Efficacy and safety-related factors of BTK inhibitors as a bridge to CAR-T therapy in R/R FL.

Although anti-CD19 chimeric antigen receptor (CAR) T cell therapy has achieved satisfactory results in relapsed/refractory (R/R) follicular lymphoma (FL), patients with R/R FL and high-risk disease characteristics, previous hematopoietic stem cell transplantation, bulky disease, and progression of disease within 2 years (POD24) had a low complete response (CR). Twenty-seven patients with R/R FL, later disease stages, higher tumor burden, or higher previous treatment lines who had received Bruton tyrosine kinase (BTK) inhibitors before anti-CD19 CAR T cell therapy, or received BTK inhibitors as combination therapy, were included in this study. The clinical response and adverse events (AEs) in anti-CD19 CAR T cell therapy were observed. All patients with R/R FL who received BTK inhibitors combined with anti-CD19-CAR T cell therapy had later disease stages, higher tumor burden, and higher treatment lines than those who did not receive BTK inhibitor combination therapy. However, no difference in the clinical response was found between the two groups. The clinical response in the POD24 group was lower than that in the non-POD24 group; however, no difference in the clinical response was found between the FL and transformed FL (tFL) groups, between the follicular lymphoma international prognostic index (FLIPI) 1 1-2 and FLIPI 1 3-5 groups, and between the FLIPI 2 1-2 and FLIPI 2 3-5 groups. The mean anti-CD19 CAR T cell peak was higher in the CAR-T group with BTK inhibitor than in the CAR-T group without BTK inhibitor. Meanwhile, a higher proportion of patients in the non-POD24 group, FL group, and PR group achieved CR after 2 months. No difference in cytokine secretion was found between the CAR-T group with and without BTK inhibitors. It was higher in the non-POD24 group, FLIPI 1 3-5 group, and FLIPI 2 3-5 group. No difference in cytokine release syndrome and immune effector cell-associated neurotoxic syndrome grades was found between the CAR-T groups with or without BTK inhibitors and between the other groups. Poor prognostic factors, other than POD24, did not affect the clinical response to BTK inhibitors in combination with anti-CD19 CAR T cell therapy in patients with R/R FL. Therefore, BTK inhibitors combined with anti-CD19 CAR-T therapy may be an effective and safe approach for patients with R/R FL and high-risk factors.Trial registration: The study was registered at http://www.chictr.org.cn/index.aspx as ChiCTR-ONN-16009862 and http://www.chictr.org.cn/index.aspx as ChiCTR1800019622.

Synergistic Effects of Zanubrutinib Combined With CD19 CAR-T Cells in Raji Cells in Vitro and in Vivo.

Background and Objects: Bruton's tyrosine kinase inhibitors are commonly used and effective for lymphoma and chronic lymphocytic leukemia (CLL). Ibrutinib might improve the effect of anti-cluster of differentiation 19 (CD19) chimeric antigen receptor (CD19 CAR) T-cell therapy in lymphoma, but the effects of zanubrutinib combined with CAR-T cells is unclear. Methods: We selected a low effect-target ratio (E:T = 1:3) to study this synergistic effect in vitro. The programed cell death protein 1 (PD-1) expression in CD19 CAR-T cells and immune phenotype of T lymphocytes were analyzed by flow cytometry (FCM). We selected CD19 CAR-T cells of a patient with diffuse large B cell lymphoma (DLBCL) to study the synergistic effect of zanubrutinib with CAR-T cells by bioluminescence imaging monitoring. The CD19 CAR-T cells expansion in mice was compared by FCM. Results: Zanubrutinib and ibrutinib had dose-dependent toxicity on both CAR-T cells and lymphoma cells. But there was no significant synergistic effect of the CD19 CAR-T cells combined with zanubrutinib/ibrutinib in vitro. The PD-1 expression in CD19 CAR-T cells increased when the CD19 CAR-T cells were co-cultured with Raji cells and decreased when ibrutinib was added in culture, but zanubrutinib had no such effect. The extinction of luciferase expression was more obvious in the polytherapy group of ibrutinib and CD19 CAR-T cell than that in the other groups. Moreover, the proportion of CAR-T cells in the combination therapy group of CD19 CAR-T cells and ibrutinib was higher than that of the polytherapy group of CD19 CAR-T cells with zanubrutinib group. The synergistic effect could be observed obviously in mice receiving ibrutinib combined with CD19 CAR-T cells. But zanubrutinib cannot perform joint therapy effect either in vitro or in mice. Conclusion: Zanubrutinib might have no joint therapy effect with CD19 CAR-T cells neither in vitro nor in mice, but the mechanism of different curative effects requires our further research and exploration.

[Clinical Characteristics and Bone Marrow Histopathology Features in Essential Thrombocythaemia Patients with Different Gene Mutation in China].

OBJECTIVE: To investigate the clinical characteristics, laboratorial and bone marrow pathological features of primary thrombocytopenia (ET) patients with different mutations of CALR, JAK2 and MPL genes. METHODS: The chinical data of 120 cases of ET in Jiangsu provincial people's hospital/ The First Affiliated Hospital of Nanjing Medical University from January 2015 to December 2017 were collected and analyzed, including 76 cases with JAK2 gene mutation, 40 cases with CALR gene mutation, 2 cases with MPL gene mutations, 2 cases without gene mutation. RESULTS: Among the ET patients, compared with the JAK2 gene mutation, CALR gene mutation showed statistically significant deareament of white blood cells and hemoglobin (P=0.001, P=0.01) and the male platelets in CALR group showed significant increament (P=0.04). Fourthermore, the average number of megakaryocytes and its cluster numbers in each hight power field of vision showed statistically significant decreament in CALR group as compared with JAK2 group (P=0.001, P=0.001), and thrombotic events in CALR group were signicantly lower than those in JAK2 group (7.5% vs 18.4%) (P=0.03). CONCLUSION: Mutations of CALR, JAK2 have different clinical characteristics and blood pathological changes of Chinese ET patients, and their clinical significance is worth to explore.

A case of myeloproliferative neoplasm with a normal complete blood cell count: A novel problem of the JAK2 era.

The present study reported a case of a myeloproliferative neoplasm (MPN) in a patient with a normal complete blood cell count. Bone marrow biopsy showed bone marrow hyperplasia, an elevated megakaryocyte count, megakaryocytic dysplasia and pleomorphic changes, multiple megakaryocyte clusters and focal reticulin fiber hyperplasia. Furthermore, genetic analysis revealed that the patient was positive for the JAK2-V617F mutation, and negative for the JAK2 exon 12 and 13 mutations and the BCR-ABL (p210) fusion gene. The patient's condition was basically stable and at the time of writing, the patient remained in a stable condition with no specific symptoms of disease. The present study also analyzed the diagnostic and clinical features of MPNs, and a literature review was performed. MPN with a normal complete blood cell count is a rare disease, and attention should be focused on this entity in the clinic.

Accelerated partial breast irradiation for breast cancer: a meta-analysis.

To evaluate the long-term effect of breast conservation with accelerated partial breast irradiation (APBI) for early-stage breast cancer, PubMed, EMBASE, Cochrane Library, Web of Science, Chinese Biomedical Literature Database, Chinese Scientific Journals Full-text Database, and China Journal Full-text Database were searched to identify relevant original published trials. Randomized controlled trials in any language comparing APBI with whole-breast radiotherapy in patients with early-stage breast cancer were included. RevMan 5 software was used for statistical analysis. Four trials involving 919 patients were included. The rate of 5- and 7-year excellent/good cosmetic results was significant {odds ratio (OR) = 2.09 [95% confidence interval (CI) = 1.21-3.62]} between two groups. The 5- and 8-year overall survival had no significant difference [OR = 1.76 (95% CI = 0.67-4.62) and OR = 0.86 (95% CI = 0.44-1.66)]. The 10-year overall survival had significant differences [OR = 0.56 (95% CI = 0.35-0.91)]. There were no differences in the 5-year local recurrence (LR)-free survival [OR = 0.65 (95% CI = 0.18-2.34)], cancer-specific survival [OR = 1.67 (95% CI = 0.39-7.12)], disease-free survival [OR = 0.84 (95% CI = 0.38-1.84)], LR [OR = 1.36 (95% CI = 0.46-3.99)], the rate of contralateral breast cancer [OR = 2.82 (95% CI = 0.73-10.89)], and distant metastasis [OR = 0.71 (95% CI = 0.22-2.31)]. APBI significantly improved the rate of excellent/good cosmetic results anywhere in the breast, shortened the treatment time, alleviated the pain, and improved the quality of life. Future large-scale, high-quality, and double-blind trials are needed.