CAR-T has ‘fundamentally changed’ outcomes in follicular lymphoma
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Follicular lymphoma is among the least common types of non-Hodgkin lymphoma, but the nature of the disease has allowed those who require treatment to benefit from the groundbreaking development of chimeric antigen receptor T cells.
CAR T-cell therapy for advanced follicular lymphoma has produced “unprecedented results,” according to Stephen J. Schuster, MD, director of lymphoma translational research at Abramson Cancer Center, as well as Robert and Margarita Louis-Dreyfus professor in chronic lymphocytic leukemia and lymphoma clinical care at University of Pennsylvania’s Perelman School of Medicine.
“CAR-T has caused a fundamental change in outcomes,” Schuster told Healio. “Durable responses to therapy were not previously achievable for this disease, particularly for patients who have been heavily pretreated and for whom previous remission lengths were measured in months and not years.”
Schuster — part of the research and development team that helped bring tisagenlecleucel (Kymriah, Novartis) to market as the first gene-edited cell therapy approved by the FDA — has clinical experience with both commercially available CAR T-cell therapies for follicular lymphoma.
In this installment of In Practice, Schuster discusses the treatment landscape for follicular lymphoma and the impact CAR-T has had on clinical care of those with advanced disease.
Healio: Is treating follicular lymphoma fundamentally different from treating large B-cell lymphoma?
Schuster: Absolutely. It is a completely different malignancy from large B-cell lymphoma, at least if there is no evidence of transformation. Historically, outcomes have been completely different when we treat follicular lymphoma compared with large B-cell lymphoma, although these are both B-cell malignancies and respond to drugs that are active in B-cell malignancies — including targeted agents, such as anti-CD20 monoclonal antibodies.
Healio: What is the prognosis for patients with relapsed or refractory follicular lymphoma?
Schuster: Aggressive B-cell lymphomas can be cured in approximately two-thirds of cases by combining a CD20-directed monoclonal antibody with chemotherapy. Although the various therapies successfully used for large B-cell lymphoma can achieve remissions in patients with follicular lymphoma, disease relapse typically occurs at some point down the road.
The paradox here is that follicular lymphoma is an indolent disease in the sense that it doesn't grow quite as quickly or make people as sick as aggressive large B-cell lymphoma. However, follicular lymphoma is stubborn. You can treat it and get it into remission, but it typically comes back, whereas with large B-cell lymphoma, it comes back and you will get a second chance — and sometimes a third — at curing it with hematopoietic stem cell transplant or CAR T cells. After that, you're done.
Patients enrolled in clinical trials for follicular lymphoma, on average, have received at least three or four prior therapies, I've seen some patients have up to 11 prior therapies in research studies for follicular lymphoma. These patients continue to respond to different therapies, but the duration of remissions get shorter and shorter until, in the end, you're stuck with the bad lymphoma even though it's "indolent."
Finally, there is a subset of approximately 15% to 20% of patients who have distinctly bad outcomes. Under the microscope, they look like low-grade follicular lymphoma, but they progress or have their first relapse within 2 years of primary therapy. If these patients receive a monoclonal antibody and chemotherapy as first-line therapy and progress within 2 years, 50% of them will die within 5 years.
Healio: Can you describe the landscape of commercially available CAR-T for follicular lymphoma?
Schuster: There are two commercially approved CAR T-cell products for follicular lymphoma. Axicabtagene ciloleucel (Yescarta, Kite Pharma/Gilead Sciences), also known as axi-cel, is driven by a CD28 costimulatory focus at the intracellular end of the chimeric receptor. Tisagenlecleucel is driven by 4-1BB costimulation. Both agents bind to CD19 on tumor cells, using the same signal chain variable fragment derived from the murine monoclonal antibody FMC63. Despite using different intracellular signaling pathways, both products stimulate T-cell-directed cytotoxicity for tumor cells, and both are capable of achieving high remission rates and durable remissions among patients with relapsed or refractory follicular lymphoma.
Healio: When should community-level clinicians consider referring their patients with follicular lymphoma to a CAR-T center?
Schuster: If you have a patient who is double refractory — that is, refractory to rituximab (Rituxan, Genentech) and an alkylating agent — then it is time to refer to a CAR-T center. Treating patients earlier with CAR-T doesn't necessarily enhance the response rate or the duration of response, but it subjects the patient to less long-term treatment-related toxicity by exposing the patient to fewer cytotoxic agents. A subsequent successful T-cell harvest to produce CAR T cells is more likely if a patient hasn't had multiple cytotoxic agents.
If you have a double-refractory patient or somebody who progressed within 2 years, I certainly would start the discussion about where they should go next.
CAR T-cell therapy increasingly is going to leave the university setting and move into the community. It's really not that hard to do. With the exception of a few patients with significant comorbidities, I’ve been doing CAR-T as an outpatient procedure since 2013 because I didn't know any better. When we started doing CAR-T at Penn, there wasn’t a body of literature, and we did not assume that these patients had to be admitted to the hospital unless necessary. After all these years, we continue to treat those with follicular lymphoma as outpatients — and with great results.
Healio: Does the wait-and-watch approach to treating follicular lymphoma still make sense given the availability of CAR-T?
Schuster: Absolutely, because some patients with follicular lymphoma will never have to be treated. I have followed some patients for 30 years without treatment. I don't want to do anything to somebody who doesn't need treatment. Some patients have a hard time getting their head around that, but I tell them, “I can always give you a side effect.” Many patients accept this strategy, but there are others who push for treatment. It is not a good idea to treat people who do not need to be treated.
Why do something that is more expensive potentially with some late unforeseeable complications? I don’t really feel the urge to tell these patients “I have a cure for you on day 1” because they may have a disease that does not progress. But once someone is resistant to CD20 monoclonal antibody therapy, that is when you should start considering CAR-T or bispecific antibodies.
Healio: How has CAR-T changed outcomes in follicular lymphoma?
Schuster: The treatment landscape has been fundamentally changed with the advent of T-cell-directed therapies, such as CAR T-cell therapy and bispecific monoclonal antibodies, which engage a patient's endogenous T cells to attack and kill a tumor cell. These new T cell-mediated therapeutic approaches have changed the prognosis for follicular lymphoma in that we now have agents with a high response and — more impressively — the remissions tend to be durable. Approximately 60% of the patients we treated in the pilot trial for tisagenlecleucel are still in remission 5 to 6 years after treatment.
The patients with follicular lymphoma who I have treated with CAR T cells would not be alive without them. These are patients who failed all therapies available at the time, so it has had a huge impact. Their quality of life goes back to being essentially normal, and a small number of patients require IV immunoglobulin for treatment of hypergammaglobulinemia.
Healio: How do you choose which commercially available product to give to your patients with follicular lymphoma?
Schuster: In most cases, I use tisagenlecleucel because the efficacy is about the same as axi-cel but with less toxicity. There have been times when manufacturing was delayed for tisagenlecleucel, so I switched to axi-cel to get the final manufactured product faster.
Another factor is that axi-cel is derived from freshly apheresed cells, which requires more logistical coordination with the manufacturer; but in the case of patients who have borderline lymphocyte counts to develop a viable treatment dose, use of axi-cel may be preferable to the freeze/thaw process used to manufacture tisagenlecleucel. So, it depends on the patient's lymphocytic count and urgency to have a final manufactured product returned in 3 to 4 weeks.
Healio: How do the safety and efficacy profiles of tisagenlecleucel and axi-cel compare among patients with follicular lymphoma?
Schuster: Among patients treated with CAR T cells, those with follicular lymphoma have had the lowest rates of cytokine release syndrome and neurotoxicity. Rates of grade 3 or greater neurotoxicity range from 10% to 12% for patients who receive 41-BB-driven CAR T cells, such as tisagenlecleucel. Conversely, high-grade neurotoxicity rates for CD28-driven CAR-T — including axi-cel — are nearly double at approximately 20%.
CRS rates also tend to be higher among those treated with axi-cel. I admit these patients to the hospital because the probability of high-grade neurotoxicity and CRS is high enough that it is safter to have them monitored and treated immediately for the adverse effects. For the other products, I have patients text me or call me with their symptoms and then I decide what the next step will be.
Healio: Is CAR-T achieving cures for some patients?
Schuster: Maybe. I have patients who were multidrug refractory and who are still in complete remission after being treated with tisagenlecleucel 6 years ago. I don't know whether 6 years is enough to call it a complete victory. This is certain, though: Both available CAR-T therapies are capable of achieving phenomenal response rates and durable responses. We have been blessed after all these years with these patients to have more than one effective product with manageable toxicity profiles. Patients with follicular lymphoma now have many reasons to be optimistic about their future..
For more information:
Stephen J. Schuster, MD, can be reached at Abramson Cancer Center, Perelman Center for Advanced Medicine, West Pavilion, 4th Floor, 3400 Civic Center Blvd., Philadelphia, PA 19104.
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