Understanding the B-Cell Receptor Pathway

Understanding the B-Cell Receptor Pathway

The B-cell receptor (BCR) pathway has recently become a target for treatment of many incurable B-cell malignancies, including mantle cell lymphoma (MCL), relapsed or refractory diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), small lymphocytic leukemia (SLL), and chronic lymphocytic leukemia (CLL). The BCR pathway is quite complex, and it has been widely studied because of its role in healthy immune function, B-lymphocyte development, and the initiation of humoral immunity. The role of the BCR pathway in many B-cell malignancies, however, has only more recently been appreciated. Multiple BCR-targeted therapies are in clinical or preclinical development.

The BCR Pathway

The BCR pathway itself, aside from its interest as a target of directed therapies, is important to healthy immune function, supporting functions intrinsic to B-cell biology, including driving the development of antigen-presenting functions in mature B lymphocytes and eliciting the development of high-affinity soluble immunoglobulins. A complete description of this complex pathway (Fig. 1) is beyond the scope of this fact sheet. Briefly, the protein tyrosine kinase LYN, which is highly expressed in B cells, is the predominant initiator of the BCR-derived signal. LYN activates immunoreceptor tyrosine-based activation motifs (ITAMs), which recruit spleen tyrosine kinase (SYK). SYK activation initiates the formation of the BCR signalosome, from which four relatively independent signaling systems diverge. All four of these pathways, which include the RAS/RAF/MEK/ERK pathway, are critical to the activation of B cells. The BCR pathway also interacts with other pathways.

A more detailed description of the pathway was presented in an original article by Jason A. Dubovsky, PhD, in the ASCO Daily News, on which this fact sheet is based. With colleagues, Dr. Dubovsky also reviewed the essential components of BCR signaling and the therapeutics emerging to target it in multiple malignancies.1

Targeting the BCR Pathway in B-Cell Malignancy

The BCR pathway is intrinsically related to the development and pathogenesis of B-cell malignancy. With the many molecular components of the BCR pathway, there is no shortage of potentially druggable targets. The relative importance of each sub-pathway may not be fully understood; nevertheless, a number of therapeutics with robust clinical potential and impressive clinical safety profiles that target this pathway have emerged.

Dasatinib was originally approved to combat imatinib-resistant chronic myeloid leukemia by targeting the BCR-Abl kinase. It has since been investigated in B-cell malignancies. In a phase II study of 15 patients who had relapsed or refractory CLL, a reduction in lymph node size was seen in nine patients, four of whom had reductions greater than 50%, with daily oral administration of 140 mg of dasatinib. Clinical responses extending beyond 12 months were observed in four patients. Myelosuppression was the primary toxicity observed.

Another phase II trial investigated the use of 100 mg of dasatinib daily with 3 consecutive days of fludarabine (40 mg/m2) in patients with refractory CLL who did not achieve a partial response (PR) with dasatinib alone. Responders (18%) were characterized by lymph node clearance that correlated with progression-free survival (PFS) and overall survival (OS).

In a phase I/II trial treating patients with recurrent or refractory non-Hodgkin lymphoma (NHL), an overall response rate (ORR) of 32% was observed. Partial response occurred in two patients with FL and in a single patient with MCL.

Fostamatinib is an investigational drug and a prodrug of the active compound tamatinib. A phase I/II clinical trial of fostamatinib was conducted in DLBCL, MCL, FL, and CLL/SLL. The phase I portion established a dose of 200 mg twice daily, which resulted in objective response rates of 22% in patients with DLBCL, 10% in those with FL, 55% in those with CLL/SLL, and 11% in those with MCL. Notably, all patients with CLL/SLL developed peripheral lymphocytosis. Overall, fostamatinib was well tolerated, generating only rare grade 3 and 4 toxicities. Hematologic toxicity was mild, and infections were uncommon.

Idelalisib is a kinase inhibitor that has been evaluated in multiple clinical trials. It is indicated for the treatment of relapsed CLL in combination with rituximab in patients for whom rituximab alone would be considered appropriate therapy because of other comorbidities, relapsed FL in patients who have received at least two prior systemic therapies, and relapsed SLL in patients who have received at least two prior systemic therapies. In a randomized controlled study of 220 patients with relapsed CLL who were unable to tolerate standard chemoimmunotherapy, there was a statistically significant improvement with idelalisib plus rituximab over placebo plus rituximab for the primary endpoint of PFS.2

In a single-arm trial of 72 patients with relapsed FL, 46% of patients achieved PR, and 8% achieved complete response (CR), with a median time to response of 1.9 months. In a single-arm trial of 26 patients with relapsed SLL, PR was seen in 58% of patients and CR in 0%.3

Idelalisib has been investigated in combination with antibody-based immunotherapies, with impressive results. For example, combinations with rituximab and/or bendamustine in patients with CLL who had previously been treated yielded an ORR of 71%.4

Ibrutinib is a kinase inhibitor indicated for the treatment of MCL in patients who have received at least one prior therapy, of CLL in patients who have received at least one prior therapy, of previously untreated CLL in patients with 17p deletion, and of patients with Waldenström macroglobulinemia. (Accelerated approval was granted for the MCL indication on the basis of ORR. According to the manufacturer, continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials.5)

In a phase II study of 111 patients with relapsed or refractory MCL, ibrutinib demonstrated an ORR of 68% and a CR rate of 21%. In an open-label trial of 48 patients with CLL who had previously been treated, the ORR was 58.3%; no patient achieved CR. In a randomized phase III trial of ibrutinib versus ofatumumab conducted in 391 patients with CLL or SLL, the ORR was 42.6% for ibrutinib and 4.1% for ofatumumab. Analysis of OS indicated a statistically significant 57% reduction in risk of death for patients in the ibrutinib arm.5

AVL-292 is an orally available covalent drug that targets Bruton’s tyrosine kinase (BTK). In a phase I clinical trial, five of six patients with CLL who received one of two doses of the drug were reported to have stable disease. In all cases, a transient peripheral lymphocytosis was observed, as is common for BCR-pathway inhibitors. A phase I dose-escalating study of AVL-292 in patients with relapsed or refractory CLL, B-cell NHL, or Waldenström macroglobulinemia was also completed, although no results have been posted on clinicaltrials.gov as of this writing.

Enzastaurin was developed as an antiangiogenic agent with the ability to block protein kinase C (PKC)–b–induced VEGF secretion. Given the critical role of PKC-b in the BCR pathway, enzastaurin found clinical potential in the realm of B-cell malignancies. A series of phase II studies of patients with relapsed or refractory DLBCL, MCL, or FL demonstrated some promise. However, a phase III study of patients with DLBCL did not meet its primary endpoint, and development of the drug was halted.

Duvelisib (formerly IPI-145) is a new therapeutic candidate that blocks both PI3Kd and PI3Kg activity. Duvelisib has shown clinical activity across a range of blood cancers, including indolent NHL and CLL. A number of ongoing clinical trials are evaluating its safety and efficacy in blood cancers. These include a phase II monotherapy study (NCT01882803) of patients with refractory indolent NHL and a phase III monotherapy study (NCT02004522) of patients with relapsed/refractory CLL.

Acalabrutinib (ACP-196) is a more selective irreversible BTK inhibitor that is specifically designed to improve on the safety and efficacy of first-generation BTK inhibitors, such as ibrutinib. In an uncontrolled phase I/II multicenter study, acalabrutinib showed promising safety and efficacy in patients with relapsed CLL, including those with the chromosome 17p13.1 deletion.6

ONO/GS-4059 is another selective BTK inhibitor in development. In a multicenter, phase I, dose-escalation study, ONO/GS-4059 showed significant activity in relapsed/refractory B-cell malignancies, without major drug-related toxicity. The drug’s selectivity should confer advantages in combination therapies.7

Take-Home Perspectives

The preclinical and clinical understanding of BCR signaling has grown exponentially during the past decade. However, a full understanding of the mechanisms by which BCR-targeted therapies yield, at least in some cases, impressive and durable clinical remissions is lacking. Nonetheless, a more comprehensive understanding of BCR inhibitors and of their in vivo molecular mechanisms of action will identify additional targets and combination therapies that hold promise for patients with B-cell malignancies that are not responsive to currently available agents.

Recent discussions surrounding BCR-targeted therapies concern their toxicities versus benefits. Research is required to improve our understanding of the inside-out signaling events in platelets that drive bleeding issues in patients who receive inhibitors of BTK and of the potential mechanism for atrial fibrillation issues in patients who receive ibrutinib.8 Another notable recent development is the recognition of BTK as an essential component of the eNAMPT pathway, which generates regulatory T cells by recruiting immunosuppressive help from nurse-like cells.9

The advent and success of BCR-targeted therapies have given the field of hematologic oncology the opportunity to focus on potentially curative therapies. However, the current agents do not produce deep remissions, and long-term therapy will be necessary, raising the potential for resistance. Therefore, development of second-generation BCR-targeted therapies and combination therapies will be vital.  

About the Article: This ASCO Fact Sheet was condensed and updated from an editorial by Jason A. Dubovsky, PhD, published previously in the ASCO Daily News. At the time of its writing, Dr. Dubovsky was a research scientist in the Division of Hematology, Wexner Medical Center, The Ohio State University. He is now an employee of Pharmacyclics.