Bone Marrow Function Research Articles

Effect of Recombinant Human Thrombopoietin (rhTPO) on Hematopoietic Reconstitution in Allogeneic Hematopoietic Stem Cell Transplantation Model

To explore the effect of recombinant human thrombopoietin (rhTPO) on hematopoietic reconstruction in allogeneic hematopoietic stem cell transplantation (allo-HSCT) model. The C57BL/6 mice were employed as the donors, and BALB/c mice as recipients. The bone marrow mononuclear cells of the donor mice were extracted and pretreated, which then were injected with 5×106 per mouse through the tail vein of the recipient to establish an allo-HSCT model. The implantation of hematopoietic stem cells in the recipient mice was detected by flow cytometry on the 28th day after transplantation. Next, the successfully modeled recipient mice were randomly divided into experimental group and control group. The rhTPO was injected into mice in the experimental group on the first day after transplantation, while the saline was injected into mice in the control group. Both groups were injected for 14 consecutive days. The peripheral blood and bone marrow hematopoiesis of the two groups were observed on day 1, 3, 7, 14, and 21 after transplantation. The expression rate of H-2Kb in the bone marrow of recipient mice was 43.85% (>20%) on the 28th day after transplantation, which indicated that the recipient mice were successfully chimerized. Meanwhile, counts of PLTs on the day 3, 7, 14, and 21 after transplantation in the experimental group were higher than those in the control group with statistical significances (P<0.05). In addition, hematopoietic function of bone marrow was suppressed in both groups on day 1, 3 and 7 after transplantation, but hematopoietic bone marrow hyperplasia was better in the experimental group than in the control group. On day 14 and 21 after transplantation, the hematopoietic function of bone marrow in the two groups was recovered, and the experimental group showed more obvious than the control group. rhTPO can effectively stimulate the production of PLTs and facilitate the recovery of white blood cells and hemoglobin after allo-HSCT, and promote hematopoietic recovery and reconstitution of bone marrow.

Targeting Arg-1 and PD-L1 in M2-Tumor Associated Macrophages Impairs Juvenile Myelomonocytic Leukemia (JMML) Cell Proliferation and Migration

Background and Hypothesis: Tumor-associated macrophages (TAMs) are a key component of tumor-infiltrating immune cells. They are largely characterized into M1 or M2 types. TAMs express an anti-inflammatory M2-like phenotype, promote tumor progression. However, the role of M2-TAMs in driving disease pathogenesis in patients with Juvenile myelomonocytic leukemia (JMML), a rare form of pediatric leukemia driven to a large extent by mutations in the PTPN11 gene, which encodes the phosphatase SHP2 is unclear. We hypothesized that in JMML, inflammatory myeloid cells including neutrophils and M2-TAMs express higher levels of arginase-1 (Arg-1) and PD-L1, which may contribute to the local suppression of immune responses and support the development of JMML.&#x0D; Methods: To study how alterations in M1/M2 macrophages contribute to JMML development, we utilized a mouse model bearing Shp2E76K mutation (Ptpn11E76K/+) which manifests the cardinal features of human JMML. We hypothesized that Shp2E76K/+ mutations enhance the function of bone marrow derived macrophages (BMDMs), including M2-TAMs and contribute to T-cell suppression.&#x0D; Results: Our analysis of the bulk RNA-sequence data from 90 JMML patients showed increase in the expression of Arg-1 and PD-1. Furthermore, single cell RNA-seq analysis of macrophages from 4 JMML patients revealed higher expression of M2-macrophage markers/genes. Our results show that in M2-TAMs, Arg-1 and PD-L1 levels are elevated in BM and spleens of Shp2E76K/+ mice compared to WT. Moreover, M2-TAMs, Arg-1 and PD-L1 levels were also higher in BMDMs derived from Shp2E76K/+ mice compared to WT. The BMDMs from Shp2E76K/+ mice have greater proliferation and migration potential compared to WT BMDMs, which was significantly reduced by inhibiting the function of Arg-1 and PD-L1.&#x0D; Conclusion: Our results show that M2-TAMs, arginase-1, and PD-L1 create a pro-tumor microenvironment, which likely contributes to the growth of JMML cells. Inhibition of Arg-1 and PD-L1 is a novel therapeutic approach to treat patients with JMML.

Safety and efficacy of laparoscopic surgery in locally advanced gastric cancer patients with neoadjuvant chemotherapy combined with immunotherapy

Objective: To investigate the safety and efficacy of laparoscopic surgery in locally advanced gastric cancer patients with neoadjuvant SOX chemotherapy combined with PD-1 inhibitor immunotherapy. Methods: Between November 2020 and April 2021, patients with locally advanced gastric cancer who were admitted to the Union Hospital of Tongji Medical College of Huazhong University of Science and Technology were prospectively enrolled in this study. Inclusion criteria were: (1) patients who signed the informed consent form voluntarily before participating in the study; (2) age ranging from 18 to 75 years; (3) patients staged preoperatively as cT3-4N+M0 by the TNM staging system; (4) Eastern Collaborative Oncology Group score of 0-1; (5) estimated survival of more than 6 months, with the possibility of performing R0 resection for curative purposes; (6) sufficient organ and bone marrow function within 7 days before enrollment; and (7) complete gastric D2 radical surgery. Exclusion criteria were: (1) history of anti-PD-1 or PD-L1 antibody therapy and chemotherapy; (2) treatment with corticosteroids or other immunosuppre- ssants within 14 days before enrollment; (3) active period of autoimmune disease or interstitial pneumonia; (4) history of other malignant tumors; (5) surgery performed within 28 days before enrollment; and (6) allergy to the drug ingredients of the study. Follow-up was conducted by outpatient and telephone methods. During preoperative SOX chemotherapy combined with PD-1 inhibitor immunotherapy, follow-up was conducted every 3 weeks to understand the occurrence of adverse reactions of the patients; follow-up was conducted once after 1 month of surgical treatment to understand the adverse reactions and survival of patients. Observation indicators were: (1) condition of enrolled patients; (2) reassessment after preoperative therapy and operation received (3) postoperative conditions and pathological results. Evaluation criteria were: (1) tumor staged according to the 8th edition of the American Joint Committee on Cancer (AJCC) TNM staging system; (2) tumor regression grading (TRG) of pathological results were evaluated with reference to AJCC standards; (3) treatment-related adverse reactions were evaluated according to version 5.0 of the Common Terminology Criteria for Adverse Events; (4) tumor response was evaluated by CT before and after treatment with RECIST V1.1 criteria; and (5) Clavien-Dindo complication grading system was used for postoperative complications assessment. Results: A total of 30 eligible patients were included. There were 25 males and 5 females with a median age of 60.5 (35-74) years. The primary tumor was located in the gastroesophageal junction in 12 cases, in the upper stomach in 8, in the middle stomach in 7, and in the lower stomach in 3. The preoperative clinical stage of 30 cases was III. Twenty-one patients experienced adverse reactions during neoadjuvant chemotherapy combined with immunotherapy, including four cases of CTCAE grade 3-4 adverse reactions resulting in bone marrow suppression and thoracic aortic thrombosis. All cases of adverse reactions were alleviated or disappeared after active symptomatic treatment. Among the 30 patients who underwent surgery, the time from chemotherapy combined with immunotherapy to surgery was 28 (23-49) days. All 30 patients underwent laparoscopic radical gastrectomy, of which 20 patients underwent laparoscopic-assisted radical gastric cancer resection; 10 patients underwent total gastrectomy for gastric cancer, combined with splenectomy in 1 case and cholecystectomy in 1 case. The surgery time was (239.9±67.0) min, intraoperative blood loss was 84 (10-400) ml, and the length of the incision was 7 (3-12) cm. The degree of adenocarcinoma was poorly differentiated in 18 cases, moderately differentiated in 12 cases, nerve invasion in 11 cases, and vascular invasion in 6 cases. The number lymph nodes that underwent dissection was 30 (17-58). The first of gas passage, the first postoperative defecation time, the postoperative liquid diet time, and the postoperative hospitalization time of 30 patients was 3 (2-6) d, 3 (2-13) d, 5 (3-12) d, and 10 (7-27) d, respectively. Postoperative complications occurred in 23 of 30 patients, including 7 cases of complications of Clavien-Dindo grade IIIa or above. Six patients improved after treatment and were discharged from hospital, while 1 patient died 27 days after surgery due to granulocyte deficiency, anemia, bilateral lung infection, and respiratory distress syndrome. The remaining 29 patients had no surgery-related morbidity or mortality within 30 days of discharge. Postoperative pathological examination showed TRG grades 0, 1, 2, and 3 in 8, 9, 4, and 9 cases, respectively, and the number of postoperative pathological TNM stages 0, I, II, and III was 8, 7, 8, and 7 cases, respectively. The pCR rate was 25.0% (8/32). Conclusion: Laparoscopic surgery after neoadjuvant SOX chemotherapy combined with PD-1 inhibitor immunotherapy for locally advanced gastric cancer is safe and feasible, with satisfactory short-term efficacy. Early detection and timely treatment of related complications are important.

Clinical effect of standardized nursing for lymphoma patients and the influencing factors of nosocomial infection.

To analyze the clinical effect of standardized nursing for lymphoma patients and the influencing factors of nosocomial infection, a total of 360 diffuse large B-cell lymphoma patients with disease recurrence or progression after first-line treatment were retrospectively selected from our hospital from January 2021 to July 2022. After standardized nursing, the overall infection rate of lymphoma patients was 2.50% (9/360), which was significantly lower than the overall infection rate of our hospital in 2021 (7.44%, 844/11342) (P < .05). The proportion of 3 kinds of pathogenic bacteria detected were G+ bacteria (33.5%), G- bacteria (53.3%), and fungi (13.2%). The pathogenic bacteria genus with the most G+ bacteria is Enterococcus, the pathogenic bacteria genus with the most G+ bacteria is Enterobacteriaceae, and the pathogenic bacteria with the most fungi is Candida albicans. Female infection rate was significantly higher than male (P < .05). There was no significant difference in nosocomial infection among different marital status/fertility status (P > .05). The nosocomial infection of patients with different hospitalization times was statistically significant (P < .05). The duration of hospitalization in the infected group was significantly higher than that in the non-infected group (P < .05). The clinical effect of standardized nursing for lymphoma patients is significant, and the influencing factors of nosocomial infection include patient gender, hospitalization frequency, and hospitalization duration.

MAD-Net: Multi-attention dense network for functional bone marrow segmentation

Radiotherapy is the main treatment modality for various pelvic malignancies. However, high intensity radiation can damage the functional bone marrow (FBM), resulting in hematological toxicity (HT). Accurate identification and protection of the FBM during radiotherapy planning can reduce pelvic HT. The traditional manual method for contouring the FBM is time-consuming and laborious. Therefore, development of an efficient and accurate automatic segmentation mode can provide a distinct leverage in clinical settings. In this paper, we propose the first network for performing the FBM segmentation task, which is referred to as the multi-attention dense network (named MAD-Net). Primarily, we introduce the dense convolution block to promote the gradient flow in the network as well as incite feature reuse. Next, a novel slide-window attention module is proposed to emphasize long-range dependencies and exploit interdependencies between features. Finally, we design a residual-dual attention module as the bottleneck layer, which further aggregates useful spatial details and explores intra-class responsiveness of high-level features. In this work, we conduct extensive experiments on our dataset of 3838 two-dimensional pelvic slices. Experimental results demonstrate that the proposed MAD-Net transcends previous state-of-the-art models in various metrics. In addition, the contributions of the proposed components are verified by ablation analysis, and we conduct experiments on three other datasets to manifest the generalizability of MAD-Net.

Clinical efficacy and safety of cefiderocol for resistant Gram-negative infections: a real-life, single-centre experience

Cefiderocol is a 'siderophore' cephalosporin active against Gram-negative bacteria, including carbapenem-resistant strains. Data on the use of cefiderocol in real life are limited. We evaluated the efficacy and safety of cefiderocol in the context of our hospital clinical practice. This was a single-centre, observational, retrospective clinical study. We collected data for all patients who received cefiderocol therapy in our hospital, with a focus on clinical outcomes and adverse events. The study cohort included 28 patients, with a median age of 73 years (25-83 years) and a high burden of co-morbidities. Up to 45 Gram-negative isolates were cultured from the study patients, the most common pathogen being Acinetobacter baumannii (31.1%). Cefiderocol was mostly prescribed for pneumonia (37.8% of cases), bloodstream infection (24.4%), urinary tract infection (22.2%) and intra-abdominal infection (20%), and largely as salvage therapy (92.8%). Of the 18 patients for whom follow-up cultures were available, 14 (77.8%) achieved eradication of the causative micro-organism. Therapeutic success (improvement/resolution of infection) occurred in 64.3% of cases at 7 days and 50% at 14 days from treatment start. Treatment failed in 9 cases (32.1%). No effects on kidney, liver or bone marrow function were observed. Cefiderocol showed fair efficacy and excellent tolerability in highly co-morbid patients with a range of multiresistant infections. It may be an option for infections due to colistin-resistant pathogens, when other regimens fail or in cases at risk of kidney dysfunction.

Immune pathophysiology of bone marrow failure

Bone marrow (BM) failure is a condition characterized by peripheral pancytopenia due to decreased BM function. It includes conditions such as acquired aplastic anemia (AA), myelodysplastic syndrome (MDS), and paroxysmal nocturnal hemoglobinuria (PNH). AA is characterized by pancytopenia and BM hypoplasia, and is primarily caused by an autoimmune mechanism involving cytotoxic T cells that damage hematopoietic stem cells (HSCs). Recent genomic research has revealed that patients with AA often exhibit clonal hematopoiesis by HSCs with genetic alterations, such as PIGA, DNMT3A, ASXL1, BCOR/BCORL1, copy-number neutral LOH of chromosome 6p (6pLOH), and HLA class I allele mutations. The genomic landscape of AA is distinct from MDS and age-related clonal hematopoiesis. Most notably, the presence of PNH-type cells and HLA class I allele-lacking cells indicates the presence of HSCs that have escaped from autoimmunity. We recently identified a common nonsense mutation at codon19 (c.19C>T, p.R7X) in exon1 (Exon1mut) of different HLA-A and HLA-B alleles, and HLA-DR loss of hematopoietic stem progenitor cells in AA patients carrying HLA-DR15. These results provide important clues for understanding the immune pathophysiology of BM failure.

Acute Myeloid Leukemia Transformed from Aplastic Anemia following Anti-thymocyte Globulin Therapy: A Case Report with Clinicopathologic and Molecular Findings

Abstract: Aplastic Anemia (AA) incidence is threefold higher in Asia compared to the western world. It is associated with pancytopenia that is induced by impaired bone marrow function. Cytopenias of at least two lineages are required for the diagnosis. Symptoms include pallor, weakness, fever, frequent infections, bruises, petechiae, and mucosal bleeding. Bone Marrow Transplant (BMT) and immunosuppressive therapy are the treatment options. Patients with Severe Aplastic Anemia (SAA) are susceptible to developing malignancies like acute myeloid leukemia (AML) or Myelodysplastic Syndrome (MDS). In this report, we present a case of SAA who transformed to AML/MDS. 5 years of post- Anti-Thymocyte Globulin (ATG), she acquired monosomy 7, RUNX1 &amp; SETBP1 gene mutations. RUNX1 and SETBP1 mutations are correlated with poor overall survival and are predicted to have a lack of response from hypo-methylating agents. As the aspect of somatic mutation is complex and still not fully understood, it should be cautiously analyzed along with morphologic and cytogenetic results.

ACMTR: Attention-guided, combined multi-scale, transformer reasoning-based network for 3D CT pelvic functional bone marrow segmentation

Automatic segmentation of pelvic functional bone marrow (FBM) in computed tomography (CT) plays a critical role in the accurate diagnosis of pelvic malignancies and treatment planning for patients. Pelvic bone marrow near the mid-axis of the body, i.e., the FBM, is the most hematopoietic. Here we propose an Attention-guided, Combined Multi-scale, Transformer Reasoning-based network (ACMTR) for accurate segmentation of pelvic FBM for intensity-modulated radiation therapy. The presented Convolution-Attention Fusion Encoder overcomes the limited receptive field of convolution as well as the class imbalance issue in pelvic FBM segmentation. We also propose a Multi-scale Transformer Global Reasoning Bottleneck module for obtaining multi-scale, global attention features for extraction of small edge tissue of the FBM. We introduce a deformable attention mechanism at the decoding path to focus on key features instead of redundant information with a minimal increase in computational complexity. The pelvic FBM CT images used in this study were from a self-constructed clinical database of 92 cases and showed two main areas of FBM: the most intense FBM area (i.e., most hematopoietic area) and the second most intense FBM area. The proposed ACMTR was compared with the popular deep learning models U-Net, VGG-Net, Attention-UNet, TransUNet, CoTr, nnUNet, and nnFormer. For the most intense and second most intense FBM areas, the proposed ACMTR achieved Dice Scores of 0.799 and 0.772 and Hausdorff Distance of 6.061 and 4.791, respectively, on test data. The implementation code is available at the following Github link:https://github.com/walynlee/ACMTR.

Sequential transarterial chemoembolisation and stereotactic body radiotherapy followed by immunotherapy as conversion therapy for patients with locally advanced, unresectable hepatocellular carcinoma (START-FIT): a single-arm, phase 2 trial

The synergy between locoregional therapies and immune checkpoint inhibitors has not been investigated as conversion therapy for unresectable hepatocellular carcinoma. We aimed to investigate the activity of sequential transarterial chemoembolisation (TACE) and stereotactic body radiotherapy followed by avelumab (an anti-PD-L1 drug) for locally advanced, unresectable hepatocellular carcinoma. START-FIT was a single-arm, phase 2 trial in patients with locally advanced hepatocellular carcinoma who were not suitable for curative treatment, conducted in two hospitals in Hong Kong and one in Shenzhen, China. Eligible patients were those aged 18 years or older with an Eastern Cooperative Oncology Group performance status 0-1, Child-Pugh liver function score A5 to B7, tumour size of at least 5 cm, a maximum of three tumour lesions, and adequate hepatic, renal, and bone marrow function. Participants received TACE on day 1, followed by stereotactic body radiotherapy (27·5-40·0 Gy in five fractions) at day 28. Avelumab (10 mg/kg) was administered 14 days following stereotactic body radiotherapy and every 2 weeks thereafter. The primary endpoint was the proportion of patients deemed amenable to curative treatment, defined as those who had a sustained complete or partial treatment response for at least 2 months and if curative treatment could be performed (ie, resection, radiofrequency ablation, or transplantation), analysed by intention to treat. Safety was also analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT03817736) and has been completed. Between March 18, 2019, and Jan 27, 2021, 33 patients (32 [97%] men and one [3%] woman) were enrolled. The median sum of the largest diameters of lesions was 15·1 cm (IQR 8·3-14·9). 21 (64%) patients had macrovascular invasion (hepatic vein [n=13], branched portal vein [n=3], or both [n=5]). Median follow-up was 17·2 months (IQR 7·8-25·8). 18 (55%) patients were deemed amenable to curative treatment: four (12%) of 33 patients had curative treatment (resection [n=2] or radiofrequency ablation [n=2]), and 14 (42%) had a radiological complete response and opted for close surveillance. 11 (33%) of 33 patients had treatment-related adverse events that were grade 3 or worse. The most common treatment-related grade 3 or worse adverse event was transient increase in alanine aminotransferase or aspartate aminotransferase (five [15%]) after TACE. Five (15%) patients developed immune-related adverse events of grade 3 or worse (three had hepatitis, two had dermatitis). To our knowledge, this is the first prospective trial using the combination of immunotherapy and locoregional treatment as conversion therapy for locally advanced unresectable hepatocellular carcinoma, with promising results. Future randomised trials with larger cohorts of patients are warranted. Merck.

812 FOLATES-RELATED ERYTHROCYTE DIVERSION LEAD TO ATRIAL CARDIOMYOPATHY/FIBRILLATION THROUGH EPCS DYSFUNCTION

Abstract Background Recent advances support the concept that pre-persistent Atrial Fibrillation (AF) and paradoxical embolism do not explain the wholeness of embolic strokes, thus suggesting a broad Atrial Cardiomyopathy (AC). Pathogenic mechanisms underlying AC are still largely unknown. Folate cycle disorders are a yet underrated dysmetabolism. MTHFR-inherited defects could hinder both endothelial and circulating endothelial progenitor cell (EPCs) functioning, therefore providing one-shot explanation to both atrial stasis (increasing atrial fibrosis and generating atrial hypocontractility even in sinus rhythm) and endothelial dysfunction (ED). Purpose This study aims to enquire for the hypothesis that: 1) atrial fibrosis (AFib – intended as a relative percentage of low voltage area in the context of left atrial endocavitary voltage mapping) would relate to folate cycle disorders (intended as both: a)MTHFR C677T inherited mutations and b)bone-marrow function disorders, here referring to erythropoiesis diversions) and 2) AF patients would show dysfunctional EPCs. Methods We studied 59 consecutive patients admitted to the cardiology Unit of the General Hospital “F.Miulli”, with preserved EF, subjected to AF ablation. AFib was quantified by bipolar peak-to-peak voltage areas (&amp;lt;0,5 mV) with respect to the wholeness of the picked voltage points. Blood count cell was evaluated by a commercial laboratory test. EPCs isolation and characterization were performed by Ficoll-Hypaque gradient and following flow cytometry analysis for cell surface antigens: CD45, CD34, CD133, VEGFR2 and KDR. EPCs functional wound healing assay was performed to determine the number of EPCs migrated to the “wound”, measuring the percentage of relative wound closure compared with matched-controls. Results Baseline characteristics did not differ between Sample and Control groups. % of Afib significantly differs between C677T MTHFR homozigosis patients (n=15) with respect to non-C&amp;//T MTHFR homozygosis patients (n=44 p &amp;lt; 0,02). Once univariate analysis was performed, subsequent multivariate analysis highlights highest fit once merged RBC, RDW-SD and folates values were inputed: Goodness of fit was proper, modelling good (Low figure - R2=0,39; p=0,0001). Either RBC, RDW-SD and folates coefficient reached significance (p &amp;lt; 0,0001; p &amp;lt; 0,01; p &amp;lt; 0,05 respectively). Number of EPCs significantly differs between AF patients and matched controls (p &amp;lt; 0,001). Conclusions Our findings support the hypothesis that genetically determined folates dysmetabolism (MTHFR dysfunction) promotes AFib via a complex cardiac-bone marrow networking involving circulating EPCs and unraveled by erythropoiesis diversions. Such results suggest a pathogenic role of folate cycle disorders in the AC development

Immune Ablation and Stem Cell Rescue in Two Pediatric Patients with Progressive Severe Chronic Graft-Versus-Host Disease

Transplantation of allogeneic hematopoietic stem cells represents an established treatment for children with high-risk leukemia. However, steroid-refractory chronic graft-versus-host disease (SR-cGvHD) represents a severe life-threatening complication, for which there is no standard therapy. After failing several lines of immunosuppressive and biological treatment, we applied an immunoablative therapy with re-transplantation of purified CD34+ donor stem cells to reset the aberrant immune system. Two pediatric patients, who had been transplanted for high-risk acute lymphoblastic leukemia, underwent the procedure. Interestingly, enough stem cells could be mobilized, harvested, and purified to be used as grafts more than one year after allogeneic transplantation under intensive immunosuppressive therapy and ongoing SR-cGvHD. With a follow-up of 8 and 22 months, respectively, both patients are without immunosuppressive therapy and do not show signs of active disease. Regeneration of skin manifestations started promptly, other damaged organs did not progress and continue to show recovery from severe fibrotic transformation. Bone marrow function is robust and T cell receptor repertoires showed polyclonal immune reconstitution. In conclusion, stem cell harvest and re-transplantation of human CD34+-selected allogeneic stem cells is possible and represents a new therapeutic option in SR-cGvHD by resetting a profoundly disturbed immune network.

AlphaBet: Combination of Radium-223 and [17 7Lu]Lu-PSMA-I&T in men with metastatic castration-resistant prostate cancer (clinical trial protocol).

[177Lu]Lu-PSMA is a radioligand therapy used in metastatic castration-resistant prostate cancer (mCRPC). Despite a survival benefit, the responses for many patients receiving [177Lu]Lu-PSMA are not durable, and all patients eventually develop progressive disease. The bone marrow is the most common site of progression. Micrometastases in this area likely receive an inadequate dose of radiation, as the emitted beta-particles from 177Lu travel an average range of 0.7 mm in soft tissue, well beyond the diameter of micrometastases. Radium-223 (223Ra) is a calcium-mimetic and alpha-emitting radionuclide approved for use in men with mCRPC with bone metastases. The range of emitted alpha particles in soft tissue is much shorter (≤100 μm) with high linear energy transfer, likely more lethal for osseous micrometastases. We anticipate that combining a bone-specific alpha-emitter with [177Lu]Lu-PSMA will improve eradication of micrometastatic osseous disease, and thereby lead to higher and longer responses. This is a single-center, single-arm phase I/II trial evaluating the combination of 223Ra and [177Lu]Lu-PSMA-I&T in men with mCRPC. Thirty-six patients will receive 7.4 GBq of [177Lu]Lu-PSMA-I&T, concurrently with 223Ra in escalating doses (28 kBq/kg - 55kBq/kg), both given intravenously every six weeks for up to six cycles. Eligible patients will have at least two untreated bone metastases visible on bone scintigraphy, and PSMA-positive disease on PSMA PET scan. Patients must have adequate bone marrow and organ function and be willing to undergo tumor biopsies. Patients with discordant disease visible on FDG PET scan (defined as FDG positive disease with minimal or no PSMA expression and no uptake on bone scan) will be excluded. Other key exclusion criteria include the presence of diffuse marrow disease, prior treatment with 223Ra or [177Lu]Lu-PSMA, or more than one prior line of chemotherapy for prostate cancer. The co-primary objectives of this study are to determine the maximum tolerated dose of 223Ra when combined with [177Lu]Lu-PSMA-I&T and the 50% PSA response rate. The AlphaBet trial is a phase I/II study combining 223Ra with [177Lu]Lu-PSMA-I&T in patients with mCRPC. We aim to enroll the first patient in Q3 2022, and recruitment is anticipated to continue for 24 months. NCT05383079.

Brentuximab vedotin plus nivolumab after autologous haematopoietic stem-cell transplantation for adult patients with high-risk classic Hodgkin lymphoma: a multicentre, phase 2 trial

After autologous haematopoietic stem-cell transplantation (HSCT), consolidation with brentuximab vedotin in patients with high-risk relapsed or refractory classic Hodgkin lymphoma has been shown to improve progression-free survival compared with placebo. Brentuximab vedotin plus nivolumab is a safe and effective treatment for relapsed or refractory classic Hodgkin lymphoma; therefore, we aimed to evaluate the safety and activity of this drug combination post-autologous HSCT consolidation in patients with high-risk relapsed or refractory classic Hodgkin lymphoma. We did a multicentre phase 2 trial at five centres in the USA. Eligible patients were aged 18 years or older with high-risk relapsed or refractory classic Hodgkin lymphoma, had an ECOG performance status of 0-2, and had adequate organ and bone marrow function. Enrolled patients received brentuximab vedotin (1·8 mg/kg) and nivolumab (3 mg/kg) intravenously starting 30-60 days after autologous HSCT on day 1 of each 21-day cycle for up to 8 cycles. Nivolumab dose reduction was not allowed. Brentuximab vedotin dose reduction to 1·2 mg/kg was permitted. If one drug was discontinued because of a toxic effect, the other could be continued. The primary endpoint was 18-month progression-free survival in all treated patients. This study is registered with ClinicalTrials.gov, number NCT03057795. Between May 3, 2017, and July 13, 2019, 59 patients were enrolled and received the study therapy. Patients initiated brentuximab vedotin plus nivolumab for a median of 54 days (IQR 46-58) after autologous HSCT and received a median of 8 cycles (8-8). 34 (58%) of 59 patients were male, 29 (49%) completed 8 cycles of brentuximab vedotin plus nivolumab, and 45 (76%) completed 8 cycles of at least one drug. The median follow-up time was 29·9 months (IQR 24·6-34·8). The 18-month progression-free survival in all 59 patients was 94% (95% CI 84-98). The most common adverse events were sensory peripheral neuropathy (31 [53%] of 59) and neutropenia (25 [42%]), and immune-related adverse events requiring corticosteroids occurred in 17 (29%) of 59 patients. No treatment-related deaths were observed. Brentuximab vedotin plus nivolumab was highly active post-autologous HSCT consolidation for patients with high-risk relapsed or refractory classic Hodgkin lymphoma, most of whom had previous exposure to either brentuximab vedotin or PD-1 blockade. Combination immunotherapy in this setting should be further studied in patients with classic Hodgkin lymphoma with further refinement of the regimen to mitigate toxic effects, particularly in high-risk patients in whom more intensive therapy to prevent relapse is warranted. Bristol Myers Squibb, Leukemia and Lymphoma Society, Lymphoma Research Foundation, and National Cancer Institute of the National Institutes of Health.

DNA-Demethylating Agents Combined with Anti-PD-1 Inhibitors Showed Activity in Patients with Relapsed or Refractory Extranodal NK/T Cell Lymphoma Who Have Failed Immunotherapy: An Exploratory Study

Background: Extranodal natural killer (NK)/T-cell lymphoma (ENKTL) is a rare aggressive type of non-Hodgkin's lymphoma associated with Epstein-Barr virus infection. Relapse or refractory (RR)-ENKTL cases are characterized by a high rate of relapse and dismal prognosis with limited therapeutic options. Immune check point inhibitors (ICIs) represent the cornerstone of treatment for RR-ENKTL; however, limited information is available of a rechallenge with ICIs after ICIs are discontinued due to disease progression. Epigenetic aberrations are critical as genetic abnormalities is the hallmarks of ENKTL. One of current promising strategies is that combining epigenetic and ICIs can overcome tumor resistance and enhance immunotherapy responses. Here, we assess the efficacy and safety of DNA methyltransferases inhibitors (DNMTi) plus anti-PD-1 therapy in RR-ENKTL. Methods: This trial enrolled eligible patients with histologically confirmed RR-ENKTL failing from asparaginase-based regimen or ICIs therapy; adequate organ function and bone marrow function; and at least one measurable or evaluable lesion or symptoms. Patients received standard dosage of anti-PD-1 antibodies plus decitabine (10mg/d, d1-5) or azacytidine (100mg/d, d1-5) every 21 days until disease progression, death, intolerable toxicity. Patients accept ASCT as consolidation after they obtained CR. The primary endpoints were objective response rate (ORR) based on Lugano 2016 criteria and clinical benefit rate. Secondary endpoints were progression-free survival (PFS), overall survival (OS) and safety. Adverse events (AEs) were defined according to CTCAE 5.0. Results: From March 2020 to May 2022, 27 eligible patients were enrolled. Median age 40 years (range, 12-77), 15 (55.6%) male, 13 (48.1%) patients with stage IV of disease at screening, 11 (40.7%) patients with PINK-E score ≥ 3 points. Among them, 5(18.5%) patients had no imaging lesions, but all peripheral blood ctDNA were positive, they had high plasma EBV-DNA level(n=3), persistent fever(n=2) associated with ENKTL. The median number of prior systemic therapies was 2 (1-5), 21（77.8%）patients received ≥ 2 lines of prior systemic therapy. Twenty-two (81.5%) patients experienced prior ICIs therapy, 23(85.2%) previously received HDACi. The median time between the last dose of prior ICIs and initiation of this trial was 0.8 months (0.8 -23). Seven (25.9%) patients received decitabine, 20 (74.1%) received azacytidine. Of 22 imaging objective response evaluable patients, 13 (59.1%) achieved response (iORR) including 10 (45.5%) patients with CR (iCR). Clinical benefit analysis of 27 patients showed that clinical response(cORR) was 63.0% (17/27), 14 (59.1%) got CR (cCR). Among 5 patients with positive ctDNA alone, 4 patients achieve clinical improvement ,ctDNA negativity(n=4), EBV clearance(n=2) or fever disappearance (n=2). Among 22 patients previously received ICIs (20 patients previously received anti-PD-1 antibody plus HDACi), of these, 11 (50%) had response. After anti-PD-1 antibodies rechallenge plus DNMTi, iORR and cORR were 58.8% (10/17), 63.6% (14/22), iCR and cCR were 41.2% (7/17), 50.0% (11/22), respectively. Anti-PD-1 antibodies rechallenge plus DNMTi yielded iORR were 72.7% (8/11) and 55.6% (5/9) in patients responded to prior ICIs therapy. The difference of efficacy between decitabine and azacytidine was no significant, iORR and cORR were 60% (3/5), 58.8% (10/17) and 71.4% (5/7), 60.0% (12/20), respectively in this study. The median follow-up time was 12.1 (1.9-28.0) months, 1-year OS rate was 70.4%, median PFS rate was 12.8months. Survival results were similar with decitabine and azacytidine cohort. Sixteen (59.3%) patients reported treatment-related AEs (TRAEs). The most frequently observed (≥10%) TRAEs were lymphopenia (44.4%), neutropenia (37.0%), hypothyroidism (25.9%), nausea (18.5%), hyperglycemia (11.1%). Conclusion: DNMTi combined with anti-PD-1 immunotherapy showed promising efficacy and manageable safety profile in RR-ENKTL for the first time. ICIs rechallenge is still an active and feasible strategy, further prospective studies are needed to clarify the role of rechallenge ICIs in this population. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Efficacy and Safety of Lenalidomide, Anti-PD-1 Antibody Combined with Orelabrutinib or Rituximab in the Treatment of Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma worldwide. Although most patients with DLBCL respond to first-line chemoimmunotherapy with R-CHOP, approximately 40% of patients will have relapsed or refractory disease. Currently, the second-line therapeutic regimen is chemoimmunotherapy followed by consolidative autologous hematopoietic stem cell transplantation (AHCT) for relapsed/refractory DLBCL (R/R DLBCL). However, the prognosis has remained poor. (Sawalha. J Pers Med. 2021). Thus, discovering effective treatment regimens for patients with R/R DLBCL has become extremely crucial. Recently, a combination regimen of lenalidomide, anti-programmed cell death protein-1 (PD-1) antibody, and rituximab demonstrated a good efficacy with an overall response rate (ORR) of 40% in R/R DLBCL (Sethi et al. Blood. 2019). Activation of the Bruton's tyrosine kinase (BTK)-mediated B-cell receptor (BCR) signaling pathway is a hallmark of DLBCL (Kapoor et al. Cell Death Dis. 2019). Orelabrutinib, a novel and potent irreversible BTK inhibitor, has shown encouraging efficacy with an ORR of 61.5% in combination with a new generation anti-CD20 antibody MIL62 in R/R DLBCL (Xu et al. Blood. 2020; Thus, we assessed the efficacy and safety of lenalidomide, anti-PD-1 antibody combined with orelabrutinib or rituximab in R/R DLBCL. Methods: This was a prospective, multicenter, single-arm, open-label, phase II study (ChiCTR2200056256). Patients aged 18 to 75 years were eligible if they had histologically confirmed R/R DLBCL, an Eastern Cooperative Oncology Group performance status of 0-2, adequate organ and bone marrow function, and survival time ≥ 6 months. Eligible patients received a combination regimen (21-day/cycle) of lenalidomide (10-25 mg, days 1-10, QD, oral), Tislelizumab (200 mg, day 1, intravenous), and orelabrutinib (150 mg, QD, oral) or rituximab (375 mg/m2, day 1, intravenous). The primary endpoint was ORR. Secondary endpoints included complete response (CR), progression-free survival (PFS), duration of response (DOR), time to response (TTR) and adverse events (AEs). Efficacy was assessed using Lymphoma Response to Immunomodulatory therapy Criteria (LYRIC, 2016). AEs were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) v 4.0. Results: Between August 2021 and March 2022, 9 patients (6 males; median age, 73 years, range 65-76) were enrolled. Among them, 8 patients were non-germinal center B-cell-like and 1 was unknown. Most patients had comorbidities (n=8, 88.9%), an Ann Arbor stage of III or IV (n=4, 44.4%), International Prognostic Index (IPI) ≥ 3 (n=4, 44.4%). All patients received lenalidomide, anti-PD-1 antibody combined with orelabrutinib regimen, and the median duration of treatment was 5 cycles (range 3-6). Among them, 4 patients (44.4%) received a second-line therapy, and 5 patients (55.5%) received ≥ third-line therapy. Before enrollment, 3 patients attained a CR as their best response during the previous therapies. Eight patients were included in the efficacy analysis. The ORR, CR and median TTR were 87.5%, 25.0%, and 2.45 months (range 1.97-2.73), respectively. Among them, 3 patients completed 6 cycles of therapy with ORR of 100% (Figure 1). The PFS and DOR were not completely mature due to the short follow-up period at the end of follow-up. Eight (80%) patients reported AEs. The most common hematological AEs were anemia (77.8%), platelet count reduced (55.6%), neutrophil count decreased (33.3%) and white blood cell count decreased (22.2%). Three patients (33.3%) discontinued treatment due to AEs (atrioventricular block, n=1; rash, n=2). In addition, the most common AEs were grade 1 or 2, and no grade 4 AEs. One patient died due to electrolyte disturbances and depression. Conclusion: Lenalidomide, anti-PD-1 antibody combined with orelabrutinib or rituximab regimen is effective and well-tolerated for patients with R/R DLBCL in this phase II study. This study provides a potential novel strategy for the treatment of R/R DLBCL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A First-in-Human Phase 1 Study of Abbv-319, an Antibody-Drug Conjugate Composed of a CD19 Antibody Linked to a Potent Proprietary Glucocorticoid Receptor Modulator, in Patients with Relapsed or Refractory B-Cell Malignancies

Background Systemic glucocorticosteroids (ie, glucocorticoid receptor modulators [GRMs]) show robust monotherapy activity against B-cell malignancies at high doses; however, they may be accompanied by steroid-associated toxicities that limit dosing. CD19 is a marker essential for B-cell proliferation and has high expression across B-cell malignancies including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and chronic lymphocytic leukemia (CLL). ABBV-319 is a CD19-GRM antibody-drug conjugate (ADC) composed of an optimized high-affinity immunoglobulin G1 antibody conjugated to a potent proprietary glucocorticosteroid payload. ABBV-319 takes advantage of both enhanced antibody-dependent cellular cytotoxicity (via afucosylation) and targeted GRM payload delivery to maximize anticancer activity while lowering the risk of systemic steroid toxicities. Preclinically, ABBV-319 demonstrates sustained antitumor efficacy in models of human B-cell malignancies that compares favorably with approved therapeutics. This phase 1 study evaluates safety and clinical activity of ABBV-319 monotherapy in patients with relapsed or refractory (R/R) B-cell malignancies. Methods This is a phase 1, first-in-human, open-label, dose-escalation, dose-expansion, biomarker/pharmacodynamic (PD) study in patients aged ≥18 years with R/R B-cell malignancies. Key eligibility criteria include measurable disease and Eastern Cooperative Oncology Group performance status of 0 or 1. In addition, patients must meet predefined criteria for adrenal, bone marrow, kidney, and liver function, coagulation parameter levels, and hemoglobin A1c levels (dose escalation only) during screening. The primary objectives are to evaluate safety, tolerability, pharmacokinetics (PK), and immunogenicity of ABBV-319 and identify a recommended phase 2 dose (RP2D). The secondary objective is to evaluate the efficacy of ABBV-319 in patients with R/R DLBCL, FL, and CLL. Exploratory objectives include evaluating the effect of ABBV-319 on QT prolongation and evaluating PD and predictive biomarkers. This study will be conducted in 2 parts - dose escalation (Part 1) and dose expansion (Part 2). Part 1 aims to determine the RP2D for ABBV-319 following a Bayesian optimal interval design, with a maximum of 2-fold increments that reduce as the dose increases. RP2D will be determined on the basis of all the data collected in Part 1 including safety, tolerability, PK, PD, and efficacy, if available. Part 2 will further evaluate ABBV-319 at the RP2D in 3 separate subtypes of B-cell malignancies - DLBCL, FL, and CLL. A total of 114 patients are planned to be enrolled - 54 patients with various R/R B-cell malignancies in Part 1, and 60 patients in Part 2 (20 patients included for each R/R B-cell malignancy subtype: DLBCL, FL, and CLL). ABBV-319 will be administered intravenously until disease progression, intolerable toxicity, or other study discontinuation criteria are met, for a maximum of ~24 months from the last patient enrolled. Safety assessments include adverse event monitoring (per National Cancer Institute Common Terminology Criteria for Adverse Events v5.0), physical examinations, vital sign measurements, and clinical laboratory testing. Dose-limiting toxicities will be assessed. PK parameters including maximum observed serum/plasma concentration (Cmax), time to Cmax, terminal plasma elimination half-life, and area under the serum/plasma concentration-time curve will be analyzed using noncompartmental methods for ABBV-319 total antibody, ADC, and unconjugated GRM payload. Antidrug antibodies (ADAs) and neutralizing ADAs may also be determined, as appropriate. Efficacy will be evaluated in terms of response per disease-specific criteria (including International Workshop on Chronic Lymphocytic Leukemia, International Workshop on Waldenstrom's Macroglobulinemia, and Lugano classification). Duration of response, time to response, progression-free survival, and overall survival will be evaluated per Kaplan-Meier analysis. QT prolongation, PD, and biomarker data will be assessed as changes from baseline and may be summarized for each scheduled postbaseline visit.

A Phase 1 Dose-Escalation Study of the Oral Epichaperome Inhibitor, Zelavespib (ZEL) in Combination with Ruxolitinib (RUX), in Patients with Relapsed Myelofibrosis: Results of the Dose Escalation Stage

Background: ZEL (PU-H71) is an oral synthetic purine-scaffold epichaperome inhibitor that selectively binds to epichaperome complexes found in cancer cells via the altered ATP binding site of disease-associated heat shock protein (HSP90). ZEL has shown efficacy in cell line and mouse models of myeloproliferative neoplasm (MPN) and specifically myelofibrosis (MF) by disrupting JAK2 protein stability, resulting in dose-dependent inhibition of cell growth and signaling. JAK2 inhibitors are the only currently approved class of therapies for intermediate/higher risk MF, but there is still an urgent unmet medical need for 2nd line and beyond therapies. An emerging approach is the add-on/add-back strategy, with the addition of the second/novel agent in the setting of suboptimal response to JAKi monotherapy. In a prior trial of ZEL as IV monotherapy in an advanced malignancy study (including both solid and hematologic malignancies), ZEL demonstrated clinical activity in patients with lymphoma and MF. Based on this efficacy signal, the tolerability profile of ZEL in hematological malignancies, and the potential for synergy between mechanisms of action, a study with ZEL in combination with RUX was initiated. The present phase 1 study is the first to establish the safety, MTD, and preliminary efficacy of oral ZEL when added to RUX in MF (NCT03935555). Methods: Patients with primary, post-polycythemia vera or post-essential thrombocythemia MF were eligible if age ≥18 years, ECOG performance status ≤2, treatment with RUX >3 months prior to start with persistent or worsening splenomegaly and disease-related symptoms (by MPN-SAF TSS), adequate cardiac, hepatic and renal function, platelets ≥ 25,000/uL, ANC ≥500/uL, and no active ocular pathology. Oral solution of ZEL was administered daily in continuous 21-day cycles in combination with each patient's stable baseline RUX dose. The initial dose of ZEL was 50 mg with each subsequent cohort dose-escalating by 50 mg QD increments. DLTs were assessed in Cycle 1 (21 days). Response was assessed by IWG-MRT and ELN criteria. Results: Eleven patients have been enrolled: 3 patients each in the 50 and 100 mg cohorts, and 5 in the 150 mg cohort following DLT-driven cohort expansion. Median age was 69 years (range 59-78). Baseline RUX dose ranged from 5-25 mg bid, with a median of 15 mg. Median number of ZEL cycles administered was 4 (range 1-25). Most AEs were Gr 1 and 2 and the most frequent were abdominal pain, diarrhea and fatigue. Gr 4 thrombocytopenia in 2 patients (150 mg) met DLT criteria with platelet nadirs of 7K and 22K during cycle 1. One patient (150 mg with symptomatic improvement) developed Grade 3 bone marrow hypoplasia after 22 cycles of treatment, an SAE judged by the Investigator to be related to treatment. To date, 2 patients (1 each at 100 and 150 mg) demonstrated symptom improvement without significant reduction in spleen size. One patient (50 mg) had stable disease maintained for 20 cycles and successfully bridged to allogeneic stem cell transplant. Allele burden, cytokine profiles, flow cytometry for biomarkers, and PK analyses are in progress and will be presented. Conclusions: The ZEL dose 100 mg QD was well tolerated and was selected as the RP2D in combination with RUX. Although ZEL has not been shown to cause myelosuppression as monotherapy, further evaluation is necessary to understand possible effects on bone marrow and megakaryocyte function when used in combination with RUX. Further exploration of the therapeutic potential of oral ZEL in the treatment of MF and other MPNs, as monotherapy and with RUX, is warranted.

First-in-Human Study of Elvn-001, a Highly Selective BCR::ABL1 Tyrosine Kinase Inhibitor, in Patients with Chronic Myeloid Leukemia Who Failed Previous Tyrosine Kinase Inhibitor Therapies

Background: Despite the benefits BCR::ABL1 tyrosine kinase inhibitors (TKIs) have provided altering the natural history of chronic myeloid leukemia (CML), resistance/lack of response and intolerability occurs. ELVN-001 is a highly selective small molecule active site inhibitor of ABL1 that does not significantly inhibit the receptor tyrosine kinases PDGFR, KIT, VEGFR2 or the Src-family (eg SRC, LCK, LYN, FYN). In vitro data also supports ELVN-001 targeting the most common CML mutation, T315I and not being a substrate for drug efflux transporters such as BCRP, which may contribute to resistance or sensitivity to other TKIs. Non-clinical data suggests ELVN-001 has a favorable absorption, distribution, metabolism, elimination and a pharmacokinetic (PK) profile supporting once daily (QD) dosing, low risk of QTc prolongation, and potential to avoid drug-drug interactions, particularly CYP-mediated. This first-in-human (FIH) study will evaluate the safety, tolerability, PK and preliminary anti-CML activity of ELVN-001 in patients (pts) with chronic (CP) or accelerated phase CML with and without T315I mutations. Objectives: The primary objectives are to determine the recommended doses for expansion (RDE) and to evaluate the safety and tolerability of ELVN-001. Secondary objectives are to assess the PK profile and preliminary efficacy. Design: A phase 1 open-label, multi-center, dose escalation and expansion study. Eligible pts are adults with CP and AP CML who are intolerant or have failed (as per ELN 2020 Recommendations) available TKIs known to be active for treatment of their CML. Other key eligibility criteria are Eastern Cooperative Oncology Group performance status 0-2, adequate bone marrow, renal and liver function, and resolved adverse effects of prior therapy. Prior marrow transplant is allowed. CML with point mutations E255, Y253, G250, F317 or Q252 are excluded. Successive cohorts will receive escalating doses of ELVN-001 starting at 10 mg QD. Dosing will be continuous in 28-day cycles until treatment failure, disease progression or unacceptable toxicity. A standard 3+3 dose escalation will be used, with PK/pharmacodynamic modeling to identify the RDEs, assuming toxicity is not dose limiting. Safety and efficacy of ELVN-001 will be further explored in CP-CML without T315I mutations and a cohort of T315I mutated CP-CML. Mutational analyses by Sanger and NGS will be conducted at baseline and end of treatment. Main Outcomes: Primary endpoints are dose limiting toxicities, adverse events, laboratory and ECG abnormalities. Secondary endpoints are PK parameters, response based on BCR-ABL transcript levels by quantitative PCR and hematology. Conclusions: This FIH study will evaluate dosing, safety, tolerability, PK profile and preliminary efficacy of ELVN-001 in CP-CML with and without T315I mutation. Study sponsor: Enliven Therapeutics. NCT05304377 ELVN-001-101 Schema: Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

An Open-Label, Multicenter,Single-Arm, Phase I Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics and Efficacy of XNW5004 in Patients with Relapsed or Refractory Hematologic Malignancies

Background: The abnormal regulation and overexpression of Enhancer of zeste homolog 2 (EZH2) was tested in advanced tumor. EZH2 inhibits the transcription of target genes by trimethylation of lysine 27 on histone H3 (H3K27me3), and its activity-enhancing mutation and abnormal expression are the decisive factor for abnormal transcription in many tumors. Besides, EZH2 significantly correlated with tumor malignancy and poor prognosis. XNW5004 is a class of small-molecule EZH2 inhibitor. Preclinical shows that XNW5004 has good safety and anti-tumor efficacy. Methods: This Chinese, open-label, single-arm, multicenter, phase I study is evaluating the safety, tolerability, Pharmacokinetics (PK), Pharmacodynamics (PD), and efficacy of XNW5004 in adult subjects with pathologically confirmed relapsed/refractory non-Hodgkin lymphoma (NHL). Eligibility criteria included an Eastern Cooperative Oncology Group (ECOG) performance score of 0-1, life expectancy ≥12 weeks, and adequate bone marrow, renal, and liver function. The study uses an accelerated titration and traditional 3+3 dose-escalated design, with a cycle of 28 days. This study reports data on pts with dose-escalated phase. Results: In the dose-escalated phase, as July 15, 2022 , a total of 15 pts were enrolled and treated with 5 dose groups of XNW5004 (from 100 mg to 1600 mg BID). The median age was 58 years (range, 47-71). Pts received a median of 3 (range, 2-7) prior lines of treatment and diagnoses of diffuse large B-cell lymphoma (DLBCL, n = 3), follicular lymphoma (FL, n = 6), mantle cell lymphoma (MCL, n = 1), marginal zone lymphoma (MZL, n = 2), small lymphocytic lymphoma (SLL, n = 1), angioimmunoblastic T-cell lymphoma (AITL, n = 1), and Waldenström macroglobulinemia (WM, n = 1). XNW5004 had a favorable safety and tolerability, and no dose-limiting toxicity (DLT) was observed at doses up to 1600 mg BID. Grade 3 treatment-related adverse events (TRAEs) occurred in 4 (26.7%) pts, including white blood cell decreased, neutrophil count decreased, lymphocyte count decreased, and platelet count decreased. No grade ≥4 adverse events (AEs) and serious TRAEs occurred. Any grade TRAEs in ≥20% of pts included nausea (33.3%), diarrhea (33.3%), alanine aminotransferase increased (26.7%), neutrophil count decreased (26.7%), white blood cell decreased (26.7%), hypertriglyceridemia (26.7%), aspartate aminotransferase increased (20%), vomiting (20%), blood lactate dehydrogenase increased (20%), blood bilirubin increased (20%), pruritus (20%), anemia (20%). With a median follow-up of 4 (range, 2-10) cycles, the objective response rate (ORR) was 33.3%, and the disease control rate (DCR) was 78% in the 9 evaluable pts. The median progression-free-survival (mPFS) and median duration of response (mDOR) were not reached. Among pts with EZH2 wild-type (WT) FL (n=5) , the ORR was 40%, the DCR was 100%, the mPFS and mDOR were not reached. In all pts with stable disease (SD), the lesions continued to shrink. One patient (Figure 2) with DLBCL (non-GCB) received 2 cycles of XNW5004, the lesions were reduced by 59.8%; and after 4 cycles of treatment, the lesions were reduced by more than 70%. One patient (Figure 3) with FL (EZH2 WT) received 2 cycles of XNW5004, the subcutaneous lesions and axillary lymph nodes were significantly reduced, PET-CT showed that uptake was strongly reduced, and the Deauville score (DS) was 5 and 3, respectively. The efficacy evaluation was partial response (PR). After 4 cycles of treatment , PET-CT showed that the metabolism of subcutaneous lesions and axillary lymph nodes continued to decrease, the DS was 2 and 1, respectively, and the efficacy evaluation was complete response (CR). In addition, the PK of XNW5004 was well. Conclusions: XNW5004 was safety, well tolerated, and efficacy in pts with different types of lymphomas despite high disease burden, with encouraging preliminary anti-lymphoma activity observed. These data support ongoing dose-escalated phase , with multiple cohort expansions at multiple doses. Internal Study identifier: XNW5004-I/II-01. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal