bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics of Oral Maribavir, a Novel Anti-Cytomegalovirus Agent, in Subjects with Renal Impairment.
Authors: Swan Suzanne , Smith William , Marbury Thomas , Schumacher Mary , Dougherty Carolyn , Mico Bruce , Villano Stephen 
Published: October 2019

Abstract
Maribavir (MBV) is an oral antiviral drug with a unique mechanism of action against cytomegalovirus (CMV). Maribavir is currently in clinical development for use in recipients of stem cell or solid organ transplants, who are vulnerable to renal impairment caused by a variety of drugs or post-transplant complications. Characterization of the pharmacokinetic (PK) profile of maribavir in patients with renal impairment was needed to determine if dose adjustment is indicated. The effect of renal function on the PK of a single 400 mg dose of maribavir was evaluated in adults with normal renal function (creatinine clearance >80 mL/min) and adults with renal impairment classified as mild, moderate, or severe, as measured by creatinine clearance 50–80, 30–<50, and <30 mL/min, respectively. Subjects requiring dialysis were not included. PK results, based on total (bound and unbound) plasma concentrations are shown in the table. Analyses of PK parameters estimated from unbound plasma concentrations of maribavir also did not show statistically significant differences between groups. Renal impairment was associated higher AUC and Cmax values as well as with reductions in the oral clearance and terminal-phase volume of distribution of VP 44469, an inactive metabolite of maribavir. Results were consistent with those of previous studies, which showed that very little maribavir was excreted unchanged in urine while about 22% of an oral dose of maribavir is recovered in urine as VP 44469. In conclusion, renal impairment does not affect the pharmacokinetics of maribavir, although plasma concentrations of the metabolite VP 44469 tended to increase with decreasing creatinine clearance. No dose adjustment of maribavir is indicated in subjects with renal impairment as classified in this study.
Mean Maribavir PK Parameters Normal Renal Function Mild/moderate Renal Impairment Severe Renal Impairment ANOVA p-value Parameter (unit) N=12 N=10 N=8 Cmax (mcg/mL) 22.6 22.0 21.5 0.869 AUC 0-∞ (mcg*h/mL) 139 145 136 0.810 T 1/2 (h) 5.51 5.61 5.28 0.780 CL/F (L/h) 3.38 3.05 3.56 0.808
Ex-Vivo Reduction of Allograft T Cell Dose Does Not Prevent Acute Graft-vs-Host Disease after Reduced-Intensity Hematopoietic Stem Cell Transplantation.
Authors: Hardy Nancy M. , Hakim Frances , Steinberg Seth , Krumlauf Michael , Babb Rebecca , Odom Jeanne , Fowler Daniel , Gress Ronald , Bishop Michael R. 
Published: October 2019

Abstract
Allograft T cell depletion (TCD) reduces acute graft-vs. host disease (aGVHD) after myeloablative hematopoietic stem cell transplantation (HSCT). Lower incidences of aGVHD reported after reduced-intensity stem cell transplantation (RIST) may reflect delayed donor T cell engraftment. We compared the incidence of aGVHD following RIST with TCD (19 patients (pts) vs. T cell replete (TCR) allografts (20 pts)(Table). There was no difference in the incidence aGVHD, occurring in 71% of TCD recipients (median onset Day 47) and 70% of TCR recipients (median onset Day 25). After TCD, 100% of those who engrafted prior to any DLI developed aGVHD compared with 56% of those who engrafted after DLI, including two pts who developed “late-acute” aGVHD after Day 100, upon completion of donor T cell engraftment. T cell engraftment after TCD was uneven: engraftment kinetics were associated with residual host circulating CD8+ T cell counts after immune depletion; and aGVHD did not occur in the setting of mixed T cell chimerism (Figure). These observations demonstrate that aGVHD can occur with very low doses (105/kg) of allograft T cells after RIST. Protection from aGVHD conferred by mixed T cell chimerism may be lost with full donor T cell engraftment. With limited donor T cell numbers, host T cells appear to determine kinetics of engraftment and of aGVHD after RIST. Figure:
Post-induction circulating CD8+ T cell counts in TCD recipients with delayed donor T cell engraftment. After TCD, all subjects who developed aGVHD did so at or after the establishment of T cell full donor T cell chimerism, and occasionally prior to any DLI.
Shaded triangle represents the theoretical area in which values would fall if subjects developed aGVHD prior to complete donor T cell engraftment. Arrows: DLI.
Patient and Transplant Characteristics and Outcomes Protocol TCD TCR Flu/Cy: Fludarabine and cyclophosphamide; EPOCH-F: Etoposide, doxorubicin, vincristine, cyclophosphamide, prednisone and fludarabine; FDC: Full donor chimerism. Median (range) Median (range) Recipient Age 43 years (32 – 56) 44 (19 – 67) CMV Risk 14/19 16/20 Pretransplant Immune Depletion Flu/Cy EPOCH-F Conditioning Regimen Flu/Cy Flu/Cy Pre-conditioning Host Cell Counts: CD3 86 (1 – 701) 140 (21 – 441) CD4, p=0.017 44 (1 – 156) 71 (12 – 191) CD8 34 (0 – 555) 55 (2 – 309) NK 58 (0 – 376) 88 (3 – 467) Day 0 CD3 Cell Count 1 (1 – 6) 5 (0 – 42) Allograft CD34+ cells/kg 7.75 x 106 (5.1 – 12.9) 7.68 x 106 (4.6–18.4) Allograft CD3+ cells/kg 1.0 x 105 (preset) 3.63 x 108 (1.5 – 8.3) Donor T cell engraftment Day +70 (14 – 180) 14 (14 – 100)
Figure Figure
Campath 1H Versus ATG for the Prophylaxis of Graft Versus Host Disease Does Not Increase the Risk of Relapse or Infections.
Authors: Shah Ami J. , Kapoor Neena , Crooks Gay M. , Kohn Donald B. , Weinberg Kenneth I. , Killen Renna , Kuo Lily , Parkman Robertson 
Published: October 2019

Abstract
Graft Versus Host Disease (GVHD) is a cause of serious morbidity and mortality in > 50% of recipients of unrelated hematopoietic stem cell transplantation (HSCT). We performed a trial using Campath 1 H pre- and post-HSCT in an attempt to decrease the incidence of GVHD without increasing the risk of infection or relapse. Patients were retrospectively compared to a population of patients who received antithymocyte globulin (ATG) pre-and post-HSCT.
Materials and Methods: 27 patients were evaluated for this study. Fourteen patients received Campath 1H and 13 patients received ATG. Demographics of patients who received Campath 1H consisted of 9 males and 5 females, with a median age of 13 years (3 years–17.8 years). Thirteen patients received unrelated BM and 1 patient received unrelated PBSC. Demographics of patients receiving ATG consisted of 9 males, 4 females with a median age of 7.4 years (21 months–19 years). Twelve patients received unrelated bone marrow (BM) and 1 patient received unrelated peripheral blood stem cells (PBSC). Diagnoses were similar between the two groups. Patients who received Campath1H received a total dose of 52 mg/m2 pre-HSCT and 20 mg/m2 post-HSCT. Patients who received ATG received a total dose of 60 mg/kg pre-HSCT and 100 mg/kg post-HSCT. GVHD prophylaxis and supportive care measures were similar in both groups.
Results: There was a significant difference in the incidence of severe (grade III and grade IV) GVHD between the two arms [Campath (0/14) vs. ATG (6/13), p=0.006]. Among the patients who were transplanted for leukemia, there was no significant difference between the two arms in terms of relapse [Campath (2/14) vs. ATG (4/9), p=0.162]. The 1- year and 2-year overall survival between the two arms was not significantly different [Campath 1H (64%) vs. ATG (69%), p=0.98]. Patients receiving Campath 1H had the presence of CD3+ T cells (>30 cells/ml) in their peripheral blood later than in those who received ATG [65 days (Campath 1H) vs. 27 days (ATG), p=0.001]. The median time to the development of a response to PHA occurred later in the Campath 1H arm [240 days (Campath 1H) vs. 90 days (ATG), p= 0.0005]. The median time to an antigen specific response also occurred later in those receiving Campath 1H [365 days (Campath 1H) vs. 150 days (ATG), p= 0.008]. Patients who received ATG had a greater chance of developing a candida infection [Campath 1H (2/14) vs. ATG (8/13) p=0.02]. Among other specific viral infections, there was no significant difference between the two groups.
Conclusions: Campath 1H is effective in decreasing the incidence of GVHD without increasing the risk of relapse. Although there is a significant delay in immune reconstitution, there was no increase in infectious complications in recipients of Campath 1H.
Dendritic Cell Type 2 Counts on Day 28 in HLA-Matched Related Allogeneic PBSCT Predicts the Incidence of Acute and Chronic GVHD.
Authors: Rajasekar Reena M. , Mathews Vikram , Lakshmi Kavitha M. , Viswabandya Auro , George Biju , Chandy Mammen , Srivastava Alok 
Published: October 2019

Abstract
Dendritic cells (DC) are antigen-presenting cells involved in induction and regulation of immune responses. We investigated the impact of the number of infused and engrafted (day 28) dendritic cells, DC1 (lin−HLA-DR+CD11c+) and DC2 (lin−HLA-DR+CD123+) on the development of acute and chronic graft-versus-host disease (GVHD). Thirty three consecutive patients with hematological malignancies who underwent HLA-matched related G-CSF mobilized allogeneic PBSCT were included in the analysis. The mean follow up was 293 days (range: 36–417). There were 20 males and 13 females (median age: 29 years, range: 15–55). Conditioning regimen was myeloablative in 25 (Bu/Cy=13; Cy/TBI = 12) and non myeloablative in 8 patients (Flu/Mel = 7; Flu/Cy = 1). All patients received cyclosporine and short course methotrexate as GVHD prophylaxis. Three of them received steroids before day 28 for treatment of GVHD. Ten patients developed acute GVHD (grade II–IV) and 11 patients had chronic GVHD. The median DC2 count in the peripheral blood on day 28 was significantly lower among patients who developed acute GVHD as compared to those who did not and there was a trend to a lower count among patients with chronic GVHD [Table 1]. Based on the day 28 DC2 count patients were divided into a low DC2 quartile (<2.3cell/ul, n=8) and the rest were grouped as high DC2 (>2.3cell/ul, n=25). The two groups were comparable with regard to patient and graft characteristics (CD34, CD133, CD3, CD4, CD4CD45RO, CD4CD45RA, CD8, CD8CD45RO, CD8CD45RA, CD19, NK, DC1and DC2 cell dose). Patients in the low DC2 quartile group had higher probability of developing acute (P=0.000) and chronic GVHD (P= 0.022). Cox regression analysis revealed that low day 28 DC2 counts is associated with higher incidence of acute GVHD (HR=11.4; 95%CI=2.9–44.9; P=0.001) and chronic GVHD (HR=7.07; 95%CI=1.9–26.6; P=0.004). In a multivariate analysis which included other standard risk factors such as female to male transplants, conditioning regimen, CD34 and CD3 cell dose, low day 28 DC2 was found to be a risk factor for acute GVHD (HR=21.1; 95%CI=3–149.9; P=0.002) together with patient age (HR=1.1; 95%CI=1–1.3; P=0.039). DC1, DC2 counts in the graft and day 28 DC1 count did not correlate with the development of acute or chronic GVHD. Excluding patients who had developed acute GVHD before day 28 (n=3), a low day 28 DC2 count (<2.3/ul) had a positive predictive value of 80% for acute GVHD and 75% for chronic GVHD. These results suggest that the DC2 count in the peripheral blood on day 28 is a strong predictor for development of GVHD in recipients of PBSC in matched related allogeneic HSCT.
Table 1: Median day 28 DC2 count and GVHD n, median DC2 x 103/ml (range) Yes No P-value Acute GVHD (II=IV) 10, 2.06(0.6–24.8) 23, 11.5(1.1–46.6) 0.004 Chronic GVHD 11, 2.4(1.1–46.6) 17, 8.19(1.6–44.9) 0.070
Functional Comparison and Longitudinal Assessment of Tri-Functional T-Cells Recognizing CMV pp65 and IE-1 Polypeptides in Hematopoietic Stem Cell and Solid Organ Transplant Recipients.
Authors: Diamond Don J. , Lacey Simon F. , La Rosa Corinna , Zhou Wendy , Gallez-Hawkins Ghislaine , Thao Lia , Longmate Jeff , Limaye Ajit , Spielberger Ricardo , Forman Stephen J. , Zaia John A. 
Published: October 2019

Abstract
Reconstitution of adaptive T-cell responses to human cytomegalovirus (CMV) is critical to protection from CMV disease following hematopoietic stem cell (HSCT) or solid organ transplantation (SOT). However, there is an incomplete understanding of which CMV antigens and epitopes are most crucial to providing protective responses. The functional status of cytotoxic T-lymphocyte (CTL) populations recognizing cytomegalovirus IE-1 and pp65 polypeptides was investigated in PBMC from either HSCT or SOT recipients. Our previous finding of differing levels of degranulation between CMV IE1 and pp65/pp50 specific T-cells was complicated by the possibility that differences were epitope and/or HLA-specific. We generalized the approach using a combined flow-based CD107a/b degranulation/mobilization and intracellular cytokine (ICC) assays using peptide libraries as antigens. These assays indicated that a significantly higher proportion of pp65-specific CTLs were in a more mature functional state compared to IE-1-specific CTLs. Degranulation/multicytokine ICC assays also indicated that a significantly higher proportion of the pp65-specific versus IE-1-specific CTLs secreted both IFN-γ and TNF-α, in addition to possessing greater cytotoxic potential. These results support our earlier findings of functional differences between CTLs recognizing individual epitopes within the IE-1 and pp65 antigens in HSCT recipients, and extend them to a broader array of HLA-restricted responses to those antigens. A report that a subset of HIV-1 specific CTLs capable of producing both IFN-γ and TNF-α was associated with improved cytotoxic activity prompted us to investigate whether degranulation, a functional correlate of cytotoxicity, was positively associated with dual cytokine production and predicted differences between IE1 and pp65-specific CD8+ T-cells. A higher proportion of pp65-specific compared to IE1-specific T-cells were present in the trifunctional IFN-γ+,TNF-α+, CD107+ population (p=0.008) in HSCT recipients. We have extended these findings to investigate the role of donor CMV status in terms of functional maturity of CMV-specific T cell response in transplant recipients. T cell maturation/function may act as a mechanistic correlate to the survival advantage of recipients receiving a stem-cell graft from CMV sero-positive donors. These principles have also been applied to investigations of a high risk population of sero-negative recipients of a sero-positive liver allograft. Data from this study will also be reviewed in the context of the model of trifunctional T cells being indicative of enhanced protective capacity against CMV disease and associated with survival.
Prophylactic Use of Intravenous Immune Globulin in the Management of Patients Undergoing Hematopoietic Stem Cell Transplantation: A Systematic Review of Literature.
Authors: Tay Jason , Fergusson Dean , Hutton Brian , Hebert Paul , Huebsch Lothar , Tinmouth Alan 
Published: October 2019

Abstract
Background: Intravenous immunoglobulin (IVIG) is a scarce resource derived from pooled plasma of whole blood through industrial fractionation. IVIG for the prevention of infections and Graft versus host disease (GVHD) after Hematopoietic Stem cell transplantation (HSCT) is one of only 5 licensed indications; however, its use in HSCT is contentious with multiple conflicting reports. Given this uncertainty, we sought to summarize and quantify the clinical effects of prophylactic IVIG in the context of HSCT.
Methods: We conducted a systematic review to summarize evidence from prospective randomized controlled trials (RCTs) addressing prophylactic IVIG use in patients undergoing HSCT. In particular, we included studies which addressed clinical outcomes and excluded studies that addressed only biochemical surrogates. The search strategy included MEDLINE (1966 to 4th week of July 2006), EMBASE (1980 to 4th week of July 2006) and all EBM Reviews (2ndquarter of 2006). A random effects model was used to summarize the outcome data.
Results: Twenty two RCTs representing 3346 patients were included in the review; 16 RCTs addressing patients undergoing allogeneic HSCT, 4 RCTs addressing patients undergoing either allogeneic or autologous HSCT and 1 trial in patients undergoing autologous HSCT. Nine RCTs (n=1462) compared conventional IVIG to no treatment, 8 RCTs (n=538) compared CMV specific IVIG to no treatment, 2 RCTs (n=950) compared 2 different doses of conventional IVIG while 3 RCTs (n=212) compared conventional IVIG to CMV specific IVIG/plasma. Eleven RCTs comparing IVIG to no treatment did not demonstrate an overall survival advantage (RR 1.01; 95% 0.92–1.12). IVIG did not attenuate transplant related mortality (RR 1.24; 95% 0.83–1.85), acute GVHD (RR 0.95; 95% 0.80–1.14), chronic GVHD (RR 1.19; 95% 0.85–1.67), interstitial fibrosis (RR 1.00; 95% 0.50–2.00) or relapse (RR 0.76; 95% 0.38–1.52). Although CMV infections were reduced (RR 0.80; 95% 0.66–0.96), this did not result in a reduction in CMV disease (RR 0.90; 95% 0.52–1.56). Of concern, the risk of hepatic sinusoidal obstruction syndrome (HSOS) was increased (RR 3.09; 95% 1.11–8.58). Several a priori defined sensitivity analyses were performed including comparisons of the type of IVIG, dose of IVIG, type of HSCT and the quality of studies.
Conclusions: There is no evidence to support the routine use of prophylactic IVIG in improving clinical outcomes in patients undergoing HSCT. Furthermore, no subgroups appear to benefit from IVIG use. The increased risk of HSOS merits further study. Given the lack of benefit of IVIG in patients undergoing HSCT, the labeled indications for IVIG should be reassessed.
Effect of Repeated Apotransferrin Administrations on Serum Iron Parameters in Patients Undergoing Myeloablative Conditioning and Allogeneic Stem Cell Transplantation.
Authors: Ebeling Freja , Parkkinen Jaakko , Sahlstedt Leila , von Bonsdorff Leni , Salo Hanna , Ruutu Tapani 
Published: October 2019

Abstract
The myeloablative preconditioning for hematopoietic stem cell transplantation (SCT) disrupts the main route of body iron turnover by temporarily halting erythropoiesis. This is followed by rapid increase in transferrin saturation and appearance of non-transferrin-bound iron (NTBI) in plasma (Sahlstedt et al, Br J Haematol 2001). We have previously shown that considerable amounts of iron can in this situation be bound by a single intravenous dose of human plasma-derived ironless transferrin, apotransferrin (Sahlstedt al, Br J Haematol 2002). NTBI is cleared from circulation by the liver, to which iron-catalyzed generation of reactive oxygen species are considered to be potentially toxic as also possibly contributing to mucositis and idiopathic pneumonia syndrome. We studied the ability of three repeated apotransferrin dosing regimens to maintain the accumulating iron in a transferrin-bound form in 20 patients receiving cyclophosphamide 120mg/kg and total body irradiation 12 Gy before SCT. The low-dose group received a total dose (including loading and maintenance doses) of 340 mg/kg, the medium-dose group 610 mg/kg and the high-dose group 1040 mg/kg starting on day −6 before SCT. Serum transferrin, total iron, NTBI and transferrin saturation were analyzed from daily samples until day +14. A significantly higher increase in serum transferrin and in serum total iron was detected in the high-dose group compared with the other dose groups and controls. On the second day after start of preconditioning, the mean increase in serum iron was 48 μmol. At the same time, the 24-hour increment in serum transferrin after the apotransferrin doses decreased by 45% pointing to uptake of transferrin-bound iron by tissues. Serum iron levels remained significantly more elevated in the high-dose group compared with controls for about 10 days, after which their decrease coincided with appearance of reticulocytes in peripheral blood. In 5/8 patients in the high-dose group, no detectable NTBI was found during the study period, whereas in the controls 75% of the samples were NBTI positive. In conclusion, even with repeated administration of relatively large doses of apotransferrin, full transferrin saturation and appearance of NTBI can be prevented in only part of the patients. Achieving complete iron binding with apotransferrin in all SCT patients would apparently require very high apotransferrin doses. The remarkable rise in transferrin saturation indicates that about 180 μmol or iron per day is initially released into circulation after start of preconditioning therapy.
Figure Figure
Comparable Results of HLA Identical Sibling Donor Peripheral Blood Hematopoietic Stem Cell Transplantation after Reduced-Intensity and High-Dose TBI-Based CD34+-Positive Cell Selection Myeloablative Preparative Regimens for High-Risk Myelodysplasia or Acute Myeloid Leukemia in First Remission: Results from a Prospective Study.
Authors: Martino Rodrigo , Valcarcel David , Pinana Jose L. , Sureda Anna , Brunet Salut , Briones Javier , Sanchez Blanca , Delgado Julio , Sierra Jorge 
Published: October 2019

Abstract
We prospectively compared the efficacy of allogeneic PBSCT from an HLA-identical sibling in adults with poor-risk AML or MDS in an early disease status (AML or RAEB type 2 in first CR after chemotherapy or RAEB type 1 with poor prognosis). Poor-risk AML/MDS was defined as the presence at diagnosis of one or more of the following: poor-risk karyoype, normal karyotype with flt-3 duplications or MLL mutations, high level of MRD after consolidation (>0.1%), and, in RAEB type 1, an IPSS3Int-2. Based only on the patients’ age, the transplant protocol consisted in conditioning with cyclophosphamide-TBI and use of CD34+-selected PBSCT (CyTBI-CD34+ group, if £ 50 y.o.) or a reduced-intensity conditioning (RIC) with fludarabine and oral busulphan (FluBu-RIC, If > 50 y.o.). Between 1998 and 2005, 74 consecutive patients entered the study (35 in the CyTBI-CD34+ and 39 in the FluBu-RIC group). Both groups differed in some baseline characteristics, mainly younger age in the CyTBI-CD34+ group (median 42 vs. 59 years, p<0.01), a higher transplant comorbidity index in the FluBu-RIC group (median 0 vs. 3 points, respectively, P<0.01), a higher proportion of AML (with respect to RAEB) in CyTBI-CD34+ group (82% vs 54%, respectively, P=0.02), and a higher proportion of poor-risk karyorypes in the FluBu-RIC group (32% vs 72%, respectively, P<0.01). The median follow-up exceeds 4 years in both groups. All patients had sustained donor-engraftment by day +60, except for one lethal graft failure in the CyTBI-CD34+ group. The 4-year probability of OS was and LFS were similar in both groups (52% and 53% in the CyTBI-CD34+ group vs. 53% and 53% in the FluBu-RIC group, respectively, P>0.8 for OS and LFS). In addition, the 4-year cumulative incidence of non-relapse mortality (NRM) was 25% (95% CI 11–38%) and 22% (95% CI 5–39%), respectively (P>0.8), while the incidence of relapse was 22% (95% CI 5–39%) and 25% (95% CI 6–44%), respectively (P>0.8). In univariate analysis, the only variable that decreased OS and LFS by increasing NRM was the patient male/donor female sex combination (n=18 cases). The OS and NRM in these 18 cases were 37% and 40%, respectively, while the 56 cases with other sex combinations had much better outcomes (66% OS and 8% NRM, P=0.004 and P==0.001 for the comparison of OS and NRM, respectively). Trends were seen for improved OS and lower NRM in the CyTBI-CD34+ group in patients less than 40 years of age (P=0.1) and in patients receiving higher doses of CD34+ cells/kg in the FluBu-RIC group (P=0.1). Our single-center results suggest comparable outcomes for RIC alloPBSCT in high-risk adults with poor-risk AML and MDS in an early disease phase.