bluuebunny/crossref_metadata_2025_split huggingface dataset:
De-Escalation or Discontinuation of TKI in Patients with Chronic Myeloid Leukemia:a Multicentral,Open-Lable, Prospective Trial in China
Authors: Luo Jie , Tan Yaxian , Zhou Xuan , Xiaoli Liu , Liu Qifa , Xu Na 
Published: November 2020

Aim:To observe and assess whether TKI can be de-escalated or discontinued without occurrence of molecular relapse in CML patients,who with continuous effective TKI over 5 years and maintain MR4.5(BCR-ABLIS≤0.0032%) at least 18 months.
Methods: In this study,we conducted half standard TKI dose or discontinued treatment in patients with CML who were aged 18 years and older and duration effective TKI treatment at least 5 years,duration MR4.5 monitored by quantitative polymerase chain reaction(Q-PCR) in recent 18 months.Blood concentration and immune function were also monitored.Molecular relapse was defined as loss of MMR(BCR-ABLIS&gt;0.1%), these patients restore the original dose at once.
Results: 44 patients were enrolled between Jan 2016,and Jun 2019,35 in de-escalation group and 9 in discontinue group.In the de-escalation group,45.7% males,median age was 48(23-75) years,valid TKI therapy duration 84(60-204) months,and median sustained MR4.5 was 25(19-160) months.Follow-up 1 year,5(14.3%) of these 35 patients occurrence of molecular relapsed(3 before 6 months,one at month 8, one at month 9),all of them showed decreases in their BCR-ABL levels after reintroduction of original TKI dose.In the discontinue arm,55.6% males,the age ranged from 28 to 56,the median effective TKI treatment was 72(60-108) months and remained of MR4.5 was 36(18-72) months.Molecular recurrence-free events were 66.7% at 12 months,3 patients relapsed events occurred in discontinuous month 1,month 6 and month 12,respectively.All of them showed great reaction when treatment was restarted.Supervised patients blood concentration between standard treatment group and half-dose group,founded half-dose group was lower than standard group(1083.61±371.80ng/ml vs. 1622.28±771.36ng/ml ,P=0.000).The immune function of the relapse and non-relapse arm was observed,in relapsed group the proportion of CD3-/CD56+ cells was declined significantly(P=0.013).
Conclusions: Treatment-free remission(TFR) has become the main therapeutic target for CML patients. With 85.7% TFR in 12 months follow-up after de-escalation TKI treatment ,our study demonstrates that de-escalated TKI would suitable for Chinese CML patients who with a sustained deep molecular response.The vivo insufficient of drug concentration and the damaged of NK cells may cause the recurrence events.

Disclosures
No relevant conflicts of interest to declare.
A Case of CD5 Positive Hairy Cell Leukemia withBRAF V600EMutation and Lymph Node Involvement; Unique Case Report and Review of the Literature:
Authors: Javidiparsijani Sara , Choi Yun Kyong , Arbini Arnaldo A. 
Published: November 2020

Objective:
Hairy cell leukemia (HCL) is distinct indolent neoplasm of small mature B cells accounting for 2% of the lymphoid leukemias. The classic immunophenotypic profile of HCL includes bright expression of B cell surface antigen and immunoglobulins and lack of both CD5 and CD10. The tumor cells are predominantly present in the spleen, peripheral blood and bone marrow. Aberrant expression of CD5 and lymph node involvement are very rare. A case of CD5(+) HCL with a documentedBRAF V600Emutation has not been previously reported. This case is also unique due to lymph node involvement by HCL. To our knowledge, this is the only case report of a documentedBRAF V600Emutated CD5(+) HCL along with lymph node involvement in the literature.
Method:
We are presenting a 45 years old man with multiple prior medical conditions including diabetes, COPD and interstitial pneomonitis with new onset of B-symptoms and neutropenia/monocytopenia. Peripheral blood flow cytometry revealed 21% CD5(+) CD10(-) monoclonal B cell population. Further workup revealed the neoplastic cells are positive for CD11c, CD103 and CD25. Bone marrow study revealed an extensive involvement of the marrow.By immunohistochemistry, the cells are also positive for CD5, CD20, BRAF and cyclin D1. Cytogenetic studies show that the cells are negative t(11;14) and molecular studies revealedBRAF V600Emutation. Reexamination of the prior wedge lung resection revealed intrathoracic lymph node involvement.
Results and conclusion:
The most common differential diagnoses of a CD5(+) B cell lymphoma involving the bone marrow is chronic lymphocytic leukemia (CLL) and mantle cell lymphoma. The key into the diagnosis of this case was marked monocytopenia that lead to addition of HCL antibody tubes despite the CD5 positivity and detection of CD25, CD103 and CD11c antigens in the leukemic cells. Bone marrow biopsy show extensive involvement by a CD5(+) cyclin D1(+) B cell lymphoma. The most important differential diagnosis in this case was mantle cell lymphoma. The diagnosis of HCL was confirmed by detection ofBRAF V600Emutation and absence of t (11;14). Retrospective examination of the intrathoracic lymph nodes show one lymph node involvement by hairy cell leukemia cells.
The patient was treated with Vemurafenib and his follow up flow cytometry revealed only 0.60% leukemic involvement. Incorporation of clinical data at the time of flow cytometric examination is essential to aid the hematopathologist in having a broader differential diagnoses and addition of appropriate tests that lead to the more accurate diagnosis and treatment.

Disclosures
No relevant conflicts of interest to declare.
Thrombopoietin Protects Neural Cells and Endothelial Cells from Apoptosis Via PI3K/AKT Pathway
Authors: Li Liang , Wang Junyan , Ye Jieyu , Yang Liuming , Chong Beng H , Yang Mo 
Published: November 2020

Background: Thrombopoietin (TPO) is a hematopoietic growth factor that regulates the production of platelets and stimulates production and differentiation. The expression of TPO and TPO receptor (c-mpl) in the central nervous system (CNS) has been identified. However, the role of TPO in neural cells and endothelial cells were not clear.
Methods: C17.2 and human umbilical vein endothelial (HUVEC) cells were treated with CoCl2, TPO, or TPO + CoCl2. TPO was added into the culture medium 48 h before CoCl2 treatment. The cell viability and apoptosis of each group were tested by Cell Counter Kit 8 (CCK-8) assay and flow cytometry. The expression of Caspase-3 and mitochondrial membrane potential (MMP) were then determined by flow cytometry with Caspase-3-PE and JC-1. The effect of TPO in the PI3K/AKT pathway was detected by using Western blot.
Results: TPO has a dose-dependent effect on the growth of C17.2 cells. LY-294002 pretreatment suppressed the TPO-induced AKT activation and abolished the prosurvival effect of TPO. Via the Bcl-2/BAX signaling pathway, TPO exerted an anti-apoptotic effect by suppressing mitochondria membrane potentials. We also investigated the protective effect of TPO on human endothelial cells. The cell viability of HUVECs decreased gradually with the enhancement of CoCl2 at a gradient of chemical concentrations (r= -0.997). CoCl2 dramatically increased apoptosis of HUVECs, whereas pre-treatment with TPO rescued cell apoptosis induced by CoCl2 (P&lt;0.01). Further investigation found that TPO decreased the expression of Caspase-3 and inhibited the reduction of MMP induced by CoCl2 (P&lt;0.05). TPO increased the activation of PI3K/AKT pathway in HUVECs.
Conclusion: TPO has a protective effect against apoptosis of neural cells and endothelial cells through activating the PI3K/AKT pathway, thus decreasing the expression of apoptosis protease Caspase-3 and inhibiting the reduction of MMP.

Disclosures
No relevant conflicts of interest to declare.
An Azaindole-Based Small Molecule Hzx-02-059 Induces Methuosis in B-Cell Acute Lymphoblastic Leukemia through the PI3K/AKT Axis
Authors: Lu Zhen , Feng Liying , Chen Qinwei , Xu Bing 
Published: November 2020

Methuosis is a newly defined nonapoptotic cell death characterized by the accumulation of large liquid-filled vacuoles in cytoplasm, which is distinct from necrosis, autophagy and apoptosis. A novel azaindole-based methuosis inducer, named HZX-02-059, displays cytotoxic effects to a series of cancer cellular models via blocking the role of PIKfyve. The discovery of HZX-02-059 sheds light on a novel therapeutic option for refractory cancer patients who have limited effective treatments. Despite significant advances in treatments, over 50% of adult patients with B-cell acute lymphoblastic leukemia (B-ALL) fail to achieve durable responses with current intensive chemotherapies, which highlight an urgent need of new therapeutic regimens for this patient population. Here, we applied HZX-02-059 to B-ALL cell lines and mice models to uncover its potential role and underlying mechanism.
Morphology changes of HZX-02-059-treated B-ALL cells were observed under the light microscope, and these treated cells were to certain extent collapsed into debris. Of note, higher concentration of this compound induced the accumulation of substantial larger vacuoles in cytoplasm. To assess the cytotoxicity of this compound, we performed cell counting kit-8 (CCK-8) and colony forming unit (CFU) assays. As expected, HZX-02-059 significantly inhibited cancer cell proliferation and reduced the capability of cell colony forming in a dose-dependent manner. Next, we carried out an EdU assay to determine the influence of HZX-02-059 on cell cycle distribution. As a result, B-ALL cells treated with HZX-02-059 were mainly blocked at G2/M phase. Western blotting was conducted to investigate the underlying molecular basis of HZX-02-059 in B-ALL. To the end, we found that HZX-02-059 negatively regulated the proteins involved in the PI3K/AKT pathway. Also, this drug decreased the expression of the pathway downstream transcription factors NF-ǐB and c-Myc, suggesting that the dysregulation of the PI3K/AKT axis is a potential mechanism of action of HZX-02-059 against B-ALL.
To further evaluate itsin vivotherapeutic effect, B-ALL patient-derived xenograft (PDX) mice were established and administrated with HZX-02-059. The result revealed a survival benefit of the treatment as compared with the control, which grants this molecule great potential for clinical usage. Thus, our results suggest that HZX-02-059 is a potent anti-BALL reagent in preclinical models that warrant further investigation of this drug as an alternative therapeutic strategy for B-ALL patients who are resistant to conventional therapies.

Disclosures
No relevant conflicts of interest to declare.
Clinical Trial to Evaluate an Approved ITP Therapy Targeting Spleen Tyrosine Kinase (SYK) for Prevention and Treatment of COVID-19 Related Complications
Authors: Dummer Wolfgang , Markovtsov Vadim V. , Tong Sandra , Masuda Esteban 
Published: November 2020

Fostamatinib is a potent SYK inhibitor that targets activation of both the innate and acquired immune systems caused by tissue damage or pathogen signals via C-type lectin receptors (CLR) as well as by antibody-antigen immune complexes via Fc receptors (Figure 1). SYK is also a key modulator of pathways involved in thrombosis formation. Fostamatinib is FDA-approved for chronic immune thrombocytopenia (ITP) and has been evaluated in over 4000 patients for treatment of allergic, autoimmune, and neoplastic disorders. Fostamatinib is well tolerated, with a consistent safety profile across a number of diseases. In rheumatoid arthritis patients, fostamatinib reduced the plasma levels of IL-6.1 The active metabolite (R406) was protective in mouse models of LPS-induced acute lung injury (ALI)2 and LPS- or antibody-induced acute kidney injury (AKI).3 SYK inhibition decreased the incidence of thrombosis in mouse models of thromboembolism,4 and the incidence of thromboembolic events was decreased in patients treated with fostamatinib compared with other treatments for ITP. These immunomodulatory effects suggest that SYK inhibition represents a new therapeutic strategy for the treatment of COVID-19, which led to design of a clinical study of fostamatinib in hospitalized COVID-19 patients.
COVID-19 patients are at risk for a potentially fatal acute respiratory distress syndrome (ARDS), cytokine storm, severe systemic capillary leak syndrome, thromboembolic events, and multi-organ dysfunction/failure. SYK is a master regulator of signal transduction pathways implicated in these COVID-19 associated complications, which involves hyperactivation of both innate and acquired immune systems. Targeting SYK could prevent the cytokine storm, downstream activation of endothelial cells and platelets, and influx of neutrophils and monocytes into lungs or kidney leading to ALI and AKI, respectively.
Methods: A randomized, double-blind, placebo-controlled, multi-center, Phase 3 study will evaluate the efficacy and safety of fostamatinib in adult, hospitalized, high-risk COVID-19 patients. Patients will be treated with fostamatinib 150mg BID for up to 28 days plus standard of care. Improvement in clinical status will be assessed using the 8-point ordinal scale.
References
1. Weinblatt ME et al.Arth Rheum2008;58:3309-18
2. Nadeem A et al.Int Immunopharm2019;68:39-47
3. Al-Harbi NO, et al.Biochimie2019;158: 102-10
4. Van Eeuwijk JMM et al.Arterioscler Thromb Vasc Biol2016;36:1247-53
Results and Conclusions: Trial in Progress

Disclosures
Dummer: Rigel:Current Employment, Current equity holder in publicly-traded company.Markovtsov:Rigel:Current Employment, Current equity holder in publicly-traded company.Tong:Rigel:Current Employment, Current equity holder in publicly-traded company.Masuda:Rigel:Current Employment, Current equity holder in publicly-traded company.
Stem Cell Mobilization Using Parathyroid Hormone Analog: A Single Institutional Review
Authors: Nwogbo Okechukwu , Le Thuy , Shikle James , Cintron Garcia Juan , Tinsley Sheila 
Published: November 2020

Objective:
Hematopoietic stem cell mobilization increases the release of immature and maturing hematopoietic cells from the marrow into the blood circulation. For successful hematopoietic stem cell transplantation an adequate number of stem cells must be mobilized and collected. For autologous stem cell transplants, a product bag CD34+ count of &gt; 5.0 x 106 CD34/kg is a target; however, patients have been successfully transplanted with doses as low as 2.0 x 106 CD34/kg.
Some patients are "poor mobilizers" and standard protocols do not result in adequate numbers of circulating CD34 cells to collect. Risk factors associated with poor stem cell mobilization include increasing age, underlying diagnosis, low premobilization platelet count, history of increasing cycles, and regimens of chemotherapy.
Teriparatide, a parathyroid hormone (PTH) analog has been used in "poor mobilizers." Two patients at our institution received the drug as part of an additional mobilization strategy.
Method:
Medical records of patients who had stem cell mobilization were reviewed. Two patients who failed routine mobilization protocol received PTH as part of an additional mobilization regimen. Clinical outcomes, collection, and engraftment data were reviewed.
Result:
Patient 1 had a diagnosis of Hodgkin Lymphoma and failed to mobilize adequately on the first attempt using filgrastim and plerixafor with peripheral blood CD34 counts of 1, 4, and 3 resulting in cancellation of stem cell collection. For the second mobilization attempt, teriparatide was added to the regimen. Peripheral blood CD34 counts improved to 8, 6, and 2 resulting in three collections with a total of 2.23 x 106 CD34/kg for reinfusion. Engraftment data showed 14 days for neutrophils and 17 days for platelets. The patient is 6 months post-transplant with no major morbidities reported, currently in maintenance therapy, and has not recurred.
Patient 2 had a diagnosis of multiple myeloma and failed to mobilize on filgrastim and plerixafor with peripheral blood CD34 counts of 2, 2, and 2 resulting in collections with a total of 0.6 x 106 CD34/kg for reinfusion. For the second mobilization attempt, peripheral blood CD34 counts of 2, 2, 2, and 0 resulting in collections with a total of 0.822 x 106 CD34/kg for reinfusion. For the third mobilization attempt, teriparatide was added to the regimen. Peripheral blood CD34 counts improved to 8 and 4 resulting in collections with a total of 1.8 x 106 CD34/kg for reinfusion. Patient expired one month after collection without reinfusion.
Conclusion:
Two patients who failed standard mobilization for stem cell collection at our institution received teriparatide as part of an additional stem cell mobilization regimen. Adequate doses of stem cell products for transplant were collected. One patient was reinfused and subsequently engrafted appropriately. Teriparatide can be used in the setting of poor mobilization.

Disclosures
No relevant conflicts of interest to declare.
A Systematic Review of Evidence Supporting the Use of Autologous Cell Vaccines in the Treatment of Hematological Malignancies
Authors: Bastin Donald , Khan Sarwat , Montroy Joshua , Kennedy Michael A. , Forbes Nicole , Martel Andre B , Baker Laura , Gresham Louise , Boucher Dominique , Wong Boaz , Diallo Jean-Simon , Fergusson Dean , Lalu Manoj , Auer Rebecca C , Kekre Natasha 
Published: November 2020

By presenting a patient's own tumor antigens to their immune system, autologous cancer cell vaccines can drive a robust polyclonal adaptive response. In this systematic review and meta-analysis, we investigated the safety and efficacy of these vaccines administered to patients with hematologic malignancies. Our primary outcomes of interest were safety and clinical response, with secondary outcomes including overall, disease-free and progression-free survival, relapse rate, correlative immune assays and health-quality related metrics. We identified 14 studies with 332 patients enrolled, of which 200 were ultimately treated with at least one dose of the vaccine. While we identified both patient-related and technical issues that might limit the feasibility of these trials, very few serious adverse events (AEs) were reported overall, with only 31.5% of patients suffering any AEs. Grade II or lower AE was observed in 10 (71.4%) of the 14 studies. Of the 3 (21.4%) reporting grade IV AEs, two observed the AE in one patient only, and one reported a 20% incidence of grade II-IV AEs. Of 58 evaluable patients, the complete response rate was 21% [95% CI, 10%-38%)] and overall response rate was 36% [95% CI, 24%-49%]. Analysis of individual patient level data (n=50) revealed a 5-year overall survival of 68.7% (SE 7.1%) and disease-free survival of 67.4% (SE 8.1%). Despite the clear safety and a signal towards efficacy, our review has identified several factors limiting administration of these vaccines, which should be considered when developing future clinical trials.
PROSPERO registration number CRD42019140187

Disclosures
Diallo: Virica Biotech: Other: Owner and Executive. Auer:Imugene: Other: Scientific Advisory Board. Kekre:Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria.
CD56briCD27+CD11b+/- NK Cells Mediated Remission of Agvhd Via Immunoregulation
Authors: Ni Ming , Zhao Peng , Kang Qian , Zhao Mei , Liu Min , Zhang Fengqi , Huang Shisi , Ma Dan , Zhang Yaming , Zhao Jiangyuan , Wang Jishi 
Published: November 2020

Background: In our previous study CD56briCD27+CD11b+/- NK cells show the potential of the remission of aGvHD, while the mechanism behind it is still unknown. Here, three hypothesis have been proposed according to further pilot experiment and literature.
Method: 74 samples of patients after allo-HSCT were collected in the affiliated hospital of Guizhou medical university. Immunomonitoring with respect to the phenotype and function of CD56briCD27+CD11b+/- NK cells was performed on rested peripheral blood mononuclear cells (PBMCs) using multiparametric flow cytometry. Furthermore, the western-blot has been performed to determine the expression of HO-1 protein in sorted CD56briCD27+CD11b+/- NK cells as well.
Result: (1) Our result shows a positive correlation between CD56briCD27+CD11b+/- NK cells and Th22, Tfh as well as Th1 like Tfh cells. Interestingly, a dramatic higher expression of homing marker CD62L has been observed on CD56briCD27+CD11b+/- NK cells. Thus we hypothesis that the CD56briCD27+CD11b+/- NK cells may migrate into the lymphoid tissues and regulate the differentiation of naïve T cells. (2) On the other hand, an elevated percentage of NKG2D has been found on CD56briCD27+CD11b+/- NK cells in patients with aGvHD. Meanwhile a high expression of Fas and exhaustion markers have been observed on CD4+ and CD8+ T cells. These results suggest that T cells may be eliminated by CD56briCD27+CD11b+/- NK cells. (3) Besides, our work displays that the expression of Heme Oxygenase-1 (HO-1) in CD56briCD27+CD11b+/- NK cells positively correlated with the secretion of IL-10. Compared with the patients with aGvHD, a higher expression of HO-1 and IL-10 in CD56briCD27+CD11b+/- NK cells has been found in patients without aGvHD at day 30 after allo-HSCT .
Conclusion: According to these findings, the CD56briCD27+CD11b+/- NK cells may result in the remission of aGvHD via immunoregulation by regulation of T cells and secretion of IL-10.

Disclosures
No relevant conflicts of interest to declare.
A Unique Case of CSF3R-Mutated Chronic Neutrophilic Leukemia with Thrombocytosis
Authors: Tizro Parastou , Yacur Melissa , Liu Min-Ling , Nava Victor E. , Aggarwal Anita 
Published: November 2020

Chronic neutrophilic leukemia (CNL) is a well-recognized, extremely rare myeloproliferative neoplasm (MPN) with only ~200 reported cases until 2017. The current WHO diagnostic criteria include leukocytosis of ≥ 25 x 109/L with ≥ 80% neutrophils/bands, &lt; 10% circulating neutrophil precursors and &lt;1% blasts (&lt;5% bone marrow blasts). Exclusion criteria includes dysplasia, or clinical/molecular diagnosis of other MPN. The WHO classification was updated in 2016 to include CSF3R T618I and other activating mutations in CSF3R as diagnostic. SETBP1 and ASXL1 mutations are frequent but unspecific in CNL and appear to be of prognostic significance. Hepatosplenomegaly and a hypercellular bone marrow with marked granulocytic hyperplasia are common in CNL, but thrombocytosis has not been reported previously.
We report a 72-year-old man with past medical history of hypertension and hepatitis C status post-treatment, who presented with WBC 38.4k/cmm, Hgb 6.3g/dl, MCV 102 fl and platelet count of 2601k/cmm. Reactive etiology of thrombocytosis was ruled out. Peripheral blood smear revealed rare blasts. Bone marrow biopsy was hypercellular (60-80%) with M:E ratio of 10:1, granulocytic and megakaryocytic hyperplasia, clustering of dyspoietic megakaryocytes, no erythroid or myeloid dysplasia and minimal patchy reticulin fibrosis suggestive of primary MPN. Chromosome analysis showed normal karyotype of 46 XY. Molecular studies were negative for BCR-ABL, JAK-2 V617F, CALR and MPL, Next Generation Sequencing revealed mutations in the CSF3R gene (Q781* and T618I) and concurrent inactivating ASXL1-G646fs*12 and activating U2AF1-Q157P mutations. These findings were compatible with a diagnosis of CNL.
We describe an unusual case of CNL confirmed by CSF3R gene mutations (T618I and Q781*) with significant thrombocytosis and without splenomegaly. Although the T618I mutation has commonly been reported in CNL, to the best of our knowledge, the Q781* mutation is novel in CNL, and has only been reported before in severe congenital neutropenia (SCN). Association of Q781* mutation in CSF3R gene with significant thrombocytosis in our patient needs further investigation.

Disclosures
No relevant conflicts of interest to declare.