Frederick L. Locke, MD
The approvals of chimeric antigen receptor (CAR) T-cell therapies have provided more options for select patients with non–Hodgkin lymphoma and acute lymphoblastic leukemia (ALL), but there can be challenges on how to optimally manage the toxicities associated with this approach.
Tisagenlecleucel (Kymriah) is indicated for patients up to 25 years of age with B-cell precursor ALL that is refractory or in second or later relapse, as well as for patients with relapsed/refractory large B-cell lymphoma after 2 or more lines of systemic therapy. Axicabtagene ciloleucel (Yescarta) is also approved for patients with relapsed/refractory large B-cell lymphoma following ≥2 prior lines of treatment.
In a presentation during the 2019 Transplantation and Cellular Therapy (TCT) Meetings, given by Frederick L. Locke, MD, it was discussed that physicians now face the challenge of managing the associated toxicities with these therapies. Based on data from pivotal trials, the 2 major types of adverse events (AEs) are cytokine release syndrome (CRS) and neurologic toxicity.
“We’re treating patients in the real world outside of the pivotal trials,” said Locke in an interview with OncLive
. “We’re giving CAR T-cell therapy as a standard of care, and in fact, the toxicity rates are similar to the clinical trials that we ran. This is really a manageable toxicity that we are seeing.”
Beyond the 2 FDA-approved CAR T-cell products, research is ongoing for a number of different CAR T-cell therapies.
In an interview with OncLive
during the 2019 TCT meeting, Locke, medical director and research director of the Immune Cell Therapy Program and the co-program leader of the Immunology Program, vice chair of the Blood and Marrow Transplant and Cellular Immunotherapy program at Moffitt Cancer Center, discussed the optimal management of CAR T-cell therapy-related AEs.
OncLive: Could you give some background to the history of CAR T-cell therapy?
: CAR T-cell therapy is an exciting cellular therapy. It’s really added a new treatment to our armamentarium against lymphomas and leukemia. CD19-directed CAR T-cell therapy is when a patient’s T cells are removed from their body, engineered with a gene that redirects them all against a singular target—in this case, CD19—and are infused back into the patient. They know where to go—and they go after the lymphoma or the leukemia.
We now have 2 FDA-approved CD19-directed CAR T-cell therapies; one is for both pediatric, adolescent, and young adult patients with ALL, called tisagenlecleucel, and that is also approved for the treatment of [patients with] relapsed/refractory large B-cell lymphoma. We also have axicabtagene ciloleucel, which is also FDA approved for the treatment of relapsed/refractory large B-cell lymphoma.
What are the biggest challenges we need to overcome with CAR T cells?
CAR T-cell therapy can lead to amazing responses that are durable in a subset of patients. We have patients who aren’t responding to any chemotherapy who can go into a complete remission, and up to 40% of patients with refractory lymphoma who aren’t responding to chemotherapy remain in remission after a CAR T-cell therapy for 2 years and counting.
That’s pretty remarkable, but unfortunately, the therapy can cause some serious toxicities. The 2 major categories of toxicity following a CAR T-cell therapy are CRS and neurologic toxicities. One of the main things we need to do as a community is to figure out all the mechanisms that lead to those toxicities and how to prevent them from becoming severe.
We can manage high fevers, but when the CRS leads to low blood pressure or hypoxia, we’ve really gone too far. We have to halt the CRS before it gets to that.
What were the key points you made in your presentation for community oncologists?
The session that I spoke at [covered] the pivotal clinical trials, what the results from these trials were for patients with ALL or DLBCL who were treated with CAR T cells, and what were the toxicity rates. What were the rates of severe CRS and severe neurotoxicity on the different trials, and how did they differ? In fact, one of the reasons that we can’t directly compare those toxicities from trial to trial and from CAR T-cell therapy to CAR T-cell therapy is because of the differences in the construct of the design and of the studies.
I also summarized the new ASBMT Consensus Grading criteria for both CRS and [immune effector cell therapy–associated] neurotoxicity syndrome, which is also called ICANS. This is a new grading criteria we expect investigators and physicians will use to treat these patients and give us a uniform playing field. Previous grading scales were different in how you graded CRS and neurologic toxicity. We now have an even playing field that we can all use.