Ibrutinib: a paradigm shift in management of CLL

Abstract

1. Summary B-cell receptor (BCR) signaling plays a vital role in B-cell malignancies; Bruton's Tyrosine Kinase (BTK) is a critical mediator of this signaling. BCR signaling, either constitutively or following antigen binding, leads to activation of several downstream pathways involved in cell survival, proliferation, and migration. The efficacy observed in studies of the BTK inhibitor, ibrutinib, confirms that BCR signaling is critical for the growth of B-cell malignancies. Ibrutinib characteristically induces redistribution of malignant B-cells from tissues into the peripheral blood, and rapid resolution of adenopathy. Further, ibrutinib therapy results in normalization of lymphocyte counts and improvement in cytopenias. Ibrutinib has been shown to have an excellent safety profile and does not cause myelosuppression. Early data from combination studies of ibrutinib with anti-CD20 monoclonal antibodies have shown more rapid responses compared to those seen with ibrutinib monotherapy. Current data strongly support continued clinical evaluation of Ibrutinib in B-cell malignancies.

Cutaneous, Purpuric Painful Nodules Upon Addition of Ibrutinib to RCVP Therapy in a CLL Patient: A Distinctive Reaction Pattern Reflecting Iatrogenic Th2 to Th1 Milieu Reversal

“…In preventing B cells from responding to stimulatory and survival factors including CD40L, BAFF, IL-6, IL-4, and TNF-a, ibrutinib leads to apoptosis and halts B-cell proliferation beyond the pre-B-cell stage. 19 However, BTK's effects, and therefore ibrutinib's effects, are not limited to B cells. The btk is involved in signaling pathways that produce a spate of cytokines.…”

An unusual case of severe anaemia and lymphocytosis

“…Coronary ischaemia has also been reported. 18 Radiotherapy can be given to patients with symptomatic bulky lymphadenopathy and those whose disease is resistant to chemotherapy and immunotherapy. 6 Recently, novel targeted treatments for CLL have become available through clinical trials.…”

A Patient with Abnormal Kidney Function and a Monoclonal Light Chain in the Urine

“…In general, rituximab can be used against the CD20-expressing clones but would have little effect against plasma cells and only partial effectiveness against CLL (70). For these other clones, the addition of alkylator, proteosome inhibitors, immunomodulatory drugs, mAb against other cellular targets, or specific kinase inhibitors, such as Bruton tyrosine kinase inhibitor, may be necessary (71,72). Autologous stem cell transplantation, although not curative, may offer patients with deeper response and prolonged remission as well as extended coverage of multiple clones (52,(73)(74)(75).…”