Ibrutinib revolutionized the CLL treatment approach and prognosis demonstrating its efficacy and safety even at extended follow-up. During the last few years, several next-generation inhibitors have been developed to overcome the occurrence of toxicity or resistance in patients on continuous treatment. In a head-to-head comparison of two phase III trials, both acalabrutinib and zanubrutinib demonstrated a lower incidence of adverse events in respect to ibrutinib. Nevertheless, resistance mutations remain a concern with continuous therapy and were demonstrated with both first- and next-generation covalent inhibitors. Reversible inhibitors showed efficacy independently of previous treatment and the presence of BTK mutations. Other strategies are currently under development in CLL, especially for high-risk patients, and include BTK inhibitor combinations with BCl2 inhibitors with or without anti-CD20 monoclonal antibodies. Finally, new mechanisms for BTK inhibition are under investigations in patients progressing with both covalent and non-covalent BTK and BCl2 inhibitors. Here we summarize and discuss results from main experiences on irreversible and reversable BTK inhibitors in CLL.

Waldenström Macroglobulinemia (WM) is a B-cell lymphoma characterized by the precursor condition IgM monoclonal gammopathies of undetermined significance (IgM MGUS). We performed a gene expression profiling study to compare the transcriptome signatures of bone marrow (BM) B-cells and plasma cells of 36 WM patients, 13 IgM MGUS cases, and 7 healthy subjects used as controls (CTRLs) by Affymetrix microarray. We determined 2038 differentially expressed genes (DEGs) in CD19+ cells and 29 DEGs genes in CD138+ cells, respectively. The DEGs identified in B-cells were associated with KEGG pathways, mainly involved in hematopoietic cell lineage antigens, cell adhesion/focal adhesion/transmembrane proteins, adherens junctions, Wnt-signaling pathway, BCR-signaling pathway, calcium signaling pathway, complement/coagulation cascade, platelet activation, cytokine-cytokine receptor interactions, and signaling pathways responsible for cell cycle, apoptosis, proliferation and survival. In conclusion, we showed the deregulation of groups of genes belonging to KEGG pathways in the comparison among WM vs. IgM MGUS vs. CTRLs in B-cells. Interestingly, a small set of genes in B-cells displayed a common transcriptome expression profile between WM and IgM MGUS compared to CTRLs, suggesting its possible role in the risk of transformation of IgM MGUS to WM.

Waldenström Macroglobulinemia (WM) is a rare indolent lymphoma with heterogeneous clinical presentation. As there are no randomised trials suggesting the best treatment option in treatment-naive patients, guidelines suggest either rituximab-combining regimens or BTK-inhibitors (BTKi) as feasible alternatives. Several factors play in the decision-making process: patients’ age and fitness, disease characteristics and genotype. Chemoimmunotherapy (CIT) represents a fixed-duration, less expensive and effective option, able to achieve prolonged time-to-next treatment even in patients with unfavourable genotypes. Immunosuppression and treatment-related second cancers may represent serious concerns. Proteasome-inhibitor-based regimens are effective with rapid disease control, although bortezomib-related neuropathy discourages the choice of these agents and treatment schedules may not be easily manageable in the elderly. BTKi have demonstrated high rates of response and prolonged survival together with the convenience of an oral administration and limited cytopenias. However, outcomes are impacted by genotype and some concerns remain, in particular the continuous drug exposure that may result in extra-haematological complications and drug resistance. Although next-generation BTKi have improved treatment tolerance, the question whether BTKi should be offered as frontline therapy to every patient is still debated. Giving fixed-duration schedule, prolonged time-to-next treatment and outcomes independent of genotype, CIT is still our preferred choice in WM. However, BTKi remain a valuable option in frail patients unsuitable for CIT.