Myelomonocytic and monocytic acute myeloid leukemia demonstrate comparable poor outcomes with venetoclax-based treatment: a monocentric real-world study.

Venetoclax (VEN), a BCL-2 inhibitor, has transformed treatment strategies for elderly and unfit acute myeloid leukemia (AML) patients by significantly improving response rates and survival. However, the predictive factors for VEN efficacy differ from traditional chemotherapy. The clinical relevance of the FAB (French-American-British) monocytic subtype, including M4 and M5, has been debated as a marker for VEN resistance. This real-world study examined 162 newly diagnosed (ND) and 85 relapsed/refractory (R/R) AML patients who received VEN-based therapy at West China Hospital, Sichuan University, from January 2019 to January 2023. We retrospectively collected clinical and treatment data from electronic medical records. The median age of the cohort was 55.5 years (range: 16.5-83.5). The composite complete remission (cCR) rate in the entire cohort was 60.7%. Specifically, among newly diagnosed (ND) patients, FAB monocytic subtypes exhibited lower cCR compared to non-monocytic subtypes (55.1% vs. 76.3%, P = 0.007). Additionally, there were no significant differences observed between M4 and M5 subtypes, both in the ND group (61.7% vs. 40.9%, p = 0.17) and the R/R group (38.2% vs. 40%, p > 0.9). Furthermore, the median follow-up was 238 (range: 7-1120) days. ND patients with monocytic subtypes had shorter overall survival compared to non-monocytic subtypes (295 days vs. not reached, p = 0.0017). Conversely, R/R patients showed no such difference (204 vs. 266 days, p = 0.72). In summary, our study suggests that the FAB monocytic subtype can predict VEN resistance and shorter survival in ND AML patients. Moreover, there is no significant distinction between M4 and M5 subtypes.

Chronic active Epstein-Barr virus infection involving gastrointestinal tract with hemophagocytic lymphohistiocytosis.

Chronic active EBV infection (CAEBV) is a lymphoproliferative disorder of T- or NK-cell type in Asian countries. CAEBV involving the gastrointestinal tract (GI CAEBV) is a rare condition with poor prognosis that may rapidly progress with hemophagocytic lymphohistiocytosis (HLH) and life-threatening complications such as GI bleeding and/or perforation. The approach to CAEBV with GI tract involvement (GI CAEBV) is still an unmet clinical need. In this case series study, we summarized the clinical features, treatment, and prognosis of seven cases of GI CAEBV with HLH, particularly focusing on its prognosis and the possible salvage therapy combining surgery, novel therapeutic agents, and/or autologous(auto-) hematopoietic stem cell transplantation (HSCT) based on successful cases from our center. GI CAEBV is often misdiagnosed as inflammatory bowel diseases and certain infections. The key to its early recognition is the integrative consideration of its systemic manifestation, serum virology, endoscopic, and imaging findings along with pathology. Surgical intervention should not be hesitated when life-threatening GI complications occur. Resection of the involved bowel segment is an effective way of controlling bleeding and reducing tumor burden. In addition to upfront allogeneic HSCT, new therapeutic modalities including PD-1 antibody and auto-HSCT may be effective in certain patients.

Nivolumab treatment of relapsed/refractory Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in adults.

Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (EBV-HLH) is a life-threatening hyperinflammatory syndrome triggered by EBV infection. It often becomes relapsed or refractory (r/r), given that etoposide-based regimens cannot effectively clear the virus. r/r EBV-HLH is invariably lethal in adults without allogeneic hematopoietic stem cell transplantation. Here, we performed a retrospective analysis of 7 r/r EBV-HLH patients who were treated with nivolumab on a compassionate-use basis at West China Hospital. All 7 patients tolerated the treatment and 6 responded to it. Five of them achieved and remained in clinical complete remission with a median follow-up of 16 months (range, 11.4-18.9 months). Importantly, both plasma and cellular EBV-DNAs were completely eradicated in 4 patients. Single-cell RNA-sequencing analysis showed that HLH syndrome was associated with hyperactive monocytes/macrophages and ineffective CD8 T cells with a defective activation program. Nivolumab treatment expanded programmed death protein-1-positive T cells and restored the expression of HLH-associated degranulation and costimulatory genes in CD8 T cells. Our data suggest that nivolumab, as a monotherapy, provides a potential cure for r/r EBV-HLH, most likely by restoring a defective anti-EBV response.

A new conditioning regimen with chidamide, cladribine, gemcitabine and busulfan significantly improve the outcome of high-risk or relapsed/refractory non-Hodgkin's lymphomas.

Previous studies highlight the need for a more active conditioning therapy in high-risk or refractory and relapsed lymphomas. Our preclinical research shows that histone deacetylase inhibitors, such as either vorinostat or chidamide, sensitize lymphoma cells to the cytotoxic combination of cladribine, gemcitabine and busulfan, leading to cell apoptosis. To evaluate the efficacy of this chidamide-cladribine-gemcitabine-busulfan (ChiCGB) combination as a new conditioning therapy, we conducted a Phase II trial, as described here. Patients with high-risk, relapsed/refractory lymphomas received ChiCGB as conditioning therapy, after transplantation with autologous peripheral stem cells. The sample comprised 105 patients in total: 60 with B-cell non-Hodgkin lymphomas (B-NHL) and 45 with T-cell or natural killer/T-cell lymphoma (NK/T). All patients eventually achieved full hematopoietic recovery. Neutrophils and platelets were engrafted at a median of 10 days (8-14) and 13 days (8-38), respectively. There was no transplant-related mortality within 100 days of transplant. Neutropenic fever, mucositis and atopic dermatitis were the observed nonhematologic toxicities. At a median follow-up of 35.4 months, 80.6% of the patients presented with no tumor progression, and the overall survival (OS) reached as high as 86.1%. Concerning the OS rate, 94.5% of patients with B-NHL and 75.4% of patients with T-cell or NK/T lymphomas survived. These findings demonstrate the safety and validity of the proposed combined therapy for high-risk and refractory/relapsed lymphomas. Our study was registered on the Clinical Trial Registry (clinicaltrials.gov, NCT03151876).

Chemical constituents and quality control of two Dracocephalum species based on high-performance liquid chromatographic fingerprints coupled with tandem mass spectrometry and chemometrics.

Two similar Dracocephalum species, namely, Dracocephalum tanguticum Maxim and Dracocephalum moldavica L, are commonly used as ethnic medicines in China. Here we describe a strategy of combining high-performance liquid chromatography with quadrupole time-of-flight mass spectrometry, as well as fingerprints and chemometrics for characterization and discrimination of chemical constituents on the two herbs. A total of 49 compounds including 33 flavonoids, 5 phenylethanol glycosides, 1 coumarin glycoside, 8 organic acids, and 2 other types of compounds were unambiguously or tentatively identified from the two Dracocephalum species. Among the compounds identified, 26 were characterized for the first time and 4 compounds, rosmarinic acid (7), salvianolic acid B (10), luteoloside (22), diosmetin-7-O-glucoside (28), were inferred as common constituents for the two herbs. Flavonoids featured in these two Dracocephalum species while their types presented significant differences. Acacetin (45) and acacetin glycosides (acatetin-7-O-glucuronide (30), acacetin-7-O-(6"-O-malonyl) glucoside (33), buddleoside (34), tilianin (35), and agastachoside (42)) were detected only in D. moldavica, which can be used to discriminate two herbal medicines. In addition, six characteristic constitutes in D. tanguticum were simultaneously quantified. Moreover, the induced chemometrics methods including similarity analysis and hierarchical clustering analysis were successfully applied for origin discrimination and quality evaluation of D. tanguticum and D. moldavica.

Chidamide represses MYC expression and might improve survival for patients with double expressor lymphoma.

Double expressor lymphoma (DEL), characterized by high expressions of both MYC and BCL-2, displays poor prognosis after current therapies. The HDAC inhibitor chidamide has been approved for treatment of T cell lymphoma, but its efficacy on B cell lymphoma is unclear. Here, by combining inhibition screening and transcriptomic analyses, we found that the sensitivity of B lymphoma cells to chidamide was positively correlated with the expression levels of MYC. Chidamide treatment reduced MYC protein levels and repressed MYC pathway in B lymphoma cells with high MYC expressions. Ectopic expression of MYC in chidamide-insensitive B lymphoma cells increased their response to chidamide. Thus, we proposed that adding chidamide into R-CHOP (CR-CHOP) might be effective for DEL, and retrospectively analyzed 185 DEL patients treated in West China Hospital. 80% of patients showed response to CR-CHOP treatment. In the median follow-up of 42 months, CR-CHOP significantly improve the survival for DEL patients with R-IPI ≤2. Totally 35 patients underwent autologous stem cell transplantation (ASCT) in remission and demonstrated a trend for better survival. Combining CR-CHOP with ASCT resulted in the most superior PFS and OS above all. For response patients, CR-CHOP reduced relapse with better PFS than R-CHOP-like regimens with or without ASCT. Taken together, our data indicated that chidamide repressed the MYC pathway in B lymphoma and is potentially efficacious to treat DEL.

The clinical features and prognostic implications of PTPN11 mutation in adult patients with acute myeloid leukemia in China.

BACKGROUND: The clinical significance of protein tyrosine phosphatase nonreceptor type 11 mutation (PTPN11mut ) in acute myeloid leukemia (AML) is underestimated. METHODS: We collected the data of AML patients with mutated PTPN11 and wild-type PTPN11 (PTPN11wt ) treated at our hospital and analyzed their clinical characteristics and prognosis. RESULTS: Fifty-nine PTPN11mut and 124 PTPN11wt AML patients were included. PTPN11mut was more common in myelomonocytic and monocytic leukemia, and was more likely to co-mutate with KRAS, KMT2C, NRAS, U2AF1, NOTCH1, IKZF1, and USH2A mutations than PTPN11wt . The overall survival for AML patients with PTPN11mut was significantly shorter than that for those with PTPN11wt (p = 0.03). The negative impact of PTPN11mut on overall survival was pronounced in the "favorable" and "intermediate" groups of ELN2017 risk stratification, as well as in the wild-type NPM1 group (p = 0.01, p = 0.01, and p = 0.04). CONCLUSION: PTPN11mut is associated with distinct clinical and molecular characteristics, and adverse prognosis in AML patients.

SECTM1-based CAR T cells enriched with CD7-low/negative subsets exhibit efficacy in CD7-positive malignancies.

CD7 has been found to be a promising chimeric antigen receptor (CAR) T cell target in several clinical trials. However, its expression on normal T cells poses additional challenges in CD7-directed CAR therapy, such as complete fratricide, contamination with malignant cells, and immune suppression due to T-cell aplasia. By taking advantage of evolved affinity between ligand and receptor, we constructed a CD7-directed CAR with the extracellular domain of SECTM1, a natural ligand of CD7, as the recognition domain. SECTM1 CAR T cells killed the majority of T cells with high CD7 expression in vitro. However, SECTM1 CAR T cells with low or negative CD7 expression survived, expanded, and showed strong cytotoxicity to CD7+ malignant cell lines and primary leukemic blasts from patients with T-cell acute lymphoblastic leukemia and acute myelogenous leukemia in vitro. It also exhibited efficacy in inhibiting xenograft tumor growth in vivo. More exploration is needed for clinical efficacy potential to patients with CD7+ malignancies.

Expression of pig7 gene in acute leukemia and its potential to modulate the chemosensitivity of leukemic cells.

We analyzed expression of p53-induced gene 7 (pig7), at the transcript level, in bone marrow samples from patients with de novo acute leukemia (AL) and normal controls by quantitative reverse transcription PCR (RT-PCR), and revealed a markedly decreased pig7 expression in the patient group, as well as in the relapsed/refractory patients compared with those at initial diagnosis. By endonuclease analysis, we detected only one form of pig7 transcript, i.e., small integral membrane protein of late endosome (simple), in AL patients. In addition, up-regulated pig7 expression could be detected in differentiated leukemic cells induced by drugs. Transient expression of pig7 in leukemic cells exhibited no evident effect on cell proliferation and differentiation, but could intensify inhibitory efficacy of etoposide (VP16) and daunorubicin (DNR). Conclusively, the present study provides the evidence that pig7 is a silenced gene affected by perturbed differentiation in acute leukemia and restoration of pig7 expression sensitizes leukemic cells to chemotherapeutic agents.

Intensive induction chemotherapy with regimen containing intermediate dose cytarabine in the treatment of de novo acute myeloid leukemia.

To improve long-term outcome of de novo acute myeloid leukemia (AML) patients by intermediate dose of cytarabine integrated in induction therapy and to explore the impact of cytogenetic abnormalities on the prognosis. Eighty-seven AML patients were treated with HAD regimen containing intermediate dose cytarabine (IDAra-C) as induction therapy, 83 from which with karyotype results were divided into three cytogenetic groups according to SWOG criteria. Complete remission (CR) rate, disease-free survival (DFS), and overall survival (OS) among different groups were evaluated. The CR rate of the 87 cases was 80/87 (92%). Median DFS and OS have not reached (NR). DFS rates at 1 and 3 years were 76.3% and 63.4%, respectively. OS rates at 1 and 3 years were 86.0% and 58.7%, respectively. According to SWOG criteria, CR rate, median DFS, and OS were 100%, NR and NR for the favorable group; 88.9%, NR, and 16 months for the intermediate group; 83.3%, 4.5 months, and 7.5 months for the adverse group. The differences among the three groups were statistically significant excepting for CR rate between adverse and intermediate groups. HAD regimen containing IDAra-C as induction chemotherapy regimen is effective in de novo AML of adult patients and can achieve higher CR rate and longer survival than standard dose of cytarabine (SDAra-C) regimen. Most of the patients were able to endure the therapy. Cytogenetics is still an important prognostic factor despite of the incorporation of IDAra-C in induction chemotherapy. The differences among the three groups were statistically significant. Am. J. Hematol., 2009. (c) 2009 Wiley-Liss, Inc.

Cancer prevalence among the rural poverty-stricken population in Northeast China.

Purpose: The burden of cancer impacts many of the world's top concerns, but little information is published about the characteristics of cancer prevalence in the poor population. Materials and methods: Data on cancer prevalence were obtained from the Health Poverty Alleviation Information System of Heilongjiang province. Prevalence was defined as all living cancer cases on October 1, 2018. Geographical area, cancer site, sex, age, educational level, and time since diagnosis were investigated. Results: There were 10,529 cancer cases among 624,869 poor rural people in Heilongjiang up to October 1, 2018, and 77% of them did not have labor ability. Females accounted for 53.4%. The top five common cancers were lung, breast, colorectal, stomach, and liver cancer. There were distinct regional, sex, and age distribution differences in cancers. The prevalence rate for overall cancers was 1,685.0 per 100,000 people, which was much higher than that of the national level. Cancer prevalence peaked at an earlier age group (65-69 year). The 5-year cancer prevalence was 80.1% of the total cases. Conclusion: Cancer imposes significant health and financial burdens in the rural poor. This study presents total and partial prevalence for the first time using actual dates from a large poor population in China, providing valuable information for tailored cancer prevention and control, quantifying the cancer burden and identifying priorities for poverty alleviation plans.

Identification and screening of cardiac glycosides in Streptocaulon griffithii using an integrated data mining strategy based on high resolution mass spectrometry.

The present study was designed to develop a practical strategy to tackle the problem of lacking standard compounds and limited references for identifying structure-related compounds in Streptocaulon griffithii Hook. f., especially those in trace concentrations, with a focus on antitumor activity. The cardiac glycosides (CGs)-enriched part was determined using in vitro bioactive assays in three cancer cell lines and then isolated using macroporous resins. The MS and MS/MS data were acquired using a high performance liquid chromatography coupled with hybrid quadrupole-time of flight (HPLC-Q-TOF-MS) system. To acquire data of trace compound in the extract, a multiple segment program was applied to modify the HPLC-Q-TOF-MS method. A mass defect filter (MDF) approach was employed to make a primary MS data filtration. Utilizing a MATLAB program, the redundant peaks obtained by imprecise MDF template calculated with limited references were excluded by fragment ion classification, which was based on the ion occurrence number in the MDF-filtered total ion chromatograms (TIC). Additionally, the complete cleavage pathways of CG aglycones were proposed to assist the structural identification of 29 common fragment ions (CFIs, ion occurrence number ≥ 5) and diagnostic fragment ions (DFIs, ion occurrence number < 5). As a result, 30 CGs were filtered out from the MDF results, among which 23 were identified. This newly developed strategy may provide a rapid and effective tool for identifying structure-related compounds in herbal medicines.

Protective effects of a Chotosan Fraction and its active components on ß-amyloid-induced neurotoxicity.

Chotosan (CTS) is a traditional Kampo prescription used to treat chronic headache and hypertension. Recent clinical studies demonstrated that CTS has ameliorative effects on dementia. This study aims to identify the anti-Alzheimer components in CTS. ß-amyloid (Aß) is considered to play a central role in the pathophysiology of Alzheimer's disease. CTS-E, a fraction of CTS, showed significant protective effects on Aß-induced neurotoxicity. High-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry was used for the qualitative analysis of it. Among the identified constituents, neuroprotective effects against Aß(25-35)-induced neurotoxicity of 10 major compounds were tested by MTT assay. Their inhibitory action on Aß(1-42) self-induced aggregation was measured by Thioflavin T-binding assay. The results showed that caffeic acid, chlorogenic acid, 1,5-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid and 4,5-dicaffeoylquinic acid had significant neuroprotective effects on Aß(25-35)-induced neurotoxicity. Besides these phenolic acids, nobiletin and hesperidin could also inhibit Aß(1-42) self-induced aggregation. In conclusion, the neuroprotective fraction, CTS-E, could protect PC12 cells from Aß-induced neurotoxicity. Anti-oxidative effects may at least partly mediate the neuroprotective effects of it. Phenolic acids from Chrysanthemi Flos and flavonoids from Citri Reticulatae Pericarpium might be the effective constituents in CTS-E.

PIG7 promotes leukemia cell chemosensitivity via lysosomal membrane permeabilization.

PIG7 localizes to lysosomal membrane in leukemia cells. Our previous work has shown that transduction of pig7 into a series of leukemia cell lines did not result in either apoptosis or differentiation of most tested cell lines. Interestingly, it did significantly sensitize these cell lines to chemotherapeutic drugs. Here, we further investigated the mechanism underlying pig7-induced improved sensitivity of acute leukemia cells to chemotherapy. Our results demonstrated that the sensitization effect driven by exogenous pig7 was more effective in drug-resistant leukemia cell lines which had lower endogenous pig7 expression. Overexpression of pig7 did not directly activate the caspase apoptotic pathway, but decreased the lysosomal stability. The expression of pig7 resulted in lysosomal membrane permeabilization (LMP) and lysosomal protease (e.g. cathepsin B, D, L) release. Moreover, we also observed increased reactive oxygen species (ROS) and decreased mitochondrial membrane potential (ΔΨm) induced by pig7. Some autophagy markers such as LC3I/II, ATG5 and Beclin-1, and necroptosis maker MLKL were also stimulated. However, intrinsic antagonism such as serine/cysteine protease inhibitors Spi2A and Cystatin C prevented downstream effectors from triggering leukemia cells, which were only on the "verge of apoptosis". When combined with chemotherapy, LMP increased and more proteases were released. Once this process was beyond the limit of intrinsic antagonism, it induced programmed cell death cooperatively via caspase-independent and caspase-dependent pathways.

Risk of MDM2 SNP309 alone or in combination with the p53 codon 72 polymorphism in acute myeloid leukemia.

A single nucleotide polymorphism (SNP) in the promoter of MDM2 gene, SNP309 T>G (a T-G exchange at nucleotide 309 in the first intron), can increase the expression level of MDM2, thereby causing an impairment of p53 tumor suppressor activity. A G-C exchange at p53 codon 72 polymorphism results in a substitution of proline (Pro) for arginine (Arg) in the transactivation domain, which was shown to alter the primary structure of the p53 protein. Both polymorphisms have been implicated in cancer. To investigate whether that MDM2 SNP309 and p53 codon 72 polymorphism should be at least partially responsible for genetic susceptibility to acute myeloid leukemia (AML), both polymorphisms were determined in a case-control study consisting of 231 AML patients and 128 normal individuals. The MDM2 SNP309G allele was associated with increased risk of AML. Furthermore, the p53 codon 72 and MDM2 SNP309 polymorphisms did not associate with age of onset and any other clinical parameters studied. When the p53 and MDM2 polymorphisms were combined, no multiplicative joint effect between the MDM2 GG and p53 Pro/Pro genotypes exists in the risk of developing AML. These results suggest that the MDM2 SNP309 homozygous GG genotype may be a genetic susceptibility factor in the pathogenesis of AML.

[The expression of midkine in acute leukemia and its significance].

OBJECTIVE: To analyze the expression of midkine (MK) gene in acute leukemia patients, and explore the relationship between the gene and leukemia. METHODS: The MK gene expression levels were detected by real-time quantitative RT-PCR (RQ-RT-PCR) in bone marrow (BM) of 181 acute leukemia (AL) patients and 31 normal controls. RESULTS: MK gene was expressed in all AL patients, normal controls and AL patients in complete remission (CR). Compared with that in control group and CR group, MK gene expression was significantly increased in AL patients (P < 0.01 and P < 0.05, respectively). No statistical difference was found between CR group and control group. The expression of MK showed a notable increase in all B-ALL subtypes (including pro-B-ALL, common-B-ALL and pre-B-ALL) as well as in adult and childhood B-ALL patients (P < 0.01). Moreover, the gene expression in B-ALL was also significantly higher than that in TALL, HAL and FAB subtypes of AML (P < 0.01). In addition, M2 patients showed significantly increased in MK expression compared with that in normal controls (P < 0.01) and in other FAB subtypes of AML (P < 0.05). Median MK expression level in M3 patients was also significantly higher than that in normal controls (P < 0.05), but there was no statistical difference between M3 and other AL subtypes excepting for M2 and B-ALL. MK expression in CD34 positive patients was significantly higher than that in CD34 negative ones (P < 0.01) and within M2 patients, MK expression was higher in patients with t (8 ;21) than in those without the translocation (P < 0.05). CONCLUSION: MK gene expression is increased with different levels in B-ALL, M2 and M3 patients, which provides novel insights into the leukemogenesis of acute leukemia.