categories were due to hepatic events.

Introduction: Severe VOD is an important regimen-related toxicity of hematopoietic SCT characterized by MOF and high mortality (>80% at d+100 post SCT). DF is a novel polydisperse oliogonucleotide with anti-thrombotic, anti-ischemic and thrombolytic properties, especially on microvasculature. DF appears to modulate endothelial cell (EC) injury in sVOD, with encouraging complete response (CR) rates, survival at d+100 post SCT and minimal toxicity reported. Methods: A multi-center, phase II trial was conducted in which patients (pts) stratified for age (30% risk). Study endpoints included CR, d+100 survival post SCT and toxicity. CR was defined as bilirubin Results: 150 pts were treated with DF, with 75 pts on each treatment arm: 129 pts underwent allo- and 21 auto- SCT. Median age was 36y (6m–63y). At DF start, median bilirubin was 5.0 mg/dL; median weight gain 12%; ascites was present in 77%; RUQ pain in 71%; hepatomegaly in 69%; abnormal portal flow in 44%; and MOF in 99% (at study entry, 7% were dialysis-dependent (DD), 7% ventilator-dependent (VD); 28% developed DD and 23% VD during treatment). Median duration of DF therapy was 19d (1–82d). Of 150 pts treated, 141 were evaluable for response: 65 pts achieved CR (46%) and 62 survived to d+100 (41%), including pts with prior DD and VD. Results for CR and d+100 survival have been analyzed by dose level according to age, prior SCT and Mylotarg use. No significant difference in CR and d+100 survival was found between the 2 doses, although in pediatric pts receiving 25 mg/kg/d, CR and d+100 survival was 67% (p=0.06). Toxicity was limited, but more attributable G3/4 events, including bleeding and hypotension, were recorded in pts on 40 mg/kg/d, although the difference was not significant (p=0.11). Preliminary US review demonstrated improvement in portal flow abnormalities with DF therapy. EC stress markers showed reduction in median levels of PAI-1 and nitric oxide with increase in Protein C in pts achieving CR (p Conclusion: DF treatment of sVOD/MOF results in a 46% CR rate and 41% d+100 survival post SCT: 25 mg/kg/d is the preferred dose. A phase 3 pivotal trial to confirm safety and efficacy is underway, comparing a prospective cohort of 80 DF-treated pts with sVOD/MOF to a matched historical group at 30 SCT centers across North America.

To the Editor: Hepatitis G virus (HGV) is a recently discovered flavivirus with sequence homology to hepatitis C virus (HCV).[1][1] The role of HGV in causing liver disease, however, is in doubt, raising the question as to whether there are other illnesses caused by this virus.[2][2] ,[3][3]

Introduction: Veno-Occlusive Disease (VOD) is a significant regimen-related toxicity of hematopoietic stem cell transplant (SCT), which when complicated by multi-system organ failure (MOF) has a case fatality rate >90%. We have treated 139 patients (pts) with VOD/MOF in a randomized, multicenter Phase II dose-finding study of Defibrotide (DF), a polydisperse oligonucleotide, with anti-thrombotic, anti-ischemic and thrombolytic properties, especially on microvasculature. Earlier studies of DF therapy for VOD/MOF have consistently shown manageable toxicity with promising complete response (CR) rates and d+100 survival post SCT. Methods: We reviewed pts to define status of renal, pulmonary, and CNS dysfunction at entry and on DF therapy. We also determined dialysis dependence (DD) and/or ventilator dependence (VD) at study entry or when newly acquired while on study. These subgroups were examined for response to treatment (CR vs no CR) and d+100 survival. Results: Of 139 pts treated, 97 had creatinine (creat) ≥ 2x admission value at study entry, of whom 42 pts had creat ≥ 3x admission value, and 12 were DD. 35 pts developed new DD on DF therapy. At entry, 69 pts had room air O2 saturation ≤ 90%, 10 were VD and 34 developed new VD on DF therapy. 33 pts were encephalopathic at study entry and 23 became encephalopathic during treatment. CR was achieved in 59/124 (48%) evaluable pts. By Kaplan Meier and on intent to treat, d+100 survival was 51/133 (38%). Pts were analyzed according to MOF (Table 1). In those with both renal and pulmonary dysfunction at study entry, 44% achieved CR and 39% d+100 survival. Pts with renal or pulmonary dysfunction at study entry, combined with encephalopathy, had a CR rate of 55% and d+100 survival of 45%. Those with MOF in all 3 systems achieved a CR rate of 50%, although d+100 survival was lower at 33%. The presence of DD at study entry or newly acquired on DF therapy reduced CR rates to 33 and 20% respectively, with a similar reduction in CR rates for VD at 20 and 25%. D+100 survival in both categories was also reduced. Conclusion: DF therapy achieved encouraging CR rates and d+100 survival in pts with MOF in up to three systems complicating VOD post SCT, and clinical benefit was seen even if pts were DD and/or VD. However, CR rates and d+100 survival were lower with DD and/or VD both at study entry and when newly acquired on DF therapy, which suggests that earlier intervention with DF may further improve outcome. Degree and Type of MOF CR D+100 survival *p

GvHD is a major cause of morbidity and mortality after allogeneic hemopoietic cell transplantation (HCT). Recent data suggest that rabbit anti-thymocyte globulin (THY) given pre-transplant is effective in reducing the incidence of GvHD. We transplanted 54 patients, 9-65 (median 49) years of age, with advanced myelodysplastic syndrome (MDS, beyond Refractory Anemia[RA], n=29), myelofibrosis (n=12), or other myeloid disorders (n=13), after conditioning with a regimen of targeted busulfan (BU; steady state level 800-900ng/ml), cyclophosphamide (CY) and THY (Thymoglobulin, Sangstat) which was given on days -3,-2 and -1. The starting dose was 4.5 mg/kg (total), to be escalated (in cohorts of 15 patients) to 6.0 and 7.5 mg/kg, dependent upon GvHD incidence and EBV reactivation ≥1000 copies). Patients also received methotrexate (MTX) + cyclosporine (CSP). Seventeen ( patients were accrued in the first cohort (2 did not receive the prescribed dose of THY), and none activated EBV; among 20 patients in the second cohort (5 with incomplete THY dose) one re-activated EBV, and, thus, the third cohort was to receive the same dose, 6 mg/kg, (n=17; two with incomplete THY dose). Donors were HLA-identical siblings in 28, and HLA matched unrelated volunteers in 26 patients. All but two patients had sustained engraftment; 32 (59%) developed acute, and 24 of 46 patients at risk (52%) developed chronic GvHD. The incidence of acute/chronic GvHD was 41%/45% for related, and 60%/36% for unrelated patients given the prescribed doses of THY (80%/85% for the 9 patients in both groups with incomplete THY dose). Relapse incidence for patients given the prescribed dose of THY was 16% for related, and 2% for unrelated recipients; it was 44% among the 9 patients who did not receive the full dose of THY. There was a suggestion that greater ‘area under the curve’ for the CY metabolite CEPM was correlated with non-relapse mortality. Overall, 38 patients (70%) are surviving with a follow-up of 3-20 (median 13) months. Concurrently, 27 patients, 11-64 (median 51) years of age, with low-risk MDS (RA) were conditioned with the identical targeted BUCY regimen (and MTX+CSP) but without THY, and transplanted from HLA-identical related (n=14) or unrelated donors(n=13). All patients engrafted, and none relapsed; 24 (89%) developed acute, and 24 of 25 patients at-risk (96%) developed chronic GvHD. Overall 18 patients (67%) are surviving at 9-39 (median 23) months; there was no difference between related and unrelated transplants. These data suggest that THY, added to targeted BUCY, reduced the incidence of acute and chronic GvHD. With EBV monitoring it may be possible to further escalate the dose of THY and further reduce the incidence of GvHD. However, because of actual or presumed toxicity, 16% of patients did not receive the prescribed dose of THY. There was no evidence for an increase in infections or relapse compared to historical data. The projected survival of patients with advanced disease is encouraging, but longer follow-up is needed.

The field of hematopoietic cell transplantation is now 35 years old, and many complications seen in the early days have been consigned to the historic record. One complication, however, was never anticipated. Cirrhosis caused by chronic hepatitis C infection has a cumulative frequency in

Fifty-two of 175 (30%) survivors of allogeneic marrow transplantation developed chronic graft-versus-hose diseases (GVHD). Five with limited chronic GVHD had an indolent clinical course with involvement of only the skin and liver. Forty-seven with extensive chronic GVHD had an unfavorable multiorgan disorder that resembled several autoimmune diseases. Thirteen patients with extensive disease (group I) were not treated and only 2 survive with Karnofsky scores >- 70%. Mortality resulted from infections and morbidity from sica syndrome, pulmonary and hepatic insufficiency, scleroderma-like skin disease, and contractures. Another 13 (group II) received a median of 8 mo prednisone and/or a brief course of antithymocyte globulin, and 3 survive without disability. The other 21 (group III) were treated with a combination of prednisone (1.0 mg/kg/q.o.d.) and either cyclophosphamide, procarbazine, or azathioprine (all 1.5 mg/kg/day) for a median of 13 mo. Combination therapy was well tolerated with only modest myelotoxicity. Fifteen in group III had a good and 4 a fair response to treatment while 2 with no response died. Azathioprine and prednisone was the most effective regimen. All therapy has been discontinued in 12 group III patients: GVHD returned in 5 (including 2 who died in spite of retreatment) while 7 remain free of GVHD for a median of 11 (range 6–30) mo observation. Only I group III survivor is disabled and 16 of the original 21 are alive 2–4 yr after transplant with Karnofsky scores of 70%-100%. Thus, combination immmunosuppression appears to favorably affect and, in some cases, premanently arrest the adverse natural course of extensive chronic GVHD.