Following Progression on CAR T-Cell Therapy, B-Cell Lymphoma Treatment Options Needed

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Victor A. Chow, MD, discusses the next steps in understanding how to treat patients with large B-cell lymphomas who progress after chimeric antigen receptor T-cell therapy.

Victor A. Chow, MD

Patients with large B-cell lymphoma who experience disease progression following CD19-targeted chimeric antigen receptor (CAR) T-cell therapy have poor long-term outcomes. Therefore, effective therapeutic strategies need to be identified for this patient population, explained Victor A. Chow, MD.

In a retrospective study that was presented during the 2018 ASH Annual Meeting, researchers at Fred Hutchinson Cancer Research Center evaluated the outcomes of 55 patients with various B-cell lymphomas who progressed on CD19-specific CAR T-cell therapy. Results showed that those with large B-cell lymphomas who show evidence for early progressive disease after receiving this type of treatment have poor outcomes. This high-risk group of patients represents an unmet need in identifying therapy options following progression, said Chow, a senior hematology/oncology fellow at the Fred Hutchinson Cancer Research Center and Seattle Cancer Care Alliance.

“We need to be thinking strategically about how to look at the next subsequent treatment for them so hopefully patients will get a sense that once their CAR T cell fails them, we’re not just giving up on them. We’re still trying to think about other options to help prolong or get them back into remission,” Chow said.

OncLive: Could you provide background to this study, which looked at disease progression after CD19-targeted CAR T-cell therapy?

In an interview with OncLive, Chow, who was the lead author of this retrospective study, highlighted the trial, its findings, and the next steps in understanding how to treat patients who progress after CAR T-cell therapy.Chow: This study really came about [because] as lymphoma specialists, we see a lot of patients, unfortunately, with relapsed/refractory large B-cell lymphomas after CAR T-cell therapies. In the last year, [there] has been a huge change and dramatic shift in terms of treatment options for patients with not many very good options. We have been seeing a lot of good outcomes from CAR T-cell therapy, but unfortunately, there is still a good proportion of patients who still relapse disease following CD19-specific CAR T-cell therapy.

How was this study designed?

What were the findings?

Our clinical question is when they come back to see us in clinic, what do we do? How do we treat them? What is the standard of care? What are their options? As amazing and good the hype is, [we are still] understanding how this therapy should be figured into the treatment algorithm when they’re back in clinic with us. One lingering question that remains is, “What do we do now?” That was behind why we wanted to look at this study.This was a retrospective study, and we looked at essentially all of the patients at our center that got any CAR T-cell product that was CD19-specific for diffuse large B-cell lymphoma, transformed follicular lymphoma, primary mediastinal large B-cell lymphoma, and high-grade B-cell lymphoma. We specifically looked for individuals who had evidence for progressive disease immediately after their CAR T-cell therapy. Generally, folks will get staged again in 28 or 30 days or so. We also looked at individuals who had late progression of disease, meaning they had evidence of complete response (CR), partial response (PR), or stable disease initially, but later on had evidence of progression of disease. We identified these individuals and looked at their outcomes.When we looked at all of our patients who had evidence for progressive disease, we identified 55 patients. Their overall survival (OS) was a median of a little over 5 months. This is taking into account both early and late progression, which is not a great outcome certainly. We can be doing more to help our patients, hopefully improving CR rates and also decreasing progressive disease rates.

What is the main takeaway from these findings?

Should you weigh the benefits and risks for each individual patient before putting them on this therapy?

When we looked at OS outcomes when we separated the 2 groups, there was a difference in OS. Those who had early progressive disease did not live as long, somewhere in the 3- to 5-month range. Those who had delayed progression lived a little bit over 1 year from a median OS standpoint. It would suggest to us that those who had delayed progressive disease probably had some additional time to think and plan about what types of therapy to use next. It’s also indicative that the disease biology and those individuals were potentially less aggressive. This is all hypothesis still, and hopefully we will generate some clinical trials that will help address these questions a little bit more.For individuals who show evidence for early progressive disease after receiving a CD19-specific CAR T-cell therapy for large B-cell lymphomas, their outcomes are very poor. This is a high-risk group and an area that is quite unmet. Understanding how to treat these patients specifically is going to be very important. How do we enroll them onto clinical trials? How do we think about the use of an allogeneic stem cell transplant for these individuals? How do we capture them at a point where they are still relatively low enough to get additional treatment? These are all questions that everyone should be asking. Another takeaway is that durable CR rates in CAR T-cell therapy are really important. As a clinician, I want to be able to tell my patients that a certain percentage of individuals after 6 months, after 9 months, after 1 year, still have a CR. It’s great to have CR at the very beginning, but it doesn’t necessarily translate to long-term disease control. That is something we should be looking at as well and trying to keep people in the durable response.I certainly think so. CAR T cells are so exciting, and when we have a new therapy, such as a cellular therapy that has so much excitement around it, a lot of research and a lot of money went into looking at its use in various settings. Right now, the approved ones are for individuals after 2 lines of therapy, but there are ongoing studies now looking at whether or not it should be used more in the upfront setting or comparing it with an autologous stem cell transplant.

What else is important to highlight regarding patient outcomes?

These are going to be determined after these prospective trials come out. [It will] help us understand when this patient relapses, should they actually move on again to get autologous stem cell transplant or should they get a CAR T-cell therapy instead? Hopefully within the next year or so we will get a little bit more information on this.Another thing to highlight about this study is again, speaking from the clinical standpoint, when we see patients who come back to us when their CAR T cells fail them, it’s quite devastating. A lot of people just have so much hope, and they’re just so excited to get this therapy because for the first time in such a long time, it provides good durable responses for a subset of individuals.

We want to be able to get these products to our patients, but we also need to be mindful that there will be a good percentage of these patients that unfortunately do not get a good response.

Chow VA, Gopal AK, Maloney DG, et al. Outcomes of patients with large B-cell lymphomas and progressive disease following CD19-specific CAR T-cell therapy. In: Proceedings from the 2018 ASH Annual Meeting; December 1-4, 2018; San Diego, CA. Abstract 94.

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