Andre Goy, MD, discusses some of the most important lymphoma data presented at the 2018 ASCO Annual Meeting and potential future directions for treatment.
Andre Goy, MD
Exciting developments in the treatment of patients with lymphoma were highlighted at the 2018 ASCO Annual Meeting, said Andre Goy, MD, holding out the possibility of treating patients without chemotherapy and even treatment-free remission.
“That would be fantastic,” he said. “Obviously, that would be the goal.”
Novel chemotherapy regimens, and the increasing use of chimeric antigen receptor (CAR) T-cell therapy and immunotherapy are opening up new possibilities for helping patients with lymphoma live longer, healthier lives, even those who had poor prognoses just a few years ago.
In an interview with OncLive, Goy, chairman and director, chief of Lymphoma, and director of Clinical and Translational Cancer Research at John Theurer Cancer Center, discussed some of the most important lymphoma data presented at the 2018 ASCO Annual Meeting and potential future directions for treatment.Goy: Five years ago, we did not think that immunotherapy would be where it is now. This was one of the first topics that is all over ASCO and is changing the field.
Obviously, the CAR T cells in lymphoma was recognized as the most significant advance by ASCO in 2018. There were several data [presented] at this year’s meeting in aggressive lymphoma. First, there was an update on duration of response from the ZUMA-1 trial. The take-home message was that it was more than 100 patients in the trial with relapsed/refractory lymphoma after at least 2 lines of therapy. This was a heavily pretreated population, and what was interesting was that the response rate was over 80% and the complete response (CR) rate over 50%.
The other interesting thing was that the response at 3 months is very predictive of outcomes. In other words, if a patient achieved a CR, many of them remained in CR. Also, some of these patients in partial response (PR) can convert into CR early in the process.
In some of these patients, there was evidence that there were persistent CAR T cells, but it's not necessary. Overall at 15 months, 59% of patients are still doing very well and in remission. That's quite remarkable in a population that would have no option otherwise.
The question becomes, “What can we do to try to predict this?” We don't have a good way to predict except we know that the area under the curve on the lymphocyte amplification is really what predicts the outcome in those patients. We are learning how to mitigate the side effects better with earlier intervention with tocilizumab (Actemra) anti—IL-6 agents and corticosteroids, and neither of them affect response, which is very critical.
We are starting to learn some factors that predict toxicity. Particularly in cytokine release syndrome (CRS) and neurotoxicity. Again, the amplification of the T cells correlates with neurotoxicity and correlates with response. The CRS does not. CRS starts around 3 to 5 days and the neurotoxicity starts around 5 to 10 days. We see the tumor burden and the inflammatory status at baseline is somewhat difficult to quantify; however, it's interesting because as we learn going forward, maybe there is a benefit to try to debulk these patients or try to bring CAR T cells in earlier in the process.
There are data that were published in CLL showing that the number of prior therapies, exposure to fludarabine-like agents, has an impact on the functional ability of those T cells to expand.
We are starting to dissect all of this and understand how we're going to build up. What is quite remarkable in the ZUMA-1 trial, and in other CAR T-cell therapies, the number of prior therapies does not affect the response.
There were also data presented from the TRANSCEND trial on JCAR017, and it was really interesting that it did as well as it did because there seems to be a little bit less CRS and it seems to be more durable and effective as an outpatient [treatment]. In a higher-dose cohort, their CR is in a high of 40% and a response rate around 80%. And that is, again, regardless of prior therapy.There are ongoing studies; there are actually more than 300 studies in the United Studies and 300 in China and Europe in CAR T-cell therapies and combinations with checkpoint inhibitors, to see how we can build up these combinations. It is very exciting.
In terms of immunotherapy, there was also the first presentation of an anti-CD47, which is a macrophage checkpoint inhibitor. That was done in combination with rituximab (Rituxan). It's early, a small study, but a proof-of-concept trial that some macrophages are very important and that's another area that will be very promising in the future.
There are a number of small molecules in solid tumors and some ongoing studies taking chemomodulators in combination with these forms of immunotherapy. This is important because the activity of checkpoint inhibitors, so far, in non-Hodgkin lymphoma, has not been very impressive outside of primary mediastinal B-cell lymphoma, and obviously in Hodgkin lymphoma where it's approved. Then we have the upcoming and ongoing trials looking at off-the-shelf CAR T cells and different constructs and dual CAR anti-CD19 and anti-CD22 in solid tumors that will be starting, as well.This was a randomized trial in the frontline setting of patients in need of therapy for follicular lymphoma who had the combination of rituximab/lenalidomide (Revlimid; R2) versus physicians’ choice of bendamustine/rituximab plus CHOP or R-CHOP. This was built as a controlled superiority trial and the results showed no difference in terms of response, progression-free survival, or overall survival.
There was a similar rate of secondary primary malignancies, which is somewhat still an issue because these patients have not received cytotoxics before—they’ve basically just received lenalidomide. As we move forward, something we have to keep an eye on, could this be an option for someone who is not a chemotherapy candidate? Definitely. I would not necessarily abandon chemotherapy at this point and we have to do a little bit more work.
I'm not 100% surprised. It’s interesting, lenalidomide as a single agent does not have great activity in follicular lymphoma. In combination with rituximab, it has been impressive across the board. We have a study ongoing with R2 with ibrutinib (Imbruvica) in non-germinal cell large cell lymphoma, and the data are very impressive. We presented data at the 2017 ASH Annual Meeting with a response rate over 65% and a CR rate of 50% and very durable.
Therefore, in follicular lymphoma, it was a very logical thing because it was a small pilot study in the relapsed setting and in the frontline setting from The University of Texas MD Anderson Cancer Center. It was very promising. It makes sense in follicular lymphoma. [This is a] disease where immunotherapy should work the best because there's clearly an immune intervention by the immune system trying to control the lymphoma.
When you give rituximab to patients, the response rate in the frontline setting is 80%, but the CR rate is 20% at most. Of patients who achieve a CR with a few sequences of rituximab at the beginning, 50% of them are fine 10 years later. In those patients, there's an anti-idiotypic immunoreaction occurring in those long responders, so lenalidomide helps to reactivate the immune system.
One of the issues is that follicular lymphoma is a spectrum of disease. There are some patients for whom we don't have a good biomarker yet, but who probably still benefit from cytotoxic chemotherapy.
We have to be cautious on jumping ship right away. As I mentioned, the secondary malignancies in someone who has never received chemotherapy is something that we need to keep an eye on. We also need to see how these patients respond to second-line therapy after receiving R2.There were some really interesting data in chronic lymphocytic leukemia presented in the frontline setting with venetoclax (Venclexta) and ibrutinib where the minimal residual disease (MRD) negativity is very impressive at over 70%. What is appealing in that study is that the trial is built to randomize stopping treatment versus continuation—maybe even with biological agents—because you reach a deep level of activity and MRD negativity in which you could be able to stop therapy. That would be fantastic. Obviously, that would be the goal.There is ongoing work looking at health economics and trying to look at how much clinical benefit there would be at scale in the real world versus multiple lines of therapy in a palliative setting.
CAR T-cell therapy is being explored versus transplant as a second-line therapy and some studies allow crossover. In very high-risk lymphoma, double-hit or triple-hit lymphoma, could that become a consolidation after induction chemotherapy once we controlled the toxicity? The off-the-shelf CAR T cells are going to be really exciting because they will potentially be much less expensive.
I’m also very excited about the ongoing studies in combination with checkpoint inhibitors where we see an increasing amplification of T cells. There was a case report at the 2018 ASH Annual Meeting of a patient who progressed on CAR T-cell therapy who was given a checkpoint inhibitor and relapsed initially, then responded. This is also a place to build up.