John G. Gribben, MD, DSc, FRCP


June 27, 2014

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A Decade of Progress in CLL

Hello. I am Prof. John Gribben, Chair of Medical Oncology at Barts Cancer Institute, St. Bartholomew's Hospital, Queen Mary University of London, in London, United Kingdom. Welcome to this edition of Medscape Oncology Insights on chronic lymphocytic leukemia (CLL). Today I will highlight key data in CLL as presented at the19th Congress of the European Hematology Association (EHA), in Milan, and will update you on other important studies.

This has been a really exciting time in CLL, in terms of understanding the biology and because of the new drugs that have become available. For most of the past decade, the progress we have made in CLL, both clinically and in the laboratory, has gone hand-in-hand but hasn't related very much to each other. The exciting point about emerging agents is that they target the biology of the disease. It's the interplay of the biology of the disease with the new treatments that is exciting the whole field.

Three agents are looking very interesting in terms of the recent data that we are seeing. First, there are the B-cell receptor tyrosine kinase inhibitors, ibrutinib and idelalisib. We have seen recent randomized clinical trial data emerging about ibrutinib. Data are also emerging about the novel BCL2 inhibitor ABT-199.

Ibrutinib Still the Agent to Beat

Let's start with ibrutinib. This is a drug that has had a great deal of interest within CLL. Ibrutinib targets Bruton tyrosine kinase (BTK), an enzyme present within B cells, which is responsible for transmitting the signal from the B-cell receptor down through a B cell. We have always known that the B-cell receptor was important in CLL, but it took having an inhibitor for us to fully understand just how important that pathway was for the pathogenesis of the disease.

Ibrutinib is a covalently binding molecule that binds to the pocket of BTK and irreversibly inhibits the ability of that molecule to transmit a signal. Using an oral agent, we are able to demonstrate in patients with CLL very impressive and durable responses. Over the past several years at the international meetings, we have seen phase 1 and 2 data emerging and demonstrating that these BTK inhibitors are very effective in the treatment of CLL. Of particular interest, they appear to be very effective in patients with high-risk disease, patients with 17p deletions, and patients with mutated and unmutated immunoglobulin gene rearrangements.

We saw at the American Society of Clinical Oncology (ASCO) meeting,[1] and updated at EHA, the results of the RESONATE trial.[2] This is the first reported randomized clinical trial comparing ibrutinib with another agent -- in this case the monoclonal antibody ofatumumab. In this study, almost 400 patients with relapsed CLL were randomly assigned to receive either ibrutinib at an oral dose of 420 mg, or ofatumumab, a standard agent approved for relapse in refractory CLL. This trial demonstrated not only a very impressive progression-free survival advantage for use of ibrutinib over ofatumumab, but it also demonstrated an overall survival advantage. This was unexpected because this was a crossover design that allowed patients who had progressed on ofatumumab to receive ibrutinib at a later time. The demonstration of the survival advantage of ibrutinib reiterates the importance of giving the most effective agent up front in our patients.

Of course, ibrutinib has recently been approved by the US Food and Drug Administration for use in patients with CLL who are refractory to therapy and who have 17p deletions. Now that we have the results from the RESONATE trial, we are able to use this drug in the United States where it is already approved. We are hopeful that this will soon lead to approval of the drug by the European Medicines Agency as well, so we will have this drug available also in Europe to treat our patients with relapsed disease.

Beating Resistance to Ibrutinib

Many ongoing trials are looking at the use of ibrutinib alone and in combination with other agents, notably rituximab, as well as other agents, which will be reported over the next few years. It is also a very exciting time because the results of the RESONATE trial were not only presented at ASCO, but were also published online in the New England Journal of Medicine[3] at the same time as ASCO. So we had full access not just to the trial presentation, but also to the full paper.

Some cases are emerging of ibrutinib resistance, and work[4] has been presented demonstrating that some of the mechanisms of resistance relate to mutations arising in the binding pocket, in the area of the BTK molecule where the ibrutinib binding becomes mutated, leading to a reduced ability to bind. Other mechanisms are being explored and examined. What is impressive, however, is that the number of patients who are relapsing and becoming resistant to ibrutinib has been rather small.

What was also very important to come out of the RESONATE trial was the finding of side effects that are often seen in patients with relapsed CLL. People were not sure whether these side effects were being exacerbated by ibrutinib. We are able to see, by comparing the side-effect profile of the ofatumumab arm with that of ibrutinib, that many of the side effects were more likely to be associated with the patient population being treated rather than being effects of the drug.

Expanding Options for CLL

Also presented at this meeting were the results of other molecules, such as idelalisib, particularly in combination with rituximab.[5,6] We are now seeing data presented about the BCL2 inhibitor ABT-199,[7] alone and in combination with obinutuzumab.[8] Altogether, that means the armamentarium that we have to treat our patients with CLL is likely to be greatly expanded, leading potentially to a paradigm shift in the way that we think about this disease.

In the educational session at EHA, we had presentations from Prof. Ghia,[9] myself,[10] and Professor Hallek[11] to address the underlying biology of the disease and question whether we can identify the patients who may benefit from these novel agents earlier in their treatment, and to start thinking about rational clinical trial design so that we can offer the right drugs to the right patients at the right time in their treatment.

Thank you for joining me for this edition of Medscape Oncology Insights. This is John Gribben, reporting from Milan.


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