Dimopoulos MA et al.  N Engl J Med  2018; 378(25): 2399-2410. doi:10.1056/NEJMoa1802917

Rule S et al.  Leukemia  2018; doi:10.1038/s41375-018-0023-2

The authors provide an overview of recent work on developing therapies targeting the B cell receptor signaling pathway in chronic lymphocytic leukemia and highlight future avenues for development. Arnason JE, Brown JR. Curr Oncol Rep 2017; 19: 61. doi:10.1007/s11912-017-0620-7

For his progressing disease, our case patient was offered a frontline clinical trial comparing bendamustine plus rituximab verus ibrutinib versus ibrutinib plus rituximab.

Ibrutinib is generally a well-tolerated agent.

Agents targeting MEK1/2 (selumetinib; AZD6244), 47 BTK (PCI-32765; ibrutinib), PIM (SGI-1776), 32 CDKs (dinaciclib) 66 and FAK (VS-4718), as well as the multi-targeted kinase inhibitor sorafenib, 67 were also shown to be largely ineffective against the standard ALL PDX panel.

Its inhibitor, ibrutinib, shows promising efficacy in patients with relapsed/refractory chronic lymphocytic leukemia/small lymohocytic lymphoma, mantle lymphoma, follicular lymphoma, activated B-cell-like diffuse large B-cell lymphoma, lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia, primary diffuse large B-cell lymphoma of the central nervous system, and marginal zone lymphomas which also have aberrant Btk activity. 159, 160 Figure 5.

NCT02157636, phase I None Ibrutinib Btk inhibitor p.o.

New methods to increase the safety of therapy are being evaluated and include the introduction of a suicide gene via Herpes simplex virus thymidine kinase and inducible caspase 9 (iCasp9), or targetable cell-surface proteins, such as truncated EGFR or CD20. 41, 74, 75 With the success of CD19-targeted CAR T cells, targeting of other cell-specific TAAs is being explored. 76, 77, 78 Selective targeting of κ or λ light chain might reduce the incidence of B-cell aplasia and result in reduction of prolonged hypogammaglobulinaemia. 79 CD30-targeted and CD123-targeted CAR T cells are also being explored for potential use in treating HL. 80, 81 Finally, incorporating chemokine or cytokine expression into the CAR-T-cell construct might improve delivery and trafficking of the cells to the tumour. 42, 43, 82, 83 Combination treatment with small-molecule inhibitors, such as ibrutinib or lenalidomide, or with immune-checkpoint inhibitors can be explored to improve CAR-T-cell activation or suppress the endogenous T-cell-inhibitory microenvironment, which might enhance treatment efficacy. 84, 85, 86 Relapses following treatment with CAR T cells are typically associated with a lack of T-cell persistence or the development of a CD19-negative tumour-cell clone. 51, 52 Strategies to increase the efficacy of CAR T-cells through modification of CAR constructs, such as the use of third-generation and fourth-generation armoured constructs, are being evaluated. 40 Another alternative approach is to infuse patients with polyspecific CAR T cells that targets multiple cell-surface proteins to prevent immune escape.

Sun and Wienster review key prognostic markers, current and emerging therapy, and the future outlook for the management of patients with chronic lymphocytic leukemia and small lymphocytic lymphoma. Sun C & Wiestner A. In:  Non-Hodgkin Lymphoma . Edited by Evens AM, Blum KA. Springer International Publishing, 2015. doi:10.1007/978-3-319-13150-4_6