A number of new treatment options have recently emerged for chronic lymphocytic leukemia (CLL) patients, including the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, phosphatidylinositol-3-kinase (PI3K) delta isoform inhibitor idelalisib combined with rituximab, the Bcl-2 antagonist venetoclax, and the new anti-CD20 antibodies obinutuzumab and ofatumumab. Most of these agents are already included into treatment algorithms defined by international practice guidelines, but more clinical investigations are needed to answer still remaining questions. Ibrutinib was proven as a primary choice for patients with the TP53 gene deletion/mutation, who otherwise have no active treatment available. Idelalisib with rituximab is also an active therapy, but due to increased risk of serious infections, its use in first-line treatment is limited to patients for whom ibrutinib is not an option. A new indication for ibrutinib was recently approved for older patients with comorbidities, as an alternative to the already existing indication for chlorambucil with obinutuzumab. The use of kinase inhibitors is already well established in recurrent/refractory disease. Immunochemotherapy with fludarabine, cyclophosphamide, rituximab (FCR) remains a major first-line option for many CLL patients without the TP53 gene deletion/mutation, and who have no significant comorbidities or history of infections, and is particularly effective in patients with favorable features including mutated IGHV status. There are a number of issues regarding novel therapies for CLL that need further investigation such as optimum duration of treatment with kinase inhibitors, appropriate sequencing of novel agents, mechanisms of resistance to inhibitors and response to class switching after treatment failure, along with the potential role of combinations of targeted agents.

Ibrutinib is the first Bruton's tyrosine kinase (BTK) inhibitor, which showed significant clinical activity in chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) patients regardless of cytogenetic risk factors. Recent results of phase III clinical trials in treatment-naïve CLL patients shift the importance of the agent to frontline therapy. Nevertheless, beside its clinical efficacy, ibrutinib possesses some off-target activity resulting in ibrutinib-characteristic adverse events including bleeding diathesis and arrhythmias. Furthermore, acquired and primary resistance to the drug have been described. As the use of ibrutinib in clinical practice increases, the problem of resistance is becoming apparent, and new methods of overcoming this clinical problem arise. In this review, we summarize the mechanisms of BTK inhibitors' resistance and discuss the post-ibrutinib treatment options.

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Lymph node microenvironment provides chronic lymphocytic leukaemia (CLL) cells with signals promoting their survival and granting resistance to chemotherapeutics. CLL cells overexpress PIM kinases, which regulate apoptosis, cell cycle and migration. We demonstrate that BCR crosslinking, CD40 stimulation, and coculture with stromal cells increases PIMs expression in CLL cells, indicating microenvironment‐dependent PIMs regulation. PIM1 and PIM2 expression at diagnosis was higher in patients with advanced disease (Binet C vs. Binet A/B) and in those, who progressed after first‐line treatment. In primary CLL cells, inhibition of PIM kinases with a pan‐PIM inhibitor, SEL24‐B489, decreased PIM‐specific substrate phosphorylation and induced dose‐dependent apoptosis in leukaemic, but not in normal B cells. Cytotoxicity of SEL24‐B489 was similar in TP53‐mutant and TP53 wild‐type cells. Finally, inhibition of PIM kinases decreased CXCR4‐mediated cell chemotaxis in two related mechanisms‐by decreasing CXCR4 phosphorylation and surface expression, and by limiting CXCR4‐triggered mTOR pathway activity. Importantly, PIM and mTOR inhibitors similarly impaired migration, indicating that CXCL12‐triggered mTOR is required for CLL cell chemotaxis. Given the microenvironment‐modulated PIM expression, their pro‐survival function and a role of PIMs in CXCR4‐induced migration, inhibition of these kinases might override microenvironmental protection and be an attractive therapeutic strategy in this disease.

Background The standard first‐line treatment for primary mediastinal B‐cell lymphoma (PMBCL) patients is rituximab‐based immunochemotherapy; however, this is not due to the result of randomized clinical trials. Aims We retrospectively investigated 53 PMBCL patient outcomes treated either with R‐CHOP‐21 or DA‐EPOCH‐R‐28. The primary endpoint was overall survival (OS). Secondary endpoints were complete remission (CR), overall response rate (ORR), progression‐free survival (PFS), and treatment‐related complications. Results Treatment with R‐CHOP‐21 resulted in a 92.0% ORR (60% CR), while DA‐EPOCH‐R yielded a 92.6% ORR (70.4% CR). There were no differences in the occurrence of grade 3‐4 hematological adverse events, but grade 1‐2 cardiologic complications (P = .003) were observed more frequently in the DA‐EPOCH‐R arm. Median PFS and OS were not achieved. The differences in estimated 12‐month PFS in R‐CHOP and DA‐EPOCH‐R group (87% vs 73.9%) and OS (100% vs 92%) were insignificant. Patients treated with R‐CHOP‐21 and autologous hematopoietic stem cell transplantation (auto‐HSCT) had an improved OS (P = .03) but not PFS (P = .43) compared to those treated solely with R‐CHOP‐21. No differences in PFS or OS were observed between patients treated with R‐CHOP‐21/auto‐HSCT and DA‐EPOCH‐R. Conclusion The results of this study suggest that R‐CHOP‐21 may be an alternative to DA‐EPOCH‐R treatment for PMBCL patients.