We studied by questionnaire 530 subjects with chronic myeloid leukaemia (CML) in Hubei Province during the recent SARS-CoV-2 epidemic. Five developed confirmed (N = 4) or probable COVID-19 (N = 1). ...Prevalence of COVID-19 in our subjects, 0.9% (95% Confidence Interval, 0.1, 1.8%) was ninefold higher than 0.1% (0, 0.12%) reported in normals but lower than 10% (6, 17%) reported in hospitalised persons with other haematological cancers or normal health-care providers, 7% (4, 12%). Co-variates associated with an increased risk of developing COVID-19 amongst persons with CML were exposure to someone infected with SARS-CoV-2 (P = 0.037), no complete haematologic response (P = 0.003) and co-morbidity(ies) (P = 0.024). There was also an increased risk of developing COVID-19 in subjects in advanced phase CML (P = 0.004) even when they achieved a complete cytogenetic response or major molecular response at the time of exposure to SARS-CoV-2. 1 of 21 subjects receiving 3rd generation tyrosine kinase-inhibitor (TKI) developed COVID-19 versus 3 of 346 subjects receiving imatinib versus 0 of 162 subjects receiving 2nd generation TKIs (P = 0.096). Other co-variates such as age and TKI-therapy duration were not significantly associated with an increased risk of developing COVID-19. Persons with these risk factors may benefit from increased surveillance of SARS-CoV-2 infection and possible protective isolation.
With the outbreak of COVID-19 ongoing, this infectious disease has been posing a significant threat to public health. However, we are still relatively inexperienced on recognizing the clinical ...characteristics of severe COVID-19 and death cases. Therefore, we hereby collected and analyzed a total of 232 cases to illustrate the clinical characteristics of such patients in Wuhan and to find notable marks for early clinical warning. We consider age, comorbidities, platelet count, albumin, D-dimer, LDH, CRP and IL-6 level might be more meaningful marks for COVID-19 prognostic evaluation.
Aggressive NK-cell leukemia （ANKL） is a rare form of NK cell neoplasm that is more prevalent among people from Asia and Central and South America. Patients usually die within days to months, even ...after receiving prompt therapeutic management. Here we performed the first comprehensive study of ANKL by integrating whole genome, transcriptome and targeted sequencing, cytokine array as well as functional assays. Mutations in the JAK-STAT pathway were identified in 48% （14/29） of ANKL patients, while the extracelinlar STAT3 stimulator IL10 was elevated by an average of 56-fold （P 〈 0.0001） in the plasma of all patients examined. Additional frequently mutated genes included TP53 （34%）, TET2 （28%）, CREBBP （21%） and MLL2 （21%）. Patient NK leukemia cells showed prominent activation of STAT3 phosphorylation, MYC expression and transcriptional activities in multiple metabolic path- ways. Functionally, STAT3 activation and MYC expression were critical for the proliferation and survival of ANKL cells. STAT signaling regulated the MYC transcription program, and both STAT signaling and MYC transcription were required to maintain the activation of nucleotide synthesis and glycolysis, Collectively, the JAK-STAT path- way represents a major target for genomic alterations and IL10 stimulation in ANKL. This newly discovered JAK/ STAT-MYC-biosynthesis axis may provide opportunities for the development of novel therapeutic strategies in treating this subtype of leukemia.
Anti-CD19 chimeric antigen receptor (CAR)-T cells not only target CD19-positive malignant lymphoma cells but also normal B cells. The utility of CAR-T cell therapy has been reported in rheumatoid ...arthritis and systemic lupus erythematosus; however, its use in Sjögren's disease (SjD) remains unknown. In this study, we describe the case of a 76-year-old woman with active SjD for 10 years who was diagnosed with diffuse large B-cell lymphoma. After receiving anti-CD19 CAR-T cell therapy, she achieved complete remission (CR) on day 28. Since the onset of her 10-year history with SjD, she was negative for antinuclear antibodies and anti-Ro-52 for the first time on day 90 after CAR-T cell therapy. Six months after CAR-T cell therapy, the CR status was maintained, serum cytokine levels returned to their normal levels, and dry mouth symptoms improved. The EULAR Sjögren's Syndrome Disease Activity Index score decreased from 5 to 2, indicating a partial remission of SjD activity compared with that before CAR-T cell treatment. In the early stage of treatment, she presented with grade 2 cytokine release syndrome and grade 1 neurotoxicity, which were completely controlled after an active intervention. This case highlights the potential application of CAR-T cells in treating autoimmune diseases, such as SjD.
Diffuse large B-cell lymphoma (DLBCL) is a highly aggressive subtype of lymphoma and related to autoimmune diseases (AIDs). Primary B-cell receptor-mediated AIDs are associated with poor clinical ...outcome of DLBCL. To further determine the role of immunological alterations on disease progression, our study integrated genomic and transcriptomic analyses on DLBCL with multiple abnormal immunologic markers.
The clinical data of 1,792 patients with newly diagnosed DLBCL were collected, with DNA- and RNA-sequencing conducted for 164 and 127 patients, respectively. Frequent gene mutations and the involved dysregulated pathways, along with gene expression pattern and tumor microenvironment alternations, were analyzed and compared based on the immune status of the patients.
DLBCL with multiple abnormal immunologic markers demonstrated a variety of characteristics including elevated serum lactic dehydrogenase level, inferior prognosis, and dysregulated cell cycle and immune response, as well as activated oxidative phosphorylation pathway and increased Th1/Th2 and Th17/Treg ratios, which were highly similar as those that occur in AIDs.
We piloted the description of the clinical and genetic features of DLBCL with multiple abnormal immunologic markers, illustrated possible mechanisms of disease progression, and provided a clinical rationale of mechanism-based targeted therapy in this subset of DLBCL.
Haemophagocytic lymphohistiocytosis is a life-threatening disease resulting from primary or secondary hyper-inflammatory disorders. The typical symptoms include persistent fever, splenomegaly, ...cytopenia and significant elevation of serum ferritin.
We report a 30-year-old Chinese female patient who was diagnosed with chronic active Epstein-Barr virus infection more than 9 months prior and has since been presenting with cutaneous lymphoproliferative disorders mimicking hydroa vacciniforme and subsequent haemophagocytic lymphohistiocytosis. Exome sequencing suggested novel digenic heterozygous STXBP2 (c.592A > C, p.Thr198Pro) and LYST (c.830A > T, p.His277Leu) mutations.
This is the first case report in which adult HLH was associated with novel digenic mutations of STXBP2 and LYST combined with Epstein-Barr virus infection. It could also be the first polygenic model report, given that the pathogenicity of other mutated genes still remains unclear. We additionally conducted an in-depth, two-generation pedigree analysis to further illustrate the mode of inheritance in this case.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
7027 Background: Approved chimeric antigen receptor (CAR) T cell therapies targeting CD19 with a single co-stimulatory domain in the treatment of relapsed/refractory B-cell non-Hodgkin lymphoma (r/r ...B-NHL) may face challenges including drug resistance and disease recurrence. This Phase 1 study was conducted to evaluate the safety and tolerability of LY007, a novel CD20-targeting CAR-T cell containing both OX40 and 4-1BB co-stimulatory domains to enhance CAR-T cell proliferation and anti-cancer cytotoxicity, for the treatment of r/r B-NHL pts. Methods: In this open-label, single-arm phase 1 trial, r/r B-NHL pts were infused with LY007 in 3 dose levels (DLs) (DL1, 0.5 x 10 6 cells/ kg; DL2, 1.5 x 10 6 cells/ kg; DL3, 5.0 x 10 6 cells/ kg) based on a standard 3+3 dose escalation design after cyclophosphamide/fludarabine lymphodepletion. The main objectives were to determine the safety and tolerability, pharmacokinetics, and preliminary efficacy of LY007. The key eligibility criteria included pts with cytologically or histologically confirmed CD20 positive r/r B-NHL according to WHO 2016 including diffuse large B cell lymphoma (DLBCL) and transformed follicular lymphoma (TFL). Results: As of December 25th, 2023, 9 pts were treated with single LY007 infusions at 3 dose levels with a median follow-up of 5.09 (range 0.92-18.10) months. The median age of treated pts was 65 years (range, 44 to 69), and 44% (4/9) of pts had received three prior lines of therapy. Their B-NHL subtypes were all DLBCL. Among the treated pts, 78% (7/9) relapsed after prior lines of treatment, 89% (8/9) had extranodal involvement, 78% (7/9) had an International Prognostic Index (IPI) score of ≥ 2, and 44% (4/9) had a maximum tumor length of ≥ 5 cm. The overall response rate (ORR) and complete response (CR) were 67% (6/9) and 33% (3/9) at day28, 83% (5/6), and 67% (4/6) at month 3 of the pts evaluable for efficacy. Among all study participants, the best reported ORR was 89% (8/9). The longest duration of remission was 12.3 months to date. The overall survival (OS) and progression-free survival (PFS) were 100% and 88.9% at 6 months, respectively. The LY007 was generally well tolerated. No dose-limiting toxicities (DLTs) were observed. And no immune effector cell-associated neurotoxicity syndrome (ICANS) or G3+ cytokine release syndrome (CRS) was reported. The most common G3+ AEs were lymphopenia (9/9), leukopenia (9/9), and neutropenia (7/9). No pts discontinued, withdrew, or died due to AE. 6 pts experienced G1/2 CRS. Pts at all 3 dose levels had good CAR-T expansion and long-term persistence, particularly in the LD3 cohort, where the highest mean cell copy number of 93,750 copies/μg DNA was achieved at day 11 and was still detectable to date. Conclusions: This phase 1 trial demonstrated that LY007 was well tolerated at the dose levels up to 5.0 x 10 6 cells/ kg and showed a favorable dose-response relationship for the treatment of r/r B-NHL. Clinical trial information: NCT06279611.
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Background: Relmacabtagene autoleucel (relma-cel) is a CD19-directed 4-1BB/CD3ζ chimeric antigen receptor T cell (CAR-T) product manufactured in China, it had been approved by NMPA for ...treatment of adults with r/r LBCL after ≥2 lines of systemic therapies based on the pivotal study (NCT04089215). Here, we report the results of relma-cel in patients with primary refractory disease after first-line standard of care (R-CHOP), an indication with poor clinical outcomes. Methods: This was an open-label, single-arm, multi-center, phase I study (NCT04812691). Eligible adults (≥18 years) met the criteria for primary refractory LBCL (not reach CR after first-line therapy). After screening and leukapheresis, patients received lymphodepletion cyclophosphamide/fludarabine followed by 100×10
6
CAR+ T cells. Results: High-risk disease characteristics were common in the study (Table). As of Nov 26, 2021, 14 patients had leukapheresis and 12 had relma-cel infusion. Among the efficacy-evaluable patients, the best ORR and CRR was 75.0% (95% CI: 42.8-94.5%) and 33.3% (95% CI: 9.9-65.1%), 3-month ORR and CRR were 41.7% (95% CI: 15.2-72.3%) and 33.3% (95% CI: 9.9-65.1%), respectively. With a median follow-up of 9.1 months, the median PFS was 10.0 months (95% CI: 0.85, NA), median DOR and OS were NA (95% CI: 2.2, NA) and NA (95% CI: 3.2, NA). Treatment-emergent adverse events (TEAE) were found in all patients. 10 (83.3%) patients had 1 or more study related Gr ≥3 TEAEs, the most common was cytopenia. 6 (50.0%) patients had Gr ≥3 prolonged cytopenia at Day 29. 6 (50.0%) patients had Gr ≤ 2 Cytokine Release Syndrome (CRS) with a median onset and duration of 6.0 and 11.0 days, no Gr ≥3 CRS observed. Neurotoxicity (NT) occurred in 2 patients (all Gr 1), the median onset and duration was 15.0 and 6.0 days. 2 deaths occurred in study due to disease progression. For 12 PK-evaluable patients, median Cmax was 36762.5 copies/μg DNA by qPCR with a median Tmax of 11 days and a median AUC1-29 of 333459.3 day×copies/μg. In 6 patients whose CAR-T cell had reached BLQ, 5 (83.3%) still had response with 4 (66.7%) patients for CR, 1 (16.7%) patients for PR. Univariate analysis did not indicate association between response and either exposure (AUC1–29) or peak concentration. Conclusions: Relma-cel was tolerable and showed promising ORR in Chinese patients with primary refractory LBCL. Evaluation of relma-cel in high risk second-line LBDL patients using a randomized trial design is planned. Clinical trial information: NCT04812691. Table: see text
Nowadays, adoptive T cell immunotherapy is emerging as a novel and potent treatment for cancer. To prepare enough effective T cells for treatment use, their rapid expansion is favorable. Our study ...compared 6 commonly used cultural media for human T cells, including serum-containing media and serum-free media, namely RPMI 1640, IMDM, Gibco OpTmizer CTS T Cell Expansion SFM, Gibco AIM-V Medium CTS, LONZA X-VIVO 15, and StemSpan SFEM with or without Dynabeads Human T-Activator CD3/CD28, on in vitro T cell expansion, apoptosis, and immune phenotype. Our study results suggest that serum-free media provide better proliferation environment for T cells. Among the 3 serum-free media, we identify OpTmizer and AIM-V as better T cell culture environments compared with X-VIVO as T cells are proved to have higher viability in the first two media. Besides, we found that in vitro human T cells keep relatively resting status among non-CD3/CD28 groups, since they have weak proliferation and apoptosis abilities. The phenotypes of T cells in different cultural environments over time indicate T cells maturation during culture duration. These results provide a firm foundation of adoptive T cell immunotherapy.
Epstein-Barr virus (EBV) associated T/NK-cell lymphoproliferative diseases (EBV-T/NK-LPDs) are a cluster of diseases that include chronic active EBV infection (CAEBV) and aggressive NK cell leukemia ...(ANKL). The pathogenesis of EBV-T/NK-LPDs is largely unclear and the treatment is difficult and in most cases a hematopoietic stem cell transplantation is needed. Hemophagocytic lymphohistiocytosis (HLH) is known to affect the prognosis of patients with EBV-T/NK-LPDs. This study reports a case of a 20-year-old male patient with repeated infectious mononucleosis (IM)-like symptoms such as high fever, splenomegaly, lymphadenopathy for more than two years. The patient had a high EBV-DNA load (NK cells were the main target cells). He was first diagnosed as CAEBV. However, the disease gradually progressed and the patient developed with high ferritin, phagocytosis and monoclonal NK cells in bone marrow, pancytopenia, increased cytokines, and elevated expression of Ki-67. Also, his NK cells had abnormal immunophenotypes and impaired function. The patient had a typical clinical course of progression from CAEBV to ANKL, accompanied by HLH complications and a poor prognosis. Herein, the detailed diagnostic and differential diagnostic process of EBV infection was shown in this report.
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