Abstract: Background: The Bruton tyrosine kinase (BTK) inhibitor zanubrutinib has demonstrated greater selectivity for BTK versus other TEC- and EGFRfamily kinases in biochemical assays, and favorable pharmacokinetic/pharmacodynamic properties in preclinical studies. In a phase 1 clinical trial, zanubrutinib showed complete and sustained 24-hour BTK occupancy in both peripheral blood mononuclear cells and lymph node biopsies from patients treated with 160 mg twice daily (Tam et al. Blood 2016;128:642). Zanubrutinib was also associated with high and durable responses in patients with WaldenstrC6m macroglobulinemia (WM) (Tam, ASCO 2020, abstract 8007; Dimopoulos, EHA 2019, abstract PF487; Trotman, EHA 2019, abstract PF481). Here we present initial safety and efficacy data from a phase 2 trial of zanubrutinib in patients with relapsed or refractory (R/R) WM. Methods: BGB-3111-210 (ClinicalTrials.gov: NCT03332173) is a pivotal, single-arm, open-label, multicenter, phase 2 study conducted in China. Patients with R/R WM aged b %18 years and with b %1 prior line of standard chemotherapy-containing regimen (with completion of b %2 continuous treatment cycles) receive zanubrutinib 160 mg twice daily until disease progression or unacceptable toxicity. The primary objective is to evaluate the efficacy of zanubrutinib as measured by major response rate (MRR), defined as the proportion of patients achieving complete response (CR), very good partial response (VGPR), or partial response (PR), as assessed by an independent review committee (IRC) according to an adaptation of the 6th International Workshop on WM response criteria. Secondary endpoints include progression-free survival (PFS), overall response rate (ORR), duration of major response, and safety. The safety analysis set includes all patients who received b %1 dose of zanubrutinib. All efficacy endpoints are analyzed in patients with pathologically confirmed WM and with baseline immunoglobulin M (or M-protein) b %5 g/L. Adverse event (AE) severity is graded according to NCI CTCAE v4.03. Results: As of August 31, 2019, a total of 44 patients with R/R WM were enrolled and treated, with a median follow-up of 18.58 months. Baseline characteristics are summarized in Table 1. For the 43 patients evaluable for efficacy (1 patient was excluded from the efficacy analysis due to baseline immunoglobulin M & lt;5g/L), MRR per IRC was 69.8% (n=30, Table 1), with b % VGPR achieved in 32.6% of patients (n=14). As of data cutoff date, median PFS and median duration of major response were not reached. The most frequently reported (b %20%) treatment-emergent AEs (TEAEs) included neutrophil count decreased (56.8%), platelet count decreased (29.5%), white blood cell count decreased and upper respiratory tract infection (27.3% each), diarrhea (25.0%), weight increased and arthralgia (20.5% each). Grade 3 or higher AEs reported in b %5% of patients included neutrophil count decreased (31.8%), platelet count decreased (20.5%), lung infection (13.6%), white blood cell count decreased (11.4%), pneumonia (9.1%), anemia and upper respiratory tract infection (6.8% each). Most bleeding events were grade 1 or 2 originating in skin or mucous membranes. Major hemorrhage (serious or grade b %3 bleeding, or central nervous system bleeding of any grade) was reported in 2 patients (4.5%). No cases of atrial fibrillation/flutter or tumor lysis syndrome were reported. Two patients died within 30 days of last study treatment: one due to acute hepatitis B and multiple organ dysfunction syndrome, both of which were related to study drug per investigator's judgment, the other due to unknown reason, which was unlikely to be related to study drug as assessed by the investigator. TEAEs leading to discontinuation of zanubrutinib (n=1 each) included lung infection, laryngeal cancer, WM (investigator reported WM as AE due to unexpected rapid progression and suspected it to be a transformation), intracranial mass, acute hepatitis B (grade 5), and multiple organ dysfunction syndrome (grade 5). Conclusions: Zanubrutinib was shown to be highly active in patients with R/R WM, as demonstrated by a high MRR, b %VGPR rate. Zanubrutinib was generally well tolerated, consistent with previous reports of zanubrutinib treatment in patients with various B-cell malignancies. Disclosures Zhou: Henan Cancer Hospital: Current Employment. Guo:BeiGene Co., Ltd.: Current Employment, Current equity holder in private company. Du:BeiGene Co., Ltd.: Current Employment, Current equity holder in private company. Huang:BeiGene: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Novotny:BeiGene USA, Inc.: Current Employment, Current equity holder in private company. Zhong:BeiGene Co., Ltd.: Current Employment, Current equity holder in private company. OffLabel Disclosure: Zanubrutinib is a small molecule inhibitor of Bruton's tyrosine kinase (BTK) that is being evaluated as a monotherapy and in combination with other therapies to treat various B-cell malignancies. Zanubrutinib is approved in the United States to treat adult patients with MCL who have received at least one prior therapy and in China for the treatment of MCL in adult patients who have received at least one prior therapy and CLL or SLL in adult patients who have received at least one prior therapy. Zanubrutinib is not approved for use outside of the United States and China.

Abstract: Although Bruton tyrosine kinase (BTK) inhibitors have demonstrated promising efficacy in patients with Waldenström macroglobulinemia (WM), data in Asian populations are scarce. This trial is the first to investigate the effect of a BTK inhibitor in Chinese patients with relapsed/refractory (R/R) WM. Patients and Methods: Patients with R/R WM with at least one prior regimen were enrolled into this single-arm, multicenter, phase II study (NCT03332173) and received zanubrutinib 160 mg twice daily until disease progression or unacceptable toxicity. The primary endpoint was major response rate (MRR), as assessed by an independent review committee. Secondary endpoints included progression-free survival, overall response rate, duration of major response, and safety. Results: Forty-four patients were enrolled. After a median follow-up of 33.0 (range, 3.2–36.5) months, MRR in all patients was 69.8%, with very good partial response or better in 32.6% of patients. All mutation groups benefited from zanubrutinib treatment (MRR in patients with MYD88L265P mutation, 73%; MRR in patients with MYD88 wild type mutation, 50%). A higher response rate was seen in the MYD88L265P/CXCR4WT population, compared with the other populations. Median progression-free survival and median duration of major response were not reached. The most frequently reported grade ≥3 treatment-emergent adverse events (AEs) were neutrophil count decreased (31.8%), and platelet count decreased and pneumonia (20.5% each). No case of atrial fibrillation/flutter occurred. Conclusions: Zanubrutinib achieved a high rate of response that was durable and deep in patients with R/R WM across all subgroups, and potentially confers a positive benefit–risk profile for WM.

Abstract: Molecular generation (MG) via machine learning (ML) has speeded drug structural optimization, especially for targets with a large amount of reported bioactivity data. However, molecular generation for structural optimization is often powerless for new targets. DNA-encoded library (DEL) can generate systematic, target-specific activity data, including novel targets with few or unknown activity data. Therefore, this study aims to overcome the limitation of molecular generation in the structural optimization for the new target. Firstly, we generated molecules using the structure-affinity data (2.96 million samples) for 3C-like protease (3CLpro) from our own-built DEL platform to get rid of using public databases (e.g., CHEMBL and ZINC). Subsequently, to analyze the effect of transfer learning on the positive rate of the molecule generation model, molecular docking and affinity model based on DEL data were applied to explore the enhanced impact of transfer learning on molecule generation. In addition, the generated molecules are subjected to multiple filtering, including physicochemical properties, drug-like properties, and pharmacophore evaluation, molecular docking to determine the molecules for further study and verified by molecular dynamics simulation.

Abstract: Many debris-covered glaciers are broadly distributed across High Mountain Asia and have made a number of contributions to water circulation for Qinghai-Tibet Plateau (QTP). The formation of large supraglacial lakes poses risks for glacier lake outburst floods (GLOFs). Therefore, it is important to monitor the movement of glaciers and to analyze their spatiotemporal characteristics. In this study we take Cuolangma glaciers in the central Himalayas as study targets, where glacier No.1 is a lake-terminating debris-covered glacier and glacier No.2 is a land-terminating debris-covered glacier. The 3D deformation time series is firstly estimated by using the Pixel Offset-Small Baseline Subsets (PO-SBAS) based on the ascending and descending Sentinel-1 datasets spanning from January to December 2018. Then the horizontal and vertical time series displacements are obtained to show their spatiotemporal features. The velocities of glacier No.1 in horizontal and vertical direction were up to 16.0 ± 0.04 m/year and 3.4 ± 0.42 m/year, respectively, and the ones of the glacier No.2 were 12.0 ± 0.07 m/year and 2.0 ± 0.27 m/year, respectively. Next, the correlation between the precipitation and the surface velocity suggests that the glacier velocity does not show a clear association with daily precipitation alone. Finally, the debris-covered glaciers evolution is evaluated which shows that the tongue of the glacier No.1 is wasting away and the transition of glacier No.2 from land-terminating to lake-terminating is a probable scenario in the later period of glacier wastage. This research can significantly serve for glacier multidimensional monitoring and the mitigation of hazardous disaster caused by debris-covered glaciers in the central Himalayas.

Abstract: Abstract 1147 Poster Board I-169 In the past twenty years, allogeneic hematopoietic stem cells transplantation (Allo-HSCT) has been accepted as the most effective treatment for many hematologic malignancies. However, the successful rate of allo-HSCT has been limited by transplantation-related mortality and malignancies relapse, no matter using traditional intensity conditioning or reduced-intensity conditioning. In this study, we presented ninety-two patients with hematopoietic malignancies received fludarabine combinasion with modified Bu/Cy (FABC) conditioning regimen before allogeneic hematopoietic stem cell transplantation. Ninety-two patients with hematological malignancies (58 males, 34 females) ranged in age from 14 to 50 (median 28) years. These patients were diagnosed with acute lymphoblastic leukemia (ALL, n=30), acute myelogenous leukemia(AML, n=24), chronic myelogenous leukemia (CML, n=33; CP, n=27; CML-AP, n=5; CML-BC, n=1), myelodysplastic syndrome ( MDS, n=3), chronic myelomonocytic leukemia (CMML, n=1), and one patient coexisted chronic myelomonocytic leukemia and T lymphoblast cell lymphoma. Fifty-five (59.8%) patients were at high risk. From June 2004 to October 2008, 92 patients gave their informed consent and received conditioning regimen with fludarabine-based modified Bu/Cy (FABC conditioning regimen) in allo-HSCT. The FABC regimen consist of cytarabine 2.0 g/ m2 on day -9, busulphan (Bu) 3.2 mg/kg per day for intravenous on days -8 to day-6, followed by cyclophosphamide (Cy) 60 mg/kg per day on days -5 and day-4, combined fludarabin 30 mg/m2 per day for three consecutive days, on days -6 to day-4, and Me-CCNU (1-(2-Chloroethyl)-3-(4-ethylnitrobiphenyl Cylohexyl4)-1- Nitrosourea) 250 mg/m2 on day -3. Graft-versus-host-disease(GVHD) prophylaxis consisted of cyclosporine A, short-term MTX and Mycophenolate Mofefil (MMF 1.0g/day, on d-8 to d-1). Anti-T-lymphocyte globulin (2.5 mg·kg-1·d -1, on d-3 to d-1) was added to patients with mismatched sibling or unrelated donors. Follow-up was performed on 30 December, 2008. Ninety-two patients engrafted successfully, the median time for ANC 〉 0.5×109/L was 12 (8 to 22) days, and for BPC 〉 20×109/L was 12 (7 -32) days. Detected by short tandem repeat (STR)-PCR, complete donor chimerism was comfirmed in all patients on day +21 or day+30. The incidence of acute GVHD was 25% (23/92), and grades 3 to 4 acute GVHD developed in 8 (8.7%) of 92 patients with in 100 days after HSCT. Chronic GVHD developed in 40(47.6%) of 84 patients who were alive more than 100 days after HSCT, and the incidence of extensive cGVHD was 35.7%(30/84). The transplant related mortality (TRM) was 19.6% (18/92), mainly from severe infection (n=7), acute or chronic GVHD (n=5), transplant associated-microangiopathy (n=2), diffusion alveolar hemorrhage (n=2), and post-transplant lymphoproliferative disorders (n=2). With a median follow-up of 16.2(1.5 to 54.5) months, 70 (76.1%) of the 92 patients were alive and 67(72.8%) were disease-free. The probabilities of OS at 1 year and 2 years was 80% and 72.5%, and DFS was 79.1% and 71.4%, respectively. These results suggest that the fludarabine-based modified Bu/Cy conditioning regimen (FABC) should reduce severe acute GVHD and accelerate hematopoietis resconsition without increasing chronic GVHD and lower leukemia relapse rates even in high-risk patients. Footnotes Corresponding author Disclosure No relevant conflicts of interest to declare.

Abstract: BACKGROUND & OBJECTIVE FMyelodysplastic syndromes (MDS) are among the most frequent hematologic malignancies. The diagnosis of MDS can be difficult, and there is a paucity of molecular markers. The pathophysiology is still largely unknown. Therefore, we investigated whether serum proteome profiling may serve as a noninvasive platform to discover novel molecular markers for MDS and establish the predictive models that may be of help to serologic diagnosis and classification of MDS. METHODS FSerum samples were collected from 14 MDS patients including to 8 Refractory anemia with excess blasts in transformation (RAEB) and 6 Refractory cytopenia with multilineage dysplasia (RCMD) and 18 non-MDS hematologic malignancies and 8 age- and sex-matched healthy subjects. Serum peptides were separated and purified with a purification kit of magnetic beads, using magnetic beads-based weak cation exchange chromatography (MB-WCX) and MB-IMAC Cu, bases on immobilized metal ion affinity chromatography on the surface of superparamagnetic microparticles. We generated serum proteome profiles by matrix-assisted laser desorption/ionization time of-flight mass spectrometry (MALDI-TOF- MS) and identified a profile that distinguishes MDS from non-MDS hematologic malignancies and healthy subjects. RESULTS FA totaI of 146 effective protein peaks were detected at the molecular range of 1.02 tO 10.25 ku, Among which 7 protein peaks were different significantly among MDS patients, non-MDS hematologic malignancies and healthy subjects (P & lt;0.05). There was also different for Peptide mass fingerprinting in MDS patients, and the samples were divided into two groups, which was identical with clinical classification about RAEB and RCMD, using 3-cross validation approach. There was significantly different expression protein between RCMD and RAEB patients, which was identified as a piece of fibrinogen peptide. The expressions of fibrinogen in RAEB subtype patients were higher than RCMD subtype patients. CONCLUSION F Using the MALDI-TOF-MS technique may help to identify serum proteomic biomarkers related to MDS. The predictive models can discriminate MDS patients from other hematologic malignancies and healthy people effectively and help to identify MDS clinical classification. The different expression of Fibrinogen between RAEB and RCMD may suggested heterogeneity of etiopathogenisis in different subtypeof MDS.

Abstract: In a human T-cell acute lymphoblastic leukemia (T-ALL) cell line (Molt-4), siRNA-mediated suppression of BCL11B expression was shown to inhibit proliferation and induce apoptosis, functions which may be related to genes involved in apoptosis (such as TNFSF10 and BCL2L1 ) and TGF-β pathways (such as SPP1 and CREBBP ). Methods The expression levels of the above mentioned genes and their correlation with the BCL11B gene were analyzed in patients with T-ALL using the TaqMan and SYBR Green I real-time polymerase chain reaction technique. Results Expression levels of BCL11B, BCL2L1 , and CREBBP mRNA in T-ALL patients were significantly higher than those from healthy controls ( P 〈 0.05). In T-ALL patients, the BCL11B expression level was negatively correlated with the BCL2L1 expression level ( r s = -0.700; P 〈 0.05), and positively correlated with the SPP1 expression level ( r s = 0.683; P 〈 0.05). In healthy controls, the BCL11B expression level did not correlate with the TNFSF10 , BCL2L1 , SPP1 , or CREBBP expression levels. Conclusions Over-expression of BCL11B might play a role in anti-apoptosis in T-ALL cells through up-regulation of its downstream genes BCL2L1 and CREBBP .