Ian W. Flinn, MD, PhD: One of the patient groups that I find most challenging to treat are patients who either have central nervous system [CNS] involvement at the time of diagnosis or those for whom you’re worried about it. They may have risk factors. Some people will use the CNS-IPI [central nervous system international prognostic index] to try to risk stratify patients. Can you tell us about your approach for patients who are either at high risk or already have it? Does that change how you treat patients? Is your work-up different? Perhaps walk us through some of your approaches.

Kami J. Maddocks, MD: At initial diagnosis to look at CNS risk, I look at double-hit status, double-expressor status, and then use the CNS-IPI, which is the IPI plus adrenal and renal. For patients who are high risk, CNS-IPI 4 to 6, and then double-hit and double expressor, I typically tend to offer CNS prophylaxis. This can be done with both intrathecal or intravenous [IV] methotrexate. If somebody is going to be able to tolerate it, my preference is to use the IV methotrexate. There’s some suggestion that that’s probably a better preventive, although we saw data at ASH [the American Society of Hematology 2020 annual meeting] that kind of questioned the benefit of all prophylaxis. But I usually will use that for 3 cycles. If somebody has CNS and systemic disease, we’ll sometimes use it with the R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone]. So, we will give it on days 1 and 2. We also sometimes will fold it in, giving it on day 15, especially if there are questions of tolerability. Or occasionally, we’ll use it at the end of treatment.

Ian W. Flinn, MD, PhD: What kind of doses are you using, out of curiosity? Say you gave it on day 15, are you giving 4 g, 6 g?

Kami J. Maddocks, MD: Three and a half mg is what we use.

Ian W. Flinn, MD, PhD: Definitely a challenging patient population. Loretta, what about the double expressors? Are you doing anything different for that patient population?

Loretta J. Nastoupil, MD: I echo all of the comments that we’ve heard. One of the things that we’ve learned from some of these prospective studies that have failed miserably is if you have too many barriers to identify these poor-risk patients, it sways them toward standard of care treatments like R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone]. You don’t have the luxury of time to pursue a trial or something more novel. And so, for the double expressors we have some potential advantages, and you usually can determine that by IHC [immunohistochemistry], and you should have that information when you’re first seeing the patient.

I think we probably do a better job of enriching our prospective studies with the double expressors. As of this point, I’m still using R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone] if I can’t get them on trial, and I have some disappointment or lower expectations in terms of outcomes. I have not pursued anything else. I know there are data suggesting that dose-adjusted EPOCH-R [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab] might be beneficial. When we look at the randomized study, it’s not powered to address this particular cohort. It’s disappointing. We don’t really see a potential benefit there.

The other thing I’ll comment on is the Mayo Clinic group did define this time from diagnosis to initiation of treatment as being another prognostic factor. When we start thinking about how we might design those next iterations of studies, if we can shorten that time by either implementing tools that can identify these poor-risk patients that are more real-time and more readily available, or enroll them into more of a standard of care approach. And then at cycle 2, maybe distinguishing with our experimental intervention. I think we’re going to have to revisit how we do studies, or we’re going to continue to have these negative phase 3 trials.

Transcript Edited for Clarity