Acute monocytic leukemia (AML-M5) is a type of acute myeloid leukemia, characterized by a dominance of monocytes in the bone marrow and peripheral blood. AML-M5 exhibits a poor prognosis compared to other AML subtypes. Despite clinical recognition, current research on AML-M5 remains relatively limited, and its underlying pathogenic mechanisms are not yet fully understood. In this study, we uncover a distinct and heightened expression of CBX4, a core component of PRC1, in the peripheral blood of individuals diagnosed with AML-M5. By generating cbx4 overexpression transgenic and deleted mutant zebrafish lines, we observe elevated cbx4 expression in monocyte/macrophage, selectively modulating their production during zebrafish hematopoiesis. Notably, aging zebrafish with cbx4 overexpression exhibit a progression to AML-M5-like hematopoiesis. Further mechanistic analyses reveal that Cbx4 regulates the fate of monocyte/macrophage lineage by suppressing runx1 expression. This suppression is achieved through the recruitment of HDAC to the runx1 promoter via cbx4, resulting in the down-regulation of the H3K27 acetylation level of runx1. These findings offer novel insights, providing potential avenues for risk assessment and molecular diagnosis of AML-M5 leukemia. Moreover, CBX4 emerges as a promising target for the diagnosis and treatment of AML-M5 leukemia.

BACKGROUND CONTEXT:Surgical intervention is often required in cases of spinal solitary bone plasmacytoma (SBP) with nerve compression. There is no sufficient evidence to ascertain the advantages of short- and long-term prognosis in such patients receiving en bloc surgery (ES) versus separation surgery (SS). PURPOSE:To evaluate both short- and long-term outcomes of ES versus SS in patients with spinal SBP. STUDY DESIGN:Multicenter mixed cohort study. PATIENT SAMPLE:From January 2000 and December 2021, 130 patients with spinal SBP were enrolled. OUTCOME MEASURES:The primary outcomes were overall survival (OS) and multiple myeloma progression-free survival (MPFS), and the secondary outcomes were postoperative neurological functions, visual analogue scale (VAS) and Karnofsky Performance Status (KPS) of the patients and short- or long-term complications. METHODS:Of the 130 included patients, 43 received ES, and the other 87 patients received SS plus radiotherapy. Operative data, relief of preoperative symptoms, survival prognosis, disease progression, and local control were compared between the 2 groups. Bias was minimized via 1:1 propensity score matching (PSM) for age, tumor location and clonal plasma cells in bone marrow. Cox regression models were performed to investigate the association between surgical strategies and primary outcomes, adjusting for confounding factors. In addition, subgroup analysis was carried out based on sex, age, tumor location, clonal plasma cells in bone marrow, and serum M-protein. Finally, a sensitivity analysis that excluded patients with cervical SBP was performed to investigate the robustness and potential sources of bias in our findings. RESULTS:Improvement of neurological symptoms, performance status and pain relief were achieved in both ES and SS groups at 3 months after surgery (both p<.05). Risk of pleural effusion was significantly higher in ES group (p=.003). The 5- and 10-year OS rate was 82.6% and 67.4% in the entire cohort, respectively. No significant difference was observed in OS between ES and SS groups (p=.190). The 5- and 10-year MPFS rate was 71.2% and 55.7% in the entire cohort, respectively, showing no significant difference between the 2 groups (p=.402). Also, Cox regression models showed no significant association of the surgical type with OS and MPFS. One of 43 patients (2.33%) in ES group and 6 of 87 patients (6.90%) in SS group developed local recurrence during the follow up periods (p=.223). Subgroup analysis showed that ES offered potentially better prognosis in terms of OS and MPFS (both p<.05) for spinal SBP with no marrow involvement, and these findings were consistent after PSM. The results of this sensitivity analysis were similar to those from the primary analysis. CONCLUSION:OS and MPFS were equally satisfactory between the patients who received SS plus radiotherapy and those who received ES. For spinal SBP with no marrow involvement, ES may prove to be a better option to achieve long-term disease control.

Primary testicular lymphoma (PTL) is a rare but aggressive form of extranodal lymphoma with a high risk of central nervous system (CNS) relapse and poor long-term survival. However, the optimal CNS prophylaxis strategy and effective prognostic models for PTL remain unclear. This study aimed to evaluate the prognostic impact of intrathecal (IT) prophylaxis and to develop a novel, simplified prognostic model in a Chinese multicenter cohort. We retrospectively collected data from a total of 55 patients with PTL, treated at three major tertiary hospitals in China. Multivariate Cox regression identified independent prognostic factors for overall survival (OS) and progression-free survival (PFS). A new risk stratification model (BL model, based on B symptoms and LDH levels) was constructed and validated using time-dependent C-index and calibration plots, and compared with the International Prognostic Index (IPI). IT prophylaxis reduced CNS relapse rates (9.1

BEN domain-containing protein 4 (BEND4) is implicated in various cancer-related processes, but its role in diffuse large B-cell lymphoma (DLBCL) remains unclear. This study examined BEND4’s impact on DLBCL prognosis through bioinformatics analysis. BEND4 expression was analyzed across the cancer cell line encyclopedia (CCLE), human protein atlas (HPA), and the cancer genome atlas (TCGA) databases. Associations between BEND4 expression and survival outcomes, prognosis, and immune infiltration levels of DLBCL were evaluated via TCGA. Gene set enrichment analysis (GSEA) identified potential BEND4 biological functions. The predictive value of BEND4 and related genes for DLBCL mortality was assessed using time-dependent receiver operating characteristic curve (ROC) analysis. Findings were validated through qRT-PCR and cell proliferation assays. BEND4 was overexpressed at mRNA and protein levels in DLBCL. High BEND4 expression correlated with shorter survival, higher disease-specific mortality, and poor prognosis, emerging as an independent risk factor. GSEA revealed associations between BEND4 and chromatin remodeling, immune response, epigenetic regulation, and signal transduction. Immune infiltration analysis showed BEND4 expression was inversely correlated with eosinophils, cytotoxic cells, and Tgd cells infiltration. ROC analysis confirmed BEND4 and related genes as key predictors of DLBCL mortality at 1, 3, and 5 years. In vitro, BEND4 inhibition did not alter Riva cells proliferation but enhanced sensitivity of Riva cells to chemotherapy, including doxorubicin. Elevated BEND4 levels were linked to poor prognosis and chemoresistance in DLBCL, potentially due to transcriptional regulation and immune suppression roles. BEND4 may represent a viable therapeutic target in DLBCL.

Objective:To explore and evaluate the efficacy and safety of a modified thiotepa-based conditioning regimen combined with autologous hematopoietic stem cell transplantation(ASCT)for the treatment of primary central nervous system lymphoma(PCNSL).Methods:In a retrospective,single center,single arm study,we collected data of 28 patients with PCNSL who underwent high-dose chemotherapy followed by autologous stem cell transplantation(HDC-ASCT)at our center from March 2021 to December 2024.The clinical characteristics of the patients,the conditioning regimen details,treatment-related toxicities and adverse reactions,post-transplant disease remission status,and survival outcomes were analyzed.Results:A total of 28 patients were included.Among them,19 patients received ASCT as first-line consolidation therapy in complete response(CR)or partial response(PR)status,and 9 patients with relapsed/refractory disease underwent salvage ASCT.The median time to neutrophil engraftment was 9 days(range:5-11 days),and the median time to platelet engraftment was 10 days(range:6-13 days).All patients achieved CR at the initial efficacy evaluation post-ASCT.The main complications during the transplantation period were febrile neutropenia(26 cases)and grade 3 diarrhea(9 cases).No transplantation-related mortality occurred.Post-ASCT,19 patients received maintenance therapy,which was demonstrated to be safe and effective.Three patients relapse,and one patient died.The median progression-free survival(PFS)and overall survival(OS)of patients were not reached.The estimated 1-year and 2-year cumulative PFS rates were 88.4％and 66.3％,respectively,while the 1-year and 2-year OS rates were both 94.1％.Conclusion:The modified thiotepa-based conditioning regimen combined with ASCT is safe and effective for the treatment of PCNSL.

The stimulator of interferon genes (STING) has been an attractive target in cancer immunotherapy. However, natural ligand cyclic dinucleotides (CDNs) and CDN derivatives have demonstrated limited efficacy in clinical trials. This limitation stems from the inherent structure of CDNs, which leads to enzymatic degradation, poor cell internalisation, rapid clearance from the tumour microenvironment, and dose-limiting toxicity. In this study, we developed an amphipathic STING agonist, termed albumin-binding CDNs (AlbiCDNs), to enhance the efficacy of c-di-GMP (CDG) via a lipid-conjugated strategy. The lipid provided a platform for albumin hitchhiking, which facilitated the cytoplasmic delivery of CDG without the use of any exogenous components. In addition, incorporating a stimuli-responsive lipid motif further enhanced the cellular release of CDG. Our results indicated that CDG-1C14, an AlbiCDN, efficiently stimulated the maturation and activation of antigen-presenting cells through STING activation. Furthermore, CDG-1C14 exhibited a significant inhibitory effect on the tumour therapeutic model. Therefore, AlbiCDN is a potent platform for cancer immunotherapy that can expedite clinical translation.

AbstractBackgroundMulti‐omics features of cell‐free DNA (cfDNA) can effectively improve the performance of non‐invasive early diagnosis and prognosis of cancer. However, multimodal characterization of cfDNA remains technically challenging.MethodsWe developed a comprehensive multi‐omics solution (COMOS) to specifically obtain an extensive fragmentomics landscape, presented by breakpoint characteristics of nucleosomes, CpG islands, DNase clusters and enhancers, besides typical methylation, copy number alteration of cfDNA. The COMOS was tested on 214 plasma samples of diffuse large B‐cell lymphoma (DLBCL) and matched healthy controls.ResultsFor early diagnosis, COMOS improved the area under the curve (AUC) value to .993 compared with the individual omics model, with a sensitivity of 95% at 98% specificity. Detection sensitivity achieved 91% at 99% specificity in early‐stage patients, while the AUC values of the individual omics model were 0.942, 0.968, 0.989, 0.935, 0.921, 0.781 and 0.917, respectively, with lower sensitivity and specificity. In the treatment response cohort, COMOS yielded a superior sensitivity of 88% at 86% specificity (AUC, 0.903). COMOS has achieved excellent performance in early diagnosis and treatment response prediction.ConclusionsOur study provides an effectively improved approach with high accuracy for the diagnosis and prognosis of DLBCL, showing great potential for future clinical application.Key points A comprehensive multi‐omics solution to specifically obtain an extensive fragmentomics landscape, presented by breakpoint characteristics of nucleosomes, CpG islands, DNase clusters and enhancers, besides typical methylation, copy number alteration of cfDNA. Integrated model of cfDNA multi‐omics could be used for non‐invasive early diagnosis of DLBCL. Integrated model of cfDNA multi‐omics could effectively evaluate the efficacy of R‐CHOP before DLBCL treatment.

OBJECTIVE:To assess the efficacy and safety of a new conditioning regimen with chidamide and BEAM for autologous hematopoietic stem cell transplantation (AHSCT) in patients with lymphoma. METHODS:Medical records and further follow-up data from 85 patients with lymphoma from May 2015 to September 2020 in our hospital were retrospectively collected and analyzed. RESULTS:Among 85 patients, 52 cases accepted BEAM regimen and 33 cases accepted CBEAM followed by AHSCT. In CBEAM group, 18 patients (54.5%) received AHSCT as salvage therapy, while only 26.9% (14 cases) for salvage in BEAM group ( P < 0.01). CBEAM conditioning resulted in shorter neutrophil engraftment of 2 days, while no significant difference was found in platelet engraftment. Although the incidence of liver impairment was higher in CBEAM group (12.1%), the grade of impairment was only Ⅰ to Ⅱ. The two conditioning regimens both achieved good complete remission rate of over 90%, and no transplant-related death occurred. The median follow-up time in the CBEAM group was 18(12, 22) months, and 39(20, 59) months in the BEAM group. There were no significantly differences in 2-year progression-free survival (PFS) and overall survival (OS) rate between the two groups (P >0.05). In patients with refractory or relapsed non-Hodgkin lymphoma, the 2-year PFS rate after transplantation in BEAM group and CBEAM group was 74.1% and 92.9%, respectively (P >0.05), indicating that chidamide may have certain advantages in prolonging PFS. CONCLUSION:CBEAM conditioning regimen has a good efficacy and safety in lymphoma patients before AHSCT, especially in refractory and relapsed non-Hodgkin lymphoma patients, suggesting that it could serve as an alternative conditioning regimen prior to AHSCT for lymphoma.

Extramedullary progression of multiple myeloma (MM) is commonly associated with a poor prognosis. However, optimal management strategies have not yet been established for the treatment of extramedullary involvement in MM. The present study reports the case of a 59-year-old female patient with MM who experienced extramedullary progression after two cycles of first-line VRD (bortezomib, lenalidomide and dexamethasone) therapy. The patient achieved remission of the extramedullary lesion following treatment with an innovative CV-MED regimen, which includes chidamide, bortezomib, mitoxantrone hydrochloride liposome, etoposide and dexamethasone. Subsequently, the patient underwent autologous hematopoietic stem cell harvesting and maintenance therapy, and remains in a progression-free survival state. The present case suggests that a chemotherapy regimen incorporating mitoxantrone hydrochloride liposomes, chidamide and bortezomib could be a promising treatment strategy for managing extramedullary involvement in MM.

Multiple myeloma (MM) is a plasma cell neoplasm characterized by numerous chromosomal number and structural abnormalities, which are of great significance for risk stratification and response evaluation of MM patients. Optical genome mapping (OGM) is a novel technology that has the potential to resolve many of the issues and limitations associated with traditional cytogenetic methods. To date, the clinical utility of OGM has been validated in the fields of cancer, reproduction, and embryonic dysplasia, et al. In this study, we compared OGM to traditional techniques for the first time in five newly diagnosed MM patients, and evaluated the potential of OGM for detecting cytogenetic aberrations and its clinical application value in MM.

Summary: Background: Frail elderly patients with newly diagnosed multiple myeloma (NDMM) have inferior survival and less benefit from high-dose therapies. This prospective study aimed to investigate the efficacy, safety, and quality of life (QoL) of induction treatment of ixazomib/lenalidomide/dexamethasone (IRd) and ixazomib/pegylated liposomal doxorubicin/dexamethasone (IDd) followed by ixazomib/dexamethasone (Id) maintenance therapy in frail, elderly patients with NDMM. Methods: From July 2019 to December 2021, this non-randomized concurrent controlled clinical study enrolled 120 NDMM patients aged ≥65 years with frailty defined by the International Myeloma Working Group (IMWG) frailty score or Mayo geriatric scoring system. The enrolled patients received 6–8 cycles of IRd or IDd followed by Id maintenance therapy for a minimum of 2 years at the discretion of physicians based on patient's clinical characteristics (chiCTR1900024917). Findings: The median age was 71 years and 55% of the patients were males. The overall response rate (ORR) was 82% and 77%, complete response (CR) rate was 25% and 12% for IRd and IDd groups, respectively. The difference in ORR of the Idd group minus the IRd group was −5.36% (95% CI: −18.9% to 8.19%), indicating that the ORR of the IDd group was neither inferior nor non-inferior to the IRd group. After a median follow-up of 34.3 months, the median progression-free survival (PFS) was 21.6 and 13.9 months, OS was not reached and 29.2 months in IRd and IDd groups, respectively. 28 and 33 patients discontinued induction therapy, 20 and 19 discontinued maintenance therapy in IRd and IDd groups, respectively. Cumulative Grade 3 or higher hematological adverse events (AEs) occurred in 10 of the 60 patients (17%) and non-hematological AEs occurred in 15 of the 60 patients (25%) in the IRd group, while 13 of the 60 patients (22%) and 21 of the 60 patients (35%) in the IDd group. Patients were observed with clinically significant improvement in QoL when compared with that at baseline in both IRd and IDd groups by evaluation per cycle (P < 0.0001). Interpretation: The results demonstrated that compared with IRd regimen, IDd regimen showed no significant advantage, but the survival of the IDd group was shorter than that of the IRd group, indicating an all-oral outpatient triplet regimen with IRd, which has low toxicity and has improved QoL, could be the viable first-line treatment option for frail NDMM patients. Funding: The Young Elite Scientist sponsorship program by bast of Beijing Association for Science and Technology (No. BYESS2023116) and Beijing Medical Award Foundation (No. YXJL-2018-0539-0073).

High-dose chemotherapy followed by autologous stem cell transplantation (HDC–ASCT) is a promising approach for patients with primary central nervous system lymphoma (PCNSL). Encouraging results have been reported with thiotepa-based conditioning; however, there is currently no consensus on the optimal conditioning regimens. To improve the tolerance and efficacy of ASCT with thiotepa-based conditioning, this retrospective, single-arm, pilot study was conducted, including 12 PCNSL patients who received ASCT with modified thiotepa-based conditioning regimens. It was found that 6 patients received ASCT as a first-line consolidation in complete response (CR)/partial response (PR) state, and 6 cases underwent salvage treatment. Among the patients, 7 (58.3%) received the mTBC conditioning regimen, 4 (33.3%) received TT-Bu, and one patient was incorporated with chimeric antigen receptor T-cell (CAR-T) cell infusion with the TT-Cy regimen. All patients achieved sustained neutrophil recovery within a median of 9 (range, 7–12) days and platelet engraftment within a median of 10 (range, 6–12) days. Furthermore, all patients were in CR status at the initial efficacy evaluation following ASCT. The main complications during hospitalization were febrile neutropenia (83.3%) and diarrhea grade 3 (50.0%). No transplantation- related mortality occurred. Maintenance therapy post-ASCT was administered in 11 cases, demonstrating its effectiveness and favorable tolerability. The estimated 1- and 3-year progression-free survival (PFS) following ASCT were 80.0% and 53.3%, respectively, while the estimated 1-and 3-year overall survival (OS) were both 100%. This study presented the modified thiotepa-based conditioning regimens and confirmed their safety and efficacy with ASCT for PCNSL patients.

The survival rate of non-Hodgkin lymphoma (NHL) has steadily improved. However, osteoporosis introduced by treatment is prevalent and associated with increased mortality and disability for patients with NHL. We aimed to investigate factors impacting bone mineral density (BMD) reduction and osteoporosis, and the trend of BMD after chemotherapy. Overall, 97 newly diagnosed patients with follicular lymphoma (FL) were retrospectively enrolled. CT attenuation values were measured to assess BMD levels. Although 73.2% of patients received calcium and vitamin D supplements, 44.3% showed significant BMD reduction, and baseline BMD and hemoglobin levels were the risk factors. 26.6% of patients newly developed osteoporosis post-chemotherapy where age and cumulative dose of glucocorticoid were risk factors. The results of 20 patients with consecutive follow-up showed that BMD continued to decline for 6 months post-chemotherapy and did not return to baseline values. Therefore, BMD evaluation and more positive anti-resorption treatments should be administered for high-risk patients.

T lymphoblastic leukemia /lymphoma (T-ALL/LBL) is a rare and highly aggressive neoplasm of lymphoblasts. We evaluated 195 T-ALL/LBL adolescent and adult patients who received ALL-type chemotherapy alone (chemo,n = 72) or in combination with autologous hematopoietic stem cell transplantation(auto-HSCT,n = 23) or allogeneic hematopoietic stem cell transplantation(allo-HSCT,n = 100) from January 2006 to September 2020 in three Chinese medical centers. 167 (85.6

OBJECTIVE:To summarize the clinical characteristics, therapeutic effect and prognostic factors of patients with Hodgkin's lymphoma (HL).METHODS:A total of 129 patients with HL diagnosed in Peking University Third Hospital from January 2010 to March 2021 who were given at least one efficacy assessment after treatment were enrolled, and their clinical data, including sex, age, pathological type, Ann Arbor stage, ECOG score, blood test, β2-microglobulin, lactate dehydrogenase level, albumin level were collected. The clinical characteristics, therapeutic effect and long-term prognosis of the patients were summarized and analyzed.RESULTS:In classical HL, nodular sclerosis HL accounted for the highest proportion of 51.6%, followed by mixed cellularity HL (36.5%), lymphocyte-rich classical HL (3.2%), and lymphocyte depletion HL (0.7%), while nodular lymphocyte predominant HL accounted for 4.8%. The 3-year overall survival (OS) rate of HL patients was 89.8%, and 5-year OS was 85.0%. The 3-year progression-free survival (PFS) rate was 73.4%, and 5-year PFS was 63.1%. Multivariate regression analysis indicated that IPI score was an independent negative factor, while hemoglobin (Hb) level was an independent positive factor for OS in HL patients. When the mediastinal mass size was 9.2 cm, it was most significant to judge the survival status of HL patients. 5-year OS and 5-year PFS were 97.4% and 76.0% in early-stage HL patients without large mass, respectively, while in patients with advanced-stage HL was 83.4% and 55.9% (both P < 0.05). After 2-4 courses of treatment, the overall response rate (ORR) of patients who received chemotherapy combined with radiotherapy was 95.0%, while that was 89.6% in those with chemotherapy alone.CONCLUSIONS:The overall prognosis of patients with HL is satisfactory, especially those in early-stage without large mass. IPI score and Hb level are independent risk factors for the prognosis of HL patients. A 9.2 cm mediastinal mass can be used as the cut-off value for the prognosis of Chinese HL patients.

Abstract: Background: 1q21+ is a common cytogenetic abnormality in multiple myeloma (MM) and is considered as an independent factor for poor prognosis, but its impact on extramedullary disease (EMD) remains unknown. Method: In our retrospective analysis, patients who met the diagnostic criteria of IMWG and first diagnosed with EMD from January 2011 to May 2022 were enrolled in the study. EMD patients were divided into 2 subgroups: 1q21+ and 1q21- according to the FISH analysis. 1q21+ abnormality was regarded as gain of 1q21 (gain [1q21], 3 copies) and amplification of 1q21 (amp [1q21], ≥4 copies). Continuous variables were analyzed by independent-sample t test or Mann-Whitney U test and categorical variables were compared using chi-square test or Fisher's exact test. Kaplan-Meier method was applied for PFS and OS curve made and differences were evaluated by Log-rank test. Cox proportional hazard models were constructed for prognostic factors analyze. Result: Patients with 1q21+ presented with advanced International Staging System stages (stage III percentage: 68.2% vs. 30.0%, P=0.006), lower level of hemoglobin (91g/dL vs. 113.5g/dL, P=0.004), higher tumor burden (BMPC infiltration≥50% : 45.0% vs. 11.9%, P＜0.001), higher level of serum β2-microglobulin (7.24 g/L vs. 3.85 g/L, P=0.003) and lactic dehydrogenase (LDH) (206.5 U/L vs. 177 U/L, P=0.019). Higher incidence of soft tissue related EMD (54.5% vs. 18.6%, P＜0.001), renal dysfunction (50.5% vs. 17.7%, P=0.002) and hypercalcemia (27.3% vs. 7.1%, P=0.011) was also observed in 1q21+ subgroup. 1q21+ was found to be strongly associated with other high risk cytogenetic abnormalities including IgH/FGFR3 translocation (22.7% vs. 4.3%, P=0.007) and IgH/MAF translocation (22.7% vs. 1.4%, P＜0.001). Patients with 1q21+ had a significantly shorter overall survival (OS) and progression-free survival (PFS) (OS: 24 months vs. 47 months, P=0.002; PFS: 14months vs. 38months, P＜0.001), and the poor survival outcome couldn't be reversed by autologous hematopoietic stem cell transplantation (auto-HSCT). Further investigation estimated the impact of cooccurrence of 1q21+ and del17p on survival outcome. For median OS, 1q21- patients without del17p was 47 months, 1q21+ patients without del17p were 28 months, 1q21- patients with del17p was 22 months, and patients presented with both 1q21+ and del17p was 18 months (p=0.02). The median PFS for 1q21- without del17p, 1q21+ without del17p, 1q21+ with del17p was 38 months, 20 months and 6.5 months respectively, while not reached for 1q21- patients (P＜0.001). Multivariate analysis suggested 1q21+ along with EMD-S, elevated LDH level and P53 deletion were independent risk factors for poor prognosis in EMD patients. For 1q21+ EMD patients, hypercalcemia, elevated LDH level and P53 deletion were defined as independent adverse risk prognostic factors. Conclusion: Taken together, our findings emphasized that 1q21+ increased the possibility of disease progression and predicted poor survival in EMD patients. 1q21+ EMD tends to be associated with other high risk disease factors. ASCT may not overcome the adverse effect of 1q21+ in EMD patients. We suggested 1q21+ should be considered as a high-risk factor and added into routine assessment of risk stratification in EMD patients.

Bruton’s tyrosine kinase inhibitors (BTKis) exhibit significant interindividual pharmacokinetics, making therapeutic drug monitoring (TDM) a promising approach for personalized therapy. However, simultaneous quantification of multiple BTKis poses technical challenges. A unified protocol for BTKis detection would be clinically desirable. Herein, we developed and validated a novel LC-MS/MS method for the simultaneous analysis of four BTKis including ibrutinib (IBR), zanubrutinib (ZAN), orelabrutinib (ORE), and acalabrutinib (ACB) and active metabolite of IBR and ACB (DIH and ACBM, respectively) in human plasma. The samples were prepared by liquid-liquid extraction using tert-butyl methyl ether. Ibrutinb-d4 (IS) was used as an internal standard. Chromatographic separation was obtained on an XBridge C18 column and connected to an LC-30AD system coupled to an API 4000+ mass spectrometer. The mobile phase comprised 10 mM ammonium acetate containing 0.1

BackgroundTherapy-related acute myeloid leukemia (t-AML) is increasingly recognized as a treatment complication in patients receiving chemotherapy, radiotherapy, or immunosuppressive agents for primary neoplasms. NUP98::PRRX1 fusion gene, caused by t(1;11)(q23;p15), is a rare recurrent cytogenetic alteration in leukemia, and only seven cases with NUP98::PRRX1 were reported so far.MethodsA 53-year-old female patient was diagnosed with t-AML after 20 months of complete remission (CR) from diffuse large B-cell lymphoma (DLBCL). Conventional karyotype, fluorescence in situ hybridization (FISH), and DNA/RNA next-generation sequence (NGS) were used to detect genetic abnormalities.ResultsAbnormal karyotype of 46, XX, t(1;11)(q25;p15), del(7)(q22) was revealed. NUP98 gene rearrangement and del(7)(q22) were verified by FISH. Further, RNA NGS detected NUP98::PRRX1 fusion transcript, and DNA NGS detected KRAS gene mutation. The patient achieved CR after a combined chemotherapy regimen containing BCL-2 inhibitor and underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT), but she died of leukemia recurrence 14 months later.ConclusionsNovel targeted drugs may provide opportunities for patients with NUP98::PRRX1 to undergo allo-HSCT. However, since the cases of carrying the NUP98::PRRX1 are limited, more patients with this genetic change need to be investigated to elucidate the prognostic significance.

In this multi-center, Phase-1 study (NCT03733717), we characterized the pharmacokinetics (PK) of the anti-CD38 antibody isatuximab (Isa) after IV administration (primary objective), and evaluated safety, immunogenicity, and preliminary anti-myeloma activity in Chinese patients with relapsed/refractory multiple myeloma (RRMM). Isa 20-mg/kg was administered weekly (QW) in cycle 1, then biweekly (Q2W). Twenty-one extensively pretreated RRMM patients (median 4 prior lines; 95.2% refractory to last regimen), received >= 1 dose of Isa. After first IV-infusion, mean maximum observed concentration was 402 mu g/mL and mean area-under-the-concentration-versus-time curve (first 1-week dosing interval) 37,000 mu gh/mL. After repeated administration, exposure (Ctrough) increased 3.11-folds (day 1/cycle 2) versus first administration (day 8/cycle 1). Safety findings were consistent with the known Isa safety profile, with no new safety signals. Any-causality, grade >= 3 treatment-emergent adverse events (TEAEs) were reported in 47.6% of patients. Serious, treatment-related AEs occurred in 2 patients. Isa treatment was generally well tolerated; only 1 patient discontinued due to TEAE. Preliminary efficacy results showed a 19.0% overall response rate (clinical benefit, 33.3%). Our results demonstrate a PK profile for Isa comparable to prior findings in Western and other East-Asian populations, as well as safety and tolerability of treatment with IV Isa 20-mg/kg QW-Q2W in Chinese RRMM patients.Trial registration: The trial was registered with ClinicalTrials.gov; NCT03733717. Date of first trial registration: 07/11/2018.