Expert consensus on microtransplant for acute myeloid leukemia in elderly patients -report from the international microtransplant interest group.

Abstract Leukocyte immunoglobulin-like receptor (LILR) B4 (also known as ILT3/CD85k) is an immune checkpoint protein that is highly expressed in solid tumors and hematological malignancies and plays a significant role in the pathophysiology of cancer. LILRB4 is highly expressed in acute myeloid leukemia (AML), and this phenotype is associated with adverse patient outcomes. Its differential expression in tumors compared to normal tissues, its presence in tumor stem cells, and its multifaceted roles in tumorigenesis position it as a promising therapeutic target in AML. Currently, several immunotherapies targeting LILRB4 are undergoing clinical trials. This review summarizes advancements made in the study of LILRB4 in AML, focusing on its structure, ligands, expression, and significance in normal tissues and AML; its protumorigenic effects and mechanisms in AML; and the application of LILRB4-targeted therapies in AML. These insights highlight the potential advantages of LILRB4 as an immunotherapeutic target in the context of AML. 

LILRB4 in acute myeloid leukemia: From prognostic biomarker to immunotherapeutic target

This study aimed to employ network pharmacology to elucidate the mechanism by which Euphorbia fischeriana Steud (EFS) exhibits the efficacy on cirrhosis. The compounds and targets of EFS were retrieved from Traditional Chinese Medicine Integrated Database and Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). Next, these compounds and targets were analyzed based on protein-protein interaction (PPI) network. Furthermore, Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling network was established based on KEGG database. We constructed a compound-compound target-intersection target-pathway PPI network, including 20 compounds, 19 intersection targets between compound targets and EFS targets. Among the 20 compounds, 8-Isopentenyl-kaempferol has the most targets, with 27 targets, followed by 3,4′,5-Trihydroxy-7-methoxy-8-isopentenylflavone, Formononetin, Isoxanthohumol, and Isokurarinone with potential targets of 26, 22, 18, and 14, respectively. Top 5 targets are HSP90AA1, PTGS2, NOS2, MAPK14, and PPARG. KEGG pathway enrichment analysis showed that pathways such as Hepatitis B, Hepatitis C, Lipid and atherosclerosis, and AGE-RAGE signaling pathway in diabetic complications were closely related to the infection and abnormal metabolism of the liver. The application of network pharmacology could identify potential targets of EFS with a low false-positive rate and provide novel insight into the mechanism of action of EFS on cirrhosis.

Analysis of the mechanism of action of Euphorbia fischeriana Steud on cirrhosis based on network pharmacology

Abstract Post-remission strategies for patients with acute lymphoblastic leukemia (ALL) are limited to the multiagent chemotherapy and allogeneic stem cell transplant (allo-SCT), and cellular therapies are seldom involved. Although chemotherapy combined with mismatched granulocyte colony-stimulating factor mobilized peripheral blood mononuclear cell infusion (microtransplant, MST) has been studied in patients with acute myeloid leukemia, its efficacy in ALL is still undetermined. We enrolled 48 patients receiving hyper-CVAD-based MST between July 1, 2009, and January 31, 2018. No acute or chronic graft-versus-host disease occurred in patients receiving MST. Four-year overall survival (OS) and leukemia-free survival (LFS) were 62% and 35%, respectively, and the 4-year relapse rate was 65%. No patient experienced non–relapse mortality. Subgroup analysis showed that OS rates were comparable between groups with different age, risk stratification, minimal residual disease status prior to MST and immunophenotype. Adult patients tended to achieve better 4-year LFS (62% vs. 26%, P = .058) and lower hematologic relapse rate (38% vs. 74%, P = .058) compared with adolescent and young adult patients. Donor chimerism/microchimerism was detectable ranging from 0.002% to 42.78% in 78% (42/54) available samples within 14 days after each infusion and at 3 months or one year after the last cell infusion. Multivariate analyses demonstrated that white blood cells <30 × 109/L at diagnosis and sufficient hyper-CVAD cycles were prognostic factors for better 4-year OS and LFS, while the B-cell phenotype and higher number of infused CD34+ cells in the first cycle were predictors for favorable 4-year LFS. The hyper-CVAD-based MST was a feasible strategy for treating ALL patients with mild toxicity.

/pdf/hyper-cvad-based-stem-cell-microtransplant-as-post-remission-1utu0y2w.pdf

Hyper-CVAD-Based Stem Cell Microtransplant as Post-Remission Therapy in Acute Lymphoblastic Leukemia

Abstract Background: Immunotherapies such as adoptive immune cell infusion and immune-modulating agents are widely used for cancer treatment, and the concomitant symptoms, including cytokine release syndrome (CRS) or immune-related adverse events (irAEs), are frequently reported. However, clinical manifestations induced by mismatched donor granulocyte colony-stimulating factor mobilized peripheral blood mononuclear cell (GPBMC) infusion in patients receiving microtransplant (MST) have not yet been well depicted. Methods: We analyzed 88 cycles of mismatched GPBMC infusion in patients with acute myeloid leukemia receiving MST and 54 cycles of chemotherapy without GPBMC infusion as a comparison. Clinical symptoms and their correlation with clinical features, laboratory findings, and clinical response were explored. Results: Fever (58.0% [51/88]) and chills (43.2% [38/88]) were the significant early-onset symptoms after GPBMC infusion. Patients possessing less human leukocyte antigen-matching loci with the donor or those with unrelated donors experienced more chills (3 [2–5] loci vs. 5 [3–5] loci, P = 0.043 and 66.7% [12/18] vs. 37.1% [26/70], P = 0.024). On the other hand, those with decreased CD4+/CD8+ T-cell ratio developed more fever (0.8 [0.7–1.2] vs. 1.4 [1.1–2.2], P = 0.007). Multivariable analysis demonstrated that younger patients experienced more fever (odds ratio [OR] = 0.963, 95% confidence interval [CI]: 0.932–0.995, P = 0.022), while patients with younger donors experienced more chills (OR = 0.915, 95% CI: 0.859–0.975, P = 0.006). Elevated ultra-sensitive C-reactive protein levels in the absence of cytokine storm were observed following GPBMC infusion, which indicated mild and transient inflammatory response. Although no predictive value of infusion-related syndrome to leukemia burden change was found, the proportion of host pre-treatment activated T cells was positively correlated with leukemia control. Conclusions: Mismatched GPBMC infusion in MST induced unique infusion-related symptoms and laboratory changes, which were associated with donor- or recipient-derived risk factors, with less safety and tolerance concerns than reported CRS or irAEs.

https://doi.org/10.1097/cm9.0000000000002611

Mismatched donor cell infusion-related syndrome following microtransplant in patients with acute myeloid leukemia

BACKGROUND
Immune-related hepatitis is one of the prevalent adverse events associated with immunotherapy, especially immune checkpoint inhibitors (ICIs). For patients without a history of liver disease, autoimmune disease, or alcohol consumption, it is not clear whether immune-related hepatitis could rapid progress to immune-related cirrhosis.


CASE REPORT
We report the case of a 54-year-old female with stage IIIB primary pulmonary lymphoepithelioma-like carcinoma (PLELC) diagnosed with immune-related hepatitis. After 15 months, a liver biopsy demonstrated the rapid progression of liver cirrhosis although systematic corticosteroid administration.


CONCLUSIONS
Long-term immune activation caused by ICIs may exacerbate the process of cirrhosis. Great attention should be paid to the rapid progression to liver cirrhosis of immune-related hepatitis in the clinic.

Could immune-related hepatitis rapidly progress to immune-related cirrhosis?

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Hyper-CVAD-Based Stem Cell Microtransplant as Post-Remission Therapy in Acute Lymphoblastic Leukemia

Mismatched donor cell infusion-related syndrome following microtransplant in patients with acute myeloid leukemia

Could immune-related hepatitis rapidly progress to immune-related cirrhosis?