Primary Refractory DLBCL Status Takes on Greater Significance in CAR T Era

Patients with suboptimal response following first-line therapy for diffuse large B-cell lymphoma (DLBCL) have worse prognoses going forward, making it crucial to identify them and select appropriate treatment, particularly when prompt action is needed. At a recent virtual Case-Based Roundtable meeting for oncologists in Michigan, Matthew Lunning, DO, Assistant Vice Chancellor of Clinical Research and Associate Vice Chair of Research of the Department of Internal Medicine at the University of Nebraska Medical Center, asked participants to discuss how they determine if patients have primary refractory and early relapsed DLBCL. This has become an important issue as these criteria have shaped the data supporting chimeric antigen receptor (CAR) T-cell therapy and other highly efficacious interventions.

Register today to join a Case-Based Roundtable near you.

DISCUSSION QUESTIONS

• How do you define primary refractory DLBCL?
• How do you define early relapse of DLBCL?

Matthew Lunning, DO: How are you defining primary refractory disease these days?

Sapna Patel, MD: [If they are] symptomatic, and also have lymphadenopathy; routine screening and imaging will also confirm that, and we will do a rebiopsy.

Lunning: Do you have a temporal definition of what you would consider primary refractory? Is it within 3 to 6 months of the end of therapy? Is it if the disease comes back within 6 months of the end of therapy, or is it just at your first PET scan after the end of treatment?

Patel: By routine screening, [I do] PET scans every 3 months.

Lunning: Dr Pounders, how are you defining primary refractory DLBCL?

Zachary Pounders, DO: Either a patient who has progression on treatment or not achieving complete response [CR] or partial response [PR], so patients who are still PET positive at the end of treatment with Deauville score of 4 or 5, I would call [as having] primary refractory disease, and early relapse is anyone who relapses within the first 6 months.

Lunning: Is anybody doing minimal residual disease [MRD] assessment in their patients with large cell lymphoma?

Rana Bilbeisi, DO: Sometimes I order ClonoSeq for those patients. We started using it more routinely. We're trying to do it every 3 months for that first year…. I don't know if we're going to keep doing it that routinely throughout like the next several years.

Lunning: At the University of Nebraska, we started to do ClonoSeq at the end of treatment evaluation, and if PET negative but ClonoSeq detectable, that's [when] we're doing active surveillance imaging. If they're PET positive, those Deauville scores of 4 can be a bit confusing, and that's where sometimes MRD can be helpful from that standpoint. You're still going to want to follow those PET scans, but it can make you a little more comfortable, especially in those areas that are hard to biopsy. If you get a negative or undetectable ClonoSeq, you feel a little bit [better] waiting on that short interval scan.

Mohammad Muhsin Chisti, MD: We get nervous about patients who don’t have CRs. These are the refractory candidates, and also early relapse, as defined as 6 months to 12 months after the initial remission. Those are the patients whose prognoses are not good. Their 2-year survival is probably 30% or so. However, we are not doing MRD. We usually do a PET scan every 3 to 4 months.

Lunning: The definition has always evolved. In a situation where you're using curative intent, you either want to follow them into a CR, or follow them with a biopsy that [shows] relapse or primary refractory disease.

The definition of early relapse has also been an evolution, because the data are often started from the time of diagnosis. When we start to look the definition from ZUMA-7 [NCT03391466], TRANSFORM [NCT03575351], and BELINDA [NCT03570892], the time is starting from the end of treatment, but when you look at a lot of the prognosis, there was a big difference between those who relapsed in 6 months and those who relapsed between 6 months and 12 months. There was a gap in those curves, and it was a bit interesting to see in those trials, with the early relapsing population extending out to those 12 months from end of therapy.^1,2 Late relapsing patients are those who are relapsing more than more than 1 year, and then you can have really late relapses where it's more likely to be an indolent lymphoma relapsing in at 3 to 5 years and 5 years and beyond. With 5 years and beyond, you start to wonder if it's a different entity in itself.

Tareq Al Baghdadi, MD: It may not make a big difference, but for the sake of definition, primary refractory is not just people who do not achieve adequate response or relapse on chemotherapy, it extends up to 6 months post treatment. It used to be 3 months, and then several years ago, they extended it to 6 months. If you relapse within 6 months, technically speaking, that is refractory disease. The early relapse within a year of treatment is most applicable to CAR T-cell therapy, and it's almost a pragmatic definition, because that's what the trials did, and that's what makes the patient eligible for treatment.

If you go back historically, 10 to 15 years ago there were studies showing that if you got rituximab and you got platinum-based reinduction for refractory disease, you got a response rate of roughly 20% which was eye-opening at the time…that's when the definition started evolving. But I would include recurrence within 6 months in the refractory category.

Lunning: Yes, I think that that's been a moving target, and the devil has been in the details in regard to the more modern clinical trials, especially when you think about the L-MIND trial [NCT02399085], which changed its definition of what primary refractory was over time. This question is somewhat relevant because when you start to try to compare trials in the relapsed/refractory setting, you often have to read into the methodology, because they sometimes try to increase the number of primary refractory patients by moving the goalposts.

Register today to join a Case-Based Roundtable near you.

DISCLOSURES: Lunning previously reported receiving honoraria and/or has served in a consultancy or advisory role for AbbVie, Acrotech, ADC Therapeutics, AstraZeneca, Astellas, Bristol Myers Squibb, Caribou, CRISPR, Daiichi Sankyo, EUSA, Fate Therapeutics, Genentech, GenMab, InstilBio, Ipsen, Janssen, Kite, Loxo, Miltenyi, MorphoSys, Novartis, Nurix, Pharmacyclics, Regeneron, Sanofi, Seagen, Takeda, and TG Therapeutics; and has received research funding from Bristol Myers Squibb, Curis, FATE Therapeutics, and Sana Therapeutics. There were no other known relevant disclosures.

REFERENCES:

1. Kamdar MK, Solomon SR, Arnason J, et al. Lisocabtagene maraleucel (liso-cel) vs standard of care (SOC) with salvage chemotherapy (CT) followed by autologous stem cell transplantation (ASCT) as second-line (2L) treatment in patients (pt) with R/R large B-cell lymphoma (LBCL): 3-year follow-up (FU) from the randomized, phase 3 TRANSFORM study. J Clin Oncol. 2024;42(suppl 16):7013. doi:10.1200/JCO.2024.42.16_suppl.7013
2. Westin JR, Oluwole OO, Kersten MJ, et al. Survival with axicabtagene ciloleucel in large B-cell lymphoma. N Engl J Med. 2023;389(2):148-157. doi:10.1056/NEJMoa2301665