bluuebunny/crossref_metadata_2025_split huggingface dataset:
Incidence, Comorbidity and Treatment Survey of Chronic Myeoloid Leukemia in Germany.
Authors: Hasford Joerg , Tauscher Martin , Hochhaus Andreas 
Published: October 2019

Abstract
Background and objectives Reliable epidemiological data about the incidence of CML, the treatment and the comorbidity profile of patients in Germany was not available. Methods Thus, we used the data base of the Bavarian association of statutory health insurance accredited physicians, which covers 83.5% of all outpatient care in Bavaria with 10.4 million people. A CML-patient was defined as the combination of an ICD 92.1 CML diagnosis plus treatment with either imatinib, interferon alfa, hydroxyurea or busulfan for at least one year. Results In 2004, there were 201 new CML cases seen which results in a crude incidence of 1.93 / 100,000 / year. Adjusted to the World Standard Population the figures are 1.357 for males and 1.063 for females. The median age was 63 (m) and 65 (f) years. Comparing the comorbidities of CML patients with all other patients > 60 years non infectious enteritis and colitis (RR: 2.99), diseases of the oral cavity, salivary glands or jaws (RR: 2.49); infectious of the skin or subcutis (RR: 2.28), surgical complications (RR: 2.13) and symptoms of the GI-tract or abdomen (RR: 2.09) occurred more often in CML-patients, whereas hypertension (RR: 0.81), IHD (RR: 0.93); other heart diseases (RR: 0.87) and cerebrovascular diseases (RR: 0.78) occurred less often. In 2006, 58.8% of the CML-patients received imatinib alone; 10.2% imatinib in combination either with HU or IFN alfa, 25.8% HU, and 7.6% IFN alfa. Discussion and conclusions The true incidence may be slightly lower (about 10%) as some chronic myeloproliferative diseases may have been miscoded as CML, but we may have missed some CML-patients who have been treated as inpatients only, too. Thus, we think that our incidence estimate, and the age and sex distribution is fairly accurate. In addition and for the first time, current treatment comorbidity data of CML-patients in Germany are available.
Association of Fc Receptor-Like Protein Family with Chronic Graft-Versus-Host Disease.
Authors: Onizuka Makoto , Toyosaki Masako , Machida Shinichiro , Suzuki Rikio , Kojima Minoru , Miyamura Koichi , Kodera Yoshihisa , Inoko Hidetoshi , Ando Kiyoshi 
Published: October 2019

Abstract
Chronic graft versus host disease (cGVHD) is the most common cause of poor outcomes after hematopoietic stem cell transplantation (HSCT), while the pathophysiology of cGVHD remains poorly understood. We have revealed the association Fc receptor-like protein 3 (FCRL3) gene -169C/T single nucleotide polymorphism (SNP) and developing cGVHD. This gene is a member of Fc receptor-like protein gene family which contains 5 genes and well known as autoimmune disease associated gene. These 5 genes make cluster lesion on chromosome 1q21 to 23. In this current study, to investigate the relationship with another Fc receptor-like protein genes and cGVHD, we used 4 microsatellite polymorphisms belong to FCRL1, 2, 3 and 4 as a linkage analysis genetic marker. And we also investigated FCRL3 -169C/T SNP and another 3 SNPs to explore haplotype and the incidence of cGVHD. We analyzed 123 case of Japanese HLA-matched sibling recipients and their donor who underwent HSCT in the Japanese Red-Cross Nagoya First hospital. Before day 100, 11 patients died from severe acute GVHD, infection, thrombotic microangiopathy or disease relapse. Therefore, we analyzed 112 recipients and 108 donors for the relationship between gene polymorphisms and chronic GVHD. We analyzed microsatellite polymorphisms and SNPs by using TaqMan® assay. Chronic GVHD occurred in 54 out of 112 (48.2%) patients in this cohort. The nearest microsatellite marker from FCRL3 gene had significant different allele frequency between cGVHD and non-GVHD recipient (p=0.0034). There were no association with another microsatellites allele and developing cGVHD. FCRL3 gene haplotypes with frequency >0.01 were -TGGG-, -CACA- and -CGCA-. Chronic GVHD patients significantly less the frequency of -CACA- or -CGCA- allele than non GVHD patients (p=0.0040). There were no significant difference in donor allele frequency and incidence of cGVHD. In conclusion, our studies show FCRL3, which is autoimmune disease associated gene, is also the candidate of cGVHD associated gene and its protective haplotype may prevent from occurring cGVHD but not homologous another FCRL proteins.
Rituximab (RTX) as Salvage Therapy for Refractory Chronic Graft-Versus-Host Disease (cGVHD).
Authors: Mohty Mohamad , Marchetti Nicolas , El-Cheikh Jean , Faucher Catherine , Furst Sabine , Blaise Didier 
Published: October 2019

Abstract
The incidence of cGVHD is likely to continuously increase as a result of the increasing use of allo-SCT (especially with reduced-intensity conditioning regimens) in older patients, peripheral blood stem cells as stem cell source, and frequent donor lymphocyte infusions, all of which are known to increase the risk of cGVHD. Standard primary treatment of cGVHD remains a combination of corticosteroids (CS) and calcineurin inhibitors. There is no standard therapy for those who fail to respond to CS, and CS-resistant GVHD is associated with high morbidity. The aim of this report was to analyze the outcome of patients treated with RTX as salvage therapy for refractory cGVHD. 15 consecutive patients experiencing severe or refractory GVHD received IV infusions of RTX (375mg/m2/infusion) at weekly intervals for 4 weeks. Responding patients were allowed to receive additional courses of maintenance therapy. Response to RTX was assessed one month after the last infusion. Patients’ characteristics, GVHD features and outcome are summarized in the Table below. RTX was administered at a median time of 178 (range, 69–1136) days after allo-SCT, and patients received a median of 5 (range, 1–12) infusions. Most have received and failed at least 2 lines of immunosuppressive therapy prior to RTX. With a median follow-up of 118 days (range, 21–834) from first infusion of RTX, no major toxicities directly related to RTX were observed. Overall, 10 patients responded to RTX administration (66%; 95%CI, 42–90%) with 3 complete remissions. In those responding patients, the patient felt improvement as soon as one week after the first RTX infusion. In addition, RTX allowed a significant reduction of CS dosage (range, 0–83%). 4 patients did not respond and died from refractory GVHD, while one responding patient died of disease progression. With a median follow-up of 461 days from onset of cGVHD (range, 91–1192), the actuarial survival rate from the first RTX infusion was 60% at one year. We conclude that despite its limited size, this cohort demonstrates evidence of beneficial activity of RTX, mainly in the classical cutaneous, mucosal and liver cGVHD. Patients with involvement of other sites are not likely to benefit much from RTX. Results achieved with RTX in the cGVHD refractory setting, pave the way for further developments. As such, the addition of RTX to prednisone for the initial treatment of cGVHD is worth further investigations, both to increase the overall response rate, and to enable a more rapid CS taper while incurring less long-term toxicity.
Table. Patients’ characteristics, transplant procedures, GVHD features and outcome.
Anti-Thymocyte Globulin Induces Higher Response Rates and Less Graft-Versus-Host Disease in Multiple Myeloma Patients Undergoing Allogeneic Stem Cell Transplantation.
Authors: Ayuk Francis , Perez-Simon José A. , Shimoni Avichai , Sureda Anna , Zabelina Tatjana , Schwerdtfeger Rainer , Martino Rodrigo , Sayer Herbert G. , Alegre Adrián , Lahuerta Juan-José , Atanackovic Djordje , Wolschke Christine , Nagler Arnon , Zander Axel R. , Miguel Jesús San , Kroeger Nicolaus 
Published: October 2019

Abstract
Preclinical experiments have shown a strong anti-myeloma effect of polyclonal anti-thymo-cyte globulin (ATG). We evaluated ATG effect in a melphalan/fludarabine-based conditioning regimen in 138 multiple myeloma (MM) patients who underwent allogeneic stem cell transplantation with (n=79) or without (n=59) ATG. More patients in the group without ATG had experienced relapse to prior auto-transplant (63% vs. 47%, p = 0.08). Patient characteristics were otherwise well matched in both groups. A median ATG dose of 30 mg/kg BW (range, 10-90 mg/kg BW) was administered on days −3 to −1. GvHD prophylaxis was performed with cyclosporine A and short-course methotrexate. Overall response (93% vs. 78%, p=0.03) and complete response (59% vs. 39%, p=0.04) at day 100 were higher in the patients treated with ATG than in those without ATG. ATG led to a lower incidence of severe grade III/IV acute GvHD (11% vs. 22%, p=0.10), and chronic GvHD (23% vs. 65%, p<0.001). The rate of complete remissions increased in patients who had received the higher ATG dose: 57% in those who received ATG ≤ 30 mg/kg BW, vs. 63% in those who received ATG > 30 mg/kg BW. The rate of OR increased from 78% in the no-ATG group to 91% in patients who received ATG ≤ 30 mg/kg BW, and to 96% in patients who received ATG > 30 mg/kg BW (p=0.02). Separate analysis of patients transplanted from a sibling donor also showed a trend to better OR (86% vs. 78%) and CR (55% vs. 39%) for patients who received ATG (all patients received ATG at a dose ≤ 30 mg/kg) compared to the non-ATG group, however due to low numbers this difference did not reach statistical significance. Though the non-ATG group contained more patients who had relapsed to prior autografting, this as has been reported before, would not influence response rates. In the multivariate analysis of prognostic factors for achievement of a CR, ATG was the only significant prognostic factor (RR: 2.57; 95% CI: 1.17-5.64; P=0.02). The estimated overall survival (OS) at three years was 53% (95% CI: 40-66%) for the ATG group (p=0.46), and 43% (95% CI: 29-57%) for the non-ATG group (p=0.46), while progression-free survival (PFS) at three years was 39% (95% CI: 27-51%) for the ATG group, and 27% (95% CI: 14-40%), for the non-ATG group (p=0.55). The current results suggest a dose dependent beneficial effect of ATG in terms of myeloma cytotoxicity as well reduction of the incidence of chronic GvHD.
Subcutaneous Alemtuzumab May Be Useful in the Treatment of Steroid-Refractory Acute Graft-Versus-Host Disease.
Authors: Gomez-Almaguer David , Ruiz-Arguelles Guillermo J. , Gonzalez-Llano Oscar , Gutierrez-Aguire Homero C. , Cantu-Rodriguez Olga G. , Jaime-Perez Jose C. , Giralt Sergio 
Published: October 2019

Abstract
Background: Acute graft-versus-host disease (GvHD) is mediated by activated T lymphocytes. Alemtuzumab is an unconjugated, humanized IgG1 kappa monoclonal antibody which targets the CD52 antigen on T lymphocytes and other cells and has been used successfully in conditioning regimens for allogeneic transplantation to remove donor T cells so as to prevent GvHD.
Patients and methods: Eighteen patients with steroid-refractory acute GvHD ≥ grade II were analyzed to evaluate the safety and efficacy of alemtuzumab. The patients received subcutaneous alemtuzumab 10 mg daily on days 1–5. The proportion of patients with grade II, III and IV were eight, eight and two, respectively. The main organ involved was the liver in four, gut in five, skin and liver in three, and skin and gut in three patients.
Results: Fifteen out of 18 patients (83%) responded to alemtuzumab with 6 (33%) complete and 9 (50%) partial responses. All three unresponsive patients died of GvHD. Ten of 15 responders are alive at a median follow-up of 9 months (range 2–23) after alemtuzumab, with limited, extensive and no signs of chronic GvHD in 1, 4, and 5 patients, respectively. Fourteen patients (78%) developed some kind of infection; eleven of them developed cytomegalovirus reactivation. All patients tolerated alemtuzumab with minimal side effects; grade 3 neutropenia and thrombocytopenia were seen in six and four patients, respectively.
Conclusions: Alemtuzumab is a well tolerated agent and has a beneficial effect in the treatment of steroid-refractory acute GvHD. Infections are common and anti-infective prophylaxis is mandatory.
DAAM2 Polymorphism and Allogeneic Hematopoietic Stem Cell Transplantation.
Authors: Yi Hyeon Gyu , Piao Cheng Zhe , Kim Inho , Kim Hye Jin , Oh So Yeon , Kim Jin Won , Kim Dae-Young , Lim Joo Han , Seo Myung-Deok , Park Seonyang , Yoon Sung-Soo , Kim Byoung Kook , Kim Chul Soo 
Published: October 2019

Abstract
Background WNT signaling pathway is known to have important functions in embryogenesis, cellular proliferation and regeneration, stem cell renewal and oncogenesis. DAAM2 is one of the key protein of WNT/PCP signaling pathway. This study examines the association of DAAM2 polymorphism and the clinical outcomes in patients treated with allogeneic hematopoietic stem cell transplantation (HSCT). Objectives and methods Candidate SNPs associated with acute graft versus host disease (GVHD) were selected using DNA chip analysis with Illumina Infinium Human-1 microarrays™ in 15 patients who treated with allogeneic HSCT for various hematologic and oncologic diseases with or without acute GVHD. Six SNPs (rs2504787, rs2504086, rs2504082, rs3004067, rs882559, and rs3004070) on DAAM2 were proven to be associated with acute GVHD, and extended genotyping was executed by Taqman™ protocol in more large population of 239 patients in single institute. Retrospective analysis for medical records was performed to define correlation of these SNPs with clinical outcomes of the patients. Results rs882559 located upstream from exon 24, was proven to be associated with acute GVHD incidence. Acute GVHD incidence was significantly lower in the patients with CC genotype of rs882559 than those with CG or GG genotype (HR 0.466, 95% CI 0.224∼0.969, p=0.0409). The allele frequency of C was 55% and that of G 44%. The genotyping disclosed CC in 77, CG in 110, and GG in 52. Multivariate analyses on various parameters including sex, age, transplant method (reduced intensity conditioning vs. conventional conditioning), stem cell source, risk group, and DAAM2 genotypes, as parameters, identified high-risk group defined in our previous study (KH Lee et al., Haematologica, 2007;92 ; HR 2.41, 95% CI 1.47∼3.94, p<0.001), age over 50 years (HR 1.70, 95% CI 1.18∼2.45, p=0.004) and codominant genotype of rs2504082, i.e., an intron mutation upsteam from exon 15 (HR 1.326, 95% CI 1.02∼1073, p=0.0378) as risk factors for a shorter survival. Interpretation and conclusions This is the first clinical study for the DAAM2 polymorphism, furthermore, and its association with clinical outcomes of allogeneic HSCT. The role of rs882559 and rs2504082 were not identified by now, but its mutation might affect to the transcription of following coding genes causing the changes of its functions. This study suggested the clinical value of DAAM2 polymorphism as a predictive parameter of clinical outcomes of allogeneic HSCT, and its importance in WNT signaling pathway.
Similar Risks for Late-Onset Chronic Kidney Disease in Myeloablative and Reduced-Intensity Allogeneic Hematopoietic Cell Transplant Survivors.
Authors: Al-Hazzouri Ahmed , Cao Qing , Burns Linda J. , Weisdorf Daniel J. , Majhail Navneet S. 
Published: October 2019

Abstract
Chronic kidney disease (CKD) has been reported in nearly 20% of recipients of myeloablative (MA) allogeneic hematopoietic cell transplantation (HCT). HCT using reduced-intensity (RIC) conditioning is associated with lower morbidity and mortality, but the risk of CKD after RIC HCT is not well known. We conducted a retrospective cohort study to compare the incidence of CKD after MA and RIC HCT. Adult allogeneic HCT recipients were eligible if (1) they received an allogeneic HCT between 2000 and 2005, (2) survived for ≥ 1 year post-HCT, and (3) had no history of CKD pre-transplant. The dose of total body irradiation in MA and RIC regimens was 1320 cGy (165 cGy twice daily × 4 days) and 200 cGy (single fraction), respectively, and was given without kidney shielding. CKD was defined as glomerular filtration rate (GFR) < 60 ml/min/1.73m2 for ≥ 3 months (National Kidney Foundation definition) anytime after 180 days post-HCT. GFR was estimated using the Modification of Diet in Renal Disease equation [GFR = 186 × (SCr)−1.154 × (Age)−0.203 × (0.742 if female) × (1.210 if African American)]. Study eligibility criteria were met by 221 patients (MA=104, RIC=117); median follow-up was 28 (range, 12–75) months for MA and 25 (range, 12–67) months for RIC group. At the time of transplant, MA recipients were younger (median age 38 vs. 54 years, P<0.01), less likely to have HTN (7% vs. 22%, P<0.01) and more likely to have a body mass index of <30 (87% vs. 72%, P=0.01). The two groups were comparable with respect to prevalence of diabetes mellitus, smoking, HCT co-morbidity index scores, incidence of acute renal failure (ARF) within the first 180 days, and duration of cyclosporine (CSA) use. A total of 60 (MA=30, RIC=30) patients developed CKD, resulting in a 3-year cumulative incidence rate of 29% (95% confidence intervals, 20–37%) in MA and 27% (18–35%) in the RIC group (p=0.44). In multivariate analysis, conditioning regimen intensity had no impact on risk of developing CKD (relative risk [RR] for MA 1.60 [0.86–2.97] vs. RIC regimen). Factors independently associated with an increased risk of CKD were age at HCT (RR 1.05 [1.02–1.08] for each year increase), acute graft-versus-host disease (RR 2.16 [1.19–3.93]) and CSA use for >6 months (RR 3.48 [2.33–2.56]). ARF within the first 180 days also predicted the risk for CKD. Compared to severe ARF [lowest GFR ≤ 30], RR of CKD was 0.40 [0.23–0.69] for moderate ARF [lowest GFR 31–59] and 0 for no ARF [lowest GFR ≥ 60]. In conclusion, CKD is frequent in long term adult allogeneic HCT survivors. RIC is associated with similar risks of CKD as MA conditioning. Older age, ARF, acute graft-versus-host disease and prolonged CSA exposure increases the risk of CKD. Continuous monitoring of renal function is necessary in allogeneic HCT survivors and studies exploring prevention strategies are needed.
Higher Mycophenolate Dose Requirements in Children Undergoing Hematopoietic Cell Transplant (HCT).
Authors: Jacobson Pamala A. , Huang Jiayin , Rydholm Nancy , Tran MyHang , DeFor Todd , Tolar Jakub , Orchard Paul J. 
Published: October 2019

Abstract
Mycophenolate mofetil (MMF), a pro-drug of mycophenolic acid (MPA), is commonly used as part of the immunosuppressive regimen after hematopoietic cell transplantation (HCT). Although MMF is widely used in HCT transplant recipients, systemic exposure has not been thoroughly studied in pediatric HCT recipients. Hence, the dosing strategies used in children undergoing kidney transplantation have been adopted or the adult dose has been extended to HCT children. Therefore, we studied mycophenolate pharmacokinetics in 19 children with median age of 17 (3–140) months with nonmalignant diseases undergoing myeloablative HCT who received mycophenolate in combination with cyclosporine for graft-versus-host disease prophylaxis. All subjects, except two, received 15 mg/kg mycophenolate intravenously every 8 hours. Pharmacokinetics were studied once between days 3–7 and again between days 10–14 post-transplant. The median [range] MPA total area under the curve (AUC)0-8 was 12.6 mcg hr/ml [4.9–49.2] and unbound AUC0-8 was 0.274 mcg hr/ml [0.037–1.4]. Unbound MPA fraction was 1.7% [0.76–5.1]. The median total mycophenolic acid glucuronide (MPAG) AUC0-8 was 269.1 mcg hr/mL [127.6–957.0]. Total and unbound MPA trough concentrations were 0.24 [0.03–2.9] and 0.005 [0–0.034] mcg/mL, respectively, with 8 hour dosing. MPA troughs were not good surrogates for overall exposure (AUC)0-8,[r2≤0.55]. MPA exposures did not change significantly between weeks 1 and 2 (p≤0.51), although several patients had an increase or decrease in AUC by 50% or more. SCr, CrCl, bilirubin, age, weight and albumin were poorly correlated with MPA AUC0-8 (all r2<0.40). Twenty % of the AUC’s achieved a total MPA target previously associated with better donor chimerism and 54% met the unbound MPA targets associated with reduced acute GVHD risk in adults undergoing nonmyeloablative transplant. These data suggest that 15 mg/kg every 8 hours may be too low. However, whether these targets are relevant in the pediatric myeloablative setting is not known. MMF given 15 mg/kg every 8 hours intravenously in our patients achieved an exposure similar to that previously observed in adult nonmyeloablative HCT recipients receiving 1gm every 12 hours intravenously. MPA exposure in pediatric HCT recipients is lower than pediatric organ transplant recipients despite receiving a 33% higher dose. Children undergoing HCT should receive an MMF dose of at least 15 mg/kg intravenously every 8 hours to achieve systemic concentrations near those proposed to be therapeutic in the adult HCT population. The optimal MPA exposure target, particularly the upper limit of safety, in children undergoing myeloablative HCT has yet to be determined.
The Effect of In Vivo T-Cell Depletion with Alemtuzumab on Reduced-Intensity Allogeneic Hematopoietic Cell Transplantation for Chronic Lymphocytic Leukemia.
Authors: Delgado Julio , Pillai Srinivas , Benjamin Reuben , Caballero Dolores , Martino Rodrigo , Lovell Richard , Thomson Kirsty , Perez-Simon Jose A. , Sureda Anna , Kottaridis Panos , Miguel Jesus San , Peggs Karl , Sierra Jorge , Milligan Donald , Mackinnon Stephen 
Published: October 2019

Abstract
Reduced-intensity allogeneic hematopoietic cell transplantation (HCT) is increasingly considered as a therapeutic option for young patients with advanced chronic lymphocytic leukemia (CLL). We report 59 consecutive CLL patients who underwent allogeneic HCT following fludarabine and melphalan conditioning at four different institutions. For graft-versus-host disease (GVHD) prophylaxis, 38 patients (Cohort 1) received alemtuzumab (20–100 mg) and cyclosporine; and 21 patients (Cohort 2) received cyclosporine plus methotrexate or mycophenolate. Donors were 47 HLA-matched siblings and 12 unrelated volunteers, 6 of whom were mismatched. Median age at transplant was 53 (range, 34–64) years and median number of previous chemotherapy regimens was 3 (1–6), with 39% of patients being refractory to fludarabine. Nine patients had previously failed an autologous HCT. Fluorescent in-situ hybridization and IgVH mutation status data were available in 33 (56%) and 31 (53%) patients, respectively, being unfavorable (17p- or 11q-) in 22 (67%) and unmutated in 24 (77%) of them. All but 1 patient engrafted, and the median interval to neutrophil recovery (> 0.5 × 109/l) was 14 (range, 10–36) days. Twenty patients (34%), mostly from Cohort 1, received escalated donor lymphocyte infusions due to mixed chimerism or disease relapse. The overall complete response rate among 53 patients with measurable disease at the time of transplantation was 70%, whereas 21% had stable disease. Grade II-IV acute GVHD was observed in 14 (37%) and 12 (57%) patients from Cohorts 1 and 2, respectively (P = 0.17). Extensive chronic GVHD was observed in 3 (8%) and 10 (48%) patients from Cohorts 1 and 2, respectively (P < 0.01). The incidence of cytomegalovirus reactivation was not significantly different between cohorts (67% vs 47%, P = 0.23). With a median follow-up of 36 (range, 3–99) months for survivors, 18 (30%) patients have died, 3 of progressive disease and 15 of transplant-related complications. The 3-year overall survival (OS), progression-free survival (PFS) and non-relapse mortality were 66% (95% CI 48–84%), 38% (20–56%) and 21% (8–34%), respectively, for Cohort 1 and 65% (44–86%), 54% (32–76%) and 29% (10–48%) for Cohort 2 (P = 0.66; P = 0.33; and P = 0.53). Despite low patient numbers, alemtuzumab seemed particularly effective for unrelated donor recipients, with a 3-year OS and PFS of 54% and 40% for Cohort 1; and 33% and 0% for Cohort 2 (P = 0.02 and P = 0.07). In conclusion, results with reduced-intensity allogeneic HCT are promising for these poor-prognosis patients. Furthermore, the alemtuzumab-based regimen was effective in reducing the chronic GVHD rate with no negative effect on NRM, PFS or OS.