DocMatter Asks: Which Relapsed/Refractory LBCL Patients Are Right for CAR-T?

In a recent post on DocMatter, Jason Westin, MD, MS, Director of Lymphoma Clinical Research at the University of Texas MD Anderson Cancer Center, asked the DocMatter community:

“In second-line therapy for relapsed/refractory large B-cell lymphoma (LBCL), which patients would you consider eligible for chimeric antigen receptor (CAR) T-cell therapy that you would not consider eligible for autologous hematopoietic stem cell transplantation (AHSCT)?”

Dr. Westin spoke with Blood Cancers Today to elaborate on his post: “The question is based largely on the fact that, for the past quarter century, the standard treatment for second-line therapy of patients with relapsed/refractory LBCL has been autologous transplant. But over the past year, we have seen results indicating that this should no longer be the case. Two recent randomized, phase III trials (ZUMA-7 and TRANSFORM) showed that CAR T-cell therapy was superior to autologous transplant.

We have a new standard of care, but with the old standard of AHSCT, the historical dogma has been that half of patients are eligible for transplant and half are ineligible based on medical issues, age, comorbidities, and organ dysfunction. There is a group of patients who were considered ineligible for AHSCT and therefore didn’t have a curative option to treat their disease. That has now shifted with the idea that CAR T-cell therapy may be the new second-line therapy option for our patients. We think there will be a group of patients who are eligible for the new standard who might have been ineligible for the old standard, so we’re effectively growing the pie for patients who are hopefully able to have a curative option.

The question is, ‘Which patients would you consider eligible for CAR-T that you would not have for AHSCT?’ That gets into cases where patients may have been borderline candidates for AHSCT with frailty or mild organ dysfunction, but we think that CAR T-cell therapy should be safe enough and have greater efficacy to try and get them into remission.

Instead of this 50/50 split we had in the past, where does the distribution shift? I coauthored a paper recently published in Blood* where we proposed a new algorithm. We think it will be more like 70/30—there will be 70% who are eligible for CAR T-cell therapy and 30% who are not. Effectively, we have recruited 20% more people who were previously not transplant eligible, but we think are CAR T-cell eligible.”

Tycel Phillips, MD, Associate Professor at the University of Michigan Rogel Cancer Center, weighed in on the question on DocMatter, commenting, “Utilization of CAR-T will likely be nuanced. I would primarily reserve this therapy for primary refractory diffuse LBCL/high-grade B-cell lymphomas. Several recent studies have indicated that there is still a role for AHSCT even in the CAR-T era and that outcomes with AHSCT might exceed or at the very least be equal to CAR-T in those who obtain at least a significant partial response to salvage therapy. Given this, in my opinion, AHSCT would still be considered the preferred option for patients who continue to demonstrate chemotherapy sensitivity. This is most likely those who have relapsed more than 12 months after completion of initial frontline therapy and possibly the gray area for those who relapse more than six months after initial therapy.

Those with primary chemotherapy-​refractory disease or those who have an early relapse (less than six months) would be expected to be resistant to salvage chemotherapy and, in my opinion, would not be appropriate for AHSCT. Given that there is still a lag from identification to receipt of CAR-T due to insurance approval, T-cell collection, manufacturing, and then return of the product to these patients, they are still likely to need another therapy prior to CAR-T, whether that is radiation, steroids, standard chemo­therapy, or other newer approved treatments such as polatuzumab, etc. So even with the approval of CAR-T in the second line, my current approach is unlikely to change in these patients.”

Dr. Phillips also expanded on his position to Blood Cancers Today: “We were all excited about the data from the TRANSFORM and ZUMA-7 studies, but I don’t think we should automatically abandon AHSCT for patients with certain aspects of relapsed diffuse LBCL. I think the approval of CAR-T in this setting will allow us to at least have a better treatment option for those with primary refractory disease or those who are early relapsed who we know don’t tend to fare very well with chemotherapy as a second-line therapy and either don’t make it to AHSCT or don’t have a durable response with AHSCT.

The caveat is that we can’t just go to CAR-T and take it off the shelf. With the manufacturing process, there is going to be a period where these patients will have to get some sort of bridging therapy. It hasn’t really revolutionized how we manage these patients in the second line, because, in my own clinical practice, while we knew we couldn’t get approval for CAR-T, we had already planned to give them the second-line treatment with the intent of trying to get them to CAR-T. We would refer them to our transplant physicians to concurrently evaluate for AHSCT or CAR-T based on the response and depth of response they had to that second-­line or bridge therapy.

We have confirmatory data that suggest, at least for primary refractory patients, it is preferable to go to CAR-T versus trying to get these patients to AHSCT in most situations. But I caution that every patient with relapsed diffuse LBCL should not be taken directly to transplant because there is a subset who likely will still have very durable responses to AHSCT without the cost and other complications associated with CAR-T.

Accessibility is probably the biggest issue with CAR-T. Even before the approval of CAR-T in the second-line setting, we only were able to get a fraction of the available patients to CAR-T, either due to inaccessibility or the patients were unwilling to come to the centers that can provide CAR-T therapy. Moving it up in line won’t fix that issue. It may actually make accessibility harder because you have more patients who are now able to get CAR-T, so manufacturing times and dates may be harder to come by.”

*Westin J, Sehn LH. CAR T cells as a second-​line therapy for large B-cell lymphoma: a ​ paradigm shift? Blood. 2022;139(18):2737-2746.