Blood Journal
Leading the way in experimental and clinical research in hematology

LYMPHOID NEOPLASIA
Ibrutinib: targeting the hidden CLL

  1. Farrukh T. Awan1
  1. 1THE OHIO STATE UNIVERSITY COMPREHENSIVE CANCER CENTER

ORCID Profiles

In this issue of Blood, Herman et al elucidate the in vivo effects of ibrutinib (a BTK inhibitor) in various disease compartments of patients with chronic lymphocytic leukemia (CLL).1

The study validates the differential impact of ibrutinib in various tumor compartments of patients treated on a small but well-designed and well-conducted clinical trial. In their study, the authors provide a link between the extent of on-target drug effects and the magnitude of clinical responses. They demonstrate rapid and sustained inhibition of the B-cell receptor (BCR) signaling pathway and progressive inhibition of the dependent NF-κB pathway in circulating CLL B cells over the first few weeks of therapy with ibrutinib. This effect was also observed in matched lymph node and bone marrow resident CLL B cells obtained at serial time points in the trial. Similarly, significant reductions were observed in the expression of activation markers CD69 and CD86, and the proliferation marker Ki-67. This provides evidence for simultaneous pathway targeting and inhibition in tumor compartments of peripheral blood, bone marrow, and lymph nodes.

The authors did not observe significant correlation in nodal responses among patients in various prognostic subgroups. A previously validated specific BCR gene signature score2 was also observed to correlate with nodal responses, regardless of risk factors, only from B cells obtained from lymph node biopsies rather than circulating B cells. However, no definite explanation was provided for the dramatic tumor reductions seen with ibrutinib other than a combination of reduced proliferation, inhibition of survival mechanisms, and slightly increased apoptosis observed in circulating cells.

The BTK gene is located on the long arm of the X chromosome at the Xq21.33-q22 locus and encodes the BTK protein that is part of the Tec family of kinases. BTK is located downstream of the BCR that has been established as the primary CLL tumor cell survival signal. It is essential for the activation of several constitutively active pathways of CLL cell survival including Erk, Akt, PLCγ2, and NF-κB along with those involved in chemokine-mediated homing and adhesion of B cells.3,4 In vivo mouse studies using various CLL models have established the significance of BTK in disease establishment and progression. Moreover, ibrutinib demonstrated significant reduction in development and progression of disease in these models.5 Together, these studies laid the foundation for further investigation of BTK targeting as a therapeutic strategy for patients with CLL.

The recent Food and Drug Administration approval of ibrutinib for the management of relapsed CLL is a landmark event that heralds a new era of targeted therapies for the management of this disease. The drug is generally well tolerated with mostly mild side effects that frequently resolve despite continuation of therapy.6 The responses observed are primarily sustained partial responses with occasional complete responses, which appear to be independent of conventional prognostic markers. Similar results were also seen in the current study. However, progression-free survival (PFS) has been shown to be inferior in patients with deletion 17p or 11q.6 Interestingly, the redistribution lymphocytosis and its persistence in some patients also do not appear to correlate with PFS.7 In addition, minimal residual disease negative state, which could potentially be used as a surrogate for PFS, is rare with single-agent use.6

A small percentage of patients treated with ibrutinib develop progressive disease or resistance to therapy, the mechanisms of which are currently being investigated and can at least be partially attributed to specific mutations in the BTK protein itself or downstream targets. With the expected rapid increase in the use of ibrutinib, similar well-designed trials are desperately needed to study not only the mechanisms of action and resistance, but also to obtain better understanding of its off-target effects. Studying the various disease compartments simultaneously will also enable us to evaluate the differential effects of these agents and tumor escape mechanisms, and will enable us to devise rational combination strategies that will hopefully result in the eventual cure of CLL.

Footnotes

  • Conflict-of-interest disclosure: F.T.A. received a career development award from the Lymphoma Research Foundation.

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