Loretta Nastoupil, MD: Why is CD19 an attractive target in relapses / refractories [diffuse] large B cell lymphoma?
John Burke, MD: It is a transmembrane glycoprotein. It regulates B cell receptor signaling. The main reason is that it is present on all B cells and malignant B cell tumors, and it can be targeted with monoclonal antibodies and other things, like CAR [chimeric antigen receptor] T cell therapy, which can bind to it. Why not tell us about the different ways to target CD19?
Loretta Nastoupil, MD: We first had the approval of CAR T-cell therapies, they are autologous CARs. This means that patients have to undergo an assessment at a treatment center, they have to have insurance approval, the cells are… sent to a central manufacturing site. Usually it takes about 3-4 weeks to get [results] of these cells. Then, they undergo lymphocyte depletion chemotherapy and an infusion of these cells, monitored in this treatment center for at least 4 weeks. Sometimes they are returned to their site of origin for late monitoring for toxicity. We currently have 3 CD19 approved DACs for relapsed large B cell lymphoma in third line or later space: Axi-cel [axicabtagene ciloleucel], tisa-cel [tisagenlecleucel], and liso-cel [lisocabtagene maraleucel]. We have approvals for CAR T[-cell] and other malignant B cell tumors, such as mantle cell lymphoma and follicular lymphoma. The reason these are effective strategies is that, in the refractory setting, we have seen lasting responses in at least 40% of patients.
The toxicities are also worth discussing as you have the acute toxicity, which is primarily cytokine release syndrome and / or ICANS. [immune effector cell-associated neurotoxicity syndrome], which is neurological toxicity. It is a specter. In my experience, CRS [cytokine release syndrome] is most often fever and is sometimes associated with hypoxia or hypotension, rarely severe target organ damage, sometimes including respiratory failure, cardiogenic shock, etc. These are rare. ICANS are more unpredictable and can have a broader spectrum, ranging from a slight tremor to complete confusion or altered consciousness where patients are no longer able to consider or answer questions, or even experience a loss of consciousness. convulsive activity or brain edema.
Fortunately, the severe end of this spectrum is rare, but it can be unpredictable outside of concept, disease burden, and sometimes the comorbidities of the patient’s functional status. The biggest problem I foresee with CAR T is that it is logistically difficult. Ideally, you should refer patients to a treatment center as soon as possible to start the insurance approval process, which takes 1 to 6 weeks. Let’s say we’re closer now, 1 to 3 weeks for most patients. That’s before we can even set them up for collection and manufacturing, which takes another 3-4 weeks. I agree that this selects patients who have a disease that will allow them this time. Then we have the acute surveillance, which is done in the treatment center, but the late surveillance for toxicity is something that we often share with our community oncologists, who are mainly monitoring the infection. Hypogammaglobulinemia can result from B-cell aplasia, which in COVID-19 can be particularly difficult, and then from prolonged or persistent cytopenia. Neutropenia, anemia, and thrombocytopenia can persist for months. These are more related to extensive immune suppression and monitoring and management of chemotherapy.
John Burke, MD: I have another question for you on CAR T’s. I don’t deal with CAR T’s, so when I see someone who needs it, I refer them to someone like you. What do you tell your patients about their likelihood of responses? [are]? Of course, you not only want a quick response, but you also want your response to last a long time. What do you see from the longer-term follow-up of these trials, and how do you advise your patients on their chances of a response? Do you see the different products behaving differently this way, or do you think they are all relatively similar, in terms of long term effectiveness?
Loretta Nastoupil, MD: If you look at the long term results, they are more similar than different. I fully recognize the characteristics of the patients, so the populations studied were different. In my clinical experience – where we have now treated over 200 standard-of-care patients with CAR T over the past 2.5 years – axi-cel is most likely to give a lasting result, even in patients who are refractory to high grade who progress rapidly. Liso-cel and tisa-cel will be better tolerated, which matters in my decision. Even though I have a patient [and] I am a little nervous that their disease progresses quickly, I admit that these are patients who have already reached me. I don’t even have direct conversation with patients on [whether] they are suitable for CAR T, it is rare.
When they come to me, it’s usually been discussed before, but I tell them we have about a 40% chance, and 40% chance is cure, 60% of patients will fail — and usually fail quickly, usually over the course of time. of the first 3 months, if they fail, that will be the time limit. If they are in a CR [complete remission] by month 3, there is a good chance that these patients will remain in complete remission and this can last for years. It’s a resource intensive situation to start with, but we quickly get our answer as to whether it’s going to work.
Transcription edited for clarity.