Matthew Lunning, DO: With the commercially available products, I think that for second-line patients who have progressed after 2 lines of therapy for their diffused large B-cell lymphoma [DLBL], you have to ask yourself the question of: Could I do an autologous stem-cell transplant? Could I get them through that transplant? If I think I can, then I think that that’s a population of patients that are CAR-T eligible.
There’s going to be a whole cohort of patients who have relapsed post-curative-intense autotransplant. In that population, that’s where it becomes more difficult because then you’re asking yourself the question: Could I do an allotransplant? Or would I give them intensive chemotherapy again? And if that answer is yes, they could potentially get a conditioning regimen for a myeloablative transplant. Once again, this population would be CAR-T eligible.
Diffused-large B-cell lymphoma doesn’t care what you’re thinking; it’s going to grow. You have to be on your toes in this setting. If this is a CAR T-cell eligible patient, you want to be thinking if you’re going to give a transplant. What’s the pace of the disease? Am I going to need to treat them after deciding to do CAR-T cell therapy, and get approval from both institution partners, insurance partners, and the company that you’re trying to receive the CAR-T cells from, to proceed forward with the patient?
Again, you’re trying to keep the patient healthy enough to get their CAR-T cell therapy while keeping their disease under control long enough so that when the cells arrive, they will be in the appropriate condition to receive the treatment. It’s a very tricky situation. It’s a mindset that I don’t know we’ve had before, at least I don’t remember, in the large-cell lymphoma.
When you’re talking to patients, we have to change our mindsets. We’re looking for disease control, but I don’t want to worsen the performance status or hurt the heart or lungs. I definitely don’t want to hurt the kidneys, because I need to give some form of lympho-depleting chemotherapy, potentially. You need to have enough reserve in case you have grade-3 cytokine release syndrome [CRS], or if you have a grade-3 or -4 neurotoxicity. Those are the eye-peering questions that we have right now.
This is very much a case-by-case basis. You can have performance status, which, if it shows a decline related to the lymphoma, may impel me to administer a more intensive chemotherapy to keep the disease under control while the CAR-T cells are arriving. You may have a patient with low disease burden, but it’s refractory to everything that has been tried against it. Even though it’s progressing slowly and the patient isn’t being affected, it’s one of those lymphomas that are going to shift gears: it’s going to shift from second to fifth gear, and eventually become life threatening.
You may have time to give bridging therapy. Now you’re definitely talking to them about symptoms and the possibility of this interim therapy. You have to be careful about how close you’re giving the bridging therapy to lympho-depleting chemotherapy or until the CAR-T infusion. You need to ask yourself if it’s possible to do early or late bridging. My mindset changes depending upon pre- and post-apheresis, or if I’m going to try and not bridge them post-apheresis.
Leo Gordon, MD: The choice of patients for CAR-T therapy is evolving. Based on the clinical trials, patients had to have relapsed/refractory diffused large B-cell lymphoma [DLBL], and 2 prior regimens, in order to qualify for CAR-T therapy. In the National Comprehensive Cancer Network [NCCN] Guidelines, we made it clear that patients who, for example, had follicular lymphoma [FL], initially were treated with a regimen containing doxorubicin [Adriamycin], such as R [rituximab (Rituxan)]-CHOP [cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate (Oncovin), prednisone (Deltasone)] or CHOP, who then developed transformation to the DLBL and could only have 1 regimen, or the CAR-T cells, whereas the clinical trials require 2 regimens for the transformation of large-cell lymphoma.
In general, we take treatments that are effective in the relapsed setting and begin to apply them earlier in the course of the disease. This is being done currently in the ZUMA7 study from Kite, which is looking at taking patients with high-risk, relapsed DLBL, and randomizing them to standard of care, which is salvage chemotherapy or second-line chemotherapy, followed by autologous stem-cell transplant, and comparing that with CAR-T cells at the time of relapse; it’s an important study. It’s going to be hard to accrue, but it’s significant. This is also being explored by Novartis and Juno Celgene group.
I can certainly see a day where, once the toxicities are well worked out and the data, much more clear, that you could begin to think of CAR-T therapy for high-risk DLBL in patients as an upfront or near-upfront treatment, just like we’re beginning to do in Hodgkin’s lymphoma with checkpoint inhibitors. The history of evolution and improvement in cancer treatment has been to take regimens and treatments that are used at the end of treatment and bring them to the beginning.
Nilanjan Ghosh, MD, PhD: The selection of patients for CAR-T therapy is based on many factors: do they meet the FDA indications? If so, we take that into consideration. There are still many patients who fit the disease criteria but are not appropriate for CAR-T therapy. It is important for us to understand the pace of the disease. We know that we can’t see a patient in consultation and offer the therapy the next day. If we understand the pace of disease and someone is progressing rapidly, then we need to know whether we can control their disease for the duration of time.
This is the clinical part of it, but there are also other things that are very important. You have to look at patient characteristics including age, comorbidities, performance status, and organ function. Are they going to be someone who will be able to withstand CRS and neurotoxicity, which can potentially occur? Finally, it’s important to look at the social support system: if the patient has a caregiver, they’re able to live close to the center, which is offering the CAR-T therapy. Lastly, there is a financial component to this as well.
Transcript Edited for Clarity