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.

The advent of BTK inhibitors has changed the treatment of patients with chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). The first-in-class BTK inhibitor ibrutinib has shown remarkable therapeutic effects and manageable toxicities in multiple clinical trials. The second-generation BTK inhibitors, including acalabrutinib and zanubrutinib, also show remarkable efficacies. However, using BTK inhibitors as monotherapies requires continuous treatment. Resistance to BTK inhibitors and severe side effects unavoidably occur during BTK inhibitor monotherapy, frequently resulting in treatment failure. The addition of the BCL2 inhibitor venetoclax to BTK inhibitor may improve the therapeutic effects and result in deeper responses, providing a potential fixed-duration treatment, especially for patients with CLL. In this review, by focusing on CLL and MCL, we discussed the rationale for the combinational use and summarized the current data on the combinations of BTK inhibitors and venetoclax in patients with CLL and MCL.

The incidence of B‐cell chronic lymphoproliferative disorders (B‐CLPDs) is significantly lower in China than that in western countries. There have been studies involving small cohorts with conflicting results regarding the spectrum of B‐CLPDs in China, and the types and immunophenotyping of B‐CLPDs in China remain largely unexplored. We conducted a retrospective analysis of 653 cases of B‐CLPDs seen in our centre from 2011 to 2015. Four‐colour flow cytometry was used to determine the expression of each immunological marker, and the diagnostic values of the immunological markers were also investigated. Chronic lymphocytic leukaemia (CLL) was the most common type of B‐CLPD, which was consistent with that in west countries. However, the proportions of CLL (55.9%), follicular lymphoma (2.6%), and hairy cell leukaemia (0.2%) were lower, while the proportion of lymphoplasmacytic lymphoma/WaldenstrÖm macroglobulinaemia (5.4%) was higher in China, as compared with western countries. With respect to immunophenotypic characteristics, CD23 (31.7%) was more frequently expressed in mantle cell lymphoma (MCL) in our cohort than that in western countries. Immunophenotyping was useful in differentiating MCL from CLL or B‐cell prolymphocytic leukaemia and lymphoplasmacytic lymphoma/WaldenstrÖm macroglobulinaemia from splenic marginal zone lymphoma. CD200 was of better diagnostic performance (accuracy: 94.6%) in differentiating CLL from MCL compared with CD23 (accuracy: 93.3%). Some cases of B‐CPLDs, however, had no definite diagnoses, which were diagnosed as CD5⁺B‐CPLDs unclassified (7.7%) and CD5⁻B‐CPLDs unclassified (15.8%). This is the largest study that systematically explores the spectrum and immunophenotyping of B‐CLPDs in Asia, confirming that spectrum of B‐CLPDs in China was different from that in western countries. The immunophenotypic features of B‐CLPDs were similar between China and western countries, although a few disparities exist. Cases with no definite diagnoses warrant further studies in the future.

Red blood cell distribution width (RDW), which measures the range of variation of red blood cell volume, has been explored as a prognostic factor in multiple types of cancer. However, the role of RDW in mantle cell lymphoma (MCL), a rare type of non‐Hodgkin lymphoma with poor outcomes, remains to be determined. Therefore, we investigated the prognostic role of RDW in MCL. We found that 21 of 76 MCL patients (27.6%) had an abnormally elevated RDW (>15.7%). Abnormally elevated RDW was significantly associated with presence of B symptoms (P = 0.0020), elevated lactate dehydrogenase (LDH) (P = 0.0010), higher leukocyte count (P = 0.0345), higher simplified Mantle Cell International Prognostic Index (sMIPI) (P = 0.0194), and lower level of hemoglobin (Hb) (P < 0.0001). It was marginally associated with increased C‐reactive protein (P = 0.0862). RDW was significantly correlated with Hb level (r² = 0.42) and LDH level (r² = 0.19). 15.8% was determined as the best cutoff of RDW in predicting the survival outcome by the X‐tile software. Survival analysis revealed that high RDW (>15.8%) predicted shorter progression‐free survival (PFS) (hazards ratio [HR]: 3.14; P = 0.0005) and shorter overall survival (OS) (HR: 4.04; P < 0.0001). High RDW independently predicted both shorter PFS (P = 0.0493) and OS (P = 0.0118). RDW also improved the prognostic stratification based on sMIPI. In conclusion, our study identified RDW as a novel prognostic factor of clinical feasibility in the prognostication of MCL.

The proto‐oncogene NOTCH1 is frequently mutated in around 10% of patients with chronic lymphocytic leukemia (CLL). This study analyzed NOTCH1 mutation status of 317 Chinese patients with CLL by Sanger sequencing. The frequencies of NOTCH1 mutation in the PEST (proline (P), glutamic acid (E), serine (S), threonine (T)‐rich protein sequence) domain and the 3′ untranslated regions (UTR) were 8.2% and 0.9%, with the most frequent mutation being c.7541_7542delCT and c.*371A>G, respectively. Clinical and biological associations were determined including NOTCH1 mutations with advanced stage (Binet stage, P = 0.010), unmutated immunoglobulin heavy‐chain variable region (IGHV) gene (P < 0.001) and trisomy 12 (+12) (P = 0.014). NOTCH1‐mutated patients had lower CD20 expression intensity than NOTCH1‐unmutated patients (P = 0.029). In addition, NOTCH1‐mutated patients had shorter overall survival (OS) (P = 0.002) and treatment‐free survival (TFS) (P = 0.002) than NOTCH1‐unmutated patients, especially for patients with NOTCH1 c.7541_7542delCT and/or c.*371A>G mutations. Patients with both mutated NOTCH1 and unmutated IGHV had shorter OS (P < 0.001) and TFS (P < 0.001) than those with unmutated NOTCH1 or mutated IGHV. These data provide a comprehensive view of the clinical relevance and prognostic impact of NOTCH1 mutations on Chinese patients with CLL.