COMMENTARY

ASH 2012: More Fuel for the Fire

Bruce D. Cheson, MD

Disclosures

November 28, 2012

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Hello again. This is Bruce Cheson from Georgetown University Hospital, the Lombardi Comprehensive Cancer Center, speaking to you for Medscape Hematology.

It's that exciting time of the year again. It's November, and what we are all waiting for is not Thanksgiving or Christmas but the upcoming American Society of Hematology (ASH) meeting. This year, there are quite a number of very interesting papers that I am looking forward to seeing.

Let's start with follicular lymphoma. My former fellow, Nathan Fowler, will be presenting the so-called final analysis of the regimen known as R-squared, or rituximab and lenalidomide (Revlimid®). In his preliminary presentations, response rates around 90% were seen in previously untreated patients with lots of complete remissions. We are finally going to see some long-term follow-up results to see how durable the responses are.

You are all probably familiar with the StiL study of R-bendamustine vs R-CHOP in frontline follicular lymphoma, presented by Mathias Rummel.[1] There was another study called the Brightstudy, conducted in North America, Australia, and New Zealand -- R-bendamustine vs R-CVP (rituximab, cyclophosphamide, vincristine, and prednisone) or R-CHOP in previously untreated follicular mantle cell lymphoma.[2] It will be very interesting to see if these results are consistent with the German data. If not, it will be very provocative and will engender lots of discussion.

Hodgkin lymphoma has not been left out at this meeting. As you know, the 2 main issues with this very curable disease are, how do we decrease therapy for patients who have low-risk disease and how do we improve the treatment of patients with high-risk disease? John Radford from the United Kingdom will be presenting results of the RAPID Trial,[3] in which patients received 3 cycles of ABVD, and if their PET scan was positive, they received another cycle of radiation. If they were PET negative, they got randomly assigned to receive involved-field radiation or no further therapy.

As you may know, the Eastern Cooperative Oncology Group (ECOG) study that was presented by Ralph Meyer in the New England Journal of Medicine[4] earlier this year looked at a similar design but without PET scans and with subtotal nodal irradiation. It suggested that survival was actually inferior if you received radiation. The study was criticized because it wasn't contemporary radiation. This study will be much more contemporary, and it will throw more fuel into the fire of the role of radiation, as will the HD10 trial from the EORTC (European Organization for the Research and Treatment of Cancer).

On the other side of things, Andrea Gallamini will be presenting the results of an Italian study.[5] In this study, patients who were PET positive after 2 cycles of ABVD received either escalated plus baseline BEACOPP or escalated plus baseline BEACOPP and rituximab. PET-negative patients received either no treatment or radiation to fields representing prior bulk disease. All of these are very controversial issues, and hopefully we will get some light shed on them.

What is really exciting are the new drug data -- not just drugs but antibodies, and not just antibodies but antibody-drug conjugates. You are all familiar with brentuximab vedotin, or SGN-35, which is the anti-CD30 linked to auristatin. This drug had amazing activity in relapsed refractory anaplastic large cell and Hodgkin lymphoma. At the ASH meeting, we will see the first data from combining it with chemotherapy such as CHOP in previously untreated anaplastic large cell and other CD30-positive lymphoid malignancies.

Another group of agents that has engendered considerable enthusiasm is the kinase inhibitors downstream from the B-cell receptor, which, when stimulated, activates a bunch of kinases through a variety of mechanisms, including phosphoinositide 3-kinase and Bruton tyrosine kinase. We have some drugs now that specifically target these pathways. The pathways themselves were responsible for maintaining longevity of the lymphoma cells and rendering them resistant to treatment. We can now block these pathways with well-tolerated oral drugs. The first of these, GS-1101 (which used to be called CAL-101), is active across a broad range of particularly indolent B-cell malignancies.

At ASH, we will see a presentation of GS-1101 with bendamustine, rituximab, or the combination of the 2 drugs in patients with relapsed/refractory chronic lymphocytic leukemia (CLL).

The other agent that has been very exciting used to be called PCI-32765 but is now known as ibrutinib. We will be seeing data for relapsed refractory CLL, including those for high-risk patients such as those with 17p deletion. These data will be very interesting. We will also see updated data in older patients (65 years of age and older) who were previously untreated and whose response rates were exceptionally encouraging. Again, this is a well-tolerated oral drug.

This drug has also shown some interesting preliminary activity in other forms of lymphoid malignancies. At the ASH meeting, we will be seeing some data on its activity in relapsed/refractory diffuse large B-cell lymphoma and, in a multicenter trial, relapsed/refractory mantle cell lymphoma.

We now have an increasing number of tools. We have the R-squared regimen, we have the kinase inhibitors, and we are putting these together in frontline follicular relapse, follicular, and even in mantle cell lymphoma to try to develop a platform of noncytotoxic regimens that may be very effective, very well tolerated, and may improve the outcome of patients with a variety of lymphoid malignancies.

I look forward to running into you at the ASH meeting. Have a good holiday season as well. This is Bruce Cheson signing off for Medscape Hematology.

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