Significance: Multiple myeloma (MM) is one of the most common hematological malignancies. Developing an effective treatment strategy for refractory/relapsed (R/R) MM represents a major challenge. In this trial, 17 R/R MM patients, who had previously experienced multiple lines of treatments, received a chimeric antigen receptor modified T (CAR T) cell preparation targeting two epitopes of BCMA, and a remarkable overall response of 88.2% was achieved. This work confirms the feasibility and importance of CAR T cell therapy in the treatment of patients with R/R MM. Meanwhile, the adverse events encountered in this study are analyzed, providing a reference for other studies. We also suggest that CAR T treatment can eventually be combined with other effective therapeutics to treat newly diagnosed MM for achieving a better result in future trials.

Background: Bruton tyrosine kinase (BTK) inhibitors have demonstrated a high degree of efficacy in the treatment of B cell malignancies characterized by constitutive B cell receptor activation, including chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Methods: The efficacy and safety of zanubrutinib, an investigational highly selective BTK inhibitor, was evaluated in this single-arm, phase 2 study of Chinese patients with relapsed/refractory CLL/SLL. The primary endpoint was overall response rate as assessed by an independent review committee. Results: Of the 91 evaluable patients, 77 (84.6%) achieved a response, with three (3.3%), 54 (59.3%), and 20 (22%) patients achieving a complete response, partial response, and partial response with lymphocytosis, respectively, after a median follow-up of 15.1 months. The estimated 12-month event-free rate for duration of response was 92.9%. The most commonly reported grade ≥ 3 adverse events (AEs) were neutropenia (44%), thrombocytopenia (15.4%), lung infection/pneumonia (13.2%), upper respiratory tract infection (9.9%), and anemia (8.8%). The 12-month overall survival rate was 96%. Eight (9.0%) patients discontinued zanubrutinib due to AEs, and seven (8.0%) patients required at least one dose reduction. Conclusion: Treatment of patients with relapsed/refractory CLL/SLL with zanubrutinib was generally well tolerated and resulted in a high overall response rate, thereby conferring a favorable benefit-risk profile. Trial registration: Prospectively registered in China public registry (CTR20160890) on December 7, 2016: http://www.chinadrugtrials.org.cn/. Retrospectively registered in ClinicalTrials.gov (NCT03206918) on July 2, 2017.

Epstein-Barr virus (EBV) positive diffuse large B-cell lymphoma (DLBCL) of the elderly is defined as patients older than 50 years alone. However, recent studies showed young patients with sound immune status could also be affected. In this study, we investigated the clinical features and outcomes of patients with EBV positive DLBCL in the different age groups using different EBER cut-off values. The prevalence of EBV positive DLBCL was 14.0% (35/250) and 10.4% (26/250) for EBER cut-off of 20% and 50%, respectively. With both EBER cut-off values, patients with EBV DLBCL shared many unfavorable prognostic characteristics, regardless of age. EBV positive patients, both in the elderly and young groups, showed significantly worse overall survival and progression-free survival than negative cases. Moreover, no significant differences of outcomes were identified between different age groups with EBV positive DLBCL. In conclusion, EBV positive DLBCL patients, regardless of age, shared similar poor prognostic features and showed worse outcome than negative cases. We suggest that the age criterion of EBV positive DLBCL of the elderly and possibly the name itself, be modified in future.

Circular RNAs (circRNAs), a novel family of non-coding RNAs, play crucial roles in cancer progression. While the existing research focuses on nuclear genome-derived (nu)-circRNAs, the biological and clinical characteristics of mitochondrial genome-derived (mt)-circRNAs remain largely unknown, especially in chronic lymphocytic leukemia (CLL). In this study, we attempted to identify the novel characteristics of mc-COX2 (mitochondrial genome-derived circRNAs [mc]), one of the mt-circRNAs that can be involved in CLL progression. mt-circRNAs were found to be highly expressed in the plasma exosomes of CLL patients. The endogenous reduction of mc-COX2 can affect mitochondrial functions, suppress cell proliferation, and induce cell apoptosis. The upregulation of mc-COX2 was positively associated with leukemogenesis and worsening survival of CLL patients. Notably, functional analysis revealed that mc-COX2, as differing from conventional nu-circRNAs, was less stable and may function through novel mechanisms other than acting as the competing endogenous RNA. We also screened and tested several chemical compounds and small-molecule inhibitors that can decrease the generation of mc-COX2. It was found that the silencing of mc-COX2 in CLL cells strengthened the anti-tumor effects of drugs used in coordination. Our findings prove that mc-COX2, a critical mt-circRNA highly expressed in plasma, derived from CLL cells and delivered by exosomes, is associated with the progression and prognosis of CLL.

B cell receptor (BCR) signaling is involved in the pathogenesis of B cell malignancies. Activation of BCR signaling promotes the survival and proliferation of malignant B cells. Bruton tyrosine kinase (BTK) is a key component of BCR signaling, establishing BTK as an important therapeutic target. Several covalent BTK inhibitors have shown remarkable efficacy in the treatment of B cell malignancies, especially chronic lymphocytic leukemia. However, acquired resistance to covalent BTK inhibitors is not rare in B cell malignancies. A major mechanism for the acquired resistance is the emergence of BTK cysteine 481 (C481) mutations, which disrupt the binding of covalent BTK inhibitors. Additionally, adverse events due to the off-target inhibition of kinases other than BTK by covalent inhibitors are common. Alternative therapeutic options are needed if acquired resistance or intolerable adverse events occur. Non-covalent BTK inhibitors do not bind to C481, therefore providing a potentially effective option to patients with B cell malignancies, including those who have developed resistance to covalent BTK inhibitors. Preliminary clinical studies have suggested that non-covalent BTK inhibitors are effective and well-tolerated. In this review, we discussed the rationale for the use of non-covalent BTK inhibitors and the preclinical and clinical studies of non-covalent BTK inhibitors in B cell malignancies.

WDR5 high expression and its effect on tumorigenesis in leukemia