bluuebunny/crossref_metadata_2025_split huggingface dataset:
Recipient and Donor KIRs Ligands Match Prevents CMV Reactivation Post-Haploidentical T Cell-Replete Transplantation
Authors: Zhao Xiang-Yu , Luo Xue-Yi , Yu Xing-Xing , Zhao Xiaosu , Lv Meng , Han Ting-Ting , Chang Ying-Jun , Huo Ming-Rui , Xu Lan-Ping , Zhang Xiao-Hui , Liu Kai-Yan , Li Dan , Huang Xiao-Jun 
Published: October 2019

Abstract
Licensed NK cells have been demonstrated to have anti-cytomegalovirus (CMV) activity. We prospectively analysed the HLA typing of donor-recipient pairs and the KIR typing of the donors in 180 leukaemia patients to assess the predictive roles of licensed NK cells and donor-activating KIR genes on CMV reactivation post-T cell-replete haplo-SCT. Multivariate analysis showed that donor and recipient KIR ligand-ligand graft-versus-host direction or host-versus-graft direction mismatch were associated with the incidence of CMV reactivation [HR=1.663, 95%CI, 1.161-2.383, P=0.006] and refractory CMV infection [HR=2.34, 95%CI, 1.28-4.27, P=0.006] post-haploidentical T cell-replete transplantation. Donor and recipient KIR ligand-ligand match decreased CMV reactivation (51.65% [46.67, 56.62%] vs. 75.28% [70.87, 79.69%], P=0.012), refractory CMV infection (17.58% [13.77, 21.40%] vs. 35.96% [31.09, 40.82%], P=0.004) and CMV disease (3.30% [1.51, 5.08%] vs. 11.24% [8.04, 14.43%], P=0.024), respectively. Meanwhile, there was a significantly increased risk of CMV reactivation in patients who accepted a KIR2DS2-positive donor compared those who accepted a KIR2DS2-negative donor (80% [71.93, 88.07%] vs. 63.87% [60.18, 67.56%], P=0.039), especially in recipient HLA-C1/C2 and donor HLA-C1C2 with KIR2DL1/2DL2/2DL3/2DS2 genotype (100%).
Conclusions: These findings suggested that donor and recipient KIR ligand-ligand match might promote the NK cell licensing process, thereby increasing NK cell-mediated protection against CMV reactivation. However, roles of donor positivity for the KIR2DS2 against CMV reactivation need to be further explored in T cell-replete haplo-SCT.

Disclosures
No relevant conflicts of interest to declare.
PRE-Transplant Positron Emission Tomography (PET) Predicts Outcomes of Patients with Hodgkin disease Undergoing Reduced Intensity Conditioning Haploidentical Transplant
Authors: Marani Carlo , Morbelli Silvia , Raiola Anna Maria , Dominietto Alida , Ferrarazzo Giulia , Nati Sandro , Congiu Marina , Bregante Stefania , Varaldo Riccardo , Gualandi Francesca , Angelucci Emanuele 
Published: October 2019

Abstract
Background. In recent years, the number of Hodgkin Lymphoma (HL) patients submitted to reduced intensity haploidentical allogeneic transplant (RIC haplo SCT) consistently increased. [Sureda et al. Curr Treat Options Oncol 2014] However, with a post alloSCT relapse rate so high as 40-60%, disease control after autoSCT relapse remains a clear unmet medical need. In respect of improving transplant outcome identification of factors influencing outcomes are warranted
Methods.We reviewed outcomes obtained in 44 consecutive HL patients who received RIC haplo SCT between September 2009 and June 2015 at our institution. The donor was haploidentical relative in all cases. All patients had received at least 3 conventional chemotherapy lines before RIC haplo SCT; most of them (72%) were refractory to front-line chemotherapy and all but one had received an autologous SCT. All patients received the same reduced intensity conditiong regime, and GvHD prophilaxis with post-transplant cyclophosphamide (Raiola et al. BBMT 2008). The median age was 31years (range 18-60). Deauville five-points scale were used to interpretate the results of pre-transplant positron-emission tomography (PET) studies, with a threshold of 4 or above considered positive. Survival curve and GvHD incidence were calculated with the method of Kaplan and Meier. Cox regression model was performed to identify pre-transplant factors influencing outcomes.
Results. All patients engrafted but 1 who showed autologous recovery. The median day for 500 neutrophils was 15 days (13-23). Three patients died in remission at 8 (cGvHD), 16 (myocarditis) and 51(pneumonia) months from SCT, respectively. Three years non relapse mortality = 8%. Risk of grade II-IV acute GvHD and 3-year chronic GvHD were 22 and 21%, respectively. With a median follow-up for surviving patients of 38 months (range 13-83), 21 relapsed (47%). All relapsed patients were treated with further therapy, mainly immuno-chemotherapy and donor lymphocyte infusion (DLI). The 3-year overall (OS) and progression free survival (PFS) were 77% and 39%, respectively. Pre-transplant PET status was the only factor influencing outcomes of the procedure (OR 5.4; 95% CI 1.7 - 16.6). In the 41 patients with available pre-transplant PET status, 19 were positive and 22 negative. Outcomes accordingly to pre-transplant PET status are shown in the following table.
Conclusions.Pre-transplant PET status is a factor influencing outcomes of relapsed/refractory HL submitted to RIC haplo SCT. Grade II-IV aGvHD was markedly reduced in patients with metabolic remission at time of transplantation.
Table Table.

Disclosures
Angelucci: Novartis oncology, celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.
Toxicity Burden of Bleomycin Treatment in Hodgkin Lymphoma: A Systematic Literature Review
Authors: Fox Kathleen M , Josephson Neil C , Richhariya Akshara 
Published: October 2019

Abstract
Introduction: Bleomycin has been a component of chemotherapeutic regimens for decades, typically among young individuals who may survive for long periods. Yet, toxicity from bleomycin may result in short-term and long-term health problems. The study objectives were to characterize the occurrence and severity of bleomycin toxicities and identify risk factors for bleomycin toxicity among patients with Hodgkin lymphoma.
Methods: A systematic literature review of the burden of bleomycin treatment in cancer patients was conducted using the PRISMA checklist. PubMed, EMBASE, and Cochrane Database were searched for English language articles between 1980 and March 2016 providing data on bleomycin toxicity in studies with >10 patients.
Results: Overall, 18 original research articles of good to moderate quality were included in the systematic review for patients with Hodgkin lymphoma. Pulmonary toxicity ranged from dyspnea, pulmonary fibrosis, and pneumonitis, to acute respiratory distress syndrome and respiratory tract disorders or infections. For Hodgkin lymphoma, the proportion of patients experiencing pulmonary toxicity was >5% in 12 of 17 studies, with 8 studies reporting toxicity in 13% - 28% of patients. Other studies (n=5) reported that 0% - 4.7% of patients experienced pulmonary toxicity. About 4% -5% of Hodgkin lymphoma patients had fatal pulmonary toxicity. Skin toxicity ranged from skin rash to dermatitis and erythema, with 1% - 5% of Hodgkin lymphoma patients experiencing skin toxicity after bleomycin exposure.
In the 4 studies that investigated risk factors for bleomycin-induced pulmonary toxicity among patients with Hodgkin lymphoma, low albumin level (<40 g/dL), treatment with anthracycline containing chemotherapy regimens and use of colony granulocyte stimulating factor concomitant with bleomycin were reported to be significant risk factors. No significant difference was found between patients with and without pulmonary toxicity in terms of exposure to radiation therapy, cumulative bleomycin dose, smoking history, or underlying lung involvement.
Conclusions: Long-term pulmonary toxicity was not consistently evaluated in the studies and may understate the true burden on patients. Many patients treated with bleomycin may experience toxicity and sometimes fatal toxicity. Since Hodgkin lymphoma is a highly curable malignant disease and to further improve patient outcomes, attention needs to be focused on reducing treatment-related toxicities, particularly long-term morbidity and death associated with pulmonary events.

Disclosures
Fox: Seattle Genetics: Research Funding. Josephson:Seattle Genetics: Employment. Richhariya:Seattle Genetics, Inc.: Employment.
Identification of Kinase-Dependent Signaling Pathways Regulated By Rap1b in Murine Platelets
Authors: Paniagua Luis , Wu Xiaogang , Pereckas Michael , Noon Kathleen , White Gilbert 
Published: October 2019

Abstract
Identifying signaling pathways regulated by Rap1b has been challenging using classical biochemical techniques. Using quantitative iTRAQ- and TiO2-based phosphoproteomics, we sought to identify protease-activated receptor 4 (PAR4) thrombin receptor-activated kinase cascades influenced by Rap1b in murine blood platelets. We identified a total of 1,783 phosphopeptides, and after screening for activation dependence, we found 7 phosphopeptides from 4 proteins that were >1.5-fold more abundant in WT compared to Rap1b-null mouse platelets and 5 phosphopeptides from 4 proteins were >1.5-fold more abundant in Rap1b-null. One protein that showed higher phosphorylation in activated WT platelets was Talin, which had 3 sites of increased phosphorylation: T430, S446, and S1201. The functions of these sites have yet to be determined, and the local sequences near these sites do not match any known kinase consensus sequences. Two of these sites, T430 and S446, are in close proximity to the Calpain cleavage site of Talin at Q432-Q433. We found Calpain cleavage of Talin was greater in PAR4-TRAP-activated Rap1b-null platelets compared to WT after 5 minutes of PAR4 stimulation. If phosphorylation inhibits Talin cleavage by Calpain, a possible explanation for the platelet defects seen in Rap1b-null platelets may be that cleavage of Talin reduces Talin clustering, and therefore integrin clustering, leading to reduced aggregation and reduced adhesion under shear. Other proteins identified include RhoGAP 18 (more abundant in WT) and ERK1/2 (more abundant in Rap1b-null). In conclusion, we have 1) used an unbiased proteomic approach to search for downstreams effectors of Rap1b during PAR4-mediated platelet activation, 2) identified 12 phosphopeptides from 8 unique proteins that had >1.5-fold difference in activated platelets from Rap1b-null mice versus WT mice, including Talin, RhoGAP18, and ERK1/2, and 3) identified a difference in Calpain-mediated Talin cleavage between activated plateles from Rap1b-null mice versus WT mice. These results suggest a signaling cascade from Rap1b to Talin, a known regulator of integrin activation. This work is supported by NIH Grant HL45000 and Blood Center Research Foundation.

Disclosures
No relevant conflicts of interest to declare.
The Novel ADCC-Optimized Human CD54 (ICAM-1) Antibody MSH-TP15e Has Potent Anti-Myeloma Activity
Authors: Klausz Katja , Burger Renate , Kellner Christian , Guenther Andreas , Peipp Matthias , Gramatzki Martin 
Published: October 2019

Abstract
Background: Monoclonal antibodies directed against various target antigens have proven efficacy in cancer therapy including hematological malignancies. Recently, daratumumab and elotuzumab became the first antibodies approved for the treatment of multiple myeloma (MM). Due to the substantial number of patients still in need for long-term disease control, the investigation of additional target structures and potent molecule formats for antibody-based therapy of MM remains important.
Methods: Human synthetic single-chain fragment variable (scFv) phage display libraries were subjected to a cellular screening approach. The MSH-TP15 clone was selected based on its binding to various MM cell lines and patient-derived CD138-positive malignant plasma cells. Intercellular adhesion molecule-1 (ICAM-1/CD54), known to be important for the interaction of malignant plasma cells with the bone marrow microenvironment, was identified as target antigen. Based on the scFv sequence, fully human IgG1 antibody variants with selected mutations in the Fc domain were constructed to generate wild-type, antibody-dependent cell-mediated cytotoxicity (ADCC)-optimized and Fc-knockout variants. First, these variants were analyzed for their capacity to kill MM cells in vitro. Apoptosis induction and growth inhibition were tested by flow cytometry and in MTS proliferation assays. ADCC and complement-dependent cytotoxicity were investigated in chromium-release assays using human serum, peripheral blood mononuclear cells or purified NK cells of healthy donors. In vivoefficacy of an ADCC-optimized variant was analyzed in the INA-6 myeloma xenograft model.
Results: The MSH-TP15 antibodies target an epitope on the N-terminal part of the extracellular domain of human ICAM-1/CD54. The antibody variants showed no anti-proliferative effects on patient-derived bone marrow stromal cells, nor directly induced apoptosis or inhibited proliferation of myeloma cells. While complement-dependent cytotoxic activity was generally absent, the Fc-engineered antibody variant MSH-TP15e significantly triggered ADCC against various MM cell lines and freshly isolated patient myeloma cells. The recruitment of human NK cells was crucial for the cytotoxic effects observed in vitro. Importantly, an ADCC-optimized variant completely prevented tumor engraftment in the INA-6 xenograft model.
Conclusions: The novel ADCC-optimized fully human antibody MSH-TP15e directed against ICAM-1/CD54 exerts potent anti-myeloma activity in vitro and in vivo. Therefore, it has promising characteristics and will be further evaluated for MM immunotherapy.

Disclosures
Guenther: Novartis: Consultancy, Honoraria; Celgene: Honoraria; Takeda: Consultancy, Honoraria.
Risk Factors and Outcome of Children with Relapsed/Refractory Acute Leukemia after T-Cell-Rich Haploidentical Hematopoietic Cell Transplantation
Authors: Kikuta Atsushi , Sano Hideki , Mochizuki Kazuhiro , Kobayashi Shogo , Akaihata Mitsuko , Ohara Yoshihiro , Takahashi Yoshinobu , Ohto Hitoshi 
Published: October 2019

Abstract
Background: T-cell rich (TCR) HLA-haploidentical SCT (haplo-SCT) is a form of T-cell therapy that has a high degree of efficacy in hematologic malignancies. Previously we reported the safety profile assessing GVHD prophylaxis that was conducted with anti-human thymocyte immunoglobulin (ATG), tacrolimus, methotrexate (MTX) and prednisolone (PSL) in unmanipulated haplo-SCT (Clin Transplant 2010, Transfus Med 2014). We evaluated efficacy and toxicity of TCR haplo-SCT in children with very high risk refractory/relapsed acute leukemia (VHR-R/R AL).
Methods: VHR-R/R AL were defined as: relapse after SCT, very early or early relapse, induction failure(2 or more) and relapse of risk factor with MLL rearrangement, Ph+, Mo7 and 5q-. From Aug 2000 to April 2014, consecutive 38 patients (pts) with VHR-R/R AL who underwent TCR-haplo-SCT were included. The median age of pts was 8.2(0.3-19.1) years old. The diagnosis included ALL (n=27), AML (n=8), M/NKL (n=3). The disease status at TCR-haplo-SCT were 18 in CR (positive MRD: 8 pts), 20 in non-CR. HLA disparities were 2/8 in 1pt, 3/8 in 9 pts, 4/8 in 28 pts. Donors included fathers (n=21), mothers (n=14), and siblings (n=3). Thirty one pts received myeloablative conditioning (TBI based: 20 pts, Bu based: 11 pts) and 34 pts of them received ATG (rabbit, thymoglobulin 2.5mg/kg) containing regimen. The GVHD prophylaxis was conducted with tacrolimus, MTX and PSL. Thirty four pts received peripheral blood stem cells and 4 pts received BM.
Results: Neutrophil engraftment (defined as >0.5x109/L) was 95% with a median day of 13 (range, 10-15). With a median 1640 days follow-up (range, 320-5510 days) in pts without events, the actuarial 3-year overall survival (OS) and disease-free survival (DFS) were 57% and 39%, respectively. On competing-risk analysis, 1-year cumulative incidences of grade II-IV acute GVHD and chronic GVHD were 71% and 63%, respectively; 3-year cumulative incidences of relapse and non-relapse mortality (NRM) were 40% and 20%. On univariate analysis, 3-year OS in pts with acute GVHD vs. without acute GVHD were 70% vs. 22% (p=.0006), in pts CR vs. non-CR at TCR-SCT were 83% vs. 32% (p=.007), in pts infused CD3 cell doses >=5 x 108/kg vs. <5 x 108/kg were 83% vs. 25% (p=.005), according to age at TCR-SCT <9 vs. >=9 were 79% vs. 34% (.008), respectively. In contrast, the occurrence of acute GVHD had no significant difference in infused CD3 cell doses.
Conclusions: These data suggest that TCR haplo-SCT following low-dose ATG containing conditioning combined with our GVHD prophylaxis is well tolerated, facilitates engraftment, and has significant anti-leukemic activity, particularly in pediatric patients with refractory/ relapsed population.

Disclosures
No relevant conflicts of interest to declare.
Sustained Natural Killer Cell Recovery Post-Autologous Peripheral Blood Hematopoietic Stem Cell Transplantation Predicts Survival in Non-Hodgkin's Lymphoma
Authors: Porrata Luis , Inwards David James , Ansell Stephen M , Micallef Ivana , Johnston Patrick B. , Nevala Wendy , Markovic Svetomir 
Published: October 2019

Abstract
Abstract
Our group recently reported a Phase III clinical trial (Porrata et al. Biology of Blood and Marrow Transplantation 2016; 22: 1017-1023) demonstrating that the infusion of the autograft-absolute lymphocyte count (A-ALC) and autograft natural killer cells (A-NKC) are survival prognostic factors in non-Hodgkin lymphoma (NHL) patients treated with autologous peripheral blood hematopoietic stem cell transplantation (APBHSCT). A limitation of our Phase III clinical trial was the short-term follow-up of just two years. Therefore, we evaluated longer follow-up and assessed the role of the infused A-ALC, infused A-NKC, and peripheral blood absolute natural killer cell count (ANKC) recovery on survival post-APBHSCT. Of the 122 patients that participated in the Phase III trial, 111 patients were able to complete APBHSCT and included in the current study. With a median follow-up of 57.2 months (range: 2.1-84.6 months), superior overall survival (OS) and progression-free survival (PFS) was observed in patients infused with an A-ALC ≥ 0.5 x 109 lymphocytes/kg [OS: HR = 0.429, 95%CI, 0.128-0.828, p < 0.01; and PFS: HR = 0.456, 95% CI, 0.177-0.863, p < 0.01] and an A-NKC ≥ 0.09 x 109 cells/kg [OS: HR = 1.58e-3, 95% CI, 1.046e-6-0.179, p < 0.003; and PFS: HR= 1.58e-3, 95% CI, 7.81e-7-0.064, p < 0.003]. Furthermore, patients that maintained an ANKC ≥ 250 cells/µl at 3 months, 6 months, 9 months and 12 months post-APBHSCT also experienced superior OS (Figure 1A) and PFS (Figure 1B)[OS and PFS times in months were evaluated from infusion date of stem cells]. In the multivariate analysis a sustained ANKC ≥ 250 cells/µl was an independent predictor for OS (HR = 0.013, 95% CI, 0.001-0.063, p < 0.0001) and PFS (HR = 0.014, 95% CI, 0.001-0.067, p < 0.0001). This study is an extension of our Phase III clinical trial showing that sustained innate immunity by measuring the ANKC correlated with superior clinical outcomes; thus providing a platform to develop innate immunity immunotherapeutic strategists directing to improve clinical outcomes post-APBHSCT in NHL patients.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
Ex Vivo T Cell-Depleted Haploidentical HCT for Children with Acute Leukemia after a Reduced-Intensity Preparative Regimen Containing Low-Dose TBI
Authors: Lim Yeon Jung , Im Ho Joon , Kang Sung Han , Kim Hyery , Koh Kyung-Nam , Choi Eun Seok , Seo Jong Jin , Suh Jin Kyung 
Published: October 2019

Abstract
Background: Recent advances in haploidentical hematopoietic cell transplantation (HHCT) enabled this transplant using haploidentical family donor to be a viable option for pediatric patients lacking matched related or unrelated donor. In our center, HHCT using ex vivo T cell-depleted (TCD) grafts after reduced-intensity conditioning (RIC) was conducted since 2008. The safety and efficacy of this transplantation modality for pediatric with acute leukemia were investigated.
Methods: Thirty-one pediatric patients with acute leukemia received ex vivo T cell-depleted HHCT at Asan Medical Center Children's Hospital between July 2008 and June 2016. Four patients received CD3-depleted grafts and 27 received TCRαβ-depleted stem cells. Among 31 patients, 9 had ALL (3 CR1, 6 CR2-3), 22 had AML (18 CR1-3, 4 NR). Seven patients had relapsed after previous allogeneic HCT. All 31 patients underwent a uniform RIC regimen consisting of low-dose total body irradiation (LD-TBI; 600 cGy), fludarabine (FLU; 180 mg/m2), cyclophosphamide (CY; 100 mg/kg), and rabbit anti-thymocyte globulin (r-ATG; 3 mg/kg).
Results: The median age at HHCT was 14 years (range, 1-19). All 31 patients achieved sustained neutrophil engraftment at a median of 10 days (range, 9-17) post-transplant. The cumulative incidence of acute GVHD grade II-III and III were 30% and 21%, respectively. None developed grade IV. Two of 26 evaluable patients developed extensive chronic GVHD. As of July 2016, 18 of the 31 patients survive free of disease with a median follow-up of 26 months (range, 2-98 months). Ten patients have died. Causes of death were relapse (n=9) and disseminated tuberculosis (n=1). Only one patient died of non-relapse cause, leading to TRM of 5.3% at 1 year. EFS and OS at 2 years for all patients were 51% and 60%, respectively. Sixteen patients with AML who received a first HHCT in any CR showed a favorable outcome (EFS of 85%), whereas, 6 patients with ALL who received a first HHCT in CR showed a poor EFS of 28%. In addition, all patients (6 with AML and 3 with ALL) who received a subsequent HCT in CR or were not in remission developed relapse.
Conclusions: This study demonstrated that our ex vivo T cell-depleted HHCT using RIC is a feasible therapy with low TRM for pediatric patients with acute leukemia. The outcome of patients with AML who received their first transplant in CR was excellent in this treatment modality. However, the outcome of ALL was poor suggesting that more intensified conditioning regimen may be required for those diseases. Furthermore, an innovative treatment strategy is warranted to improve the outcome for patients with relapsed or refractory acute leukemia.

Disclosures
No relevant conflicts of interest to declare.