bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combination of Dasatinib and Pediatric-Inspired Regimens in Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: A Single-Center Prospective Study
Authors: Guang ji Zhang , Wang Jianxiang , Wang Ying , Wei Hui , Mi Yingchang 
Published: November 2019

Background: Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is a rare subtype of acute lymphoblastic leukemia with a poor long-term prognosis. Recent studies suggested that the addition of tyrosine kinase inhibitor (TKI) to the traditional chemotherapy treatment has significantly improved Ph+ ALL patients response rates, disease-free survival, and overall survival (OS). Dasatinib, a second-generation tyrosine kinase inhibitor, can pass the blood-brain barrier and possesses a stronger inhibitory effect on both SRC kinase and BCR-ABL. In theory, it might be beneficial in Ph+ ALL treatment. This prospective, single-arm study assesses the efficacy of a combination of dasatinib and pediatric-inspired regimens in Ph+ ALL patients.
Methods: 30 patients from the Institute of Hematology and Blood Diseases Hospital were enrolled in this study from January 2016 to April 2018. Eligible subjects were newly diagnosed Ph+ ALL adult patients. Chemotherapy regimens were initiated after the pediatric-inspired regimens, and standard induction chemotherapy was given for four weeks. Seven courses of consolidation or hematopoietic cell transplantation (HCT) were given to those who have achieved hematological complete remission (HCR). The primary objectives of this study were the HCR and molecular complete response (MCR), the major molecular response (MMR), the overall survival (OS), and the hematologic relapse-free survival (HRFS). The median follow-up time was 28 months. The trial registration number is NCT02523976.
Results : 30 subjects were enrolled in this study with a median age of 37.5 years (range 19-50 years). All patients achieved HCR after four weeks of induction therapy with a cumulative MCR rate of 87.5%(21/24). The median HRFS and median OS were 19.5 (range 2-40 months) and 21 (range 7-41 months), respectively. The molecular response, assessed through monitoring of BCR-ABL transcript expression, revealed that 61.3% of the patients reached MMR and MCR after three months of treatment. Additionally, the results indicated that patients who achieved MCR in the first three months had a better HRFS (p=0.038). Fifteen of the patients (50%) proceeded to stem cell transplantation (SCT) within the first HCR period (SCT in HCR1). Only 13.3% (2/15) of the SCT cohort relapsed, and 20% (3/15) died. It is worth mentioning that the SCT in HCR1 cohort had better HRFS (P=0.03). Most adverse events were reversible, and none of the subjects had pulmonary hypertension.
Conclusion: These findings indicate that an early MCR (3 months) has a positive impact on patients survival and that Dasatinib, combined with pediatric-inspired regimens, is effective and leads to a high MCR in patients with newly diagnosed Ph+ALL.

Disclosures
No relevant conflicts of interest to declare.
Chronic Myeloid Leukemia in Adolescents and Young Adults: A Single Institute Experience
Authors: Yassin Mohamed A , Abdulla Mohammad Abdul-Jaber , Chandra Prem , Aldapt Mahmood B , Hamad Yasser , Akiki Susanna Jane , Kassem Nancy , Nashwan Abdulqadir Jeprel , Nur Ula 
Published: November 2019

Background and Objectives:
CML is a myeloproliferative neoplasm characterized by the dysregulated production and uncontrolled proliferation of mature and maturing granulocytes with fairly normal differentiation. It mainly affects adults, and is rarely seen in children. The average age at diagnosis of CML is around 64 years. There are few studies describing CML in adolescents and young adults. In Qatar we have one of the largest cohorts of adolescents and young adults with CML. This study aims to study this cohort and find out if there are any differences from older patients with CML.
Methods:
A retrospective analysis of 169 patients with CML treated at NCCCR over a 23-year period, 83 of them are younger than 40 years at diagnosis (adolescents and young adults) vs. 86 age 40 or older at diagnosis (controls). Comparison was done of all characteristics at diagnosis, including: gender, BMI, ethnicity, CBC parameters, spleen size, Sokal score, bone marrow findings, treatment modality, with response assessment using ELN guidelines.
Results:
Both groups were matched with regards to gender and ethnicity. Adolescents and young adults had higher WBC count and larger spleen on diagnosis compared to controls (174.1 vs. 142.2; and 18.0 vs. 15.6). 4 young patients presented in blast-phase vs. 1 in control group. 5 adolescents and young adults underwent allogeneic stem cell transplant vs. 1 patient in the control group. During a mean follow up of 70.7 months in adolescents and young adults vs. 72.7 months in the control group there were 2 deaths vs. 1 respectively. However, there were no other significant differences between the two groups, with regards to TKI used, or response at 1 year / latest assessment.
Conclusions:
Based on this data we may conclude that CML present more aggressively in adolescents and young adults as compared with older patients, however there is no difference in outcome. This might reflect different underlying etiology / better tolerance to treatment in the younger group.
Table

Disclosures
No relevant conflicts of interest to declare.
Dose-Adjusted Granulocyte Colony-Stimulating Factor Plus Dexamethasone Achieves More CD34+ Cell Mobilization and Earlier Engraftment in Haploidentical Hematopoietic Stem Cell Transplantation
Authors: Li Chenglong , Yang Xi , Dai Jingying , Tang Ningning , Zheng Hong , Wang Chunsen , Huang Xiaobing 
Published: November 2019

Introduction: Previous studies have showed that higher doses of CD34+ cell were associated with more rapid neutrophil and platelet engraftment, lower probabilities of graft rejection, as well as reduced transplant-related mortality. The aim of this study was to investigate the effects of G-CSF (Filgrastim) plus dexamethasone in CD34+ cell mobilization and engraftment in T-cell replete haploidentical hematopoietic stem cell transplantation(HHSCT) which was based on G-CSF-primed bone marrow and peripheral blood graft.
Methods: A total of 79 healthy donors, who underwent bone marrow (BM) harvest and peripheral blood Stem Cells (PBSCs) collection between January 2015 and June 2019, were investigated. In G-CSF group, G-CSF was administered subcutaneously at a dose of 5μg/kg once a day from 1st to 5th day, while BM and PBSC were harvested on the 4th day and 5th day, respectively. In Dose-Adjusted G-CSF+Dex group, G-CSF was administered subcutaneously at a dose of 5μg/kg once a day on the 1st and 2nd day, then twice a day from the 3rd to 5th day; 5mg dexamethasone was injected intravenously before BM collection on the 4th day and before PBSC apheresis on the 5th day, respectively. All 79 recipients with hematological malignancies underwent HHSCT based on modification of BU/CY (busulfan/cyclophosphamide) and Anti-human T Lymphocyte Rabbit Immunoglobulin (ATG-F). All recipients received cyclosporine A, mycophenolate mofetil, and short-term cyclophosphamide as GVHD prophylaxis.
Results: There were no significantly statistical differences between these two groups on characteristics of both recipients and donors. In Dose-Adjusted-G-CSF+Dex group, more mono nuclear cells (MNCs) were collected from BM and PB in comparison to the cells collected in the G-CSF group (p<0.001). There was a significant difference between the two groups on CD34+ cell counts from PB (p=0.002), which led to a significant difference on CD34+ cells in mixture allografts (p=0.04). In DA-G-CSF + Dex group, more CD34+ cells achieved earlier neutrophil (p=0.001) and platelet (p<0.001) engraftment compared with G-CSF group.
Conclusion: Compared to G-CSF alone, dose-adjusted G-CSF plus dexamethasone on healthy donors can lead to more collection of MNCs and CD34+ cells in mixture allografts, which achieves earlier neutrophil and platelet engraftment.

Disclosures
Zheng: Pfizer: Research Funding.
Downregulation of Transcription Factor LRF/ZBTB7A Increases Fetal Hemoglobin Expression in β-Thalassemia/Hemoglobin E Erythroid Cells
Authors: Chumchuen Sukanya , Pornsukjantra Tanapat , Khamphikham Pinyaphat , Anurathapan Usanarat , Sripichai Orapan , Songdej Duantida , Hongeng Suradej 
Published: November 2019

LRF/ZBTB7A is a transcription factor that has been recently identified as a new key regulator of fetal hemoglobin (HbF; α2γ2) production in erythroid cells. Reduction of LRF/ZBTB7A expression led to increases in levels of HbF in human CD34+ hematopoietic stem and progenitor cell (HSPC)-derived erythroblast and in human immortalized erythroid line (HUDEP-2). Since reactivation of γ-globin gene is associated with the improvement of clinical manifestations of β-hemoglobinopathy patients, decrement in LRF/ZBTB7A expression might be a substantial interest as a novel target for gene therapy in β-thalassemia. In this study, we investigated the effects of LRF/ZBTB7A downregulation in erythroid cells derived from β-thalassemia/HbE patients in order to evaluate its therapeutic potential. The hematopoietic CD34+ progenitor cells were collected from 3 patients and 3 healthy normal individuals' peripheral blood and subjected for in vitro erythroblast culture. The cells were transduced with lentivirus carrying LRF/ZBTB7A specific shRNA, and used untransduced cells and non-targeted control shRNA (shNTC) as experimental controls. The LRF/ZBTB7A shRNA reduced LRF/ZBTB7A transcript and protein to nearly undetectable levels. Interestingly, downregulation of LRF/ZBTB7A increased expression of γ-globin, ε-globin and ζ-globin in both adult normal and β-thalassemia/HbE derived cells, whereas α-globin, β-globin and δ-globin expression were decreased. As previously reported, we found that the LRF/ZBTB7A knockdown produced a robust increase in HbF levels in both normal (43.3±9.0% vs. 5.9±2.1% in shNTC) and β-thalassemia/HbE erythroblasts (78.1±3.5% vs. 26.3±3.9% in shNTC). Noteworthy, the delay of erythroid differentiation was observed in the LRF/ZBTB7A knockdown cells of both derived from β-thalassemia/HbE patients and normal control, suggesting an additional role of LRF/ZBTB7A in regulating erythroid maturation. These data support the manipulation of LRF/ZBTB7A as one of the most interesting gene therapy candidates for treating the β-thalassemia, but the effect on erythroid cell maturation is needed to be concerned and required further investigation.

Disclosures
No relevant conflicts of interest to declare.
Ruxolitinib, a JAK1/JAK2 Selective Inhibitor, Ameliorates Gastrointestinal and Cutaneous Pathogenesis in MHC-Mismatched Preclinical Models of Acute and Chronic Graft-Versus-Host Disease
Authors: Huarte Eduardo , Parker Melissa , Juvekar Ashish , Oliver Julian , Yao Wenqing , Smith Paul 
Published: November 2019

Background: Allogeneic hematopoietic cell transplantation (alloHCT) is potentially curative for a variety of hematologic malignancies. However, rather than targeting tumor cells, alloreactive donor T cells may attack healthy recipient tissue triggering graft-versus-host disease (GVHD) resulting in morbidity and mortality. Acute GVHD (aGVHD) clinically presents with gastrointestinal (GI) pathology and is primarily T cell mediated. In contrast, chronic GVHD commonly demonstrates skin inflammation and fibrosis with an autoimmune-like phenotype. Pharmacological inhibition of JAK/STAT signaling has the potential to regulate aberrant immune cell functions involved in the pathogenesis of acute and chronic GVHD.
Aim: Characterize the effectiveness of ruxolitinib to modulate in vitro and in vivo immunological mechanisms that are described to be critical in acute and chronic GVHD pathogenesis.
Materials and Methods: MHC-mismatch aGVHD was induced in recipient BALB/c mice receiving C57BL/6 donor transplant. Sclerodermatous cGVHD was induced in C57BL/6 mice using LP/J strain donor splenocytes and bone marrow cells. Ruxolitinib or vehicle was orally administered twice daily. Efficacy was assessed by GVHD symptom scores, cachexia, and histological analysis of end organ damage.
Mixed lymphocyte reactions (MLR) were cultured for five days in the presence of ruxolitinib for changes in activation markers and cytokine release.
Results: Ruxolitinib treatment ameliorated daily aGVHD severity scores with concomitant reduction of GI tract infiltration and tissue damage. Overall aGVHD mice survival was significantly improved with JAK1/2 inhibition. Therapeutic ruxolitinib treatment initiated after cGVHD symptom onset significantly inhibited the chronic-progressive symptom phenotype and reduced tissue markers of inflammation and fibrosis. Ruxolitinib demonstrated concentration-dependent inhibition of activated T cells and reduced JAK-STAT signaling cytokines considered relevant in GVHD inflammation.
Conclusion: Ruxolitinib, a potent and selective JAK1/2 inhibitor, significantly ameliorated pro-inflammatory pathways in vitro and in vivo which are thought to be highly relevant for acute and chronic GVHD pathogenesis. On May 24, 2019, the FDA approved ruxolitinib for steroid-refractory acute graft-versus-host disease (aGVHD) in adult and pediatric patients 12 years and older. Ruxolitinib is currently being evaluated in clinical trial (REACH3: NCT03112603) for patients with steroid-refractory cGVHD.

Disclosures
Huarte: Incyte corporation: Employment, Equity Ownership. Parker:Incyte corporation: Employment, Equity Ownership. Juvekar:Incyte corporation: Employment, Equity Ownership. Oliver:Incyte corporation: Employment, Equity Ownership. Yao:Incyte corporation: Employment, Equity Ownership. Smith:Incyte corporation: Employment, Equity Ownership.
Identification of a Novel Indel Mutation in GATA-1 Gene In Vivo and Verified Its Defective Function in Vitro
Authors: Huang Junbin , Huang Lifeng , Lu Yingsi , Zhu Chengming , Chen Chun 
Published: November 2019

GATA-1 is a zinc finger TF encoded by the GATA-1 gene located on the short-arm of the X-chromosome. Most of GATA-1 mutations were located in exon2 or 3. We describe a male infant presented with dyserythropoietic anemia, who is harbored a novel GG deletion of exon6 in GATA-1 gene and varified its disrupted function in vitro. We confirmed that: (1) by using an unique GATA-1 antibody, which corresponded to amino acids 394-413 of human GATA1, the mutation of the proband led to GATA-1 protein and mRNA defective expressions in both peripheral blood and bone marrow; (2) demonstrated the expression of the GATA-1 mutated form is restricted to erythroblasts and red blood cells, consisted with the proband's abnormal erythropoiesis; (3) temporary transfection of GATA-1-wt(wild type) and GATA-1-indel in Hela cell line, which has no expression of GATA-1 originally, resulted in normal and defective expression both in protein and mRNA leve, respectively; (4) in a manipulated K562 cell line, that its GATA-1 had been knocked down by shRNA, stable transfection GATA-1-indel can not rescue K562 from GATA-1 deficiency.. Our reseach provide new insights into the clinically relevant in vivo function of the C-terminal domain of GATA-1 in human hematopoiesis and the results were validated in two seprerated cell line.

Disclosures
No relevant conflicts of interest to declare.
Review of Therapeutic Erythrocytapheresis in Patients with Thalassemia Major
Authors: Wall Erika , Bolster Lauren 
Published: November 2019

Introduction
Therapeutic erythrocytapheresis, or red cell exchange (RCE) is a non-invasive procedure in which a patient's erythrocytes are removed from the bloodstream while being replaced with erythrocytes from blood donors. RCE is commonly used as a transfusion technique in patients with sickle cell disease (SCD) to help treat and prevent complications associated with sickling of erythrocytes and iron overload. In the rare blood disorders (RBD) clinic at the University of Alberta in Edmonton, Canada, RCE has been utilized as a therapeutic adjunct to traditional chelation therapies for patients with thalassemia major with uncontrolled iron overload. The aim of this study is to describe and review the rate of observed complications or benefits associated with RCE in patients with thalassemia major.
Methods
Patients with a documented diagnosis of thalassemia major who were enrolled in the RCE program via the RBD clinic were identified. Charts were retrospectively reviewed from time of initiation of RCE to the time of most recent RCE or clinic follow up. Complications were documented and analyzed, then compared to standard rates of complications of iron overload in patients with thalassemia major.
Results
Seven (7) patients with were identified for analysis. The average age of patients enrolled was 30 years. One hundred percent (100%) of patients had confirmed diagnosis of thalassemia major by hemoglobin electrophoresis. 85.7% of patients were of male sex. Six (85.7%) patients were on chelation therapy (3 patients on Jadenu plus Ferriprox; 3 patients on Jadenu alone). On average RCE was performed every 3.85 weeks. Of the patients analyzed during RCE, 85.7% had hepatic iron overload and 42.9% had cardiac dysfunction. 71.4% had evidence of extramedullary hematopoiesis. Two patients had syncopal events while on RCE. Two patients developed red cell antibodies during RCE. Improvements in iron overload correlated with initiation of dual chelation therapy in the three patients who were on maximal dual chelation.
Conclusions
Although RCE is a useful transfusion strategy in patients with SCD with less iron loading than simple transfusion, it does not appear to have the same benefits in patients with thalassemia major. Improvements in myocardial and hepatic T2* scores correlated with being on dual chelation therapy rather than with the frequency or duration of RCE. There was evidence of significant extramedullary hematopoiesis in 5 of the 7 patients on RCE possibly due to poor hemoglobin increment. Given the observed increase in extramedullary hematopoiesis, syncope, and antibody formation associated with RCE, and lack of benefit in reducing iron overload, we do not recommend its use as a treatment in patients with thalassemia major.

Disclosures
No relevant conflicts of interest to declare.
An Autosomal Dominant SCID Form Due to a Gain of Function Mutation in the RAC2 Gene
Authors: Lagresle-Peyrou Chantal , Olichon Aurélien , Sadek Hanem , Roche Philippe , Tardy Claudine , Da Silva Cindy , Garrigue Alexandrine , Fischer Alain , Moshous Despina , Collette Yves , Picard Capucine , Casanova Jean-Laurent , André Isabelle , Cavazzana Marina 
Published: November 2019

Severe combined immunodeficiencies (SCIDs) form a heterogeneous group of life-threatening genetic disorders defined by the absence of autologous T cells and an intrinsic or extrinsic defect in the B-cell compartment. In our cohort, three newborn patients with bone-marrow hypoplasia associated with clinical and biological features of SCID received allogenic hematopoietic stem cell transplantation in the first weeks of life. To identify the molecular defect involved in this life threatening SCID form, we performed whole-genome sequencing on patient's fibroblasts. The same heterozygous, dominant missense mutation was found in the RAC2gene encoding for the RAC2 GTPase (p.G12R). By biochemical analyses we demonstrated that arginine substitution at position 12 leads to sustained activation of the RAC2 signalling pathway; the G12R mutation is therefore a gain of function mutation. In cord blood hematopoietic cells, we observed that the mutation disrupts mitochondrial activity and blocks hematopoietic stem/progenitor cells (HSPCs) differentiation toward the myeloid and lymphoid lineages. Altogether, our data emphasize the involvement of the RAC2 signalling pathway during hematopoeisis and might thus explain the severity of the patients' clinical and immunological phenotype.
The present study is the first to report an autosomal dominant form of SCID and suggest that RAC2 gene sequencing should be considered for patients with SCID clinical presentation.

Disclosures
Cavazzana: Smartimmune: Other: Founder of Smartimmune.
Safety and Anti-Tumor Activity Study of Loncastuximab Tesirine and Ibrutinib in Diffuse Large B-Cell or Mantle Cell Lymphoma
Authors: Depaus Julien , Bryan Locke J. , Ungar David , Dautaj Ilva , Wagner-Johnston Nina D. 
Published: November 2019

Introduction:
Loncastuximab tesirine (Lonca) is an antibody-drug conjugate (ADC) comprising a humanized anti-CD19 antibody conjugated to a pyrrolobenzodiazepine dimer toxin. In a Phase 1, first-in-human study (ADCT-402-101), Lonca demonstrated single agent anti-tumor activity with manageable toxicity in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL). Ibrutinib is a small-molecule inhibitor of Bruton's tyrosine kinase (BTK), a mediator of the B-cell-receptor signaling pathway implicated in the pathogenesis of B-cell cancers. BTK plays a crucial role in B-cell-receptor signaling, resulting in activation of pathways necessary for B-cell trafficking, chemotaxis, and adhesion. In vitro data show synergy between the two compounds, providing the rationale for studying them in combination.
Study Design and Methods:
This is a Phase 1b (ADCT-402-103; NCT03684694), open-label, dose escalation (Part 1) and expansion (Part 2) trial of Lonca combined with ibrutinib in patients with R/R DLBCL or MCL. The key inclusion and exclusion criteria for this study are reported in Table 1. This trial will evaluate the safety and tolerability, preliminary anti-tumor activity, pharmacokinetics, pharmacodynamics, and immunogenicity of this combination. Patients will receive Lonca once every 3 weeks for a total of 2 doses, and ibrutinib daily for up to 1 year. Patients with a partial response or stable disease at the second disease evaluation may receive 2 additional doses of lonca. During Part 1, the dose of Lonca will be escalated using a classic 3+3 design. The dose of ibrutinib will be fixed. Part 2 will consist of up to 2 expansion cohorts, one for each of the DLBCL and MCL populations. All patients in Part 2 will receive the dose of Lonca determined in Part 1, with a fixed dose of ibrutinib. The trial opened in February 2019 and recruitment is ongoing.
Study sponsored by ADC Therapeutics SA, with the support of Pharmacyclics LLC, an AbbVie company, which supplies ibrutinib (http://clinicaltrials.gov/show/NCT03684694).

Disclosures
Ungar: ADC Therapeutics: Employment, Other: Stock options;equity interest. Dautaj:ADC Therapeutics: Employment, Other: Stock options. Wagner-Johnston:Jannsen: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees.