bluuebunny/crossref_metadata_2025_split huggingface dataset:
Use Of Unrelated Donors In Elderly Patients (age >60 years) Undergoing Reduced-Intensity Conditioning Hematopoietic Stem Cell Transplantation For Hematologic Malignancies
Authors: Jean El-Cheikh , Raynier Devillier , Sabine Fürst , Roberto Crocchiolo , Angela Granata , Catherine Faucher , Bilal Mohty , Samia Harbi , Reda Bouabdallah , Norbert Vey , Luca Castagna , Christian Chabannon , Blaise Didier 
Published: October 2019

Abstract

Objectives
The lower morbidity and mortality of reduced-intensity conditioning (RIC) regimens have allowed allogeneic hematopoietic cell transplantation (HCT) in older patients. However, there are only limited data on the feasibility and outcomes of URD HCT in elderly patients.The aim of the study was to compare the outcome in OS and PFS for patients transplanted using unrelated donor (URD) in patients age 60 or older.

Patients and methods
We retrospectively analyzed outcomes in 62 consecutive hematologic malignancy patients aged > or =60 years (median, 62 years; range: 60-70 years) undergoing reduced intensity conditioning regimens (RIC) from URD. In this study, URD was used only when a MRD was not available.
Then we compared the outcome of 17 elderly patients (age >65 years) with 44 younger patients aged between 60 and 65 years. Patient, disease and transplant characteristics are shown in Table 1.

Results
No patients experienced graft rejection. The median HCT comorbidity index score was 2 (range, 0 to 6). With a median follow up of 36 months (range, 5-74), the cumulative incidence of grades II to IV acute GVHD was 28% and of grades III to IV acute GVHD, 13%. At 2 years, the cumulative incidence of chronic GVHD was 27%, progression-free survival (PFS) was 62%, overall survival (OS) was 63%, and relapse was 14%. Non relapse mortality (NRM) was 24% at 2 years.
The cumulative incidence of grade II–IV Acute GVHD was 43% for the younger group and 17% for the older group (P = 0.056). The cumulative incidence of chronic GVHD was not different between the two groups (23% vs. 45% (p=0.3), respectively). Two-year OS and PFS was 57% versus 86% (P = 0.059) and 55% versus 86% (P = 0.03), in the younger and the older group respectively. The 2-year NRM and relapse was 26% versus 14% (P = 0.4) and 19% versus 0% (P = 0.04), in the younger and older group respectively.

Conclusions
This retrospective study suggest that RIC HCT from URD is a safe and effective option for patients aged > or =60 years or older, and in the absence of suitable related donors, well-matched URD may offer a very reasonable alternative, and that does not appear to be associated with a detrimental outcome. However these results are encouraging showing once again that with an adequate selection, age is not a definitive limitation.

Disclosures:
No relevant conflicts of interest to declare.
Is Rituximab Needed With High Dose Chemotherapy and Autologous Stem Cell Transplant When Patients With Non-Hodgkin’s Lymphoma Have Been Exposed To It?
Authors: Gul Zartash , Anderson Stephan , Slone Stacey , Chhabra Saurabh , Monohan Gregory , Howard Dianna , Lawson Amber , Hayslip John 
Published: October 2019

Abstract

Introduction
The value of Rituximab with High dose chemotherapy and autologous stem cell transplant (auto-HCT) has been evaluated in some retrospective studies. It is noted that the addition Rituximab to auto-HCT results in significant improvement in overall (OS) and disease free survival (DFS). However, it is unclear that the addition of Rituximab with auto-HCT would result in significant benefit in patients who have received prior Rituximab based therapy.

Methods
We retrospectively evaluated twenty seven consecutive patients who had B cell non-Hodgkin's lymphoma (NHL) and underwent auto- HCT at Markey cancer center between January 2010 and December 2012. All patients received 375 mg/m2of Rituximab with chemotherapy. Rituximab was not administered with high dose chemotherapy (BEAM: BCNU, Etoposide, Cytarabine and Melphalan) prior to auto-HCT. All patients received GCSF starting day 5 after auto-HCT.

Results
There were 27 patients who underwent auto-HCT for NHL. Median age of the patients was 60 years (36-72 years). Nineteen patients were male and 8 patients were female. Fifteen patients were in complete remission (CR) and the rest were in partial remission (PR). Patients had: Diffuse large B cell lymphoma (DLBCL=11 patients): Mantle cell lymphoma (MCL=13 patients): follicular lymphoma (3 patients). Median CD 34 count of infused cells was 4.14 x 106 cell/kg (2.26- 9.45). Median time to neutrophil recovery was 11 days (9-14). Median lymphocyte count at day 30 after auto HCT was 1130 x 10 6/l (320- 5180). After a median follow up of 7.9 months (3.0- 32.4) eight patients had relapsed. Five patients who had relapsed had refractory disease before auto-HCT. Non -Relapse mortality (NRM) is shown in figure 1. Median overall survival and disease free survival were not reached. Seventy percent patients had not relapsed. We did not find any factors associated with relapse.

Conclusion
We performed a retrospective study to evaluate the impact of Rituximab with high dose chemotherapy and in patients with NHL. Review of literature showed that median 2 year and 5 year OS was 80% and 69% in patients who received Rituximab with auto HCT. Median 2 year DFS was 67%. In our study 70% patients were relapse free at a median follow up of 8 months. We would need a longer follow up to determine the efficacy of Rituximab with auto- HCT in patients with NHL who had prior exposure to Rituximab.

Disclosures:
Off Label Use: The use of Thymoglobulin® for GVHD prevention. Hayslip:Sanofi: Research Funding; Janssen: Research Funding; Pfizer: Research Funding; Celgene: Research Funding.
Assisted Administration Of Subcutaneous 5-Azacytidine to The Patient's Home. Significant Reduction Of Indirect Costs Incurred By Care Recipients and Unpaid Caregivers Together With a Total Adhesion To The Treatment Schedule and Same Safety
Authors: Iuliano Francesco , Iuliano Eleonora , Perricelli Alessia , Pomillo Angelo , Luci Maria , Cervo Gianluca 
Published: October 2019

Abstract

Background and aim
Administration of azacitidine is planned in-patient daily, there is no experience of its administration to the patient's home. The aim of this work was to evaluate the feasibility of a program of home administration of azacitidine able to reducing the cost-of-illness, to increase adherence to treatment while maintaining the same safety of the therapy given in hospital.

Material and methods
Between Jan 2008 and Dec 2012, 22 consecutive patients, (MDSs, n = 15; CMML, n = 4; AML, n = 3), were enrolled in the study.
The pharmacoeconomic analysis included assessment of direct costs ( hospital inpatient, physician inpatient, physician outpatient, emergency department nursing home care, specialists’ and other health professionals’ care, diagnostic tests, prescription drugs and drug sundries, and medical supplies),indirect costs incurred by care recipients and unpaid caregivers, including time, productivity and travel cost.

Results
Azacitidine 75 mg/m2/day was administered as a subcutaneous injection for 7 consecutive days every 4 weeks, Median age of the patients was 71 years (range, 65–83). Median number of courses delivered to each patient was 9 (range, 3–31) Hematologic responses (CR/PR/mCR) were induced in 6 patients (27.0%) Median number of treatment courses to achieve any response was 2 (range, 1–6) Adverse events were evaluated for the first 6 courses for all patients, for a total of 124 courses. Major adverse events were cytopenia and cytopenia-related infection. Grade 3 or higher neutropenia was 64.4%) but incidence of febrile episode requiring intravenous antibiotics was 8,4% slightly lower than reported from the pivotal clinical study. Grade 3 or higher non-hematologic toxicities were infrequent. Injection site reaction 0.4 and site pain 0% Median follow-up duration of surviving patients was 46.9 months (range, 11.8–55.5). Of the 14 patients who were RBC transfusion dependent at baseline, 48.0% of these patients became RBC transfusion independent during the treatment period. Adherence to treatment was 100%.
In our experience, despite the high percentage of elderly patients of whom 36% living in rural area, it was possible to give treatment to all patients with 100% adherence. There has been a reduction in direct medical costs due to less use of hospitalization, a reduction of indirect costs by 63% due to the lower number of working days lost and a drastic reduction of travel costs, with the same efficacy and safety of administration.

Disclosures:
Off Label Use: drug administration at patient home instead of hospital.
Cardiovascular Complications Of Thalassemia Patients In The Iron Chelation Therapy Era
Authors: Tantiworawit Adisak , Tapanya Suebsakul , Phrommitikul Arintaya , Norasetthada Lalita , Chai-adisaksopha Chatree , Rattarittamrong Ekarat , Hantrakool Sasinee , Taechacharn Sucharawee , Nawarawong Weerasak 
Published: October 2019

Abstract

Background
Cardiac complications are the most common cause of death in thalassemia, accounting for up to 71% in the past. Iron chelation therapy is given to patients with iron overload to prevent these complications. The cost effectiveness of iron chelation therapy was arguable.
This study aims to evaluate the prevalence of cardiac complication and the correlation between risk factors in iron chelation therapy era.

Method
This is a cross sectional study from June 2011- May 2012. All thalassemia aged > 15 years old were enrolled. Clinical data and hemoglobin typing were reviewed. Echocardiography and CMR T2*, a technique represent cardiac iron deposition used to evaluate cardiac function, were used to evaluate cardiac complications.

Results
Ninety one patients were enrolled, 63.7% were females, median age of 31 years (16-75). There was 49.5 % homozygous β thalassemia, 31.9% β thalassemia/Hb E disease, 18.7% Hb H disease. Half of patients were transfusion dependent and 63.7% underwent splenectomy. Eighty four percent of patients received iron chelation therapy but few of them got their preferable choice in adequate dosage. Patients with serum ferritin levels more than 1,000 ng/ml. received deferoxamine, deferiprone or deferasirox.
Even with the iron chelation therapy, mean serum ferritin level was still high at 3,820 ng/ml for the whole group.
CMR T2* was more sensitive in detecting cardiac function. The CMR T2* showed shorter signal (≤ 20 msec) in 11.1%. Only 8.2% had impaired ejection fraction <55% by echocardiography. The CMR T2* ≤ 20 msec was significant correlated with higher maximum ferritin 5,739.14 ng/ml compared to 3,614 ng/ml (p=0.001). Pulmonary hypertension was found 7 patients (12.7%) and 71.42% had underwent splenectomy.

Conclusion
From our study, the CMR T2* is the sensitive method for detecting cardiomyopathy and highly correlated with serum ferritin levels. Splenectomy remains the major risk factor for pulmonary hypertension.
The incidence of cardiac complications has decreased with iron chelation therapy for maintaining acceptable serum ferritin levels but the problem with cardiomyopathy and pulmonary hypertension still exist. Early detection, more sensitive implementation and aggressive iron chelation therapy are necessary to prevent these complications.
The majority of the patients in Thailand which are under universal health-care coverage scheme could not get access to more effective and expensive iron chelator. Regular and adequate chelation plays a major role in the prevention of cardiac complications and the achievement of better quality of life.

Disclosures:
No relevant conflicts of interest to declare.
Bendamustine and Rituximab Achieve a Major Survival Improvement Of Patients With Morbus Waldenström In Routine Care
Authors: Weide Rudolf , Feiten Stefan , Friesenhahn Vera , Heymanns Jochen , Kleboth Kristina , Thomalla Jörg , van Roye Christoph , Köppler Hubert 
Published: October 2019

Abstract

Introduction
Progress has been made in diagnosis and treatment of patients with Morbus Waldenström who receive their treatment within prospective clinical trials. Due to necessary inclusion and exclusion criteria only a very limited number of patients are treated in studies. Therefore results from clinical trials can't be transferred into routine care. Little practice data are available how patients with Morbus Waldenström are diagnosed and treated in routine care and whether improvements in survival are achieved.

Methods
A retrospective analysis of all patients with Morbus Waldenström who were treated in an oncology group practice in Germany between 1995-2012. Relevant clinical data concerning diagnosis, treatment and survival were transferred from clinical files into a database and analyzed statistically using SPSS and SURVSOFT.

Results
52 patients with a median age of 67 (36-84) were identified. 67.3% were male and 32.7% female. Distribution according to IPSSWM-stage was: 21.2% low risk, 61.5% intermediate risk, 17.3% not evaluable (in most cases due to lacking β2 microglobulin data). 59.6% needed therapy with a median of 3 therapies (1-12). Regimens most frequently applied were: Bendamustine-containig (74.2%), Rituximab-containing (74.2%), Bendamustine+Rituximab-combinations (61.3%) and Chlorambucil-containing (45.2%). 6.5% of patients were treated within a clinical trial. Median overall survival was 12 years (0-19). Median relative survival was 13.6 years. 10-year relative survival was 86%. 10-year relative survival according to IPSSWM-stage was as follows: low risk 92%, intermediate risk 71%. Median overall survival of the patients who never needed any therapy was 11 years compared to 12 years of those patients who needed therapy. Median relative survival for patients who never needed therapy was not reached yet, median relative survival of the patients who needed therapy was 13.6 years.

Conclusions
Systemic treatment of patients with Morbus Waldenström in routine care consists mainly of Bendamustine, Rituximab and Bendamustine+Rituximab-combinations. Employment of the most active chemoimmunotherapies leads to a marked prolongation of survival compared to historical controls and registry data.

Disclosures:
No relevant conflicts of interest to declare.
GFI1B Mutation Causes a Platelet Function Defect With Reduced Alpha-Granule Content and Abnormal Aggregation Response
Authors: Ward Christopher M , Morel-Kopp Marie-Christine , Chen Qiang , Liang Hai Po , Ng Ashley P. , Roberts Andrew W. , Bahlo Melanie , Stevenson William s 
Published: October 2019

Abstract
GFI1B is a transcription factor important for erythropoiesis and megakaryocyte development, but previously unknown to be associated with human disease. We have identified a family with an autosomal dominant bleeding disorder associated with thrombocytopenia, red cell anisopoikilocytosis and platelet dysfunction. The severity of bleeding is variable with some affected individuals experiencing spontaneous bleeding while other family members only exhibit abnormal bleeding with surgery. All affected individuals had a moderate thrombocytopenia ranging from 72-149 x109/L with an elevated mean platelet volume. Platelet function was perturbed with prolonged collagen/epinephrine closure times on the PFA-100 (294 vs 125 sec, P <0.001). Platelet aggregation studies were abnormal, with an absent collagen response and primary aggregation only with ADP, arachidonic acid and adrenaline. Genetic linkage analysis and massively parallel sequencing were performed on 16 family members to localize the mutation causing the disease phenotype to chromosome 9. A single nucleotide insertion was identified in GFI1B that predicts a frameshift mutation in the fifth zinc finger DNA-binding domain. This mutation alters the transcriptional activity of the protein as determined by luciferase production from the TGFBR3 and GFI1B promoters. Aberrant transcriptional activity was associated with a marked reduction in platelet alpha-granule content as measured by electron microscopy (1.3 vs 3.1 alpha-granules per 1µm2, P<0.001) with similar changes in platelet protein expression. Proteomic analysis of platelet lysates demonstrated altered levels of cytoskeletal proteins, including talin, vinculin and myosin light chain 6. GFI1B mutation represents a novel human bleeding disorder and the described phenotype identifies GFI1B as a critical regulator of platelet number and function.

Disclosures:
No relevant conflicts of interest to declare.
Effects of GLI1 and CTNNB1 Knockdown on Notch Signaling and Proliferation of AML and T-ALL Cell Lines
Authors: Okuhashi Yuki , Takahashi Yusuke , Ohtaka Mika , Shiratori Erika , O Shijyun , Itoh Mai , Tohda Shuji 
Published: October 2019

Abstract
Objective: Although Hedgehog (Hh) and Wnt signaling pathways are known to play a role in cancer cell growth, their specific effects on leukemia cells are not fully understood. Previously we reported that the Hh inhibitor, cyclopamine, and the Wnt inhibitor, quercetin, suppressed the growth of leukemia cells. However, a specific inhibitory role of these chemical compounds on Hh and Wnt signaling could not be confirmed since these compounds also have off-target effects. Therefore the effects of specific inhibition of Hh and Wnt signaling pathways must be investigated in detail. In our previous study, we reported that small interfering RNA (siRNA)-mediated knockdown of NOTCH1 and NOTCH2 suppressed growth of T-ALL cell lines. In this context, the relationship between Hh, Wnt, Notch and mTOR signaling; known to regulate stemness; has not been fully elucidated. To address these questions, the effects of siRNA-mediated knockdown of GLI1 and CTNNB1 (Catenin beta 1), which respectively mediate Hh and Wnt signaling, on cell proliferation as well as Notch and mTOR signaling were studied in AML and T-ALL cell lines.
Methods: Two AML cell lines (NB4 and THP-1) and 2 T-ALL cell lines (DND41 and Jurkat) were used in this study. siRNAs targeting GLI1 (siGL), CTNNB1 (siCT), NOTCH1 (siN1) or control siRNA were transfected into cells by using the pipette tip chamber-based electroporation system. The effects of siGL and siCT transfection on cell proliferation were examined using a colorimetric WST-8 assay and by observing cytospin preparations of the harvested cells. The effects on mRNA and protein expression were examined by quantitative RT-PCR and immunoblotting, respectively.
Results: Transfection with siGL and siCT selectively suppressed the expression of GLI1 and CTNNB1, respectively. siRNA treatment did not lead to any significant effects on cell proliferation or morphology in all tested cell lines. In NB4 cells, GLI1 as well as CTNNB1 knockdown increased the level of NOTCH1, the cleaved NOTCH1 fragment (active form of NOTCH1), HES1, and phosphorylated mTOR protein. In the other cell lines, the expression of these proteins was not significantly altered by siGL and siCT.
Discussion: siRNA-mediated knockdown experiments suggested that Hh and Wnt signaling had insignificant effect on the proliferation of the leukemia cell lines used in this study. We report a novel interaction, namely, the activation of Notch and mTOR signaling by the suppression of Hh and Wnt signaling in NB4 cells. The molecular mechanism and significance of this phenomenon as well as its translation to other cell lines needs further examination. We propose that this finding must be taken into account when Hh- and Wnt-targeted therapy against leukemia are developed.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
Depletion of CD45RA+ Cells from Mobilized Peripheral Blood Stem Cell (PBSC) Collections As an Integral Part of Hematopoietic Stem Cell Transplantation (HSCT) and Cellular Therapy (CT)
Authors: Law Ping , Eldridge Paul W. , Houston James , Triplett Brandon M. , Shook David R , Leung Wing 
Published: October 2019

Abstract
Clinical scale depletion of CD45RA+ naïve T cells from leukapheresis collections can be achieved using CliniMACS (Bone Marrow Transplant. 2013, 1-7). In this study, PBSC collections depleted of CD45RA+ cells were infused as part of CT treatment protocols for pediatric patients with hematologic malignancies and solid tumors in 2 separate clinical trials. Between Sep 2012 and May 2014, a total of 25 CD45RA+ cell depletion procedures was performed for 25 patients. Mobilized PBSC leukapheresis units were collected (using Spectra) from HLA haplo-identical donors and held overnight in cold prior to cell selection. Characterization of the products before and after CD45RA+ cell depletion is shown in Table 1. Depletion of all CD45RA+ cell averaged to 3.39-log while depletion of CD3+CD45RA+ T cells was > 3.76-log, as this subset of cells became undetectable in 8 (out of 25) final products. CD34+ cell recovery was 65.4%, similar to that of CD3+CD45RO+ T cells (65.1%), which constituted > 99% of all T cells after depletion. From the PBSC collection, each patient received a median dose of 0.009 x 106 CD3+CD45RA+ cells/kg and 11.1 x 106 CD34+ cells/kg. The final product contained a substantial amount of CD14+ monocytes (median = 22.0%, range: 7.0 – 46.4), few CD56+ NK cells (3.1%, range: 1.3 – 8.1) and almost no CD19+ B cells (0.04%, range: 0.01 – 0.30). After processing the cells were resuspended in Plasmalyte + 5% human serum albumin and infused as soon as possible. There was no reported contamination (growth of bacteria – aerobic or anaerobic and fungus) in the final cell products and no infusion related adverse events were observed. In conclusion, we have demonstrated clinical scale depletion of naïve T cells can be achieved consistently and the final cell product can be safely infused into patients as part of HSCT and / or CT program.
Table 1: Cell Populations (Median & ranges) Before and After CD45+ Cell Depletion Before Depletion After Depletion Total Nucleated Cells 3.97 x 1010 (1.55 – 6.60) 1.47 x 1010 (0.43 – 2.92) % CD34+ Cells 0.85% (0.29 – 2.30) 1.45% (0.32 – 4.63) % CD3+ T Cells 22.8% (11.5 – 50.9) 13.1% (3.9 – 37.7) % CD45RA+ Cells 39.6% (27.2 – 64.1) 0.05% (0.01 – 0.79) % CD3+ CD45RA+ Naïve T Cells 12.3% (4.3 – 29.2) 0.01% (0 – 3.42) % CD3+ CD45RO+ Memory T Cells 6.5% (2.0 – 15.6) 13.0% (3.9 – 37.5)

Disclosures
No relevant conflicts of interest to declare.