Bruce D. Cheson, MD


May 23, 2014

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Time to Move Brentuximab Up Front?

Welcome back to Medscape Hematology. This is Bruce Cheson, from Georgetown University Hospital, The Lombardi Comprehensive Cancer Center, in Washington, DC.

It is almost time for the American Society of Clinical Oncology (ASCO®) meeting in Chicago. I am just going to discuss a few of the highlights of the leukemia and lymphoma sessions and try to stimulate your interest in going to see these interesting abstracts.

As you know, brentuximab vedotin (formerly SGN-35) is a very important drug in the management of patients with Hodgkin’s lymphoma. It was approved by the US Food and Drug Administration because of a response rate of around 76% in patients who have relapsed or refractory disease, even after autologous transplant. Thus, the natural tendency would be to move a drug like this to earlier in the course of the disease, and that is one of the abstracts that is being presented at ASCO.

The group, led by Massimo Federico, conducted a pilot phase II trial[1] of brentuximab followed by ABVD (adriamycin, bleomycin, vincristine, dacarbazine) and showed a very impressive response rate to the brentuximab in the frontline setting, which leads to 2 possibilities. The first is to incorporate it into a frontline regimen, which already is being done in a multinational study. The second is to use it in patients who cannot tolerate chemotherapy, using it as a single agent to get them into condition so that they can tolerate chemotherapy.

For patients who relapse, brentuximab is their only option. Another abstract will be presented on the combination of sirolimus and an HDAC inhibitor, vorinostat, in patients with heavily pretreated Hodgkin lymphoma.[2]

For patients with relapsed or refractory B-cell lymphoma, we have many treatments. In previous Medscape video blogs, we have talked about the kinase inhibitors and the pro-apoptotic drugs, but also of interest have been antibody drug conjugates; studies of two of these will be presented at ASCO: SGN-CD19A[3] and a maytansine conjugated monoclonal antibody, SAR3419.[4] The data are promising in both studies and are certainly worth your attention.

Several groups of investigators have made the interesting observation that men seem to do worse than women in rituximab-based therapies. There have been some pharmacokinetic differences observed between men and women, which may explain these differences in outcomes. Michael Pfreundschuh and his group[5] conducted the SEXIE R-CHOP-14 trial in their German High Grade Non-HodgkinLymphoma Study Group and made some interesting observations of the impact of modifying rituximab dose on the basis of pharmacokinetics.

For mantle cell lymphoma, we have a new drug, ibrutinib, which is very active. But in the frontline setting are there better regimens? Hyper-CVAD-R has been used extensively but seems to be fading from popularity because of its toxicities and unclear advantage over other approaches. A study will be presented of R-CHOP,[6] which is clearly an inferior regimen in mantle cell lymphoma vs VR-CAP, which is a bortezomib-containing regimen. When you compare one agent against another agent that does not work very well, what happens is generally predictable.

Using PET to Modify Therapy

Modifying therapies on the basis of predictive factors and prognostic factors is of great interest. A GELA/LYSA study[7] looked at PET-driven approaches to patients with diffuse large B-cell lymphoma in a study of ACVBP or CHOP, and suggests that PET may play a role in the management of those patients.

What I find particularly intriguing is a pooled analysis from 3 multicenter studies that will be presented by Judith Trotman.[8] Three publications now show that patients who are positive on PET scan for frontline follicular lymphoma after treatment have significantly worse outcomes than those who are negative on PET scan, regardless of other response criteria features. Once you throw PET in there, you can really distinguish patients into markedly distinct groups. Trotman and colleagues have pooled the data from these 3 trials -- the PRIMA study, the GELA/LYSA study, and an Italian study. These data are important because not only can you better predict patient's outcomes, but you may be able to intervene earlier in the patients with a poor prognosis and perhaps influence their survival. Such studies are in discussion.

How else can we monitor patients other than with PET? There are interesting data showing that perhaps blood studies can also be of value. There is cellular vs acellular tumor DNA from immunoglobulin genes in patients with diffuse large B-cell lymphoma, and a report on that strategy will be presented.[9]

In chronic lymphocytic leukemia, all of the action is on the intracellular pathways. Susan O’Brien will be presenting a 3-year follow up of the ibrutinib data.[10] Let us see whether the data hold up with prolonged observation in regard to safety, efficacy, and particularly the challenging patients with the 17P deletion.

Along with ibrutinib, idelalisib, and ABT-199, other drugs are of potential interest and more are coming along all the time. One of these is GS-9973, a selective Syk inhibitor of spleen tyrosine kinase, which has also shown activity in CLL. That report will be presented.[11] However, even though single-agent activity is promising, combinations with other drugs such as idelalisib have resulted in untoward effects; indeed, in one study that combination was shut down because of toxicity.[12] We cannot just take these biological targeted therapies, throw them together, and expect that everything will be great, because unexpected complications may occur. These therapies should be tried in the context of a carefully controlled clinical trial.

These and other important studies will be presented at the ASCO annual meeting. This is Bruce Cheson, signing off from Medscape Hematology. Hope to see you in Chicago.


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