Andre Goy, MD, discusses the recent success with CAR T-cell therapy, and what is on the horizon for this therapeutic option across hematologic malignancies.
Andre Goy, MD
Adding to the excitement of the FDA’s August 2017 monumental approval of tisagenlecleucel (Kymriah) in acute lymphoblastic leukemia (ALL), the agency recently approved the CD19-directed chimeric antigen receptor (CAR) T-cell therapy axicabtagene ciloleucel (axi-cel; Yescarta) as a treatment for adults with relapsed/refractory non-Hodgkin lymphoma (NHL).
The decision was based on complete remission rates in the phase II ZUMA-1 trial, a multicenter trial that evaluated axicabtagene ciloleucel in patients with refractory NHL. The approval was specifically for those with large B-cell lymphoma following 2 prior therapies, including for patients with diffuse large B-cell lymphoma (DLBCL). Axicabtagene ciloleucel is also indicated for primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL transformed from follicular lymphoma.
In an interview with OncLive, Andre Goy, MD, chairman and director, chief of Lymphoma, and director of Clinical and Translational Cancer Research at John Theurer Cancer Center, Hackensack Medical Center, discussed the recent success with CAR T-cell therapy, and what is on the horizon for this therapeutic option across hematologic malignancies.Goy: The approval of tisagenlecleucel as the first CAR T cell approved in patients aged 13 to 25 years with relapsed/refractory ALL is a milestone in medicine well beyond oncology. This is the first approval of a live-cell, gene-modified therapy in the United States, and [is] a game changer.
This was based on the phase II B2202 (ELIANA) trial, which was a multicenter trial with a drug developed by the University of Pennsylvania and then developed further by Novartis. It showed an activity that was very impressive in a difficult population because the patients had already gone through stem cell transplantation—it’s a population with no real, durable options. The response rate was 85% with a 53% to 58% complete response (CR) rate. What was very impressive was that these CRs were all minimal-residual disease (MRD) negative in the bone marrow. Many of these CRs were quite durable, so this is very impressive and potentially a cure for these patients.
The upcoming [CAR T-cell] is going to be in relapsed/refractory diffuse large-cell lymphoma, a very aggressive disease [Editor’s Note: This interview was conducted prior to the October 18 approval of axicabtagene ciloleucel]. This is something that is going to be very important because there is no option in that setting. A very small subset of these patients can enjoy long-term benefit of an allogeneic transplant, but the disease is often too fast. This might serve as a breach to an allogeneic transplant, and will be based on the results of the phase II ZUMA-1 trial. The manufacturing success in that trial was 99%, and the median time from the collection to the treatment was around 17 days. The activity was an 85% response rate and a 55% CR rate, and, with over 1 year of follow-up, we still have 40% of patients in remission. This is unprecedented in this population. What was very impressive was that there was no impact on primary refractory bulky disease and they saw the same responses. This is going to be an opportunity to offer an option for patients who have no real durable options.
Based on that, at our center, we will be opening a CAR T-cell unit. This is going to be a dedicated unit, as this treatment is a very difficult thing to manage in terms of toxicity. This is a very important question. The patients must be monitored in the context of a bone marrow or stem cell transplant unit with easy access to an intensive care unit (ICU), because many of these patients have severe complications.
In the ALL trial [of tisagenlecleucel], about 40% of patients had grade 3/4 cytokine release syndrome (CRS) toxicity and slightly a little less in the large cell lymphoma trial. What is happening is that there are 2 main types of toxicity.
The way this therapy works is that the T cells expand quite rapidly. The "cytokine storm" or CRS usually occurs within the first 2 to 3 days to the first 2 weeks. It consists of fever, cytopenia, or there could be hypertension or something that looks like sepsis—which we treat like a sepsis. Eventually, multiorgan failure occurs, as well. In the second aspect of toxicity is encephalopathy associated with CAR T cell; that can go from confusion to speech troubles and motor difficulty to eventually comatose and seizure. This usually occurs 1 to 2 weeks after CRS. This is again managed with supportive care and, obviously, steroids if needed. There is a clear correlation with the amplification of the T cells and neurological toxicity.
Obviously, this requires a specialized environment with access to the ICU, multidisciplinary team, infectious disease specialists, neurologists, ICU folks, and bone marrow transplant team onboard to manage these patients. This is important because there are no great predictors yet on who will have that reaction. Again, what is important to understand is that the…speed of multiplication of these cells is clearly what commissioned a response and toxicity profile, particularly when it comes to neurological toxicity.
One thing that I want to add is that because of the toxicity profile, these patients [should not go to a] community hospital. The patients must go somewhere that is accredited to deliver this type of therapy. John Theurer Cancer Center is one of those centers, because we have been a part of the clinical trials. There will be 10 centers opening for large cell lymphoma, and more opening for ALL as we speak, and patients will have to be referred.
Another thing that will be important for our colleagues to know is that although these responses can be durable and potentially [lead to] cure, some of these patients did not have an early CR and took 9 months to achieve one. Clearly, there is something in the persistence of the CAR T cell that is important.
The next question is, “How can we do better?” We need to work on mitigating those toxicities, but also adding on additional therapies such as studies that are ongoing with ibrutinib (Imbruvica) or checkpoint inhibitors in combination with CAR T cells.This is the level of care of an ICU and an autologous stem cell transplant (ASCT) unit. You need a ratio of nurses and a lot of education. Only the nurses who are dealing with acutely ill ASCT patients deal with CAR T-cell patients. We have trained them to detect and CRS and carefully monitor neurological toxicity, so that they can intervene early. That is a multidisciplinary approach of infectious disease specialists, neurologists, transplant doctors, and hematologists; they are all on board to carefully monitor these patients together to make sure we get the optimal outcome.