® titled “Improving Outcomes in Relapsed/Refractory Diffuse Large B-Cell Lymphoma.” I am Dr John Leonard from Weill Cornell Medical Center/New York-Presbyterian Hospital in New York, New York. Joining me today in this discussion are my colleagues: Dr Nathan Fowler, from The University of Texas MD Anderson Cancer Center in Houston, Texas; Dr Kami Maddocks, from The Ohio State University Comprehensive Cancer Center in Columbus, Ohio; and Dr Matthew Lunning, from the University of Nebraska Medical Center in Omaha, Nebraska.

This is a great lineup of speakers, and I’m really excited to be talking to all of you today. We’re going to focus our discussion on a number of topics pertaining to the use of novel agents in relapsed and refractory diffuse large B-cell lymphoma. We’ll discuss newly available agents, the latest research in the field, the impact of clinical trial, and other aspects of decision-making as we choose therapy for patients with diffuse large B-cell lymphoma. Let’s get started on our first topic.

I wanted to introduce our discussion by highlighting some of the current approaches and unmet needs in diffuse large B-cell lymphoma. As this audience knows, R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] chemotherapy is the standard therapy for most patients with DLBCL [diffuse large B-cell lymphoma]. We do have different subsets of DLBCL that we may at times treat differently than with R-CHOP. In some cases—for instance, primary mediastinal lymphoma and double-hit lymphomas—we may choose R-EPOCH [rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin]. But for most patients, we stick with R-CHOP. One exception is the mini R-CHOP regimen, or a dose-reduced version of R-CHOP in cases of patients who are older and have comorbidities, and may not be able to tolerate standard R-CHOP. I’m going to ask our panel, and I’ll start with Dr Lunning. Are there any other patients besides what I mentioned that you might treat with other regimens? If so, what else is out there that you commonly use for DLBCL patients? Or is my summary pretty much in line with what is described?

 I agree. The double-hit population is always interesting. EPOCH [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin] is commonly used and we have the results of the CALGB-50302 trial, which had some of those patients in it and randomized dose-adjusted EPOCH vs. R-CHOP. One of the things I often think about when I’ve seen these patients in the second line—because I have either relapsed the disease or pride every progressive—is whether they were dose-adjusted during their EPOCH. That’s in the CALGB study, where the median number of dose-increase or dose-adjustment was 3 mg/m2. For those, if you’re not dose-adjusting and looking at twice weekly CBCs [complete blood counts] to either dose reduce—because sometimes the regimen may be too toxic at the current doses—or consider going up on the dose if they meet parameters because that’s how it was initially studied. The first publication was in 1993, so we’re over 2 decades of using EPOCH in diffuse large B-cell lymphoma. We should try to stick to how the recipe was made if you’re going to use it.

Nathan, what about MD Anderson’s approach? When I visited there some time ago, there were patients receiving infusional doxorubicin. It’s a place that’s been on the cutting edge. What is new there? What are people doing in practice for large cell lymphoma up front?

 is a tough word because it suggests we treat everybody with a similar frontline regimen—CHOP [cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone]–based approaches with rituximab, as Matt pointed out, are the standard of care. We tweak those, for example, in patients who are maybe a little bit older. We, almost universally, use infusional doxorubicin over 24 to 48 hours, still outpatient, but we often send patients with a pump.

As Matt pointed out, double-hit patients pretty much all get R-EPOCH [rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin]. There is this gray zone, no pun intended, for patients who don’t have double-hit histology but present with a very aggressive large-cell lymphoma. For these patients with a really high Ki-67, the pathologist comes back and says it’s an aggressive-looking disease under the microscope and maybe the PET [positron emission tomography] scan is really high or they have a lot of high symptoms or high LDH [low-density lipoprotein].

For those patients a lot of my colleagues will lean towards R-EPOCH. This is gestalt; these patients may not have a positive MYC, but they have something else driving this tumor to behave more aggressively. Those are the 2 scenarios in patients who are chemotherapy eligible. That’s a different conversation, and I’d sure might be interested to hear what other people do in patients that won’t tolerate chemotherapy.

Kami, for your approach with higher-risk patients, is there anything different you do as far as prognostic scores or other high-risk features that cause you to deviate from R-CHOP?

 The only thing I would add in this, in adding to R-CHOP, is looking at patients who are at high risk for CNS [central nervous system] progression or relapse and there’s a CNS-IPI [International Prognostic Index] score in calculating that. In patients who are high risk, we’ll add methotrexate for prophylaxis, either as IT or IV. Typically we would do 4 intrathecal treatments or 3 intravenous treatments of methotrexate and also do this in the double-hit patients to whom we give dose-adjusted R-EPOCH. Otherwise, I approach it similarly to everyone here.

I would like to summarize the unmet needs, and I’m going to ask all of you to put your thoughts in on this. It seems like the main unmet need is obviously to cure more patients. We cure the majority of patients, but we certainly want to cure those patients, whether they’re identified by prognostic scores or pathology or other features. We want to improve tolerability of treatment as well. Certainly getting R-CHOP is manageable for most people, but we would like to do something better.

To some degree, we’d like to get away from chemotherapy. It would be nice at some point, if it was better tolerated, to have an approach that didn’t include chemotherapy, cured more patients, was easier to tolerate, and was hopefully affordable. Those are some of the key things. Any other thoughts on unmet needs as you approach it? Matt, what are your thoughts beyond that?

 It’s about trying to get more of the IPI 3 to 5s into the up-front clinical trials in diffuse large B-cell lymphoma, and finding mechanisms to do that as we’ve spent a lot of resources. The CALGB study was a multiyear study. As we move into the next generation of the Alliance for Clinical Trials in Oncology study, for instance, which is looking at that really high-risk population, it is about finding novel strategies to really capture those patients, so the data we see at the end is reflective of the real-world experience in large-cell lymphoma. We are really trying to work on novel strategies to get those patients into the randomized clinical trials.

Nathan H. Fowler, MD, MD Anderson Cancer Center

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