Clinical Cases in Relapsed and Refractory DLBCL - Episode 7

Case 1: Therapeutic Options After CAR T-Cell in Relapsed/Refractory DLBCL

Kami Maddocks, MD: Prior to CAR [chimeric antigen receptor] T-cell, the most difficult population similarly were those patients … who were refractory to salvage chemotherapy or relapsed after transplant. As was mentioned … somewhere probably about 40% of patients that were given CAR T will have good outcomes, but we still have 60% of patients who are going to progress or not respond. This is probably 1 of the more difficult populations for us to treat. How do you … approach treatment?

Loretta Nastoupil, MD: If they’re a trial candidate … I have the luxury of a number of trials. I think what looks intriguing currently is data presented by Steve Schuster at the last ASH [American Society of Hematology 2020 meeting] incorporating a CD20 bispecific antibody. We do see some complete response rates in post-CAR T-Cell. That is a strategy that is only available on trial but may be available in the next 1 to 2 years that might be an effective strategy.

We have explored using checkpoint inhibitors because we have seen T-cell exhaustion as a particular mechanism of resistance. We have an investigator-initiated study looking at the incorporation of [pembrolizumab], plus lenalidomide and rituximab, specifically for these CAR T failures, the phase 1 dose-finding study. … We see some patients have meaningful response and durability of that response. There are several targeted agents…. But we have new immune modulators. We have other agents targeting the microenvironment that might be strategies, in addition to other CARs that might be either bispecific or dual antigen targeting.

Ian Flinn, MD, MPH: There are so many different options for this patient, but unfortunately … this patient population has a very poor outcome. … This is the group of patients that were chemotherapy refractory before going into CAR T-cells and now often have this highly follicular relapse after CAR T-cells. There are standard options for this patient population, and while there are many different ones, from BR polatuzumab to MOR208 and lenalidomide, to a variety of selinexor, there are a variety of different options. Unfortunately, their success rate is low. Loretta’s point about getting patients on to clinical trials is important.

That 1 clinical trial that she mentioned with mosunetuzumab with CD20 bispecific antibody .... T-cells really took me by surprise. I would not have thought that someone who just failed a CAR T-cell therapy would respond to, was commonly sort of a lesser cellular therapy approach to patients with relapsed disease. That was an important outcome and I think we’ll find more pointed outcomes from some other clinical trials.

Jason Westin, MD, MS, FACP: I completely agree with all that’s been said. This is a dangerous situation. If somebody progresses after CAR T-cells, often they still have cytopenias or frail; this is a dismal prognosis. However, as Dr Nastoupil mentioned, we’ve had some home run responses in this group. The clinical trial that she mentioned of the checkpoint antibody plus lenalidomide. I’ve enrolled a few patients of mine on that study and I have a couple of them that are more than a year out now doing well. It’s not hopeless, but it’s something where clinical trials are needed.

The only other thing I would add to the discussion is that there are a new generation of CAR T-cells coming that show great promise that don’t use the patient’s own cells. It’s a donor cell. It’s an allogeneic CAR T-cell. Many of these cells are modified in a way to avoid graft-vs-host disease. The T-cells are genetically crisper or other genetic modifications modified to reduce their ability or prevent their ability to have a reaction versus the host cells. But they show incredible responses.

And at the ASCO [American Society of Clinical Oncology] meeting in 2020, Dr Neil Abu from our group presented a trial with early results showing that these might be as good or potentially even better than the autologous cells. The data is still very immature, but the current CAR T-cells we’re talking about may not be the final result for what we use for these patients in the future.

Kami Maddocks, MD: And not only is it difficult to find treatment that works in these patients, but these patients often have residual toxicity from their other therapies, cytopenias, and it can even hard if you have treatment for it, for the patient to tolerate. This is an area where we need better treatments and better options.

Transcript edited for clarity.