Lazaros J. Lekakis, MD, discusses the promise of CAR T cells and some unanswered questions with this rapidly emerging therapy.
Lazaros J. Lekakis, MD
CAR T-cell therapy has brought newfound hope to patients with relapsed acute lymphoblastic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL), where the outlook had traditionally been bleak, said Lazaros J. Lekakis, MD.
In patients with DLBCL, the CD19-directed CAR T-cell product axicabtagene ciloleucel (axi-cel; Yescarta) has not only generated excitement in the clinical trial space, but recent data have suggested the benefit is expanding in the real-world setting. Early results of a real-world population study demonstrated a median progression-free survival (PFS) of 6.18 months—in the ZUMA-1 trial, median PFS was 5.8 months.1 The overall response rate was 79% by day 30 post-infusion and 82% overall.
In ALL, the CD19-targeted product tisagenlecleucel (Kymriah) garnered attention for its encouraging data in the ELIANA study. In updated data presented at the 2018 ASH Annual Meeting, the 2-year relapse-free survival rate with the therapy was 62%.2
Lekakis, an associate professor of clinical medicine at Sylvester Comprehensive Cancer Center, University of Miami Health System, said that there are several unanswered questions to address moving forward. For example, CAR T cells are associated with a unique toxicity profile that researchers are still trying to tackle.
In an interview during the 2019 OncLive® State of the Science Summit™ on Hematologic Malignancies, Lekakis discussed the promise of CAR T cells and some unanswered questions with this rapidly emerging therapy.Lekakis: At this point, CAR T cells are indicated for relapsed/refractory CD19-positive ALL in children and in adults up to age 25. In DLBCL, it has used for patients who have become refractory to standard therapies and autologous stem cell transplant.It has been huge. When we are talking about patients with DLBCL who have failed R-CHOP chemotherapy and salvage chemotherapy, we cannot take them to transplantation. These patients are eligible for clinical trials, but usually they do not do well. However, with CAR T-cell therapy, even [80% of] refractory patients respond, with 58% of them achieving a CR. After a follow-up of 26 months in the ZUMA-1 trial, 37% of patients are alive without evidence of disease.The current research is trying to use bispecific CAR T cells that are targeting not only CD19 but other antigens, such as CD22. Sometimes, we see CD19-negative clones that escape from the CAR T-cell attack. In multiple myeloma, we have the CAR T cells from multiple companies against BCMA. There are also different companies combining CAR T cells with PD-1/PD-L1 inhibitors to try to evade the T-cell exhaustion. This also keeps them alive and in expansion for many weeks in the body of the patient. Also, the triplet combinations of CD19-specific CAR T cells with agents, such as lenalidomide (Revlimid) and rituximab (Rituxan) have shown promise.The real-world data for the use of axi-cel was very surprising because a lot of the people in the community thought the ZUMA-1 data wouldn't reproduce in real life. There were very strict exclusion criteria for that study. However, the real-world data with more than 200 patients treated without being on a clinical trial saw a CR rate that was pretty much the same as ZUMA-1.
Apparently, it was not only the trial that gave us those results, but it was reproduced in real life. We are talking about 37% of patients without evidence of disease; those patients are now probably cured because very few relapses happen after a 6-month cutoff.The main one is why some patients do not keep their response; they respond and then relapse. It's not only the CD19-negative escape; there seems to be other factors at play. One of them is the tumor microenvironment that might defend the cancer from the attack of the CAR T cells. The T-cell exhaustion is another important issue. Therefore, many strategies are being [evaluated] in clinical trials now.
The other challenge is the toxicity. How do we treat this? There are a lot of unanswered questions. For newer, grade 3/4 toxicities, we give high-dose steroids. We also sometimes do this for grade 2 neurotoxicity. We don't know the actual impact of the corticosteroids on the T cells. The other thing we don't know enough about is how to treat a very rare complication that is called cerebral edema, which is the worst case of neurotoxicity that a patient can have. Also, how do we prevent this? It only happens in 1% to 2% of patients, but it's mostly fatal.
Another unanswered question is, “When these patients with DLBCL achieve a CR, should we take them right to transplant or should we wait?” About 58% of patients get into CR, but 37% are alive at 26 months without evidence of disease. Therefore, the question is, “Should we try to combine it with a drug targeting another antigen?” We know that the CAR T cells will leave the body eventually and become exhausted, so what else should we do to help the patient? When is the best time to do a stem cell transplant? If those patients relapse, though, there is very little that we can do.When the patient is refractory to initial chemotherapy with RCHOP, we are talking about aggressive DLBCL, I would immediately refer the patient and start preparations for next steps. We don't want to lose any time. Even if those patients respond to salvage chemotherapy, their response will last for a very short duration of time. If I take those patients to transplant, the relapse rate is very high.