bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase 2 Trial of Concurrent Monosialotetrahexosylganglioside in the Prophylactic Treatment of Bortezomib-Induced Peripheral Neuropathy in Patients of Multiple Myeloma
Authors: Wang Liang , Xia Zhongjun , Chen Xiaoqin 
Published: October 2019

Abstract
Backgrounds
Bortezomib is an important drug in the treatment of multiple myeloma (MM), and peripheral neuropathy (PN) is a significant dose-limiting toxicity of bortezomib. No effective prophylaxis has been defined for PN. Monosialotetrahexosylganglioside (GM), a nerve-protecting drug, is often used to promote growth of nerve and function restoration of damaged nerve. The role of GM in the prophylaxis of bortezomib-induced PN in MM patients has never been investigated.
Methods
A phase 2 clinical trial was conducted in newly diagnosed MM patients to evaluate the value of GM in the prophylaxis of bortezomib-induced PN. All eligible patients were treated with VD (bortezomib 1.3mg/㎡,subcutaneous injection, d1 ,8,15,22, and dexamethasone 40mg, po,d1 ,8,15,22, 4 weeks a cycle) or CyBorD (cyclophosphamide 300mg/㎡,po,d1 ,8,15, bortezomib 1.3mg/㎡,subcutaneous injection, d1 ,8,1 5,22, and dexamethasone 40mg, po,d1 ,8,15,22, 4 weeks a cycle) for at least 4 cycles. GM was used at a dosage of 100mg/day intravenously at d1 -2, 8-9, 15-16, 22-23. No other nerve-protective drugs or thalidomide-containing regimens were allowed. The primary endpoint was overall incidence rate of PN (the grade of PN was recorded according to CTCAE v3.0). The secondary endpoints included duration of PN, complete response rate after 4 cycles of treatment, 1-year PFS and OS rate. (This trial was registered in ClinicalTrial.gov, NCT02093910).
Results
From February 2014 to February 2015, 25 patients of newly diagnosed MM were enrolled. The median age was 55 years old (37-75), and male to female ratio was 19:6. 5 patients had ISS stage I disease, 6 patients with stage II, and the remaining 14 patients with stage III. All patients received a median of 4 cycles (range 2-9) of Bortezomibcontaining regimens. At the time of data analysis, 84% of patients had at least partial response, 48% had at least very good partial response, and 24% had complete response. 7 patients experienced PN after a median of 2 cycles (range 1-4) of treatment, resulting in the overall PN rate of 28%. Among these 7 patients, only 1 patient (4%) had grade 2 PN, leading to dose reduction of bortezomib, and all other patients had grade 1 PN. During treatment, 1 patient (4%) had grade 2 diarrhea, and another 1 patient (4%) had herpes zoster infection. The concurrent use of GM did not introduce new side effects and seemed not compromise the efficacy of bortezomib. At a median follow up time of 8 months, 1-year PFS rate and OS rate were speculated to be 69.8% and 100%, respectively.
Conclusions
The early-term analysis of this phase 2 trial found it feasible to concurrently use GM and bortezomib-containing regimens, and GM had the potential role of reducing bortezomib-induced PN rate and severity without compromising efficacy. This needs to be validated in future phase 3 randomized clinical trials.

Disclosures
No relevant conflicts of interest to declare.
The Impact of Driver Mutations of JAK2, Calr, or MPL in Patients with Myelofibrosis Undergoing Hemopoietic Stem Cell Transplantation
Authors: Bacigalupo Andrea , Pozzi Sarah , van Lint Maria Teresa , Bregante Stefania , Barosi Gianni , Pietra Daniela , Rumi Elisa , Milanesi Chiara , Cazzola Mario 
Published: October 2019

Abstract
Introduction. The vast majority of patients with primary myelofibrosis (PMF) have been shown to carry driver mutations of JAK2, CALR (calreticulin gene) or MPL ì, and these molecular leasions may impact the clinical course of the disease. In a recent paper (Blood 2014;124:1062) patients with CALR mutation, had a lower risk of developing anemia, thrombocytopenia, marked leukocytosis, thrombosis and showed better overall survival, than either JAK2 -mutant or triple-negative patients.
Aim of the study. The aim of the present study was to assess whether CALR exon 9 mutation, conferred a survival advantage in MF patients undergoing a hemopoietic stem cell transplant (HSCT).
Patients. All patients were selected for transplant by two authors (AB and GB) and grafted in Genova.
Patients are outlined in 2 groups: 15 with CALR mutation and 31 with wild-type CALR; the latter included 21 patients with JAK2 (V617F), 7 patients with MPL mutation and 3 patients triple negative. There were no significant differences, between the 2 groups in terms of DIPSS, spleen size, circulating CD34+ cell count, donor type, year of HSCT and conditioning regimens.
Mutation status. Granulocyte JAK2 (V617F) mutation status and mutant allele burden were assessed using a quantitative polymerase chain reaction (qPCR)-based allelic discrimination assay on a Rotor-Gene 6000 real-time analyzer (Qiagen), as previously described.1,2 Patients without JAK2 (V617F) were evaluated for MPL exon 10 mutations using a high-resolution melt (HRM) assay or Sanger sequencing.3,4 Patients with nonmutated JAK2 and MPL were studied for CALR exon 9 mutations as reported in our original paper or by Sanger sequencing, as described elsewhere.4
Results. With a median follow up of over 500 days for both groups, we could find no significant differences in CALR -mutated patients as compared to the remaining ones: transplant related mortality (26% vs 29%, respectively); relapse (20% vs 39%, p=0.2), relapse related death (20% vs 22%) and survival (47% vs 52%, p=0.7).
When dissecting the patients with wild-type CALR, we could indeed see a survival advantage for the small number of MPL -mutated patients (n=7): when these were compared against all the others (n=39), again with similar disease and transplant characteristics, survival was 86% vs 44% (p=0.04) and relapse 14% vs 36% (p=0.2). In multivariate analysis, DIPPS was the only predictor of survival.
Conclusions. These data suggests that CALR mutation does not confer a survival advantage in PMF patients undergoing an allogeneic HSCT. MPL mutation, on the other hand, though present in a very small number of patients, may be worth investigating further in a larger number of patients.

Disclosures
No relevant conflicts of interest to declare.
Reconstitution of Epstein-Barr Virus-Specific T Lymphocytes at the Early Stage of Allogeneic Stem Cell Transplantation
Authors: Lin Ren , Fan Zhiping , Zhao Ke , Jiang Qianli , Sun Jing , Liu Qifa 
Published: October 2019

Abstract
Backgroud:
Epstein-Barr virus (EBV) infection/reactivation is an common complication following allogeneic stem cell transplantation (allo-HSCT) which usually occure at the early stage after transplantation. EBV-specific cytotoxic T lymphocytes (EBV-CTLs) are considered to provide protection from EBV infection/reactivation and associated diseases in recipients of allo-HSCT. Herein, we evaluated the levels of EBV-CTLs early after transplantion and investigated the associaton between the reconstitution of EBV-CTLs and EBV infection/reactivation after allo-HSCT.
Methods:
Thirty patients undergoing allo-HSCT between November 2013 to September 2014 were enrolled in this study. Of these patients, 16 received HLA-matched donor and 14 received HLA-mismatched transplantation. Antithymocyteglobulin was given in 20 patients. EBV-CTLs were tested using Enzyme-linked immunospot assay (ELISPOT) presenting 9 peptides derived from 3 EBV proteins in +30, +90 and +180 days after transplantation.
Results:
EBV-CTLs, although low levels, were detected in 90% (27/30) patients in +30 days after HSCT. In most patients, EBV-CTLs levels in +90 days was significantly higher than +30 days and returned to normal levels within +180 days after HSCT. Thirteen patients developed EBV infection/reactivation within the median time of 48 (range, 23-110) after transplantation. EBV-CTLs levels had no significant difference among the patients with or without infection/reactivation in +30 days while the patients with EBV infection/reactivation had higher EBV-CTLs levels than those without in +90d after HSCT.
Conclusion:
Reconstitution of EBV-CTLs seems rapid in both HLA-matched and -mismatched donor transplantation. The association between EBV infection/reactivation and EBV-CTLs levels at monthly intervels after HSCT should be studied further.

Disclosures
No relevant conflicts of interest to declare.
The Relationship Between Some Cytokines and Graft Versus Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation in Thalassemia Major Patients
Authors: Wu Xuedong , Chen Libai , Xu Yanjun , Wen Jianyun , Ruan Yongsheng , He Yuelin , Li Chunfu 
Published: October 2019

Abstract
Background: Research has shown that the relationship between cytokines and graft versus host disease is close, but there are still a lot of cytokines and graft versus host disease relationships which are not clear. At the same time, thalassemia patients with graft versus host disease may exist in particularity.
Objects: To investigate the relationship between some cytokines and graft-versus-host disease after allogeneic hematopoietic stem cell transplantation in β-thalassemia major patients.
Methods: The study included 16 patients who developed graft-versus-host disease (GVHD) after receiving hematopoietic stem cell transplantation in the Department of Pediatrics in Nanfang Hospital between the time period of 2011 July to 2015 March. We observed the dynamic variation of interleukin 6 (IL-6), interleukin 8(IL-8), interleukin 12(IL-12), tumor necrosis factor-α(TNF- α) and macrophage migration inhibitory factor(MIF) in 16 patients before onset of GVHD, when GVHD occurred, at fourth and seventh day after onset of GVHD, and when GVHD almost disappeared.
Results: There was a significant difference in serum levels of interleukin-6, interleukin-12, tumor necrosis factor-α, macrophage migration inhibitory factor at different times. The highest levels of different cytokines appeared when GVHD occurred, followed by those at seventh day after it occurred. There was also a significant difference in serum levels of interleukin-8 at different times, and the highest level appeared at fourth day after GVHD occurred. There is a significant positive correlation between IL-6 and IL-12,IL-12 and TNF-α,IL-12 and MIF,TNF- α and MIF when GVHD occurred. There is a significant positive correlation between IL-12 and TNF-α when GVHD occurred and on the fourth day . There is a significant positive correlation between IL-12 and TNF-α,IL-12 and MIF,TNF-α and MIF when GVHD appeared on the seventh day. There is a significant positive correlation between IL-6 and IL-12,IL-12 and TNF-α,IL-12 and MIF,TNF-α and MIF when GVHD almost disappeared.
Conclusion: The dynamic expression of IL-6,IL-8,IL-12,TNF-α and MIF can estimate the immune function of β-thalassemia major patients who develops graft-versus-host disease after allogeneic hematopoietic stem cell transplantation, and can be used as the immunobiology indicators for the early diagnosis of graft-versus-host disease. IL-6, IL-8, IL-12, TNF-α and MIF may have correlation with each other in different time of graft versus host disease.

Disclosures
No relevant conflicts of interest to declare.
Complete Resolution of Extensive Chronic Graft-Versus-Host Disease with Ibrutinib
Authors: Scholoff Audrey , Obi Gloria , Baker Kelty R. , Carrum George , Kamble Rammurti T 
Published: October 2019

Abstract
We herein document a complete response of extensive chronic graft-versus-host disease (cGvHD) to a Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib. A 41 years old female with primary refractory MCL underwent mismatched unrelated donor (MMUD) allogeneic hematopoietic stem cell transplantation in December 2011 (conditioning with CY/TBI and alemtuzumab, graft=6.6x 106/kg CD-34+ cells, tacrolimus alone for GVHD prevention). Following engraftment on day 11, she developed grade III acute GvHD involving the skin and gut on day 17 of transplantation that persisted beyond 100 days post-transplant. Her cGvHD was treated with steroids, but remained active and extensive. Despite persistent cGvHD and 100% donor chimerism she relapsed in July 2012. Treatment with radiation and bendamustine with rituximab failed. By December 2013, the patient had extensive cGvHD manifesting as scleromatous skin thickening, oral ulcers and sclerosis of the buccal mucosa, ocular dryness and diarrhea, and was started on ibrutinib1 560 mg once daily for relapsed MCL. After 8 weeks of therapy, cGvHD had begun to improve. Oral steroids were reduced and ultimately stopped after 26 weeks of ibrutinib; after 30 weeks treatment all cGvHD manifestations resolved completely. A complete remission for MCL was documented at 8 weeks of ibrutinib initiation. Currently she continues to be on 560 mg daily ibrutinib without cGvHD exacerbation or MCL relapse for 22 weeks and 52 weeks, respectively. Chronic graft versus host disease (cGvHD) is mediated donor T cells. The role of B cells in the pathogenesis of cGvHD is increasingly recognized. Two murine studies have explored the role of ibrutinib in cGVHD-like syndromes, one in which there is T cell driven sclerodermatous cGvHD and a second in which there is Ab driven multiorgan system cGvHD that includes bronchiolitis obliterans (BO). Administration of ibrutinib decreased the incidence and severity of sclerodermatous, and improved pre-existing lesions and also improved pulmonary fibrosis and reduced BO. Animals lacking BTK and ITK did not develop cGVHD, indicating that these molecules are critical to cGVHD development. Our report provides the evidence that BTK inhibition led to complete resolution of cGvHD and supports exploration of its role in future clinical trials.

Disclosures
No relevant conflicts of interest to declare.
Pretransplantation Positron Emission Tomography Predicts Outcome Following Autologous Stem Cell Transplantation for Relapsed or Refractory Hodgkin Lymphoma
Authors: Dulery Remy , Marjanovic Zora , Aoudjane Malek , Corre Elise , Lemonnier Marie-Paule , Vekhoff Anne , Coppo Paul , Mohty Mohamad 
Published: October 2019

Abstract
Despite high-dose therapy followed by autologous stem cell transplantation (ASCT), roughly 50% of patients with relapsed or primary refractory Hodgkin lymphoma can be cured. To identify poor risk patients who could benefit from post-ASCT treatments, we carried out an analysis of 32 patients treated at Saint-Antoine Hospital. The study included 18 males and 14 females with a median age of 31.8 years (range, 17.5-64.8). Ann Arbor staging was I-II in 14 patients and III-IV in 18 patients. Only 2 patients did not have adverse prognosis factors at diagnosis. Sixteen patients had received more than 1 salvage therapy (ST) prior ASCT, among whom 4 patients had received Brentuximab-Vedotin. Patients were evaluated with computed tomography and fluorodeoxyglucose-positron emission tomography (PET) prior to ST and again before ASCT. Relapse had occurred less than 12 months after the 1st treatment in 17 patients. Twelve patients had never achieved complete remission before ASCT. Disease status at transplant was complete remission in 16 patients, partial response in 16 patients and progressive disease in 1 patient. TEP was positive in 4 patients.
After a median follow-up of 66,9 months (12.6-139.4), the cumulative incidence of relapse was 43.75%, the event-free survival (EFS) 50% and the overall survival (OS) 81.2%. PET status before ASCT clearly identified poor risk patients (5-year OS 25% and 89.3% for PET-positive and negative patients respectively, p=0.002) and was the only significant factor associated with OS by multivariate analysis [HR: 6.52; 95% CI 1.3-32.67] (p=0.023).
In conclusion, pre-ASCT PET status appears to be the main prognosis factor in patients with relapsed or refractory Hodgkin lymphoma. Studies evaluating new conditioning regimens, post-ASCT maintenance with Brentuximab-Vedotin or tandem allogeneic stem cell transplantation are warranted for pre-ASCT PET-positive patients.
Figure 1. Overall survival according to TEP status at transplant (log-rank P value) Figure 1. Overall survival according to TEP status at transplant (log-rank P value)

Disclosures
Coppo: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees.
Is HLA-Haploidentical Hematopoietic Stem Cell Transplantation a Valid Alternative Option for Patients with Combined Paroxysmal Nocturnal Hemoglobinuria and Aplastic Anemia (AA/PNH Syndrome)?
Authors: Chen Feng , Depei Wu , Tang Xiaowen , Miao Miao , Fu Chengcheng , Qiu Huiying , Xue Shengli , Ma Xiao , Jin Zhengming 
Published: October 2019

Abstract
Background In the era of eculizumab, indentifying patients with PNH who may benefit from allogeneic stem cell transplantation(SCT) is challenging, especially for those who have no HLA-matched donors. Several recent studies have shown that HLA-haploidentical SCT for patients with hematological malignancy can achieved comparable outcomes with HLA-identical sibling transplantation. There are very few reports on the use of HLA-haploidentical SCT for AA/PNH. The aim of the present study was to assess the long-term clinical outcome of HLA-haploidentical SCT in patients with AA/PNH.
Methods Total of 9 AA/PNH patients received HLA-haploidentical SCT between Oct 2010 and Oct 2014 at our institution. The patients were aged 13 to 54(median 24 years). The median interval from the diagnosis to transplantation was 48 months (range 2-180). Of the 9 HLA-haploidentical donors, 3 were siblings, 2 fathers, 2 mothers, 1 son and 1 daughter. 8 patients received myeloablative conditioning regimen consisting of busulfan, cyclophosphamide and ATG (anti-thymocyte globulin), 1 patient who underwent salvage HLA-haploidentical SCT after the graft failure of double umbilical cord blood transplantation received conditioning including reduced-intensity total body irradiation, cyclophosphomide and ATG. G-CSF-mobilized bone marrow and peripheral blood stem cells were transplanted as graft. Prophylaxis for graft-versus-host disease(GVHD) consisted of cyclosporine or tacrolimus + mycophenolate mofetil + short-term methotrexate.
Results All 9 patients were engrafted successfully. The median time of neutrophils (ANC) reached to 0.5×109/L and platelets (PLT) reached to 20×109/L were 12 (range 11-26) days and 15 (range 11-120) days, respectively. 2 patients developed grade Ⅱ acute GVHD, 2 patients developed limited chronic GVHD. After a median follow-up time of 14.0 (range 4.0-30.8) months, the 2-year OS probability was 72.9±16.5%. 2 patients died of treatment-related mortality, including severe pulmonary infection (n=1) and transplant-associated thrombotic microangiopathy (n=1),respectively. No patients were documented to have a recurrence of a PNH clone after SCT.
Conclusion This study showed that long-term outcomes of HLA-haploidentical SCT in patients with AA/PNH were comparable to that of HLA-matched donor SCT ( the 2-year OS probability was 80.5±10.2%, P=0.02) at our institution. HLA-haploidentical SCT should be considered as a valid alternative therapeutic option for AA/PNH patients without HLA-matched donors.

Disclosures
No relevant conflicts of interest to declare.
A Highly Sensitive Assessment Tool for the Gene Editing Efficiency of Sickle Cell Disease Hemoglobin Beta Gene
Authors: Borjigin Mandula , Kmiec Eric Brian , Wu Rigumula 
Published: October 2019

Abstract
In sickle cell disease, a single point mutation in hemoglobin β gene (HBB) results in the substitution of valine for glutamic acid at position 6 of the β globin protein sequence, causing the deformation of red blood cells into a sickle (or crescent) shape. With the development of powerful gene editing tools, scientists are initiating the correction of the point mutation of HBB gene in CD34+ hematopoietic stem cells and induced pluripotent stem cells. Although the results are very exciting, the evaluation method of the gene editing is primitive. Currently, the modification at the mutation site is identified and quantified using Restriction Fragment Length Polymorphism (RFLP), which involves PCR amplification, restriction enzyme digestion and gel electrophoresis. The accuracy of the gene editing efficiency depends heavily on the quantification of the DNA bands in the gel images, which is inherently imprecise. We have developed a novel technique to quantify the correction efficiency of HBB gene editing using a fluorescence tagging of the edited DNA sequence. This method provides excellent sensitivity and accuracy, and saves time and labor, eliminating a process of gel electrophoresis. We demonstrate the assessment of gene editing in HBB of K562 cells, in which the wild type HBB (βA gene) is converted to mutant βs using the gene editing tools (i.e. Transcription Activator-Like Effector Nucleases (TALENs) and single-stranded oligo deoxynucleotides (ssODNs)). We present limited information here due to the sensitivity of the intellectual property, but will discuss in detail the experimental procedures and data at the American Society of Hematology meeting.

Disclosures
No relevant conflicts of interest to declare.
Subcellular Localization of Beta Hemoglobin Using pSNAPf fusion Protein
Authors: Jaffar Samia , Metzenberg Aida , Adams Gregor B. 
Published: October 2019

Abstract
Abstract: Much of what is known about hemoglobin relates to its structure and function. However, there is a great deal to learn about its assembly. The application of new technologies has allowed us to investigate the process of hemoglobin synthesis extensively. It has been shown that heme, synthesized in the mitochondria, is exported into the cytoplasm where it rapidly binds with apoglobin synthesized by polyribosomes. In this study,subcellular localization of newly synthesized alpha and beta subunits of human hemoglobin were examined using fluorescence microscopic imaging of cultured human erythroleukemic cells (cell line HEL 92.1.7). Experiments were used to determine the location of newly synthesized protein subunits. This paper will highlight the current knowledge of hemoglobin assembly, function and cellular interactions; and illustrate how cellular labels can be used to investigate this protein. It is hoped that future experiments will help to determine more details of the mechanism of globin assembly, which will be useful in the investigation of hemoglobinopathies.

Disclosures
No relevant conflicts of interest to declare.