Investigations of the prognostic value of RUNX1 mutation in acute myeloid leukemia patients: Data from a real-world study.

RUNX1 is one of the recurrent mutated genes in newly diagnosed acute myeloid leukemia (AML). Although historically recognized as a provisional distinct entity, the AML subtype with RUNX1 mutations (AML-RUNX1mut) was eliminated from the 2022 WHO classification system. To gain more insight into the characteristics of AML-RUNX1mut, we retrospectively analyzed 1065 newly diagnosed adult AML patients from the First Affiliated Hospital of Soochow University between January 2017 and December 2021. RUNX1 mutations were identified in 112 patients (10.5%). The presence of RUNX1 mutation (RUNX1mut) conferred a lower composite complete remission (CRc) rate (40.2% vs. 58.4%, P＜0.001), but no significant difference was observed in the 5-year overall survival (OS) rate (50.2% vs. 53.9%; HR=1.293; P=0.115) and event-free survival (EFS) rate (51.5% vs. 49.4%; HR=1.487, P=0.089), even within the same risk stratification. Multivariate analysis showed that RUNX1mut was not an independent prognostic factor for OS (HR=1.352, P=0.068) or EFS (HR=1.129, P=0.513). When patients were stratified according to induction regimen, RUNX1mut was an unfavorable factor for CRc both on univariate and multivariate analysis in patients receiving conventional chemotherapy, and higher risk stratification predicted worse OS. In those who received venetoclax plus hypomethylating agents, RUNX1mut was not predictive of CRc and comparable OS and EFS were seen between intermediate-risk and adverse-risk groups. The results of this study revealed that the impact of RUNX1mut is limited. Its prognostic value depended more on treatment and co-occurrent abnormalities. VEN-HMA may abrogate the prognostic impact of RUNX1, which merits a larger prospective cohort to illustrate.

Preemptive inotuzumab ozogamicin eradicated measurable residual disease in Ph-negative acute lymphoblastic leukemia relapsed post CD19 CART therapy.

There are no reports of application of inotuzumab ozogamicin (InO) for the treatment of MRD in r/r B-ALL. We firstly report the efficacy of InO for a patient experienced morphological relapse after HSCT and molecular relapse after CART therapy.

Case Report: Blinatumomab therapy for the treatment of B-cell acute lymphoblastic leukemia patients with central nervous system infiltration.

The treatment of B-cell acute lymphoblastic leukemia (B-ALL) with central nervous system (CNS) involvement poses a significant clinical challenge because most chemotherapeutic agents exhibit weak permeability to the blood-brain barrier (BBB). In addition, current anti-CNS leukemia treatments often bring short or long-term complications. Immunotherapy including chimeric antigen T-cell therapy and bispecific antibody have shown profound treatment responses in relapsed/refractory B-ALL. However, there is a lack of data on the efficacy of bispecific antibody in treating B-ALL with CNS involvement. Here, we report two ALL patients with CNS leukemia who received blinatumomab. Case 1 was diagnosed with chronic myeloid leukemia in lymphoid blast phase. The patient developed CNS leukemia and bone marrow relapse during the treatment with dasatinib. Case 2 was diagnosed with B-ALL and suffered early hematologic relapse and cerebral parenchyma involvement. After treatment with one cycle of blinatumomab, both patients achieved complete remission in the bone marrow and CNS. Furthermore, this is the first report on the efficacy of blinatumomab in treating CNS leukemia with both of the cerebral spinal fluid and the cerebral parenchymal involvement. Our results suggest that blinatumomab might be a potential option for the treatment of CNS leukemia.

Rapid molecular response to dasatinib in Ph-like acute lymphoblastic leukemia patients with ABL1 rearrangements: case series and literature review.

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subtype with a poor prognosis under conventional chemotherapy. Ph-like ALL has a similar gene expression profile to Philadelphia chromosome-positive (Ph+) ALL, but is highly heterogeneous in terms of genomic alterations. Approximately 10-20% of patients with Ph-like ALL harbor ABL class (e.g. ABL1, ABL2, PDGFRB, and CSF1R) rearrangements. Additional genes that form fusion genes with ABL class genes are still being researched. These aberrations result from rearrangements including chromosome translocations or deletions and may be targets of tyrosine kinase inhibitors (TKIs). However, due to the heterogeneity and rarity of each fusion gene in clinical practice, there is limited data on the efficacy of tyrosine kinase inhibitors. Here, we report three cases of Ph-like B-ALL with ABL1 rearrangements treated with the dasatinib backbone for the CNTRL::ABL1, LSM14A::ABL1, and FOXP1::ABL1 fusion genes. All three patients achieved rapid and profound remission with no significant adverse events. Our findings suggest that dasatinib is a potent TKI for the treatment of ABL1-rearranged Ph-like ALL and can be used as a first-line treatment option for such patients.

Flumatinib plus venetoclax as an effective therapy for Philadelphia chromosome-positive acute myeloid leukemia: A case report.

Philadelphia chromosome-positive acute myeloid leukemia (Ph + AML) is a rare type of AML with a low survival rate and poor prognosis. We first report a Ph + AML patient who remained in long-term remission after the combination of flumatinib and venetoclax, which could provide corresponding treatment ideas for clinical practice.

Chidamide: Targeting epigenetic regulation in the treatment of hematological malignancy.

Epigenetic alterations frequently participate in the onset of hematological malignancies. Histone deacetylases (HDACs) are essential for regulating gene transcription and various signaling pathways. Targeting HDACs has become a novel treatment option for hematological malignancies. Chidamide is the first oral selective HDAC inhibitor for HDAC1, HDAC2, HDAC3, and HDAC10 and was first approved for the treatment of R/R peripheral T-cell lymphoma by the China Food and Drug Administration in 2014. Chidamide was also approved under the name Hiyasta (HBI-8000) in Japan in 2021. In vitro studies revealed that chidamide could inhibit proliferation and induce apoptosis via cell cycle arrest and the regulation of apoptotic proteins. In clinical studies, chidamide was also efficacious in multiple myeloma, acute leukemia and myelodysplastic syndrome. This review includes reported experimental and clinical data on chidamide monotherapy or chidamide treatment in combination with chemotherapy for various hematological malignancies, offering a rationale for the renewed exploration of this drug.

Comparing the efficacy of salvage regimens for relapsed/refractory B-cell acute lymphoblastic leukaemia: a systematic review and network meta-analysis.

The complete remission (CR) rate and overall survival (OS) of relapsed/refractory (R/R) B-cell acute lymphoblastic leukaemia (B-ALL) are not satisfactory. The available salvage regimens include standard chemotherapy, inotuzumab ozogamicin, blinatumomab and cluster of differentiation (CD)19 chimeric antigen receptor T cells (CAR T), and the NCCN guidelines recommend all of these therapies with no preference. Dual CD19/CD22 CAR T-cells have emerged as new treatments and have shown some efficacy, with high CR rates and preventing CD19-negative relapse. However, direct comparisons of the CR rate and long-term survival among the different salvage therapies are lacking. Databases including PubMed, Embase, Web of Science and Cochrane were searched from inception to January 31, 2022, for relevant studies. The outcomes of interest were complete remission/complete remission with incomplete haematologic recovery (CR/CRi) rates and 1-year overall survival (OS) rates. Odds ratios (ORs) were generated for binary outcomes, and the mean difference (MD) was generated for consecutive outcomes by network meta-analysis. CD19 CAR T-cells demonstrated a significantly better effect in improving the CR/CRi rate than blinatumomab (OR = 8.32, 95% CI: 1.18 to 58.44) and chemotherapy (OR = 16.4, 95% CI: 2.76 to 97.45). In terms of OS, CD19 CAR T-cells and dual CD19/CD22 CAR T-cells both had a higher 1-year OS rate than blinatumomab, inotuzumab ozogamicin and chemotherapy. There was no significant difference between CD19 CAR T-cells and dual CD19/CD22 CAR T-cells in terms of 1-year OS and CR/CRi rates. CD19 CAR T-cells are effective in inducing CR, and CD19 CAR T-cells and dual CD19/CD22 CAR T-cells show benefits for overall survival. More high-quality randomized controlled trials and longer follow-ups are needed to confirm and update the results of this analysis in the future.

Rapid and Efficient Response to Gilteritinib and Venetoclax-Based Therapy in Two AML Patients with FLT3-ITD Mutation Unresponsive to Venetoclax Plus Azacitidine.

The presence of FLT3-ITD mutation is associated with relapse and poor survival in AML patients. Venetoclax combined with hypomethylating agents (VEN+HMA) was approved for the frontline treatment of elderly or unfit AML patients, which leads to noteworthy impacts on AML management. The combination therapy is associated with encouraging efficacy in FLT3-mutated AML among both newly diagnosed unfit and relapsed/refractory patients. However, we found that two AML patients with FLT3-ITD mutation did not respond to venetoclax plus azacitidine (VEN+AZA). Given that the combined efficacy of venetoclax and the FLT3 inhibitor has been proved in pre-clinical models of FLT3+ AML, it is a scientific rationale to investigate venetoclax combined with the FLT3 inhibitor in AML patients with FLT3-ITD mutation. This is the first report of assessing the safety and response of gilteritinib (the first and only targeted second-generation FLT3 tyrosine kinase inhibitor approved by the US FDA) and venetoclax-based therapy in two AML patients with FLT3-ITD mutation unresponsive to VEN+AZA, which may bring new hope to FLT3 mutated patients who are unresponsive to VEN+HMA.

Efficiency of anti-VEGF therapy in central nervous system AML relapse: A case report and literature review.

There have been few reports on the treatment of central nervous system (CNS) acute myeloid leukemia (AML) relapse. This case study demonstrates that bevacizumab may be a viable treatment option when combined with IT chemotherapy as maintenance therapy for those with CNS leukemia.

[The Clinical Significance of HPV L1/PD-L1 Tests Combined with Colposcopy for Cervical Precancerous Lesions and Cervical Cancer].

OBJECTIVE: To explore the expression of human papilloma virus (HPV) L1 protein and programmed cell death ligand-1 (PD-L1) protein in cervical precancerous lesions and cervical cancer, to analyze the correlation between HPV L1 and PD-L1 expression tests combined with colposcopy and the occurrence and development of of cervical lesions, and to determine the significance of the combined examination for auxiliary differential diagnosis. METHODS: 260 patients with high-risk HPV (HR-HPV) infection who were treated at West China Second University Hospital, Sichuan University from January, 2018 to January, 2020 were included in the study. 260 cervical cytology specimens were collected, of which 218 cervical histology specimens were collected, of which 202 cases underwent colposcopy. Among the 260 cervical cytology specimens, 40 were of cervical inflammatory cells, 40 were of low-grade squamous intraepithilia lesions (LSIL) with mild atypical hyperplasia, 80 were of high-grade squamous intraepithilia lesions (HSIL) with moderate and severe atypical hyperplasia, and 100 were of cervical carcinoma cells (CCC). Among the 218 cervical histology specimens, 15 were of chronic cervicitis tissue, 20 were of cervical intraepithelial neoplasia (CIN) 1, 32 were of CIN 2, 51 were of CIN 3, and 100 were of cervical cancer (CC). Among the 260 patients, 202 underwent colposcopy. Immunocytochemistry and immunohistochemistry were used to assess the expression of HPV L1 protein and PD-L1 protein, and real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to assess the level of PD-L1 mRNA in chronic cervicitis tissues and CC. The sensitivity, specificity, positive predictive value and negative predictive value of HPV L1 and PD-L1 tests combined with colposcopy in the detection of cervical lesions were studied. RESULTS: ①In the cervical cytology group, the positive rate of HPV L1 expression was 82.50%, 57.50%, 11.25%, and 3.00% in cervical inflammatory cells, low-grade squamous intraepithilia lesions (LSIL), high-grade squamous intraepithilia lesions (HSIL) and CCC, respectively, showing decreasing levels of positive expression rate ( P<0.05). In the cervical histology group, the positive rate of HPV L1 expression was 86.67%, 65.00%, 34.38%, 11.76% and 4.00% in chronic cervicitis tissues, CIN 1 group, CIN 2 group, CIN 3 group and CC group, respectively, showing decreasing levels of positive expression ( P<0.05). ②In the cervical cytology group, the average positive expression scores of PD-L1 in the cervical inflammatory cells, LSIL group, HSIL group, and CCC group were 0.25±0.12, 1.05±0.67, 1.39±0.11 and 2.14±0.17, respectively, showing increasing levels of positive expression scores ( P<0.05). In the cervical histology group, the average positive expression scores of PD-L1 were 0.28±0.24, 1.21±0.79, 1.56±0.26, 1.80±0.24, and 2.10±0.19 in the chronic cervicitis tissue, CIN 1 group, CIN 2 group, CIN 3 group and CC group, respectively, showing increasing levels of positive expression scores ( P<0.05). The relative expression of PD-L1 mRNA in chronic cervicitis tissue and CC is 1.02±0.04 and 1.81±0.22, respectively ( P<0.05). ③The sensitivity and specificity of diagnosis of cervical tissue CIN2 and abovelesions, HPV L1 detection alone was 95.8%, 47.2%, PD-L1 detection alone was 96.5%, 32.8%, colposcopy alone was 77.5%, 70.8%, HPV L1/PD-L1 tests combined detection was 92.4%, 64.5%, HPV L1/PD-L1 detection combined colposcopy was 71.6% and 89.6%, respectively. The sensitivity and specificity of the HPV L1/PD-L1 combined test for the diagnosis of CIN3 and above cervical lesions were 71.9% and 86.1%, HPV L1/PD-L1 combined with colposcopy were 50.5% and 100.0%, respectively. CONCLUSION: The specificity of HPV L1/PD-L1 detection combined with colposcopy for CIN2 and above lesions is higher than that of HPV L1 detection alone, PD-L1 detection alone and colposcopy alone. HPV L1/PD-L1 detection combined with colposcopy detection for CIN3 and above lesions has an important auxiliary diagnostic value.

[HPV E7 Function in DNA Damage Response of Cervical Intraepithelial Neoplasia.]

OBJECTIVES: To determine the function of human papillomavirus (HPV) E7 in DNA damage response of cervical intraepithelial neoplasia (CIN) 3 cells. METHODS: Samples of CIN 3 and child foreskin tissues were collected,with pathologically confirmed HPV positive and negative,respectively.Collagenase A was used for digesting tissues prior to primary culture.The HPV negative cells were infected with lentivirus E7 and pLV.Proteins(53BP1,NBS1,BRCA1 and RPA32) responsive to DNA double break damages were detected by indirect immunofluorescent staining after 0-8 h treatment with X-ray (2 or 5 Gy). RESULTS: After treatment with 2 or 5 Gy X-ray,53BP1,NBS1,BRCA1 and RPA32 foci in HPV+ cells increased compared with HPV- cells (P<0.05).Less 53BP1,RPA32,BRCA1 and NBS1 foci positive cells (foci>5) were found in E7 infected cells than in pLV infected cells(P<0.05).Both of them reached the peak at 6 h (2 Gy) or 4 h (5 Gy). CONCLUSIONS: We have successfully established a model to detect the function of HPV E7 in DNA damage response using primary culture of CIN fibroblasts.With the progression of CIN,HPV E7 can inhibit DNA double break repair.

[Concentrations and ozone formation potentials of BTEX during 2008-2010 in urban Beijing, China].

Benzene, toluene, ethylbenzene and dimethylbenzene are typical anthropogenic emitted organics in the atmosphere, which not only endanger human health but also actively participate in photochemical reactions, generating O3 and secondary organic aerosols. In order to investigate the pollution level and its ozone formation potentials, concentrations of BTEX and O3 were parallel measured by the passive sampler and analyzed using GC-MS and ICS-90 during 2008-2010 in urban Beijing. The results show that toluene was the most abundant compound (8.7 +/- 3.1) microg x m(-3), followed by benzene, ethylbenzene and m/p-xylene, with concentrations of (7.1 +/- 3.3), (4.2 +/- 1.4) and (3.4 +/- 1.5) microg x m(-3), respectively. Concentrations of BTEX peaked in winter, followed by autumn, summer, and spring, with values of (26.8 +/- 12.1), (25.9 +/- 4.9), (24.7 +/- 2.8) and (16.8 +/- 1.4) microg x m(-3), respectively. Benzene concentrations were the highest in winter, while for toluene, the concentration was higher in summer than that in winter. Based on the maximum incremental reactivity scale, m/p-xylene was found to be the dominant contributor to ozone formation among BTEX. The ozone formation potentials of BTEX in Beijing were 65.2, 60.2, and 75.7 microg x m(-3) in 2008, 2009, and 2010, respectively, which were consistent with the measured values of 80.5, 65.0, and 101.9 microg x m(-3) during the corresponding period. Vehicular emission and solvent evaporation were the major sources of BTEX. Concentrations of benzene were affected by coal heating in winter, whereas BTEX concentration was more influenced by solvent evaporation in summer, which had an important contribution to the formation of O3 in urban Beijing.