bluuebunny/crossref_metadata_2025_split huggingface dataset:
Risk Factor of Hepatic Veno-Occlusive Disease: Analysis of Clinical Data of 5024 Patients Extracted from the Database of the Japan Marrow Donor Program.
Authors: Sakai Miwa , Ohashi Kazuteru , Yamashita Takuya , Akiyama Hideki , Sakamaki Hisashi 
Published: October 2019

Abstract
Hepatic veno-occlusive disease (VOD) is one of the most serious complication of hematopoietic stem cell transplantation (HSCT). Various factors have been identified as increasing the risk of hepatic VOD, but few of them have been associated with a significantly increased risk. We retrospectively analyzed the clinical data of 5024 transplant recipients (median age28, range 0–68) which extracted from the Japan Marrow Donar Program. The diagnosis of VOD was made according to the McDonald’s criteria, and 324 out of 4833 patients (6.7%) were eventually diagnosed with VOD. The possible risk factors based on the previous studies were counted on an initial univariate analysis, and cumulated significant factors were further analyzed for their potential value for VOD development in multivariate analysis. Variables correlated with an increased risk of VOD were: time of transplant >2 times (relative risk (RR) 2.7; p=0.006), pretransplant disease status (RR 2.3; p=0.000), prior liver disease (RR 2.1; p=0.017), ABO blood type mismatch (RR1.7; p=0.000). In patients receiving either busulfan or melphalan for conditioning increased VOD risk (RR 1.5 and 1.8; p=0.007 and 0.002, respectively). In our multivariate analysis, stem cell source, and prophylactic use of heparin and Ursodiol had no significant effect on VOD development. This analysis might contribute to revise the previously reported risk factors for VOD and the data could be used to know which patients might be suitable subjects for new trials for VOD prevention.
Role of Zoledronic Acid in Treating Osteoporosis in Post-Allogeneic Bone Marrow Transplant Patients - A Phase II Trial.
Authors: Chamarthy Usha Sree , Rao D. Sudhaker , Divine George , Khan Shahzad , Janakiraman Nalini 
Published: October 2019

Abstract
Introduction: Multiple risk factors exist for the development of osteoporosis in patients undergoing allogeneic hematopoietic stem cell transplant. Bone loss is greatest during the first year, predominantly the first 40 days. Bisphosphonate therapy combined with calcium and Vitamin D supplementation in allogeneic stem cell transplant patients may be one useful strategy to prevent the accelerated bone resorption.
Study Design: A Phase II clinical trial studying the role of zoledronic acid (Zometa, Novartis Pharmcaeutical Corporation) in treating post-allogeneic bone marrow transplant(BMT) osteoporosis was undertaken. The study included adult patients undergoing allogeneic BMT for malignant and non-malignant disorders. Patients with plasma cell dyscrasias, thyrotoxicosis, primary and secondary hyperparathyroidism were excluded. Patients received zoledronic acid (4 mg IV over 15 minutes) pre-transplant and every three months thereafter for a total of 4 doses. All patients concomitantly received daily calcium (1000mg) and Vitamin D (400IU) supplements (oral or intravenous). Serial bone density(BMD) measurements at lumbar spine, total hip and forearm using DEXA were scheduled to be done at baseline (pre-transplant), 6 weeks, 6 months, 12 months, and 24 months. Urine NTX was a measured as a surrogate marker for bone turnover.
Results: 22 patients were enrolled between January 2002 and August 2005. BMD data were available at baseline on 20 patients, at 6 weeks on 11 patients, at 6 months on 11 patients, at 1 year on 9, and on 5 patients on 2 years. Random coefficient analyses were performed. A statistically significant reduction in total hip BMD was observed (−3.6%, p<0.001). The reduction for the lumbar spine (−1.1%) was not significant (p=0.416). The observed BMD change was positive at the forearm (+2.4%) and statistically significant (p=0.047). Post-transplant urine N-telopeptide (NTX) measurements were higher than baseline. Severe hypocalcemia (12%) was the only adverse effect attributable to the study drug.
Discussion: Review of recent literature implies that the degree of increased bone resorption pre- and post-BMT is highest at the femoral neck/total hip and can be up to 7.8% in the absence of bisphosphonate therapy. Our data indicates that zoledronic acid helps curtail the expected reduction in bone loss. Bisphoshonate therapy may be needed more frequently and for longer duration. Calcium/Vitamin D supplementation may need replenished more rigorously. Using urine NTX measurements concurrently with BMD to monitor bone turnover and response to treatment is indicated until standards of therapy are established. In conclusion, bisphosphonate therapy with zoledronic acid does impact standard of care for patients after allogeneic stem cell transplantation.
Costs of Imatinib, Costs of Transplants and Gross National Income Per Capita Impact on Transplant Rates for Chronic Myeloid Leukemia in European Countries.
Authors: Gratwohl Alois , Baldomero Helen , Schwendener Alvin , Gratwohl Michael , Frauendorfer Karl , Urbano-Ispizua Alvaro 
Published: October 2019

Abstract
Hematopoietic stem cell transplants (HSCT) are among the most expensive medical procedures. As a consequence, transplants are preferentially done in more wealthy countries. This significant dependency between transplant rates (number of transplants per 10 million inhabitants) and gross national income (GNI) per capita has been well described. We noticed a different pattern in HSCT for chronic myeloid leukemia (CML) in recent years. We did investigate the evolution of transplant rates for leukemias in Europe in respect to the economy of the participating 38 countries. Using World Bank definitions, countries were grouped according to their GNI per capita into low (A), middle (B), and high income (C) countries and trends of transplant rates for CML and acute myeloid leukemia (AML) were computed with regression analyses from 1991 to 2004. Transplant rates increased for AML in significant dependency with GNI per capita from 0.1 (A), 0.3 (B) and 12 (C) in 1991 to 2.8 (A), 22 (B) and 47 (C) in 2004. Transplant rates were distinct by World Bank category and the increase presented in all three groups with a near linear clear predictability as illustrated by the R2 ’s of 93.55, 94.34 or 98.76 (Groups A, B, C). A different pattern was observed for CML. Initially transplant rates did increase from 0.1 (A), 0.7 (B) and 13 (C) in 1991 to 0.28 (A), 15 (B) and 28 (C) in 1999, distinct by World Bank category and with a similar linear prediction pattern as for AML (R2 96.39, 95.75, 95.35 for groups A, B, C). Transplant rates then declined for CML in high income countries (C), they remained at the same level in middle income countries to the extent that comparable transplant rates (15, 15) were observed for middle and high income countries in recent years. We compared costs. Costs for one year treatment with Imatinib (400 mg daily dose) in the different participating European countries ranged between 28 000 and 44 000 Euros with a median of 30 411 Euros (mean 32 417 Euros). Costs for an allogeneic HSCT from an HLA identical sibling ranged from 26 515 Euros to 180 000 Euros with a median of 63 450 Euros (mean 72 173 Euros). Cost comparisons indicate that cost for an allogeneic HSCT correspond to 0·9 to 5·9 (median of 2·0, mean 2·3) years of drug treatment. Data suggest that Imatinib has replaced HSCT preferentially in countries with high income. HSCT remains a cost effective procedure in countries with middle income. Cost considerations appear to impact on the choice between a once in a lifetime procedure or continuous drug treatment. Integration of cost analyses into the decision algorythms will become of increasing importance.
Allogeneic Hematopoietic Stem Cell Transplantation Cures CLL: A Retrospective Analysis from the SFGM-TC Registry.
Authors: Michallet Mauricette , Lê Quoc-Hung , Vernant Jean-Paul , Nicolini Franck E. , Harousseau Jean-Luc , Colombat Philippe , Deconninck Eric , Cazin Bruno , Blaise Didier 
Published: October 2019

Abstract
This retrospective study concerned 471 B-CLL patients registered in the SFGM-TC registry from Apr 1,984 to Feb 2,005, who underwent either autologous transplantation (n=313, 138 F and 175 M, median age = 54, 236 PBSC and 77 BM) or allogeneic transplantation (n=158, 78 F and 80 M, median age = 49, 76 PBSC, 81 BM and 1 cord blood cell transplant from 17 related and 141 unrelated donors). Among alloT patients, 50 were ABO incompatible and 70 sex-mismatched. The median interval diagnosis-transplantation was 32 months for autoT and 51 months for alloT. Just before conditioning 302 autoT and 143 alloT were evaluated for the disease status: 100 and 26 patients were in CR, 170 and 55 were in PR, 4 and 13 in stable disease (SD), 28 and 49 in progressive disease (PD) for autoT and alloT respectively. Among alloT patients, 73 received reduced intensity conditioning (RIC) and 85 standard conditioning (72 Cyt+TBI, 33 Fluda+TBI, 23 Fluda+Bu+ATG, 8 Cyt+Bu and 21 other). Before autoT the conditioning consisted of 224 Cyt+TBI, 45 BEAM and 44 other. After alloT, 71 patients developed an aGVHD ≥ grade II and 60 developed a cGVHD (25 limited and 35 extensive). The non-relapse mortality at 1 year was 29%. With a mean follow-up of 28 months for autoT and 40 months for alloT, the probabilities of 3-year, 5-year and 8-year overall survival were 80%, 66%, 45.5% after autoT and 52%, 48% and 35% after alloT respectively. An analysis aimed to determine the percentage of long-term survivors, or patients censored on the final plateau of survival curves was performed on alloT and autoT groups. A mixture model, gfcure with Splus statistical package determined the percentages of long-term survivors and its adequacy was verified graphically. The percentage of long-term survivors for the autoT group was 1.2%, with a mean survival length for uncured population of 160 months. Fig A shows that both curves were close and consequently shows good adequacy and the absence of a final plateau. The percentage of long-term survivors for alloT was 34.03% (figure1). Fig B shows rather good adequacy. The study of the impact of usual prognosis factors (age, time diagnosis-transplant, sex match, HLA match, CMV status, type of conditioning, BM or PBSC, ABO compatibility and disease status before transplantation) on the percentage of long-term survivors showed that only the status of disease at transplant had a significant impact: (CR vs SD or PD, HR: 0.11 [0.02–0.5] p=0.01 and PR vs SD or PD, HR: 0.30 [0.09–0.96] p=0.04). This study pointed out the possibility of curing B-CLL patients who responded to conventional chemotherapy with allogeneic transplantation rather than with autologous transplantation.
Figure Figure Figure Figure
Lack of Predictive Value of KIR-HLA Genotypes for Autologous Transplant Outcome for Multiple Myeloma.
Authors: Hsu Katharine C. , Tricot Guido , Haessler Jeff , Pinto-Agnello Clara , van Rhee Frits , Fox Michelle , Dupont Bo 
Published: October 2019

Abstract
In allogeneic hematopoietic cell transplantation (HCT), donor alloreactive natural killer (NK) cells can prevent leukemia relapse and prolong survival. Donor NK alloreactivity has been shown to be influenced by the killer Ig-like receptor (KIR) repertoire of the donor and the HLA class I KIR ligand phenotype of the recipient. In T-cell depleted HLA-identical sibling HCT, it has been shown that lack of recipient class I ligand for donor inhibitory KIR is associated with improved outcome in acute myelogenous leukemia. In the normal population, more than 60% of individuals lack class I ligand for one or more of their inhibitory KIR. Because autoreactive NK cells are known to occur in normal individuals with low frequency, we sought to determine if these same NK clones driven by autologous KIR-HLA interactions might expand and play a role following treatment involving autologous stem cell infusion for hematologic malignancy. 233 patients with multiple myeloma who underwent high-dose chemotherapy with autologous stem cell infusion were evaluated with HLA and KIR genotyping. KIR-HLA genotype combinations were then correlated with event-free survival (EFS) and overall survival (OS) following autologous HCT. Cox regression models were fit to examine the association of KIR-HLA combinations with the hazards of mortality and relapse. We found that there was no association between lack of KIR ligand for inhibitory KIR and improved EFS (p=0.69) or OS (p=0.36), nor was there any association between presence of specific activating KIRs and transplant outcome. Furthermore, the cumulative effect of more than one activating KIR did not affect outcome, including the specific combination of KIR2DS1 and KIR2DS2 (EFS p=0.86 and OS p=0.67), which have been previously reported to be associated with lower leukemia relapse in allogeneic HLA-identical HCT. The combination of activating KIR with their known or putative HLA ligands was also not associated with improvement in transplant outcome. Patients were also evaluated for KIR haplotype (AA versus AB and BB). There was no association between KIR haplotype and DFS (p=0.59) or OS (p=0.96). These data suggest that KIR genotypes and KIR-HLA genotype combinations are not associated with improved outcome in multiple myeloma patients undergoing autologous HCT. This implies that NK cells in autologous HCT do not significantly impact outcome, either because they are not expanded in the post-HCT period or because they have no activity against autologous multiple myeloma cells.
Selective Depletion of CD25+ Host-Reactive Donor Lymphocytes from Allografts Preserves a CD25− CD4+foxp3+ Fraction of T Cells and Thereby Provides a Source for Efficient Reconstitution of Regulatory T Cells and Additional GVHD Control.
Authors: Mielke Stephan , Rezvani Katayoun , Solomon Scott R. , Savani Bipin N. , Nunes Raquel , Yong Agnes , Schindler John , Read Elizabeth J. , Vitetta Ellen S. , Barrett A. John 
Published: October 2019

Abstract
We previously showed that removal of host-reactive donor T cells from allografts by anti-CD25 immunotoxin (IT) is clinically feasible and reduces the frequency of severe graft-versus-host-disease (GVHD) in a high-risk group of elderly patients undergoing matched-sibling transplantation (Blood, 2005,106:1123). However, it is possible that the concurrent removal of CD4+CD25+ regulatory T cells (Tregs) with alloactivated CD25+ T cells could precipitate more GVHD if depletion of alloreacting cells were incomplete. We, therefore, studied the recovery of Tregs in 16 patients receiving CD25-IT-treated stem cell grafts during the first 150 days after transplantation. Tregs were characterized by surface phenotyping for CD3, CD4, CD25 and CD27, intracellular staining for forkhead protein3 (foxp3) and quantitative real time PCR for foxp3 gene. We also measured Tregs in 13/16 donors (Don), 10/16 SD products and 13/16 patients pretransplant (Pre). Patients received a median of 1.0 (0.2–1.5) ×108/kg selectively depleted (CD25−) CD3+ T cells and a stem cell product containing 0.25 ×104/kg (0.1–5.0) residual unselected CD3+ T cells. Lymphocyte recovery was prompt with a median lymphocyte count of 613/μL (215–2883/μL) and median 97% donor T cell chimerism at day+30. Despite CD25-depletion, patients reconstituted sufficient levels of CD4+foxp3+ T cells at day+30. These CD4+foxp3+ T cells underwent further expansion and reached their highest median levels 150 days post transplantation (Figure A). Interestingly, all SD-products contained a significant fraction of CD4+foxp3+ Tregs that persisted after complete CD25-depletion. These cells were exclusively CD25− CD4+foxp3+ Tregs and represented 1.5–4.8% of the CD4+ cells in the SD product. Of note, the Treg content of the donor was associated with the risk of GVHD development posttransplant. Acute grade II GVHD was restricted to 5 patients whose donors had significantly fewer Tregs compared to those with no or grade I GVHD (Figure B). In this study we show efficient Treg reconstitution despite giving a CD25-depleted SD allograft. We identified a population of CD25− CD4+foxp3+ Tregs in the SD product. Such cells have been shown to exert regulatory function in mice. Our results suggest that Treg recovery following SD is derived from a major contribution of CD25− Tregs which escape the depletion process in addition to a residual fraction of CD25− and CD25+ Tregs delivered with the stem cell product. All these Treg fractions may undergo marked expansion post-transplant and provide additional GVHD protection if the removal of alloreacting T cells by the SD procedure were incomplete.
Figure Figure
Cord Blood Transplantation from Unrelated Donor for Treatment of Childhood Acute Myeloid Leukemia: A Japan Cord Blood Bank Network Analysis.
Authors: Isoyama Keiichi , Kato Koji , Takanashi Minoko , Azuma Hiroshi , Nagamura-Inoue Tokiko , Kai Shunro , Oda Megumu , Nakabayashi Masao , Kato Shunichi 
Published: October 2019

Abstract
Results of cord blood transplantation (UCBT) from unrelated donor in childhood acute myeloid leukemia (AML) in Japan have not been previously reported. We analyzed 162 children receiving UCB transplants for AML [78 in low risk group (first or second complete remission; CR1 or CR2 and 84 in more advanced stage (high risk group)). Poor prognosis cytogenetic abnormalities were identified in 32 cases. Most patients received a 1 or 2 HLA antigens-mismatched UCB transplants. The median number of collected nucleated cells (NCs) was 4.7 x 107/kg. Cumulative incidence (CI) of neutrophil recovery was 79.5% +/− 3.2%%(71.5% +/− 5% in high risk group, and 88.3% +/− 3% in low risk group). The median time to neutrophil recovery was 27 day. In multivariate analysis, the significant factor influencing neutrophil engraftment was low risk group. Platelet recovery was 58.7% +/− 4.0%, acute graft-versus-host disease (GVHD) was 50% +/− 5%, and transplantation-related mortality (TRM) was 29.9% +/− 5%(13.6% +/− 4.4% in low risk group, and 51.4% +/− 10% for children in high risk group). The 5-year CI of relapse was 29% +/− 3% and was associated with disease status. The 5-year event-free survival (EFS) was 38.5% +/− 3% (55.6% +/− 7.9% in low risk group, and 22.8% +/− 5.8% for high risk group). The 5-year over all survival (OS) was 39.8% +/− 3% (65.6% +/− 8% in low risk group, and 17.4% +/− 5% for high risk group). In multivariable analysis, a low risk group was associated with good 5-year survival rates. Poor cytogenetic features had no significant influence on OS and EFS, respectively. We conclude that UCBT is a therapeutic option for children with very poor-prognosis AML and who lack an HLA-identical sibling.
Impact of HLA Allele Mismatch on the Outcome of Patients with Reduced-Intensity Allogeneic Haematopoietic Stem Cell Transplantation from Unrelated Donors: Analysis of 103 Patients of the French Registry.
Authors: Toma Andrea , Balere-Appert Marie-Lorraine , Chir Zina , Boiron Jean-Michel , Bordigoni Pierre , Socie Gerard , Vernant Jean-Paul , Renaud Marc , Milpied Noel-Jean , Michallet Mauricette , Deconninck Eric , Guyotat Denis , Garban Frederic , Sirvent Anne , Contentin Nathalie , Blaise Didier , Raffoux Colette , Buzyn Agnes 
Published: October 2019

Abstract
Reduced-intensity conditioning regimens (RIC) had become a classical strategy of allogeneic hematopoietic stem cell transplantation (HSCT) and many patients are now transplanted with unrelated donor. The aim of this restrospective study was to evaluate the impact of HLA mismatches between donor (D) and recipient (R) at the allelic level on survival after RIC. We analyzed 103 patients registered in France from Jan 1999 to Dec 2003 with a median age of 46 years (18–67). All patients had hematologic malignancies: AL (n=35), MM (n=18), CLL (n=5), NHL (n=11), HD (n=9), CML (n=12), MDS (n=9), and MPS (n=4). 39% of the patients were in an advanced phase of the disease at time of HSCT. Anti-thymocytes globulins (ATG) were part of the conditioning regimen for 77% of patients. The main source of stem cells was PBSC (n=65). Seventy-one D/R pairs (69%) were 10/10 HLA match at the allelic level. Mismatches concerned 5, 6, 15, 2 and 7 D/R pairs for HLA-A, -B, -C, -DRB1 and -DQB1, respectively. The results showed that 96% of patients engrafted. Acute GVHD grade II to IV and grade III/IV occurred in 46% and 19% of patients, respectively. The risk of developing cGvHD was 45% at 2 years. Overall survival (OS) was 42% at five years. Among the 47 patients alive, the median disease free survival (DFS) was 28 months. Among non-HLA parameters studied, the only factor associated with a good OS was the diagnosis of lymphoid disease (HD or NHL or CLL) (p=0.003). Recipient age <46y was only associated with less acute GvHD grade II to IV (p=0.008). Among HLA mismatches, we found that HLA-A and/or -B allelic mismatches had a negative impact on OS (p=0.006), DFS (p=0.006), acute GvHD grade II to IV (p=0.05). On the other hand, HLA-C or -DQB1 mismatches did not impact on OS, DFS, acute or chronic GvHD. We could not analyze DRB1 mismatch since there was only 2 patients reported. In conclusion, HSCT following RIC, with match or mismatch unrelated donors, is a feasible approach with best results observed for patients with lymphoid malignancies (NHL, CLL or HD). Among allelic HLA mismatches, HLA-A and/or -B seemed to be deleterious as compared to HLA-C or DQB1. These results help to identify most suitable donors and patients who are likely to benefit from RIC with unrelated donors when there is not a fully HLA match donor available.