CAR-T Progress Continues in Non-Hodgkin Lymphoma, But Guidelines Need Updating

Miguel Perales, MD

CAR T-cell therapy has emerged as a promising therapy for select patients with non-Hodgkin lymphoma (NHL), but as research continues and the treatment is used in a real-world setting, overarching guidelines must be set in place, explained Miguel-Angel Perales, MD.

“The results of CAR T cells in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma are very promising,” said Perales. “We'll have to see what the role of CAR T cells is for these diseases, but it's definitely a therapy that's very effective.”

For example, updated results of the phase II ZUMA-1 trial demonstrated a 2-year overall survival rate of 51% in patients with refractory large B-cell lymphoma in patients who received axicabtagene ciloleucel (axi-cel; Yescarta), which is currently approved for patients with relapsed/refractory NHL. Additionally, the progression-free survival (PFS) rate was 39% at 2 years and the median PFS was 5.9 months.

Next steps with this treatment approach includes the ongoing phase III ZUMA-7 trial (NCT03391466), which is comparing axi-cel with high-dose chemotherapy and autologous stem cell transplant for patients with relapsed/refractory DLBCL.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Perales, deputy chief of the Adult Bone Marrow Transplant Service and director of the Adult Bone Marrow Transplantation Fellowship Program at Memorial Sloan Kettering Cancer Center, discussed the evolving role of CAR T-cell therapy in DLBCL and follicular lymphoma.

OncLive: How is CAR T-cell therapy being used in DLBCL and follicular lymphoma?

Perales: As far as CAR T-cell therapies are concerned, there are 2 approved products: tisagenlecleucel (Kymriah) and axi-cel. These were approved over the last 18 months, primarily in patients with DLBCL in third-line therapy—patients who relapse after autologous transplant or those who are ineligible for autologous transplant because they failed salvage therapy.

We're now starting to see real-world experience with these drugs. There was an abstract presented the 2018 ASH Annual Meeting as well as an update at the 2019 ASCO Annual Meeting from a large consortium of centers that reported real-world experience [with these drugs]. The results are similar to what we saw in the initial clinical trials, which is validating.

In particular, when we look at the types of patients who we're treating with CAR T-cell therapies today, the label is based on what was reported in the study. About 43% of patients who were treated in the real world [with these agents] would not have qualified for the trial. People are not deviating from the actual indication, which is primarily DLBCL or transformed follicular lymphoma, but they are looking at some of the other parameters around patient eligibility, including comorbidity factors. Therefore, patients with low platelets and those with active deep vein thrombosis are now allowed to be treated.

When we look at the results side by side of the real-world experience with the ZUMA-1 clinical trial experience, we see that the safety and efficacy results seem very similar. The one limitation is that the follow-up was less than 4 months [with the real-world experience than with the trial] follow-up. We have to put that in context and obviously want to see an update at the 2019 ASH Annual Meeting, where we will probably see a longer follow-up. Most of us suspect that we will see similar results in the real-world experience that was translated from what was predicted by the clinical trials. We've now treated a number of patients with both products of commercial CAR T cells, and our experience has been very much in line with what we saw with clinical trials.

What questions do we still have with CAR T-cell therapy?

One of the big questions is, “Now that we have approval in patients who failed autologous transplant, can CAR T-cell therapy actually replace autologous transplant?” We're currently doing 3 large multicenter, multinational trials. There is the ZUMA-7 trial, which takes patients in first-line relapse and randomizes them to proceed straight to CAR T-cell therapy or get salvage autologous transplant. That large multicenter trial has completed accrual and we should expect results in the next 18 to 24 months.

Other companies are performing trials with similar designs, but are different because all patients received salvage therapy and then are randomized to CAR T cells or autologous transplants. We will have to receive the results of their studies to see if CAR T cells can replace autologous transplant. We will also have to do a cost-effective analysis because CAR T cells are expensive. We'll have to see if the clinical results [of CAR T cells versus autologous transplants] are similar [to determine] where we end up in terms of using CAR T cells.

What does the future of CAR T cells look like?

As we explore additional indications, we would move up CAR T cells in earlier lines of therapy. For example, there were studies in mantle cell lymphoma; there were also studies looking at combining CAR T cells with checkpoint inhibitors. We need to see the results of those studies.

The results in follicular lymphoma are very promising. There were results presented by a group from University of Pennsylvania of a very small series—of about 14 patients—but the survival curves are fantastic. Another [study] looked at a small series of patients with follicular lymphoma compared with patients who had transformed follicular lymphoma. You could see that those with follicular lymphoma did much better than those with transformed [follicular lymphoma] and their results were in line with the results from University of Pennsylvania.

What is the safety profile of CAR T-cell therapy?

The main toxicities of CAR T-cell therapy that we see are cytokine release syndrome (CRS) and neurotoxicity. One of the issues around understanding the studies and comparing their results is that they were conducted with different grading systems: one by the University of Pennsylvania, one by Memorial Sloan Kettering Cancer Center, and CAR T cell-therapy-associated TOXicity (CARTOX). It becomes very confusing now that, in the real world, we are treating patients side by side with different CAR T cells from different companies.

The issue is whether to use the grading system that was used in the original clinical trial and follow the management guidelines from that. The risk is that, if you switch grading systems or management systems, you could potentially overtreat or undertreat a patient. A year ago, the American Society for Transplantation and Cellular Therapy (ASTCT) convened a group of investigators to develop new consensus guidelines for grading, published earlier in 2019.

We now have a vague clinically based screening system for CRS and for immune effector cell-associated neurotoxicity syndrome (ICANS). The grading system for CRS is quite similar to the original classification from 2014; however, there are some nuances.

The other big question is how to manage patients. If you look at the labels for the different drugs, they have very different management guidelines. A group of investigators put out the CARTOX paper and the National Comprehensive Cancer Network has issued guidelines. There's a lot of confusion around that; in response, the ASTCT convened another group of investigators in July 2019. A number of experts in the field and I are now developing consensus guidelines for treatment.

We're trying to develop a consensus approach that can apply to all products. We recognize that the different products have different levels of toxicity, both in terms of the rate of toxicity and how quickly they occur. We have to take into account patient factors, disease factors, and product factors. We want to articulate guidelines that apply across the board [for future CAR T-cell products] and not be specifically for the 2 commercial products today. That's why we're thinking about this in terms of, "What type of product are you using? What type of patient? What are the risk factors?” [We want to] provide guidance around how we should best manage complications in those patients.

What do you want fellow physicians to know about CAR T-cell therapy?

In terms of CAR T cells, these are very active agents in patients with relapsed/refractory lymphoma, where otherwise we would not see any great treatment options. The number of patients that we predicted would be treated was much higher than what we are actually treating. This is not just happening at our center, but this is happening across the board at other centers that do CAR T cells.

Unfortunately, we're seeing a lack of referral for patients for CAR T cells. Some physicians in the community may think that the treatment is too toxic and are concerned about referring that patient. They may think that patient is not eligible for CAR T cells, or they may think it's not the right time to send them. Whenever you have a patient with relapsed DLBCL, that patient is potentially eligible for CAR T cells, either on a clinical trial or with a commercial product. It's important to refer them for consultation or at least have a discussion with one of the centers that is administering CAR T-cell therapy to see if that patient could benefit from that treatment.

Locke FL, Ghobadi A, Jacobson CA, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1—2 trial. Lancet Oncol. 2019;20(1):31-42. doi:10.1016/S1470-2045(18)30864-7.