Clonal haematopoiesis of indeterminate potential and atrial fibrillation: an east Asian cohort study.

BACKGROUND AND AIMS: Both clonal haematopoiesis of indeterminate potential (CHIP) and atrial fibrillation (AF) are age-related conditions. This study investigated the potential role of CHIP in the development and progression of AF. METHODS: Deep-targeted sequencing of 24 CHIP mutations (a mean depth of coverage = 1000×) was performed in 1004 patients with AF and 3341 non-AF healthy subjects. Variant allele fraction ≥ 2.0% indicated the presence of CHIP mutations. The association between CHIP and AF was evaluated by the comparison of (i) the prevalence of CHIP mutations between AF and non-AF subjects and (ii) clinical characteristics discriminated by CHIP mutations within AF patients. Furthermore, the risk of clinical outcomes-the composite of heart failure, ischaemic stroke, or death-according to the presence of CHIP mutations in AF was investigated from the UK Biobank cohort. RESULTS: The mean age was 67.6 ± 6.9 vs. 58.5 ± 6.5 years in AF (paroxysmal, 39.0%; persistent, 61.0%) and non-AF cohorts, respectively. CHIP mutations with a variant allele fraction of ≥2.0% were found in 237 (23.6%) AF patients (DNMT3A, 13.5%; TET2, 6.6%; and ASXL1, 1.5%) and were more prevalent than non-AF subjects [356 (10.7%); P < .001] across the age. After multivariable adjustment (age, sex, smoking, body mass index, diabetes, and hypertension), CHIP mutations were 1.4-fold higher in AF [adjusted odds ratio (OR) 1.38; 95% confidence interval 1.10-1.74, P < .01]. The ORs of CHIP mutations were the highest in the long-standing persistent AF (adjusted OR 1.50; 95% confidence interval 1.14-1.99, P = .004) followed by persistent (adjusted OR 1.44) and paroxysmal (adjusted OR 1.33) AF. In gene-specific analyses, TET2 somatic mutation presented the highest association with AF (adjusted OR 1.65; 95% confidence interval 1.05-2.60, P = .030). AF patients with CHIP mutations were older and had a higher prevalence of diabetes, a longer AF duration, a higher E/E', and a more severely enlarged left atrium than those without CHIP mutations (all P < .05). In UK Biobank analysis of 21 286 AF subjects (1297 with CHIP and 19 989 without CHIP), the CHIP mutation in AF is associated with a 1.32-fold higher risk of a composite clinical event (heart failure, ischaemic stroke, or death). CONCLUSIONS: CHIP mutations, primarily DNMT3A or TET2, are more prevalent in patients with AF than non-AF subjects whilst their presence is associated with a more progressive nature of AF and unfavourable clinical outcomes.

Golidocitinib, a selective JAK1 tyrosine-kinase inhibitor, in patients with refractory or relapsed peripheral T-cell lymphoma (JACKPOT8 Part B): a single-arm, multinational, phase 2 study.

BACKGROUND: Golidocitinib, a selective JAK1 tyrosine-kinase inhibitor, has shown encouraging anti-tumour activity in heavily pre-treated patients with relapsed or refractory peripheral T-cell lymphoma in a phase 1 study (JACKPOT8 Part A). Here, we report the full analysis of a phase 2 study, in which we assessed the anti-tumour activity of golidocitinib in a large multinational cohort of patients. METHODS: We did a single-arm, multinational, phase 2 trial (JACKPOT8 Part B) in 49 centres in Australia, China, South Korea, and the USA. Eligible patients were adults (aged ≥18 years) with relapsed or refractory peripheral T-cell lymphoma who had received at least one previous line of systemic therapy and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were given oral golidocitinib 150 mg once daily until disease progression or other discontinuation criteria were met. The primary endpoint was the CT-based objective response rate, assessed by an independent review committee (IRC) per Lugano 2014 classification. The activity analysis set included all patients who received at least one dose and whose pathological diagnosis of peripheral T-cell lymphoma had been retrospectively confirmed by a central laboratory and who had at least one measurable lesion at baseline assessed by IRC. The safety analysis set included all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT04105010, and is closed to accrual and follow-up is ongoing. FINDINGS: Between Feb 26, 2021, and Oct 12, 2022, we assessed 161 patients for eligibility, of whom 104 (65%) were enrolled and received at least one dose of study drug; the activity analysis set included 88 (85%) patients (median age 58 years [IQR 51-67], 57 [65%] of 88 were male, 31 [35%] were female, and 83 [94%] were Asian). As of data cutoff (Aug 31, 2023; median follow-up was 13·3 months [IQR 4·9-18·4]), per IRC assessment, the objective response rate was 44·3% (95% CI 33·7-55·3; 39 of 88 patients, p<0·0001), with 21 (24%) patients having a complete response and 18 (20%) having a partial response. In the safety analysis set, 61 (59%) of 104 patients had grade 3-4 drug-related treatment-emergent adverse events. The most common grade 3-4 drug-related treatment-emergent adverse events were neutrophil count decreased (30 [29%]), white blood cell count decreased (27 [26%]), lymphocyte count decreased (22 [21%]), and platelet count decreased (21 [20%]), which were clinically manageable and reversible. 25 (24%) patients had treatment-related serious adverse events. Deaths due to treatment-emergent adverse events occurred in three (3%) patients: two (2%) due to pneumonia (one case with fungal infection [related to golidocitinib] and another one with COVID-19 infection) and one (1%) due to confusional state. INTERPRETATION: In this phase 2 study, golidocitinib showed a favourable benefit-risk profile in treating relapsed or refractory peripheral T-cell lymphoma. The results of this study warrant further randomised clinical studies to confirm activity and assess efficacy in this population. FUNDING: Dizal Pharmaceutical.

Clonal Hematopoiesis and Acute Ischemic Stroke Outcomes.

OBJECTIVE: The effect of clonal hematopoiesis of indeterminate potential (CHIP) on the manifestation and clinical outcomes of acute ischemic stroke (AIS) has not been fully elucidated. METHODS: Patients with AIS were included from a prospective registry coupled with a DNA repository. Targeted next-generation sequencing on 25 genes that are frequently mutated in hematologic neoplasms was performed. The prevalence of CHIP was compared between patients with AIS and age-matched healthy individuals. A multivariate linear or logistic regression model was used to assess the association among CHIP and stroke severity, hemorrhagic transformation, and functional outcome at 90 days. RESULTS: In total, 380 patients with AIS (mean age = 67.2 ± 12.7 years; 41.3% women) and 446 age-matched controls (mean age = 67.2 ± 8.7 years; 31.4% women) were analyzed. The prevalence of CHIP was significantly higher in patients with AIS than in the healthy controls (29.0 vs 22.0%, with variant allele frequencies of 1.5%, p = 0.024). PPM1D was found to be most significantly associated with incident AIS (adjusted odds ratio [aOR] = 7.85, 95% confidence interval [CI] = 1.83-33.63, p = 0.006). The presence of CHIP was significantly associated with the initial National Institutes of Health Stroke Scale (NIHSS) score (ß = 1.67, p = 0.022). Furthermore, CHIP was independently associated with the occurrence of hemorrhagic transformation (65/110 clonal hematopoiesis positive [CH+] vs 56/270 CH negative [CH-], aOR = 5.63, 95% CI = 3.24-9.77, p < 0.001) and 90-day functional disability (72/110 [CH+] vs 99/270 [CH-], aOR = 2.15, 95% CI = 1.20-3.88, p = 0.011). INTERPRETATION: CH was significantly associated with incident AIS. Moreover, particularly, sequence variations in PPM1D, TET2, and DNMT3A represent a new prognostic factor for AIS. ANN NEUROL 2023;94:836-847.

Long-term efficacy and safety of tucidinostat in patients with relapsed or refractory peripheral T-cell lymphoma: final analysis of phase IIb results.

Not available.

Clinical characteristics and treatment outcomes of Asian patients with T-cell large granular lymphocytic Leukemia: a single-center analysis of 67 cases.

Large granular lymphocytic (LGL) leukemia is a clonal lymphoproliferative disorder of LGLs derived from cytotoxic T lymphocytes or natural killer cells. However, the clinical features and treatment responses are still not fully understood because of the rarity of the disease. To describe and assess a cohort of patients with T-cell large granular lymphocytic leukemia (T-LGLL). Single-center, retrospective, observational study. We retrospectively collected the clinical data of patients diagnosed with T-LGLL at Seoul National University Hospital since 2006. We included 67 patients in this study. The median age at diagnosis was 60 years. Additionally, 37 patients (55%) were symptomatic, and 25 (37%) had splenomegaly; 54 patients (81%) required treatment. Cyclophosphamide (n = 35), methotrexate (n = 25), and cyclosporin A (n = 19) were used most frequently for treatment, and their overall response rates were similar: cyclophosphamide (77%), methotrexate (64%), and cyclosporin A (63%). Splenomegaly was associated with an increased response rate to first-line therapy and a decreased complete response rate. Thrombocytopenia was associated with decreased response rates to cyclophosphamide, methotrexate, cyclosporin A, and steroids. In contrast, a high LGL number (> 2000/µL) in the peripheral blood smear was associated with increased response rates to cyclophosphamide, methotrexate, cyclosporin A, and steroids. This study describes the clinical features and treatment outcomes of patients with T-LGLL, providing valuable information for clinical decision-making regarding T-LGLL treatment.

Real-world outcome of patients with extensively pretreated multiple myeloma who were treated with selinexor and dexamethasone: a Korean multicenter retrospective analysis.

The outcomes of patients with myeloma after exposed to penta-classes are extremely poor. Selinexor is the first approved exportin inhibitor for those patients, but intractable toxicities may limit its use. This retrospective study evaluated the real-world efficacy and safety of selinexor plus dexamethasone (XD) and involved 48 patients with multiple myeloma, who were treated from November 2020 to October 2022. Their median age was 64 years, and the median number of prior lines of therapy was 6. The overall response rate was 25%, and the median progression-free survival (PFS) was 2.1 months (95% confidence interval (CI), 1.7-2.5). Patients on a reduced initial dose, delayed treatment, and dose reduction had better PFS. After XD treatment failure, 17 patients received subsequent therapy and had a median PFS of 2.4 months. The median overall survival was 4.6 months (95% CI, 2.3-6.9). Among the patients, 12 (25%) and 17 (35%) experienced dose reduction and delayed treatment, respectively. Our data show that the real-world efficacy of XD treatment in heavily pretreated patients was modest and that improving treatment adherence through reducing initial doses or delaying treatments may improve patient outcomes.

Effects of tertiary palliative care on the pattern of end-of-life care in patients with hematologic malignancies in Korea.

INTRODUCTION: Patients with hematologic malignancies (HMs) often face challenges in accessing palliative care (PC) and receiving quality end-of-life (EOL) care. We examined factors associated with referrals to tertiary PC and the effects of tertiary PC on EOL care in patients with HMs. METHOD: We included patients with HMs who were admitted to a university-affiliated hospital and died during hospitalization between January 2018 and December 2021. We investigated the receipt of PC consultations, patient characteristics, and EOL care indicators. RESULTS: Overall, 487 patients were included in the analysis, with 156 (32%) undergoing PC consultation. Sex, residence, disease status, and admission purpose were factors associated with the likelihood of PC consultation, and there has been an increasing trend in the frequency of consultations in recent cases. A higher proportion of patients who received PC completed advance statements and life-sustaining treatment documents. Patients who received PC had lower rates of aggressive EOL care, including chemotherapy and intensive care unit admission, than those who did not receive PC. Notably, PC reduced the number of blood transfusions. CONCLUSION: Tertiary PC aims to reduce aggressive EOL care through patient-centered goal-of-care discussions. Therefore, there is an imperative need for concerted efforts toward seamless integration of PC.

Safety of Extended Pirtobrutinib Exposure in Relapsed and/or Refractory B-Cell Malignancies.

INTRODUCTION: Pirtobrutinib, a highly selective, noncovalent (reversible) Bruton tyrosine kinase inhibitor, has demonstrated promising efficacy in B-cell malignancies and is associated with low rates of discontinuation and dose reduction. Pirtobrutinib is administered until disease progression or toxicity, necessitating an understanding of the safety profile in patients with extended treatment. METHODS: Here we report the safety of pirtobrutinib in patients with relapsed/refractory B-cell malignancies with extended (≥12 months) drug exposure from the BRUIN trial. Assessments included median time-to-first-occurrence of adverse events (AEs), dose reductions, and discontinuations due to treatment-emergent AEs (TEAEs) and select AEs of interest (AESIs). RESULTS: Of 773 patients enrolled, 326 (42%) received treatment for ≥12 months. In the extended exposure cohort, the median time-on-treatment was 19 months. The most common all-cause TEAEs were fatigue (32%) and diarrhea (31%). TEAEs leading to dose reduction occurred in 23 (7%) and discontinuations in 11 (3%) extended exposure patients. One patient had a fatal treatment-related AE (COVID-19 pneumonia). Infections (73.0%) were the most common AESI with a median time-to-first-occurrence of 7.4 months. Majority of TEAEs and AESIs occurred during the first year of therapy. CONCLUSIONS: Pirtobrutinib therapy continues to demonstrate an excellent safety profile amenable to long-term administration without evidence of new or worsening toxicity signals.

Risk factors for resistant gram-positive bacteremia in febrile neutropenic patients with cancer.

BACKGROUND: Gram-positive bacteria are frequently resistant to empirical beta-lactams in febrile neutropenic patients with cancer. As microbiology and antibiotic susceptibility changes, we reevaluated the risk factors for resistant Gram-positive bacteremia in febrile neutropenic patients with cancer. METHODS: Episodes of bacteremic febrile neutropenia in Seoul National University Hospital from July 2019 to June 2022 were reviewed. Resistant Gram-positive bacteria were defined as a pathogen susceptible only to glycopeptide or linezolid in vitro (e.g., methicillin-resistant staphylococci, penicillin-resistant viridans streptococci, and ampicillin-resistant enterococci). Episodes were compared to identify independent risk factors for resistant Gram-positive bacteremia. RESULTS: Of 225 episodes, 78 (34.7%) involved resistant Gram-positive bacteremia. Multivariate analysis revealed that breakthrough bacteremia while being administered antibiotics (adjusted odds ratio [aOR], 6.794; 95% confidence interval [95% CI], 3.130-14.749; P < 0.001) and catheter-related infection (aOR 4.039, 95% CI 1.366-11.946; P = 0.012) were associated with resistant Gram-positive bacteremia. Chronic liver disease (aOR 0.231, 95% CI 0.059-0.905; P = 0.035) and hypotension at bacteremia (aOR 0.454, 95% CI 0.218-0.945; P = 0.035) were inversely associated with resistant Gram-positive bacteremia. CONCLUSIONS: Resistant Gram-positive bacteria should be considered in breakthrough bacteremia and catheter-related infection in febrile neutropenic patients with cancer.

Noncanonical immune response to the inhibition of DNA methylation by Staufen1 via stabilization of endogenous retrovirus RNAs.

DNA-methyltransferase inhibitors (DNMTis), such as azacitidine and decitabine, are used clinically to treat myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Decitabine activates the transcription of endogenous retroviruses (ERVs), which can induce immune response by acting as cellular double-stranded RNAs (dsRNAs). Yet, the posttranscriptional regulation of ERV dsRNAs remains uninvestigated. Here, we find that the viral mimicry and subsequent cell death in response to decitabine require the dsRNA-binding protein Staufen1 (Stau1). We show that Stau1 directly binds to ERV RNAs and stabilizes them in a genome-wide manner. Furthermore, Stau1-mediated stabilization requires a long noncoding RNA TINCR, which enhances the interaction between Stau1 and ERV RNAs. Analysis of a clinical patient cohort reveals that MDS and AML patients with lower Stau1 and TINCR expressions exhibit inferior treatment outcomes to DNMTi therapy. Overall, our study reveals the posttranscriptional regulatory mechanism of ERVs and identifies the Stau1-TINCR complex as a potential target for predicting the efficacy of DNMTis and other drugs that rely on dsRNAs.

Effects of indoor environments and outdoor air pollutants in residential areas on acute exacerbation in patients with severe asthma.

This study aimed to determine the effects of indoor environment (IE) and outdoor air pollutants (OAPs) in residential areas on acute exacerbation (AE) in patients with severe asthma. A total of 115 participants were recruited. To characterize IE, we used structured questionnaires and estimated OAP concentrations using a land-use regression model. Participants who were exposed to passive smoking and lived in houses where the kitchen and living room were not separated showed a significantly higher rate of AE (p = 0.014 and 0.0016, respectively). The mean concentration of PM2.5 in residential areas during the last 3 years was significantly higher in participants with AE than that in those without AE (19.8 ± 3.1 vs. 21.0 ± 2.5 µg/m3, p = 0.033). Moreover, the serum level of 8-hydroxy-2'-deoxyguanosine significantly increased in participants with AE compared to those without AE (56.9 ± 30.0 vs. 94.7 ± 44.5 ng/mL, p = 0.0047) suggesting enhanced oxidative stress in those with AE.

ITDetect: a method to detect internal tandem duplication of FMS-like tyrosine kinase (FLT3) from next-generation sequencing data with high sensitivity and clinical application.

Internal tandem duplication (ITD) of the FMS-like tyrosine kinase (FLT3) gene is associated with poor clinical outcomes in patients with acute myeloid leukemia. Although recent methods for detecting FLT3-ITD from next-generation sequencing (NGS) data have replaced traditional ITD detection approaches such as conventional PCR or fragment analysis, their use in the clinical field is still limited and requires further information. Here, we introduce ITDetect, an efficient FLT3-ITD detection approach that uses NGS data. Our proposed method allows for more precise detection and provides more detailed information than existing in silico methods. Further, it enables FLT3-ITD detection from exome sequencing or targeted panel sequencing data, thereby improving its clinical application. We validated the performance of ITDetect using NGS-based and experimental ITD detection methods and successfully demonstrated that ITDetect provides the highest concordance with the experimental methods. The program and data underlying this study are available in a public repository.

dCas9-Mediated PCR-Free Detection of Oncogenic Mutation by Nonequilibrium Nanoelectrokinetic Selective Preconcentration.

Cutting-edge nanoelectrokinetic technology in this work provides a breakthrough for the present clinical demands of molecular diagnosis to detect a trace amount of oncogenic mutation of DNA in a short time without an erroneous PCR procedure. In this work, we combined the sequence-specific labeling scheme of CRISPR/dCas9 and ion concentration polarization (ICP) mechanism to separately preconcentrate target DNA molecules for rapid detection. Using the mobility shift caused by dCas9's specific binding to the mutant, the mutated DNA and normal DNA were distinguished in the microchip. Based on this technique, we successfully demonstrated the dCas9-mediated 1-min detection of single base substitution (SBS) in EGFR DNA, a carcinogenesis indicator. Moreover, the presence/absence of target DNA was identified at a glance like a commercial pregnancy test kit (two lines for positive and one line for negative) by the distinct preconcentration mechanisms of ICP, even at the 0.1% concentration of the target mutant.

Genetic assessment of pathogenic germline alterations in lysosomal genes among Asian patients with pancreatic ductal adenocarcinoma.

BACKGROUND: Lysosomes are closely linked to autophagic activity, which plays a vital role in pancreatic ductal adenocarcinoma (PDAC) biology. The survival of PDAC patients is still poor, and the identification of novel genetic factors for prognosis and treatment is highly required to prevent PDAC-related deaths. This study investigated the germline variants related to lysosomal dysfunction in patients with PDAC and to analyze whether they contribute to the development of PDAC. METHODS: The germline putative pathogenic variants (PPV) in genes involved in lysosomal storage disease (LSD) was compared between patients with PDAC (n = 418) and healthy controls (n = 845) using targeted panel and whole-exome sequencing. Furthermore, pancreatic organoids from wild-type and KrasG12D mice were used to evaluate the effect of lysosomal dysfunction on PDAC development. RNA sequencing (RNA-seq) analysis was performed with established PDAC patient-derived organoids (PDOs) according to the PPV status. RESULTS: The PPV in LSD-related genes was higher in patients with PDAC than in healthy controls (8.13 vs. 4.26%, Log2 OR = 1.65, P = 3.08 × 10-3). The PPV carriers of LSD-related genes with PDAC were significantly younger than the non-carriers (mean age 61.5 vs. 65.3 years, P = 0.031). We further studied a variant of the lysosomal enzyme, galactosylceramidase (GALC), which was the most frequently detected LSD variant in our cohort. Autophagolysosomal activity was hampered when GALC was downregulated, which was accompanied by paradoxically elevated autophagic flux. Furthermore, the number of proliferating Ki-67+ cells increased significantly in pancreatic organoids derived from Galc knockout KrasG12D mice. Moreover, GALC PPV carriers tended to show drug resistance in both PDAC cell line and PDAC PDO, and RNA-seq analysis revealed that various metabolism and gene repair pathways were upregulated in PDAC PDOs harboring a GALC variant. CONCLUSIONS: Genetically defined lysosomal dysfunction is frequently observed in patients with young-onset PDAC. This might contribute to PDAC development by altering metabolism and impairing autophagolysosomal activity, which could be potentially implicated in therapeutic applications for PDAC.

Oral HDAC inhibitor tucidinostat in patients with relapsed or refractory peripheral T-cell lymphoma: phase IIb results.

Tucidinostat (formerly known as chidamide) is an orally available, novel benzamide class of histone deacetylase (HDAC) inhibitor that selectively blocks class I and class IIb HDAC. This multicenter phase IIb study aimed to investigate the efficacy and safety of tucidinostat, 40 mg twice per week (BIW), in patients with relapsed/refractory (R/R) peripheral T-cell lymphoma (PTCL). The primary endpoint was overall response rate (ORR) assessed by an independent overall efficacy review committee. Between March 2017 and March 2019, 55 patients were treated, and 46 and 55 were evaluated for efficacy and safety, respectively. Twenty-one of 46 patients achieved objective responses with an ORR of 46% (95% confidence interval : 30.9-61.0), including five patients with complete response (CR). Responses were observed across various PTCL subtypes. In angioimmunoblastic T-cell lymphoma, there were two CR and five partial responses (PR) among eight patients, achieving an ORR of 88%. The disease control rate (CR + PR + stable disease) was 72% (33/46). The median progression-free survival, duration of response, and overall survival were 5.6 months, 11.5 months, 22.8 months, respectively. The most common adverse events (AE) (all grades) were thrombocytopenia, neutropenia, leukopenia, anemia, and diarrhea. The grade ≥3 AE emerging in ≥20% of patients included thrombocytopenia (51%), neutropenia (36%), lymphopenia (22%), and leukopenia (20%). Importantly, most of the AE were manageable by supportive care and dose modification. In conclusion, the favorable efficacy and safety profiles indicate that tucidinostat could be a new therapeutic option in patients with R/R PTCL (clinicaltrials gov. Identifier: NCT02953652).

A phase 1/2, open-label, multicenter study of isatuximab in combination with cemiplimab in patients with lymphoma.

Patients with relapsed or refractory lymphoma have limited treatment options, requiring newer regimens. In this Phase 1/2 study (NCT03769181), we assessed the safety, efficacy, and pharmacokinetics of isatuximab (Isa, anti-CD38 antibody) in combination with cemiplimab (Cemi, anti-programmed death-1 [PD-1] receptor antibody; Isa + Cemi) in patients with classic Hodgkin lymphoma (cHL), diffuse large B-cell lymphoma (DLBCL), and peripheral T-cell lymphoma (PTCL). In Phase 1, we characterized the safety and tolerability of Isa + Cemi with planned dose de-escalation to determine the recommended Phase 2 dose (RP2D). Six patients in each cohort were treated with a starting dose of Isa + Cemi to determine the RP2D. In Phase 2, the primary endpoints were complete response in Cohort A1 (cHL anti-PD-1/programmed death-ligand 1 [PD-L1] naïve), and objective response rate in Cohorts A2 (cHL anti-PD-1/PD-L1 progressors), B (DLBCL), and C (PTCL). An interim analysis was performed when the first 18 (Cohort A1), 12 (Cohort A2), 17 (Cohort B), and 11 (Cohort C) patients in Phase 2 had been treated and followed up for 24 weeks. Isa + Cemi demonstrated a manageable safety profile with no new safety signals. No dose-limiting toxicities were observed at the starting dose; thus, the starting dose of each drug was confirmed as the RP2D. Based on the Lugano 2014 criteria, 55.6% (Cohort A1), 33.3% (Cohort A2), 5.9% (Cohort B), and 9.1% (Cohort C) of patients achieved a complete or partial response. Pharmacokinetic analyses suggested no effect of Cemi on Isa exposure. Modest clinical efficacy was observed in patients with cHL regardless of prior anti-PD-1/PD-L1 exposure. In DLBCL or PTCL cohorts, interim efficacy analysis results did not meet prespecified criteria to continue enrollment in Phase 2 Stage 2. Isa + Cemi did not have a synergistic effect in these patient populations.

Comparison of the effect of DLI according to cell sources in relapsed AML after allogeneic stem cell transplantation.

For relapsed acute myeloid leukemia (AML) patients who received allogeneic hematopoietic stem cell transplantation, donor lymphocyte infusion (DLI) is an effective therapy. However, the cell source of DLI remains a topic of debate. In this study, we aimed to compare the efficacy and safety of G-CSF mobilized cells (G-DLI) with conventionally collected DLI (C-DLI). A total of 81 patients (50 C-DLI vs. 31 G-DLI) were assessed for clinical outcomes. There were no statistically significant differences in the baseline characteristics between the two groups including AML risk, donor types, interval from relapse to DLI, and infused CD3+ cell count. Although not statistically significant, complete remission (CR) and chimerism conversion rates were higher in G-DLI than in C-DLI: 51.6% vs. 28.0%, P = 0.057 and 42.3% vs. 28.2%, P = 0.363, respectively. There was no difference in acute graft-versus-host disease (GVHD) incidence and severity of acute GVHD between the two groups. The median overall survival (OS) of the G-DLI and C-DLI groups was 139 days and 106 days, respectively (P = 0.58). In conclusion, G-DLI appears to be a safe and an equally efficacious substitute for C-DLI, which is more readily available.

Clinical outcomes after incomplete cycles of R-CHOP for diffuse large B-cell lymphoma: 10 years' real-world experience in a single institute.

Although the current standard of care for diffuse large B-cell lymphoma (DLBCL) is six cycles of rituximab/cyclophosphamide/doxorubicin/vincristine/prednisolone combination chemotherapy (R-CHOP), a larger than expected number of patients cannot complete planned six cycles for various reasons in the real world. We aimed to evaluate the prognosis of patients with DLBCL after incomplete treatment by analyzing the chemotherapy response and survival according to the cause of discontinuation and the number of cycles. We analyzed a retrospective cohort of patients diagnosed with DLBCL who underwent incomplete cycles of R-CHOP at Seoul National University Hospital and Boramae Medical Center from January 2010 to April 2019. A total of 1183 patients were diagnosed with DLBCL, of which 260 (22%) did not complete six cycles of R-CHOP. The most common cause of discontinuation of chemotherapy was life-threatening infection, and the most common pathogen was Pneumocystis jirovecii. Overall survival (OS) and progression-free survival (PFS) were significantly better in patients who achieved complete response (CR) or partial response (PR) at the first response evaluation. Patients underwent three or more cycles of chemotherapy had a longer OS than those who did not. In patients with limited-stage disease, consolidative radiotherapy showed a significant improvement in OS and PFS. Advanced stage, high comorbidity score, and poor primary response to chemotherapy were poor prognostic factors in patients with unplanned treatment shortening. This study provides real-world outcomes for patients who could not complete the planned six cycles of R-CHOP.

Identification of novel Carnobacterium maltaromaticum strains in bone marrow samples of patients with acute myeloid leukemia using a metagenomic binning approach.

The aim of this study aimed to examine the existence of a bacterial metagenome in the bone marrow of patients with acute myeloid leukemia (AML). We re-examined whole-genome sequencing data from the bone marrow samples of seven patients with AML, four of whom were remitted after treatment, for metagenomic analysis. After the removal of human reads, unmapped reads were used to profile the species-level composition. We used the metagenomic binning approach to confirm whether the identified taxon was a complete genome of known or novel strains. We observed a unique and novel microbial signature in which Carnobacterium maltaromaticum was the most abundant species in five patients with AML or remission. The complete genome of C. maltaromaticum "BMAML_KR01," which was observed in all samples, was 100% complete with 8.5% contamination and closely clustered with C. maltaromaticum strains DSM20730 and SF668 based on single nucleotide polymorphism variations. We identified five unique proteins that could contribute to cancer progression and 104 virulent factor proteins in the BMAML_KR01 genome. To our knowledge, this is the first report of a new strain of C. maltaromaticum in patients with AML. The presence of C. maltaromaticum and its new strain in patients indicates an urgent need to validate the existence of this bacterium and evaluate its pathophysiological role.

PD-1 and TIGIT downregulation distinctly affect the effector and early memory phenotypes of CD19-targeting CAR T cells.

CD19-targeting chimeric antigen receptor (CAR) T cells have become an important therapeutic option for patients with relapsed and refractory B cell malignancies. However, a significant portion of patients still do not benefit from the therapy owing to various resistance mechanisms, including high expression of multiple inhibitory immune checkpoint receptors. Here, we report a lentiviral two-in-one CAR T approach in which two checkpoint receptors are downregulated simultaneously by a dual short hairpin RNA cassette integrated into a CAR vector. Using this system, we evaluated CD19-targeting CAR T cells in the context of four different checkpoint combinations-PD-1/TIM-3, PD-1/LAG-3, PD-1/CTLA-4, and PD-1/TIGIT-and found that CAR T cells with PD-1/TIGIT downregulation uniquely exerted synergistic antitumor effects. Importantly, functional and phenotypic analyses suggested that downregulation of PD-1 enhances short-term effector function, whereas downregulation of TIGIT is primarily responsible for maintaining a less differentiated/exhausted state, providing a potential mechanism for the observed synergy. The PD-1/TIGIT-downregulated CAR T cells generated from diffuse large B cell lymphoma patient-derived T cells also showed robust antitumor activity and significantly improved persistence in vivo. The efficacy and safety of PD-1/TIGIT-downregulated CD19-targeting CAR T cells are currently being evaluated in adult patients with relapsed or refractory large B cell lymphoma (ClinicalTrials.gov: NCT04836507).