Martin Dreyling, MD, PhD


October 09, 2014

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A Little Help From My Friends

Hello. I'm Martin Dreyling, professor of medicine at the University of Munich Hospital in Grosshadern. I am very happy to welcome you to this edition of Medscape Oncology Insights on hematologic malignancies. I will highlight some of the key developments in lymphoma, updated here at the 2014 Congress of the European Society for Medical Oncology (ESMO) in Madrid. What is the major theme of this congress? It is fair to say that we are moving from chemotherapy to targeted therapy. One example is the educational symposium focusing on basic science of hematologic malignances, titled "Targeting Signaling Pathways in Lymphoma: Are We Close to the End of the Chemotherapy Era?"[1] Is this really the case?

Let's have a look at the data. Have any major changes during the past few months moved us in this direction? For mantle cell lymphoma, which has been the most refractory disease for chemotherapy alone, targeted approaches achieve rather high response rates. Is this the end of chemotherapy? Who will guide us through this jungle of molecular approaches?

The "fab four" will help us. I'm not referring to the musical group the Beatles, but to the compounds registered to date in malignant lymphoma: bortezomib, ibrutinib, idelalisib, temsirolimus, and lenalidomide [BIITLs]. These five compounds are not only registered, but they have had a very strong impact. They are listed in the current ESMO guidelines on malignant lymphoma.[2] They have nicely been summarized in their pocket guidelines. You can access these on your smartphone because they are also available as an app. All of these guidelines have been summarized and updated during the past 1-2 years.

Chronic Lymphocytic Leukemia: Compounding Our Knowledge

What's the news? Let's take a closer look. When it comes to chronic lymphocytic leukemia (CLL), in Europe we now have a registration for some of these compounds in the B-cell receptor pathway. There are two major competitors so far: ibrutinib, the BTK inhibitor; and idelalisib. What have we learned during the past year about the efficacy of these compounds? For CLL, it's prime time to move away from giving chemotherapy only. We are not only moving to the third generation of the anti-CD20 antibodies (eg, obinutuzumab) but also to substitute these new compounds for chemotherapy. We will probably have to redo all of our work with respect to sensitivity, predictors of response rates, and mechanisms of resistance. To give you a rough idea: If we combine rituximab with some of these compounds, there are some antagonistic effects, at least in vitro. Some of these data have been published and some will be presented at the next American Society of Hematology meeting.

On the other hand, we have learned during the past couple of months that these compounds achieve not only high response rates but ongoing remissions as well. We now have insights into the mechanisms of resistance, for both ibrutinib and idelalisib. Just this year, there was an article in the New England Journal of Medicine[3] describing the mechanisms, some of which are expected (eg, point mutations in the target genes) and others that are unexpected (such as alternative signal pathways). We have a lot to learn about the optimal use of these compounds. That is the aim of current and future studies. So far, we definitely know that for CLL with p53 deletions or mutations, these compounds should be considered in first-line.

Follicular Lymphoma: Defying the Status Quo

Let's move on to follicular lymphoma. In follicular lymphoma, the European study groups have been in favor of rituximab combined with chemotherapy for quite some time. It is still considered the standard of care in these patients in the first line of treatment. However, we are trying to move on and rid ourselves of chemotherapy in these rather indolent diseases. We have known for 10 years that the major prognostic marker in follicular lymphoma is the immune reaction of the host. Is it a more specific T-cell mechanism, or is it a more nonspecific macrophage infiltration? This has been addressed in a number of studies, but we are not able to transform that into clinical practice. This indicates that this disease is sensitive to targeted therapy.

At least for relapsed disease, we have some interesting data for idelalisib. In the last stages of the disease, when patients are already resistant to our standard of care (alkylating drugs and anti-CD20 antibodies), even in these high-risk patients we achieve a response rate of more than 50%, which is quite striking.[4] These remissions are ongoing, lasting for months and even years.

Now the challenge is how to implement that in an intelligent way. To share some of these thoughts for the future, the major European study groups are now starting up first-line trials that attempt to skip chemotherapy. A good example is the RELEVANCE trial,[5] which compares standard-of-care R-chemotherapy vs R-squared (rituximab [Rituxan®] plus lenalidomide [Revlimid®]). Lenalidomide is an interesting drug because it's oral and easily administered, and there is some interaction with rituximab. We come back to the role of the immune reaction in follicular lymphoma. The synergy between rituximab and the anti-CD20 antibodies of these immune-modulating drugs is strong. That has been confirmed clinically by the high response rates of the R-squared regimen and also by the ongoing remissions. The major aim of the RELEVANCE trial (a huge phase 3 trial with more than 1000 patients) is to determine whether this targeted approach is as good as or better than R-chemo.

The other very promising compounds (eg, idelalisib and ibrutinib) are the small molecules that inhibit the B-cell receptor. Idelalisib is already registered. All major study groups are exploring how to apply these targeted approaches in first-line treatment of patients who are skipping chemotherapy. Chemotherapy is skipped within the design, so we will learn which patients are specifically sensitive to one or another drug. That is the major challenge for the next couple of years—to develop predictive markers to decide which of these large amounts of different compounds are most applicable for all patients.

Bortezomib for Mantle Cell Lymphoma: Oldie but Goodie

What about mantle cell lymphoma? This is a disease where we have a lot of challenges. In first-line, we achieve high response rates. Some of these responses are ongoing for a couple of years, but once the disease relapses it becomes much more challenging to treat. With chemotherapy, we have only achieved short remissions. This is the field where, even outside of clinical trials, targeted approaches play a major role.

What about bortezomib, the oldest one of all these agents? Even for the old guy bortezomib we have new data from a randomized trial[6] comparing the standard R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone] plus or minus bortezomib. Quite strikingly, this achieved a major benefit of 10 additional months of progression-free survival even in first-line therapy. In fact, this was the first confirmation of the role of biological therapies in first-line of this aggressive disease.

Ibrutinib achieves a response rate of more than 70% in heavily pretreated patients, and many of these remissions are ongoing.[7] I didn't believe the data when I first heard them. I thought, "It's too good to be true, but it's true." On the other hand, mantle cell lymphoma is not dependent on just one gene—one alteration—so sooner or later we have to move in the direction of combining our approaches. This is progressive work.

The same holds true for idelalisib and lenalidomide. Temsirolimus was criticized for low response rates in the initial registration trial.[8] When we take a closer look at the data presented here at this meeting, we have some real-life scenarios. All of a sudden, the response rate of temsirolimus[9] is closer to 50%, and with the combination of rituximab and temsirolimus, the response rate rises to 80%.

These are very interesting data, and they make the point that these three diseases are now in position to be treated with molecular approaches. We have to learn much during the next 5 years about how to apply these different instruments and tools in the distinct kinds of diseases.

That was just a short overview of what is happening here at ESMO in the field of hematologic malignancies. Thank you for joining me for this edition of Medscape Oncology Insights. This is Martin Dreyling, reporting from ESMO 2014 in Madrid.


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