bluuebunny/crossref_metadata_2025_split huggingface dataset:
Outpatient Based Autologous Hematopoietic Stem Cell Transplantation Is a Feasible Therapeutic Option for Patients with Chronic Inflammatory Demyelinating Polyneuropathy: The Mexican Experience
Authors: Murrieta-Álvarez Iván , Bojalil-Álvarez Lorena , Cantero-Fortiz Yahveth , García-Villaseñor Elizabeth , León-Peña Andrés A. , Priesca-Marin José Manuel , Olivares-Gazca Juan Carlos , González-López Elías , Gomez-De Leon Andres , Ruiz-Delgado Guillermo J. , Gomez-Almaguer David , Ruiz-Argüelles Guillermo J. 
Published: November 2021

Abstract
Introduction
Several autoimmune disorders such as multiple sclerosis, Stiff man syndrome or chronic inflammatory demyelinating polyneuropathy (CIDP) can benefit from autologous hematopoietic stem cell transplantation (HSCT) due to its immunomodulatory effects at short- and long-term. Here we present the results from the conduction of an outpatient HSCT procedures in 16 patients with CIDP.
Methods
Prospective study of HSCT in persons with CIDP recruited since 2015. Patients with and without previous immunomodulatory therapy were enrolled and a 3-month wash-out period was recquired; previous or current use of walking support was not a contraindication. All patients signed a consent before starting the study and the study protocol was approved by Clínica Ruiz IRB. Before the conditioning, all participants underwent a comprehensive evaluation. On day -11 and -10, patients received cyclophosphamide (Cy) at 50 mg/kg, followed by a 7-day course of G-CSF previous to cell collection (day -2) through apheresis using a Mahurkar catheter. Then, on day -2 and -1 a second round of Cy at 50 mg/kg was given (Figure 1). Transfusions and antimicrobial prophylaxis were administered per local protocol. Upon hematological recovery (&gt;500 ANC) all patients received a rituximab infusion at 1000 mg.
Results
Sixteen patients with CIDP underwent screening for transplantation clearance and all of them proceeded to HSCT. Of those, 8 (50%) patients were male. Median age at transplantation was found to be 44 years (SD 10.5). Walking support was employed at the time of HSCT by 7 (44%) patients and most frequent previous therapy was intravenous immunoglobulin in 4 (25%) patients. On average a mean 8.5x10 6/kg (SD 4.2) of CD34 + cells were infused. The mean nadir neutropenia was found to be 0.11x10 9/L (SD 0.13) and the median time of granulocytes recovery was 7.0 days (SD 2.9) while median time of platelet recovery was 5.5 days (SD 3.0). One (6%) patient was admitted to hospital due to febrile neutropenia and 4 (25%) patients required red-blood cell and platelet transfusion support. In 3 of 5 persons the need of walking support reverted.
Conclusions
Our experience suggests that people with CIDP may undergo HSCT with no major complications on an outpatient basis. Hospital admissions, hematological recovery, and infectious complications seem to be relatively low-severity complications that could be manage with standard protocols.
Figure 1 Figure 1.

Disclosures
Gomez-Almaguer: Bristol-Myers-Squibb: Honoraria, Speakers Bureau; Roche: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau.
Momelotinib Is a Highly Potent Inhibitor of FLT3-Mutant AML
Authors: Azhar Mohammad , Kincaid Zachary , Kesarwani Meenu , Wunderlich Mark , Latif Tahir , Starczynowski Daniel , Azam Mohammad 
Published: November 2021

Abstract
Approximately one-third of AML patients harbor kinase activating mutations in FLT3. Several small-molecule first generation FLT3 tyrosine kinase inhibitors (TKIs) have been evaluated in the last two decades, but none could induce a durable response possibly due to poor pharmacokinetics and target selectivity. Second generation FLT3 inhibitors such as, quizartinib, gilteritinib, and crenolanib, were designed for greater selectivity with a narrow kinome-profile and better pharmacokinetic properties, but they failed to induce a durable response. Possibly due to intrinsic resistance conferred by growth factor signaling in the bone marrow resident leukemic cells, which serve as a reservoir to develop resistance resulting to disease relapse. Activation of Jak2 signaling by chemokines and cytokines from the stroma have been reported to confer TKI refractoriness. Recent studies from Martin Carroll's group showed that both GMCSF and IL-3 confer resistance by activating JAK2 signaling, which can be suppressed by combined FLT3 and JAK2 inhibition. However, so far, it is not established whether upfront FLT3/Jak2 inhibition will provide durable response.
For instance, AML patients who achieved complete remission lacking FLT3-ITD clones showed better overall survival than patients with measurable MRD, suggesting that eradicating the FLT3-ITD clones will have a deeper response with better overall survival. Thus, an ideal FLT3 inhibitor should be able to suppress FLT3-ITD resistant mutants, and growth factor activated JAK2 signaling while sparing c-KIT receptor and hERG to avoid myelosuppression and cardiotoxicity, respectively. Here we show that Jak2 inhibitor, momelotinib, is an equipotent type-I FLT3 inhibitor (Fig 1A-D). Biochemical and structural modeling revealed that it binds to an active conformation of FLT3 kinase. Therefore, like gilteritinib, it efficiently suppresses the resistance conferred by activation loop mutations (Fig1 E-H). Moreover, its lack of activity against c-KIT and inhibition of ACVR1 provides additional benefit in alleviating myelosuppression and anemia, which is commonly observed with currently used JAK2 and FLT3 inhibitors (ruxolitinib, fedratinib, and quizartinib). Perhaps more interestingly, momelotinib efficiently suppressed the disease in a preclinical model of AML using NSGS mice which recapitulates cytokine induce refractoriness as usually observed in clinical setting (Fig1 I-L). Our preclinical data provide evidence that momelotinib is an equipotent dual JAK2/FLT3 inhibitor and suppresses resistance conferred by both activation-loop mutations and growth-factor signaling. These data provide evidence that momelotinib treatment will have clinical activity in FLT3-mutated AML. Thus, warrants its clinical evaluation.
Figure 1 Figure 1.

Disclosures
Starczynowski: kurome Inc: Consultancy.
Effect of Thrombospondin-1 on Apoptosis of Human Megakaryocytic Leukemia Cells
Authors: Kong Huimin , Jiang Qianli , Su Weiqing , Luo Yi , Ge Hui , Li Liang , Chong Beng H , Yang Mo 
Published: November 2021

Abstract
Background: Thrombospondin 1 (TSP-1) is an extracellular matrix protein that interacts with a wide array of ligands including cell receptors, growth factors, cytokines, and proteases to regulate various physiological and pathological processes. TSP-1 induces apoptosis of endothelial and cancer cells via its receptor CD36. This study was to investigate the effect of TSP-1 on apoptosis of human megakaryocytic leukemia cell line Meg-01 and its possible mechanism.
Methods: The expression of CD36 antigen in Meg-01 cells was detected by flow cytometry and immunocytochemistry. Meg-01 cells were cultured for 48 hours with TSP-1 and CD36 antibody FA6-152 at different concentrations, to investigate the effect of TSP-1 on the growth of megakaryocytes. The early apoptosis and the activity of the apoptotic protease caspase-3 were detected by flow cytometry. Bone marrow cells of mice were cultured for CFU-MK and stained with acetylcholine to detect the differentiation of megakaryocytes.
Results: CD36 antigen was detected on the surface of Meg-01 cells by flow cytometry and immunocytochemistry. TSP-1 (5 μg/mL) inhibited the proliferation of Meg-01 cells, but not M-07e cells (CD36 -). After the addition of CD36 antibody FA6-152 (5, 10 and 25 μg/mL), the inhibitory effect of TSP-1 was significantly reduced. TSP-1 (2.5, 5 and 7.5 μg/mL) exerted a pro-apoptotic effect by increasing the expression of Annexin V (P&lt;0.01) and caspase-3 activation (P&lt;0.01). Addition of FA6-152 (25 μg/mL) can significantly reduce the apoptosis induced by TSP-1 in Meg-01 cells. In addition, TSP-1 (5, 10 and 25 μg/mL) repress the formation of CFU-MK in mouse bone marrow cells, while β-TG did not. This repression was relieved efficiently by FA6-152 (25 μg/mL).
Conclusion: TSP-1 could inhibit the proliferation of Megakaryocyte cell line Meg-01 cells, and induce it`s apoptosis. TSP-1 may induce apoptosis of Meg-01 cells via CD36 or caspase-3, which provides a potential new drug choice for clinical treatment of megakaryocytic leukemia.

Disclosures
No relevant conflicts of interest to declare.
IL-1 Via IRAK1/4 Sustains Acute Myeloid Leukemia Stem Cells Following Treatment and Relapse
Authors: Ho Tzu-Chieh , Kawano Hiroki , LaMere Mark W. , Guo Naxin , Chiu Yu-Chiao , Wang Jian , Jordan Craig T. , Dokholyan Nikolay V. , Calvi Laura M. , Singh Rakesh Kumar , Becker Michael W. 
Published: November 2021

Abstract
Current treatment options for relapsed acute myeloid leukemia (AML) are limited and ineffective for the majority of patients. In AML, primitive leukemia stem cells (LSCs) and pre-leukemic populations are able to maintain the disease and drive relapse. Thus, therapies targeting LSC populations may increase the overall survival of AML patients. In this study, we aim to identify the drivers favoring LSC expansion following treatment and relapse and develop potential therapies for AML. The transcriptome analyses of 12 pairs of functionally defined LSC fractions at diagnosis and relapse revealed significant changes of IL-1 signaling in AML patients. We demonstrated that the protein expression levels of interleukin-1 receptor type I (IL1R1) and its complex member interleukin-1 receptor accessory protein (IL1RAP) were both up-regulated in human leukemia stem and progenitor cells (LSPCs) at diagnosis or in relapse compared to normal hematopoietic stem and progenitor cells (HSPCs). Knockdown of IL1R1 and IL1RAP suppressed the clonogenicity and engraftment growth of primary human AML cells but showed low impacts on HSPCs in the normal bone marrow. Additionally, knockout of IL1R1 in leukemia MLL-AF9 mice significantly reduced the LSC frequency and prolonged the overall survival rate. To target IL-1/TLR signaling in LSCs, we performed iterative structure-activity relationship (SAR) guided medicinal chemistry, in silico modeling and leukemia cell line reporter assays to screen and identify a novel interleukin-1 receptor-associated kinase 1/4 (IRAK1/4) inhibitor (termed UR241-2). UR241-2 robustly inhibits IL-1/TLR signaling in AML cells including the activation of NF-κB following IL-1 stimulation. UR241-2 repressed LSPC function as assessed by colony-forming unit assays in primary human AML cells at diagnosis and in relapse while minimally impacting normal HSPC function. Taken together, our findings demonstrate the important role of IL-1/TLR signaling in supporting AML LSC expansion following treatment and relapse and suggest that targeting IL-1/TLR signaling using the novel IRAK1/4 inhibitor, UR241-2, can target LSC function to improve patient outcomes in AML.

Disclosures
No relevant conflicts of interest to declare.
An Autosomal Dominant Form of Ras-Related C3 Botulinum Toxin Substrate 2 (RAC2) Is Associated with Haematopoiesis Failure
Authors: Lagresle-Peyrou Chantal , Olichon Aurélien , Sadek Hanem , Roche Philippe , Tardy Claudine , Sorel Natael , Bessot Boris , Da Silva Cindy , Fischer Alain , Moshous Despina , Collette Yves , Picard Capucine , Casanova Jean-Laurent , André Isabelle , Cavazzana Marina 
Published: November 2021

Abstract
Severe combined immunodeficiencies (SCIDs) constitute a heterogeneous group of life-threatening genetic disorders that typically present in the first year of life. Reticular dysgenesis (RD) is an autosomal recessive form of human Severe Combined Immunodeficiency (SCIDs) characterized by the absence of blood neutrophils and T lymphocytes. This pathology is due to biallelic mutations in the adenylate kinase 2 (AK2) gene, encoding for a mitochondrial protein which regulates the homeostasis of adenine nucleotides.
In three newborns presenting a RD-like clinical phenotype as frequent infections and a profound leukopenia, we identified an heterozygous dominant missense mutation in the gene coding for Rac Family Small GTPase 2 (RAC2) protein (p.G12R). Hematopoietic stem cell transplantation (HSCT) performed soon after birth was successful in two out of the three patients attesting that the inherited defect was intrinsic and not micro-environmental. RAC2 protein belongs to the Rac subfamily of RHO small GTPases. In the inactive GDP-bound state, RAC2 is located in the cytosol and upon stimulation, the active RAC2-GTP-bound form translocates to the plasma membrane. Unlike the other members of the Rac subfamily (RAC1 and RAC3), RAC2 is mostly expressed on hematopoietic cells and during T cell differentiation.
To gain insight into the disease, we transduced human hematopoietic stem and progenitor cells (HSPCs) with a lentiviral construct containing the RAC2 mutated form. The mutation inhibits HSPCs proliferation and differentiation toward the myeloid and lymphoid lineages reproducing the patients' clinical phenotype. In this condition, we also observed high apoptosis level and an alteration of mitochondrial activity and Ros production. In a biochemical model, we demonstrated that the substitution of the glycine (G) amino-acid by a bulky flexible arginine (R) may prevent GTP hydrolysis. Lastly, our findings suggest that RAC2 gene sequencing must be considered in newborn screening programs for SCID detection.
To decipher the mechanisms regulating RAC2 functions, we studied the impact of the p.G12R mutation on a human AML cell line expressing RAC2 protein. Our preliminary data highlight that the cell cycle and mitochondrial activity are disrupted by G12R mutation. By holotomography, we also observed morphological changes and accumulation of lipid droplets into the cells. All these data suggest that RAC2 defective signalling pathway is linked to cell metabolism imbalance and further investigations are ongoing to better understand how RAC2 controls cell energy demand, especially during differentiation.

Disclosures
Cavazzana: Smart Immune: Other: co-founder.
Targeted Therapy in CD38 + Acute Myeloid Leukemia
Authors: Hu Naibo , Gao Chao , Zhang Yuhui , Teng Guangshuai , Wang Yan , Du Chenxiao , Bai Jie 
Published: November 2021

Abstract
The expression rate of CD38 in acute myeloid leukemia is high. It is reported that the expression of CD38 in myeloid leukemia is stable and can be used as a potential therapeutic target for leukemia. Daratumumab is a therapeutic drug targeting CD38. It is widely used in myeloma, but it has not been applied in AML. The prognosis of 4 patients with acute myeloid leukemia treated with CD38 monoclonal antibody combined with demethylating drugs / traditional chemotherapy was reviewed. Patient demographic data and clinical characteristics see table 1. One patient with de novo AML in the high-risk group achieved remission after Dara combined with azacytidine and venetoclax. The other three patients were suffering Relapsed/Refractory AML. Two of them achieved remission after Dara combined with azacytidine and venetoclax. The patient, who was non-remission after Dara combined with IA chemotherapy (Idarubicin, Cytosine Arabinoside), achieved remission after CART targeting CD38. In this paper, four cases were reported, and the rationality of CD38 targeted therapy was further analyzed.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
Ruxolitinib Therapy during Hematopoietic Cell Transplantation for Myelofibrosis
Authors: Tan Yaxian , Luo Jie , Luo Dongmei , Liang Hanying , Liu Xiaoli , Liu Qifa , Xu Na 
Published: November 2021

Abstract
Background :The beneficial effects of JAK 1/2 inhibitors (JAKi) ruxolitinib in MF patients have led to control of disease related symptoms,but ruxolitinib has been limited by their inability to deplete the malignant stem cell clones. Allogeneic hematopoietic cell transplantation (HCT) is currently the only treatment with proven curative potential for myelofibrosis (MF). Previous research suggested pre-HCT ruxolitinib may improve post-HCT outcome because of ruxolitinib accelerate engraftment, improve graft function, decrease the risk and severity of graft-versus-host disease (GVHD). However,HCT in PMF with higher non-relapse mortality (NRM),In the present study, we aimed to prospectively assess the effects of Rux therapy during HCT period(NCT04526223).
Objective Preliminarily investigate the safety and efficacy of ruxolitinib in myelofibrosis patients during the peri-transplantation period.
Method: To prospectively analyze the clinical data of 26 patients with myelofibrosis who were used DAC bridge BF as conditioning treatment and treated with ruxolitinib(5mg bid +6d to +60d) during the peri-transplantation period.
Results: 26 patients were eligible if they had primary myelofibrosis (PMF) as defined by the 2008 World Health Organization classification or secondary MF as defined by the IWG for Myeloproliferative Neoplasms Research and Treatment criteria and met the criteria for Intermediate-1 (Int-1), Int-2, or high-risk disease by the DIPSS scoring system at the time of enrollment. Patients consenting to treatment with Rux for at least 8 weeks prior to HCT and could receive Rux (5mg bid +6d to +60d) during the peri-transplantation period. DAC bridge BF as Myeloablative regiment, There have been no episodes of cytokine release syndrome and all patients achieved sustained engraftment. Neutrophil reconstitution was obtained in 26 patients with a median time of 15 (10 to 31) d; platelet reconstitution was obtained in 26 patients with a median time of 26(12 to 68) d. Acute GVHD occurred in 26 patients (46.15%) , of which 1(3.8%) were ш°; chronic GVHD occurred in 9 patients (34.6%), 1 patients with extensive chronic GVHD. There patients relapsed and two patients died because of resistance to alvage treatment . With a median follow-up 336 (70-993) days，no patient died of non-relapse mortality (NRM)., overall survival is 92.3% (95% CI: 0.73, 0.97) and DFS is 88.5% (95% CI: 0.63, 0.96) at1 year post-HCT.
Conclusion: This study demonstrates that Ruxolitinib therapy during HCT is well tolerated and suggests that during-HCT Rux may improve post-HCT outcome.
Keywords: Ruxolitinib;Hematopoietic Cell Transplantation;Myelofibrosis

Disclosures
No relevant conflicts of interest to declare.
Using the Iron Chelator Deferasirox to Overcome Drug Resistance in Mantle Cell Lymphoma
Authors: Samara Aladin , Shapira Saar , Lubin Ido , Raanani Pia , Granot Galit 
Published: November 2021

Abstract
Mantle cell lymphoma (MCL) is a difficult-to-treat B-cell malignancy characterized by the t(11,14) translocation, resulting in cyclin D1 (CD1) overexpression. In addition to CD1 overexpression, pathways such as the B-cell receptor, PI3K/AKT/ GSK3β, NFκB and Wnt have been reported to be deregulated in MCL. Despite advancements in MCL treatment, most patients still relapse. Although the introduction of ibrutinib to relapsed/refractory MCL significantly improved the outcome of MCL patients, ibrutinib resistance has become a clinical obstacle. MCL treatments are thus pursued by studying novel agents with a broad spectrum of targets or by rationally combining existing therapies aiming for synergistic antitumor activities. Deferasirox (DFX) is a clinically approved iron chelator with only few side effects. DFX has been reported to exert anti-tumoral and synergistic effects in several types of cancers by affecting a multitude of targets. We have previously shown that DFX exerts a vigorous anti-tumoral effect via growth inhibition and induction of apoptosis in MCL cells through ROS elevation, triggering of oxidative stress, induction of DNA damage, modulation of PI3K/AKT/GSK3β signaling and most importantly by elimination of CD1 expression. The capacity of DFX to affect a multitude of targets establishes a solid basis for a possible synergistic interaction with other drugs, such that may overcome drug resistance in MCL. In this study we focused on assessing the efficiency of DFX combined with the established therapeutic-agents etoposide, cytarabine and ibrutinib in MCL cell-lines. We found that DFX synergizes with etoposide, cytarabine and ibrutinib, prompting remarkable anti-tumoral effects in MCL cells with combination index (CI) values &lt; 1. Interestingly, the DFX-drug combinations achieved synergism regardless of the innate sensitivity of the cell-lines to the treatment: ibrutinib-resistant cells restored their sensitivity to the drug when it was combined with DFX. In addition, we found that the sensitivity of MCL cells towards the drugs correlated with the drugs ability to induce CD1 degradation. In agreement, DFX co-treatment enhanced CD1 degradation, especially in resistant cells.
We show here that DFX is a putative promising drug-sensitizing agent for the treatment of MCL. DFX-co-treatment not only enhances the efficacy of the tested drugs, but also restores the anti-proliferative activity of the drugs in resistant MCL cells. To the best of our knowledge, this study is the first to provide evidence on the potential of DFX to overcome drug resistance in MCL.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
Preliminary Results of Zanubrutinib-Containing Regimens in DLBCL and Cerebrospinal Fluid Distribution of Zanubrutinib
Authors: Zhang Yan , Li Yanan , Zhuang Zhe , Wang Wei , Wei Chong , Zhao Danqing , Li Jian , Zhou Daobin 
Published: November 2021

Abstract
Background: Zanubrutinib is a second-generation Bruton's tyrosine kinase (BTK) inhibitor. The safety and efficacy of zanubrutinib in CNS lymphoma are unknown, as well as its brain distribution through the blood-brain barrier.
Objective: A retrospective study of zanubrutinib-containing regimens was performed in patients with DLBCL to evaluate the efficacy of zanubrutinib. Paired plasma and cerebrospinal fluid (CSF) samples were collected to assess zanubrutinib's permeability through the BBB.
Methods: Consecutive DLBCL patients treated with zanubrutinib-containing regimens from August to December 2020 in PUMCH were recruited. Paired plasma and CSF samples were collected at a fixed time point after zanubrutinib administration. Plasma and brain zanubrutinib quantification was performed by liquid chromatography-tandem mass spectrometry.
Results: Totally 13 patients were enrolled, including primary CNS lymphoma (n=8) and systemic DLBCL (n=5). 53.8% (7/13) were refractory/relapsed, 84.6% (11/13) had CNS involvement. Overall response rates (ORRs) were 84.5% and 81.8% in the whole population and CNS involved cases, respectively. A total of 23 time-matched plasma-CSF sample pairs were collected. The mean peak concentration of zanubrutinib in the CSF was 2941.1 pg/ml (range, 466-9032.0). The corrected mean CSF/plasma ratio by protein binding of 94.0% was 42.7±27.7% (range, 8.6-106.3%), indicating the good penetrating ability through the BBB of free drug. The CSF/plasm ratio was not influenced by sex, DLBCL subtype, co-administrated BBB penetrating drugs or plasma drug concentration.
Conclusion: This preliminary study revealed the efficacy of zanubrutinib-containing regimens in DLBLC, especially CNSL, for the first time. The excellent BBB penetration of zanubrutinib supports its further investigation in CNS lymphomas.

Disclosures
Li: Astellas Pharma, Inc.: Research Funding.

OffLabel Disclosure:
Zanubrutinib is a selective Bruton Tyrosine kinase(BTK) inhibitor and is approved for WM, MCL and CLL/SLL in the Unite States and China. BTK inhibitors such as ibrutinib and tirabrutinib are highly effective in CNS lymphoma and have good penetration ability of brain-blood-barrier. We supposed that zanubrutinib should be effective in DLBCL and CNS lymphomas just as other BTKi,so we prescribed zanubrutinib in this study.