Ocular adverse events following CAR-T cell therapy: A pharmacovigilance study and systematic review.

The rise of immuno-oncology, including the use of chimeric antigen receptor T-cell (CAR-T) therapy is bringing in a new wave of cancer treatments, particularly in hematologic malignancies. However, data on their adverse events, particularly of the eye, is under-reported. To assess the ocular adverse events associated with the six FDA-approved CAR-T cell therapies, a disproportionality analysis utilizing the FAERS database was conducted from the first quarter of 2017 to the third quarter of 2023, as well as a systematic review of case reports of ocular events following CAR-T cell therapy up to December 20, 2023. A total of 53 ocular adverse events were identified from the FDAs FAERS database. The adverse events most frequently observed were mydriasis and xerophthalmia with tisagenlecleucel (Kymriah). The systematic review resulted in 8 case reports encompassing 19 patients which included a total of 27 events. This study demonstrates the importance of anticipation of potential ocular adverse events by ophthalmologists and oncologists as they can greatly contribute to morbidity in patients with cancer.

Efficacy analysis of blinatumomab in treatment of relapsed/refractory B-cell acute lymphoblastic leukemia / 白血病·淋巴瘤

Objective:To explore the efficacy and safety of blinatumomab in treatment of relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL).Methods:The data of 8 patients with relapsed/refractory B-ALL treated with blinatumomab in Shanghai Zhaxin Traditional Chinese and Western Medicine Hospital from September 2020 to December 2021 were retrospectively analyzed, and their clinical characteristics, overall survival, lymphocyte subsets, cytokines, tandem transplantation and adverse reactions were analyzed.Results:The median follow-up time of 8 patients was 143 d (range: 41-534 d). Five of the 8 patients were alive; among them, 4 of 6 patients assessed to be in minimal residual disease (MRD)-negative complete remission (CR) and 1 of 2 patients assessed to be in non-remission at the time of belintuzumab discontinuation were alive. The median duration of treatment with belintuzumab was 28 d (10-56 d), and it was 23 d (10-56 d) for patients with MRD-positive at baseline and 28 d (25-31 d) for the 4 non-remission patients. Six patients achieved MRD-negative CR after treatment, of which 4 were assessed as MRD-positive at baseline and 2 were assessed as non-remission at baseline. All 4 patients with MRD-positive CR achieved MRD-negative CR after treatment with belintuzumab, including 1 patient with Philadelphia chromosome-positive (Ph +) ALL bridged to autologous hematopoietic stem cell transplantation, and 1 patient with Ph + ALL and 1 patient with Ph - ALL received sequential allogeneic hematopoietic stem cell transplantation and had persistent MRD-negative CR. Two of the 4 non-remission patients achieved MRD-negative CR after treatment with belintuzumab, including 1 patient with Ph + ALL bridged to autologous hematopoietic stem cell transplantation, and 1 patient with Ph - ALL received sequential allogeneic hematopoietic stem cell transplantation, and the 2 patients had persistent MRD-negative CR. Leukocyte counts and neutrophils decreased in both MRD-positive CR and non-remission patients after receiving belintumomab. The proportion and absolute number of CD3 + T and CD3 + CD8 + T lymphocytes in patients with MRD-positive CR were higher than those in patients without remission, and both decreased after drug administration. Median interleukin-6 (46.23, 1.42 pg/ml), interleukin-8 (17.85, 2.10 pg/ml), interleukin-10 (7.43, 1.49 pg/ml) and interferon-γ (11.82, 0.39 pg/ml) levels were elevated in MRD-positive CR and non-remission patients at week 3 of treatment. Grade 1 cytokine release syndrome occurred in 1 case with clinical manifestations of fever, which improved after drug suspension. Three cases developed infections, 2 of which were pulmonary and 1 of which was upper respiratory tract infection. No immune effector cell-associated neurotoxic syndrome was observed. Conclusions:Belintumomab is effective for MRD clearance in relapsed/refractory B-ALL with manageable adverse reactions, providing an effective therapeutic option for bridging hematopoietic stem cell transplantation to prolong the survival of patients.

[CAR T-cell therapy for malignant B-cell lymphoma : A new treatment paradigm]. / CAR-T-Zellen zur Behandlung von malignen B-Zell-Lymphomen : Ein neues Therapieprinzip.

Following the first demonstration of efficacy of anti-CD19-directed chimeric antigen receptor (CAR) T cells in a patient with relapsed chronic lymphocytic leukemia (CLL) in 2011, pivotal studies for this innovative therapy were initially conducted in multiple relapsed or refractory (r/r) childhood and young adult acute B­cell leukemia and in aggressive adult B­cell lymphoma. The studies demonstrated efficacy even in chemotherapy-refractory disease, resulting in the first approval of autologous and genetically engineered T cells for the treatment of r/r B­cell acute lymphoblastic leukemia (B-ALL) in the US for the product tisagenlecleucel (Kymriah®, Novartis) back in 2018. Approval for the treatment of r/r aggressive B­cell lymphoma followed shortly thereafter for tisagenlecleucel and axicabtagene ciloleucel (Yescarta, Kite/Gilead). This review focuses on the treatment of aggressive B­cell lymphoma and other CD19 positive B­cell lymphomas by summarizing the study results of clinically tested CAR T cells, discussing possible resistance mechanisms, and providing an outlook on ongoing studies with new target antigens for the treatment of B­cell lymphomas.

The whole process management principles of chimeric antigen receptor T-cell therapy for lymphoma at Peking University Cancer Hospital / 白血病·淋巴瘤

Chimeric antigen receptor T (CAR-T) cell has achieved excellent efficacy in hematological tumors, especially for lymphoma. Many products have been approved to market all over the world, and 2 products targeting CD19 have been approved to treat relapsed and refractory large B-cell lymphoma in China. The current experiences of using CAR-T cells come from previous clinical studies. How to use CAR-T cells in a standardized and rationalized way is still a challenge faced by our clinicians. Based on the CAR-T cell treatment experiences from Peking University Cancer Hospital and the latest research progresses in CAR-T in China and abroad, this article will elaborate on patient screening, peripheral blood mononuclear cell collection, bridging treatment, lymphocyte depletion chemotherapy, CAR-T cell infusion, the monitoring and treatment of adverse events after infusion, and long-term follow-up after infusion, in order to guide clinicians to better use CAR-T cell and to bring maximum benefits to patients.

[A multivariate model for predicting induction response and prognosis in core binding factor acute myeloid leukemia].

Objective: To evaluate the efficacy and prognostic factors in core binding factor (CBF) acute myeloid leukemia (AML) under current therapy modalities, therefore optimizing the treatment strategies. Methods: Standard cytological and immune methods including next generation sequencing (NGS) were used for risk stratification. Complete remission (CR) rate, disease-free survival (DFS) and overall survival (OS) were assessed by multivariate Logistic and Cox regression models in a total of 206 adults (aged 16-65 years) with CBF-AML, including 152 AML patients with t(8;21) and 54 with inv(16). Results: The CR rate of inv(16) patients after first course was 54/54(100%), significantly higher than that of t(8;21) patients [127/147(86.4%), P=0.005]. The fusion transcript level and KIT mutation were independent factors related to CR rate in t(8;21) patients (P=0.044 and 0.027; respectively). DFS and OS in inv(16) patients tended to be more superior than that in t(8;21) patients (P=0.066 for DFS; P=0.306 for OS; respectively). Multivariate Cox identified negative expression of CD(19) and female gender the independent predictors of inferior DFS in t(8;21) patients (P=0.000 for CD(19); P=0.006 for sex; respectively). Analysis of combining CD(19) with gender indicated that females/CD(1)(9-)subpopulation had significantly poor DFS than did males/CD(19)(+) ones (Bonferroni-P<0.000 01). The number of mutations in each patient, FLT3-ITD and additional karyotype abnormalities did not affect CR rate and DFS (all P>0.05). Conclusions: Patients with inv(16) have better induction response than those with t(8;21). High level of fusion transcripts and positive KIT mutation are associated with low CR rate in t(8;21) patients. Negative CD(19) expression and female gender are independent predictors of inferior DFS in t(8;21) patients.

A multivariate model for predicting induction response and prognosis in core binding factor acute myeloid leukemia / 中华内科杂志

Objective@#To evaluate the efficacy and prognostic factors in core binding factor (CBF) acute myeloid leukemia (AML) under current therapy modalities, therefore optimizing the treatment strategies.@*Methods@#Standard cytological and immune methods including next generation sequencing (NGS) were used for risk stratification. Complete remission (CR) rate, disease-free survival (DFS) and overall survival (OS) were assessed by multivariate Logistic and Cox regression models in a total of 206 adults (aged 16-65 years) with CBF-AML, including 152 AML patients with t(8;21) and 54 with inv(16).@*Results@#The CR rate of inv(16) patients after first course was 54/54(100%), significantly higher than that of t(8;21) patients [127/147(86.4%), P=0.005]. The fusion transcript level and KIT mutation were independent factors related to CR rate in t(8;21) patients (P=0.044 and 0.027; respectively). DFS and OS in inv(16) patients tended to be more superior than that in t(8;21) patients (P=0.066 for DFS; P=0.306 for OS; respectively). Multivariate Cox identified negative expression of CD19 and female gender the independent predictors of inferior DFS in t(8;21) patients (P=0.000 for CD19; P=0.006 for sex; respectively). Analysis of combining CD19 with gender indicated that females/CD19-subpopulation had significantly poor DFS than did males/CD19+ ones (Bonferroni-P<0.000 01). The number of mutations in each patient, FLT3-ITD and additional karyotype abnormalities did not affect CR rate and DFS (all P>0.05).@*Conclusions@#Patients with inv(16) have better induction response than those with t(8;21). High level of fusion transcripts and positive KIT mutation are associated with low CR rate in t(8;21) patients. Negative CD19 expression and female gender are independent predictors of inferior DFS in t(8;21) patients.

Expression of IL-10+CD19+ regulatory B cells in peripheral blood of patients with chronic hepatitis B inaction / 中华检验医学杂志

Objective To investigate the population and role of IL-10+ CD19+ regulatory B cell (Breg) in patients with chronic hepatitis B.Methods Patients with acute hepatitis B (AHB) (n =28),chronic hepatitis B (CHB) (n =31) and normal subjects (n =25) were collected from Changshu No.2 People's Hospital between 2011 June and 2012 October.Peripheral blood mononuclear cells (PBMC) were isolated and stimulated with CpG ODN 2006 and PMA.Flow cytometry was used to analyze the population of IL-10-CD19 + Breg,CD4 + CD25high Treg,and ELISA was used to analyze the concentration of IL-10 in culture supernatant.Results The population of Breg in Peripheral blood of the CHB group [1.28％ (1.05％-2.20％)] was higher than that in the AHB group [0.87％(0.55％-1.22％)] and the HCs group [0.89％ (0.51％-1.37％)] (P =0.001,0.006),and the difference between the AHB group and the HCs group was not statistically significant (P=0.669).Breg in the CHB group [14.30％ (10.70％-16.70％)] was higher than that in the AHB group [10.30％ (7.05％-13.30％)] and the HCs group [10.40％(6.85％-12.60％)] (P =0.003,0.001),treg in the CHB group [5.80％ (4.20％-9.10％)] was also higher than that in the AHB group [4.05％ (2.53％-5.40％)] and the HCs group [4.50％ (2.55％-5.50％)] (P ＜0.001,P =0.005),and there was no significantly difference between the AHB group and the HCs group (Breg:P =0.796 ; Treg:P =0.227).Spearman correlation analysis showed that Breg was positively correlated with Treg in the CHB group (r =0.50,P =0.004),however there was no significantly correlation in the AHB group and the HCs group (r =-0.15,P =0.462; r =0.09,P =0.669).The concentration of IL-10 in the CHB group was higher than that in the AHB group and the HCs group (P ＜ 0.001),and the difference between the AHB group and the HCs group was not statistically significant (P=0.341).Spearman correlation analysis showed that IL-10 were positively correlated with the population of Breg in the CHB group (r =0.409,P =0.022).Conclusion The poluations of regulatory B cell and regulatory T cell increased in patients with chronic hepatitis B,and Breg cell might play the immune regulation role through secreting IL-10 in chronic HBV infection.

Changes of CD19 + CD5 + B cells in endometriosis / 中国医师杂志

ObjectiveTo explore the changes of the frequency and cytokine production of CD19 + CD5 + B cells in Endometriosis before and after treatment.MethodsFlow cytometry and quantitative PCR were used to assess the frequency,cytokine expression of CD19 + CD5 + B cells in the peripheral blood,peritoneal fluids and endometrium biopsies of 35 patients with Endometriosis and 29 patients with myoma of uterus (control subjects).Changes in the CD19+ CD5+ B cell compartment in the peripheral blood were compared before and after treatment.ResultsAll 35 endometriosis patients had higher frequencies(all P ＜0.01 ) of CD19+ CD5 + B cells in the peripheral blood,peritoneal fluids and endometrium biopsies [ (13.1 ± 1.9)％,(12.1 ±2.0)％,(11.7 ± 1.7)％] than 29 control subjects[ (2.9 ±0.8)％,(2.6 ±0.9)％,(2.8 ±1.1 )％ ].CD19 + CD5+ B cells from endometriosis patients expressed higher IFN-γ[ (7.2 ± 1.0) × 103,(7.9±1.3) ×103,(7.4±1.1) ×103 copies] than control subjects [ (1.9±0.7)×103,(2.2±0.8)×103,(2.0 ±0.5) × 103 copies).The endometriosis patients also had higher IL-10 production of CD19 + CD5 + B cells [ (6.4 ±0.9) × 103,(6.8 ± 1.2) × 103,(6.1 ±0.8) × 103 copies] than control subjects [ ( 1.7 ±0.5) × 103,(2.1 ±0.9) × 103,( 1.6 ±0.4) × 103 copies].Compared with control subjects,the endometriosis patients had a clinical response to treatment demomtrated a significant decrease in CD19 + CD5 + B cells in the peripheral blood[ ( 13.1 ± 1.9)％ vs (7.3 ± 1.2)％ ],expressed lower IFN-γ [ (7.2 ± 1.0)×103 copies vs (3.3 ±0.6) × 103 copies],produced less IL-10 [(6.4 ±0.9) × 103 copies vs (3.2 ±0.7) × 103 copies].ConclusionsCD19+ CD5 + B cells might play an important role in the pathogenesis of endometriosis through higher IFN-γand IL-10 expression.

Changes of CD19 + CD5 + B cells and BAFF in endometriosis / 中国医师杂志

Objective To explore the changes of frequency, BAFF expression and sensitivity to apoptosis of CD19 + CD5 + B cells in endometriosis patients and investigate the relationship between CD19 +CD5 + B cells and endometriosis. Methods Flow cytometry and quantitative PCR were used to assess the frequency, BAFF expression and sensitivity to apoptosis of CD19+ CD5 + B cells in the peripheral blood,peritoneal fluids and endometrium biopsies of 39 patients with endometriosis and 31 patients with myoma of uterus ( control subjects). Results: All 39 endometriosis patients had higher frequencies ( all P ＜ 0. 01 ) of CD19 + CD5 + B cells in the peripheral blood, peritoneal fluids and endometrium biopsies than that in 31 control subjects. CD19 + CD5 + B cells from endometriosis patients expressed higher BAFF, and were more resistant to CD95L-induced apoptosis than the cells from control subjects ( P ＜ 0. 01 ). Conclusion CD19 + CD5 + B cells might play an important role in the pathogenesis of endometriosis through higher BAFF expression and more resistance to CD95L-induced apoptosis.

Dynamic changes and significance of subsets of blood lymphocyte in 206 adult sev ere acute respiratory syndrome patients / 中华传染病杂志

Objective To study the changing of subsets of blood lymphocyte in adult SARS patients and its effect on the clinical features and prognosis. Methods According to the clinical characteristic diagnostic standards of SARS recommended by the Ministry of Health of China, 206 of hospita lized SARS patients were divided into 3 groups: Mild-Moderate group included 13 3 patients; severe group 50 patients and death group 23 patients, and cells coun t changes of CD4 +, CD8 +, CD19 + and CD16 +. Statistic analyses were perfor med to analyze the relationship of immune changes and clinical features and prognosis. Results The counts of CD4 +, CD8 +, CD19 + lymphocytes in mild-moderate group were h igher than severe group, while lowest in death group (P0.05), there were significanl y difference in CD4 +, CD8 +,CD19 + and CD16 + cell counts among three grou ps(P

Expression of BLyS and CD38 molecules on peripheral blood lymphocytes of patients with systemic lupus erythematosus / 中国病理生理杂志

AIM: To investigate the expression of B lymphocyte stimulator(BLyS) and CD38 molecules on peripheral blood lymphocytes of patients with systemic lupus erythematosus(SLE). METHODS: Twenty-two patients with SLE and fourteen healthy subjects entered the study. Isolated peripheral blood lymphocyte were stained for the lymphocyte surface markers BLyS, CD19, and CD38, and then was measured by flow cytometry(FACS). RESULTS: BLyS + lymphocytes, CD19 + lymphocytes, and CD19 +CD38 + lymphocytes were increased significantly in patients with SLE( P

Effect of lupus recipe on immune system and lymphocyte subsets proliferation in splenic cells of lupus-prone BXSB mice / 中国病理生理杂志

AIM: To investigate the effects of lupus recipe on immune system and lymphocyte subsets proliferation in splenic cells in BXSB mice. METHODS: Eighteen male BXSB mice model was used in the experiment. The model mice were divided into three groups: un-treated model group, lupus recipe (LR) treated group, and prednisone treated group. All model mice were killed in 10 weeks. The control group consisted of 6 syngeneic normal C57BL/6 male mice. The levels of total IgG and anti-dsDNA antibody in serum were detected by ELISA. The percentages of lymphocyte subsets (CD3+, CD4+, CD8+ T lymphocytes and CD19+, CD23+ B lymphocytes) were detected by using flow cytometry analysis. RESULTS: (1) The serum levels of total IgG and anti-dsDNA antibody in un-treated model group were higher than that in other groups. There was no differences among LR treated group, prednisone treated group and control group. (2) The percentages of CD3+, CD4+, CD8+ T lymphocytes and CD19+, CD23+ B lymphocytes in model group were obviously higher than that in normal control. (3) Compared to un-treated model group, the percentages of CD4+, CD8+ T lymphocytes and CD19+, CD23+ B lymphocytes in LR or prednisone treated group were significantly reduced, which closely reached the levels in normal group. CONCLUSIONS: The immune functions of T and B lymphocytes in BXSB mice are up-regulated. LR inhibits the activation of T and B lymphocytes, reduces the serum levels of IgG and auto-antibody production.