Chow Stresses Need to Identify B-Cell Lymphoma Treatment Options After Progression on CAR T-Cell Therapy

Victor A. Chow, MD

As chimeric antigen receptor (CAR) T-cell therapies become more widespread, more patients with large B-cell lymphomas are relying on this option after relapse; however, a portion of patients will still progress after CAR T-cell treatment.

A group at the Fred Hutchinson Cancer Research Center sought to explore the outcomes of these patients who progress after treatment with CAR T cells. Their retrospective study looked at 55 patients with various B-cell lymphomas who progressed after treatment with CD19-specific CAR T cells. They found that individuals with large B-cell lymphomas who show evidence for early progressive disease after receiving CD19-targeted CAR T-cell therapy have poor outcomes. This high-risk group of patients represents an unmet need in identifying treatment options following progression, said Victor A. Chow, MD

“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.

In an interview withTargeted Oncologyduring the 2018 ASH Annual Meeting,Chow, a senior hematology/oncology fellow at the Fred Hutchinson Cancer Research Center and Seattle Cancer Care Alliance, highlighted the key takeaways from these study findings and the next steps toward understanding how to treat patients who progress after CAR T-cell therapy.

TARGETED ONCOLOGY:Can you provide us with some background to this study looking at disease progression after CD19-targeted 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 that still have relapsed disease following CD19-specific CAR T-cell therapy.

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, understanding how this therapy should be figured into the treatment algorithm when they’re back in clinic with us, 1 lingering question that remains is, what do we do now? That was really behind why we wanted to look at this study.

TARGETED ONCOLOGY:How was this study designed?

Chow: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, 30 days, or so. We also looked at individuals that 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.

TARGETED ONCOLOGY:What were results from this?

Chow: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.

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 a 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.

TARGETED ONCOLOGY:What is the main takeaway from these findings?

Chow:I think the main takeaway is 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 really 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. I think that is something we should be looking at as well and trying to keep people in the durable response.

TARGETED ONCOLOGY:Do you think you should weigh the benefits and risks for each individual patient before putting them on this therapy?

Chow: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 to an autologous stem cell transplant. These are going to be determined after these prospective trials come out to 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.

TARGETED ONCOLOGY:What else is important to highlight in regard to the outcomes for these patients?

Chow: