Research Progress in Treatment of Chronic Lymphocytic Leukemia --Review / 中国实验血液学杂志

Chronic lymphocytic leukemia (CLL) is a low-grade lymphoproliferative tumor that occurs frequently in middle-aged and elderly people. Early and precise intervention can effectively improve the clinical prognosis of CLL patients. In the past, chemotherapy was the main treatment plan. With the development of molecular biology and the continuous advent of immune targeting drugs, targeted drugs targeting B cell receptor signaling pathway have shown high clinical application value in the diagnosis and treatment path of CLL. Cellular immunotherapies such as CAR-T also offer hope for patients with relapsed and refractory CLL. Allogeneic hematopoietic stem cell transplantation and multi-drug combination have also shown remarkable results in clinical practice. The purpose of this article is to review the latest research progress in the treatment of CLL.

Multicenter Prospective Study of Different Induction Regimens of Azacytidine in Treatment of Elderly Patients with Acute Myeloid Leukemia / 中国实验血液学杂志

OBJECTIVE@#To observe the efficacy and safety of different induction regimens of same total dosage of azacitidine (Aza), including standard dose (standard dose group) and low-dose long-term (adjusted dose group), in the treatment of elderly acute myeloid leukemia (AML).@*METHODS@#A total of 103 elderly patients with AML (non-acute promyelocytic leukemia) from January 2020 to June 2021 were enrolled. Aza was administered at the standard dose of 75 mg/(m2·d) for 7 days in the standard dose group (50 cases), while at 100 mg/d for 7-12 days in the adjusted dose group (53 cases). The administration days in adjusted dose group was calculated based on the total standard dose of the patient's single course of treatment. The efficacy and safety between standard dose group and adjusted dose group were compared. Subgroup analysis were performed in the two groups for Aza alone, Aza combined with BCL-2 inhibitor, and Aza combined with low-dose chemotherapy for efficacy and safety.@*RESULTS@#There were no significant differences in overall response rate (ORR), incidence of adverse reaction, and 1-year overall survival (OS) rate between standard dose group and adjusted dose group (P >0.05). The ORR of combination was higher than that of Aza alone (P < 0.05), while there was no significant difference in ORR between Aza combined with BCL-2 inhibitor and Aza combined with low-dose chemotherapy (P >0.05). The combination of BCL-2 inhibitor did not increase the incidence of adverse reactions compared wtih Aza alone. There was a higher risk of myelosuppression and pulmonary infection with a combination of low-dose chemotherapy than with a combination of BCL-2 inhibitor and Aza alone (P <0.05). No significant difference was observed in 1-year OS between Aza alone, Aza combined with BCL-2 inhibitor, and Aza combined with low-dose chemotherapy (P >0.05).@*CONCLUSIONS@#Both two induction regimens can be used in elderly AML patients who cannot tolerate intensive chemotherapy with similar overall effectiveness and safety. Aza combined with low-dose chemotherapy may result in increased ORR and an increased incidence of serious adverse reactions, and may not result in longer survival compared with Aza alone. Aza combined with BCL-2 inhibitor not only has similar effect in complete remission, objective response rate, and OS compared with Aza combined with low-dose chemotherapy, but also has higher safety.

Ibrutinib combined with CAR-T cells in the treatment of del (17p) chronic lymphocytic leukemia with BCL-2 inhibitor resistance: a case report and literature review / 中华血液学杂志

Objective@#To improve the knowledge and experience of ibrutinib combined with CAR-T cells in the treatment of high-risk chronic lymphoblastic leukemia (CLL) patients or small lymphocytic lymphoma (SLL) with TP53 gene aberration.@*Methods@#One case of del (17p) CLL patients with BCL-2 inhibitor resistance was treated with ibrutinib combined with CAR-T cells, successfully bridged to allogeneic hematopoietic stem cell transplantation (allo-HSCT) , and the relative literatures were reviewed.@*Results@#The patient was a young female with superficial lymph node enlarging at the beginning of the onset. Lymph node biopsy was confirmed as small lymphocytic lymphoma (SLL) without del (17p) . The disease progressed rapidly to CLL/SLL with del (17p) and bone marrow hematopoietic failure 2 years later. Firstly, the patient was treated with BCL-2 inhibitor (Venetoclax) , and the enlarged lymph nodes shrank significantly 2 months later. After 3 months, the disease progressed rapidly. The spleen was enlarged to 16 cm below the ribs, the neck lymph nodes was rapidly enlarged, and the superior vena cava syndrome appeared, which were mainly attributed to venetoclax resistance; so BTK inhibitor (ibrutinib) was used continuously after venetoclax discontinuation. Partial remission (PR) was achieved without lymphocytosis after 2 months, then ibrutinib was combined with CAR-T cells targeting CD19 antigen. Grade 1 of cytokine release syndrome (CRS) appeared after CAR-T cells infusion, and the complete remission (CR) was achieved after 1 month both in bone marrow and peripheral blood, with minimal residual disease (MRD) negative, then bridging allo-HSCT after 2 months of combined therapy.@*Conclusion@#CLL/SLL patients with TP53 aberration have poor prognosis because of rapid progression, drug resistance, etc. Ibrutinib combined with CAR-T cell therapy can quickly achieved complete remission.

Ibrutinib combined with CAR-T cells in the treatment of del (17p) chronic lymphocytic leukemia with BCL-2 inhibitor resistance: a case report and literature review / 中华血液学杂志

Objective: To improve the knowledge and experience of ibrutinib combined with CAR-T cells in the treatment of high-risk chronic lymphoblastic leukemia (CLL) patients or small lymphocytic lymphoma (SLL) with TP53 gene aberration. Methods: One case of del (17p) CLL patients with BCL-2 inhibitor resistance was treated with ibrutinib combined with CAR-T cells, successfully bridged to allogeneic hematopoietic stem cell transplantation (allo-HSCT) , and the relative literatures were reviewed. Results: The patient was a young female with superficial lymph node enlarging at the beginning of the onset. Lymph node biopsy was confirmed as small lymphocytic lymphoma (SLL) without del (17p) . The disease progressed rapidly to CLL/SLL with del (17p) and bone marrow hematopoietic failure 2 years later. Firstly, the patient was treated with BCL-2 inhibitor (Venetoclax) , and the enlarged lymph nodes shrank significantly 2 months later. After 3 months, the disease progressed rapidly. The spleen was enlarged to 16 cm below the ribs, the neck lymph nodes was rapidly enlarged, and the superior vena cava syndrome appeared, which were mainly attributed to venetoclax resistance; so BTK inhibitor (ibrutinib) was used continuously after venetoclax discontinuation. Partial remission (PR) was achieved without lymphocytosis after 2 months, then ibrutinib was combined with CAR-T cells targeting CD19 antigen. Grade 1 of cytokine release syndrome (CRS) appeared after CAR-T cells infusion, and the complete remission (CR) was achieved after 1 month both in bone marrow and peripheral blood, with minimal residual disease (MRD) negative, then bridging allo-HSCT after 2 months of combined therapy. Conclusion: CLL/SLL patients with TP53 aberration have poor prognosis because of rapid progression, drug resistance, etc. Ibrutinib combined with CAR-T cell therapy can quickly achieved complete remission.

Expression of Bcl2 inhibitor of transcription 1 and E-cadherin in different regions of cervical squamous cell carcinoma and their relationship with expression of P16INK4a / 第二军医大学学报

Objective: To determine the expression of anoikis factor Bcl2 inhibitor of transcription 1 (Bit1), epithelial-mesenchymal transformation (EMT) marker E-cadherin and P16INK4a in tumor budding and central tumor of cervical squamous cell carcinoma, and to explore the significance of Bit1 and E-cadherin expression in the process of obtaining high invasiveness of cervical cancer and their relationship with P16INK4a expression. Methods: A total of 77 paraffin-embedded specimens of cervical squamous cell carcinoma were collected from the Department of Pathology of Gansu Provincial Cancer Hospital between 2014 and 2018. The expression levels of Bit1, E-cadherin and P16INK4a in tumor budding and central tumor of these specimens were detected by immunohistochemistry. Taking the median scores of protein expression in the central tumor and tumor budding as dividing points, the specimens were divided into high expression group and low expression group. The differences of Bit1 and E-cadherin expression under different p16INK4a expression and their relationship with the clinicopathological characteristics of the patients were analyzed. The correlation between Bit1 and E-cadherin expression in central tumor and tumor budding was explored. The χ2 test, continuous correction χ2 test and Spearman rank correlation analysis were used for statistical analysis. Results: In 77 cases of paraffin-embedded specimens of cervical squamous cell carcinoma, the high expression rates of P16INK4a, E-cadherin and Bit1 in central tumor and tumor budding were 32.5% (25/77), 67.5% (52/77) and 63.6% (49/77), and 67.5% (52/77), 33.8% (26/77) and 37.7% (29/77), respectively, and the differences were significant (χ2 18.935, 17.561 and 10.391, all P < 0.01). Both in central tumor and in tumor budding, there were no significant differences in Bit1 or E-cadherin expression between high and low P16INK4a expression regions (all P < 0.05). In central tumor, the low expression of Bit-1 was related to lymphovascular invasion and lymph node metastasis (χ2 5.053 and 4.400, both P < 0.05). In tumor budding, the low expression levels of E-cadherin and Bit-1 were both associated with lymph node metastasis (χ2 5.580 and 7.573, both P < 0.05). Spearman rank correlation analysis showed that there was positive correlation between E-cadherin and Bit1 expression in central tumor and tumor budding (r 0.287, P = 0.011; r 0.236, P < 0.039). Conclusion: The increased invasiveness of cervical cancer may be related to the decreased expression of Bit1 and E-cadherin and the increased expression of P16INK4a. Cervical cancer cells may acquire high invasiveness by inhibiting Bit1 to obtain anoikis resistance and affecting the EMT, but P16INK4a is not involved in this process.

Bcl-2: research progress from target to launched drug / 药学学报

Apoptosis is an important self-stabilizing mechanism of multicellular organisms, which plays a vital role in the development of normal living organisms and the maintenance of tissue homeostasis. The abnormalities in apoptosis often lead to body lesions including tumors. Studies have shown that Bcl-2 protein with anti-apoptosis activity is an important target in the treatment of cancer. After nearly two decades of efforts, many small molecule Bcl-2 inhibitors have been discovered to induce cell apoptosis. The small-molecule Bcl-2 inhibitor, venetoclax, was developed based on fragment-based drug design strategy and approved by the FDA in 2016 for clinical application. This agent is the first approved small-molecule drug inhibiting Bcl-2 through protein-protein interaction to induce cell apoptosis. The achievement of venetoclax benefits from a combination of drug discovery technologies and represents a milestone in the history of drug discovery. In this review we will introduce the current progress in Bcl-2 inhibitors.