B-Cell Receptor Inhibition Paints a Complex Picture in CLL

Francesco Forconi, MD

Treatments such as idelalisib (Zydelig) and ibrutinib (Imbruvica), which inhibit the B-cell receptor (BCR) pathway, have shown success in the treatment of patients with chronic lymphocytic leukemia (CLL).

However, BCR is extremely variable, and targeting it with the currently available therapeutic agents is not necessarily sufficient for all patients, explains Francesco Forconi, MD, associate professor of Hematology, University of Southampton, United Kingdom.

The picture of BCR is complex, says Forconi, and a better understanding of it could result in more benefit for patients.

BCR immunoglobulin heavy-chain variable (IGHV) status is one factor that should be considered.

Patients who have an unmutated IGHV gene tend to have a poorer prognosis, while those with a mutated IGHV gene often have a better prognosis, says Forconi. Clinical data also suggest that those with unmutated CLL have more complete responses during BCR-associated inhibition.

In an interview with OncLive from the 2016 European Hematology Association Congress, Forconi discusses his research¹ into BCR structure and its function in CLL. Additionally, he highlights important links between BCR and IGHV status, the role of immunoglobulin signaling, expanding the efficacy of BCR inhibitors, and other future venues for CLL treatment.

OncLive: What is the goal of your research?

Forconi: CLL is a disease with a very variable outcome. A lot of effort has been spent understanding variable outcomes through genetics. However, the functional unit of any B cell is the BCR. If you remove it, the B cell disappears. In CLL, if you change the signaling capacity, the cell changes behavior.

It has now just been published that the ability of CLL to progress depends on the BCR immunoglobulin (IgM) levels and the BCR signaling levels. Those cells that have a stronger capacity through IgM—which means they have a higher level of IgM on the cell surface—will progress more rapidly than those that have low IgM signaling capacity or lower IgM levels. Clearly, it is an important molecule.

This molecule can be targeted now and very effectively. There is a need to understand the BCR functions—in CLL and other B-cell tumors—and how to improve its therapeutic attack.

What questions remain regarding this research?

One question that remains is, “Why is the BCR variable, and can this variability be targeted therapeutically and more effectively?” We know from BCR-associated kinase inhibitors that therapeutic targets can be very effective. We also know that it is not necessarily sufficient.

However, one way is to understand how B-cell signaling is influenced, what other pathways influence that, and how BCR-signaling inhibitors can be associated with other known genotoxic and chemotherapeutic agents.

How could a better understanding of B-cell signaling and function improve the treatment paradigm of CLL?

Clearly, the goal for any patient is to have an effective treatment that is nontoxic. Treatment with BCR-associated inhibitors has been a remarkable and exciting finding because the efficacy is not accompanied by serious toxicity. They are very easy-to-manage compounds that are very effective. Now, the point is to add additional efficacy without adding more toxicity by considering drugs that are not genotoxic and are not chemotherapeutic agents.

What are the next steps for this research?

Moreover, we may like to consider how those genetic influences may be targeted. There are micro-RNA or epigenetic influences through DNA methylation that alter BCR signaling, and there are drugs that could be used in this setting to control, for example, methylation.

What are you hoping that oncologists will take away from this research?

BCR is the functional unit for the normal B cell, and it is key to understanding the behavior of patients with CLL. We have 2 subtypes of CLL—1 with BCR-mutated immunoglobulin genes and 1 with BCR-unmutated immunoglobulin genes. Therefore, the key information is that these 2 subsets behave differently, hence the prognosis of CLL.

The second key information is between the 2 subsets, where the levels of the signaling capacity are different to the point that they change progression of the 2 subsets and within the 2 subtypes of CLL individuals. Oncologists need to use IgM signaling as a new tool to define prognosis of the aggressiveness of CLL.

The third message is that signaling capacity can be targeted through new small molecules. That must be one take-home message, with the consideration that these might not be sufficient.

1. Forconi F. B-cell receptor structure and function in CLL. Presented at: 2016 European Hematology Association Congress; June 9-12, 2016; Copenhagen, Denmark.

We plan to underpin the mechanisms of BCR signaling, which are the cascades that are involved through specific BCR signaling and regulate or control BCR signaling. One example is signaling through IL4-mediated JAK-STAT inhibition but, clearly, there are also genetic influences that may alter BCR signaling.