The therapeutic arsenal of CAR T-cell products for hematologic malignancies is rapidly growing, but exactly how this new approach fits in with other available options is not yet clear, said the authors of a recent review.
Writing in the ASCO Educational Book, Saar Gill, MD, PhD, of the University of Pennsylvania Perelman School of Medicine, and Jennifer Brudno, MD, of the National Cancer Institute, noted that at the time the paper was published, there were five anti-CD19 CAR T-cell products approved by the FDA for seven indications in lymphoid malignancies.
"As experience accrues from clinical trials and from the real world, the next challenge will be to learn, in a systematic and rigorous manner, the appropriate place of CAR T-cells among the assortment of chemotherapy, immunotherapies, and small-molecule pathway inhibitors available to our patients," the authors said. "The unique promise of CAR T-cells is as a one-and-done treatment with curative potential because of prolonged immuno-surveillance, which will likely justify their high initial economic and logistic burdens."
Although neither Gill nor Brudno were available for an interview, the following discussion of current clinical issues and considerations with CAR T-cell therapy in hematologic malignancies was taken from the article and from presentations they made at the most recent ASCO Annual Meeting.
You mentioned that the available CAR T-cell products received regulatory approval on the basis of some modestly sized, single-arm studies. Have subsequent real-world reports validated those studies?
Subsequent real-world registry reports have largely validated those obtained in the pivotal trials: the complete response (CR) rate for tisagenlecleucel [tisa-cel] in B-cell acute lymphoblastic leukemia was 81% in the pivotal ELIANA trial and 86% in 255 patients treated in the real world, and the estimated 12-month event-free survival rates were 50% and 52%, respectively.
In large B-cell lymphoma treated with axicabtagene [axi-cel], the CR and 12-month progression-free survival rates were 58% and 44%, respectively, in the pivotal ZUMA-1 trial compared with 64% and 45%, respectively, among 275 patients treated in the real world. In large B-cell lymphoma treated with tisa-cel, the CR rate in the pivotal JULIET trial was 40% compared with 40% among 155 real-world patients.
With multiple CART T-cell products approved for large B-cell lymphoma, how do you select the best treatment option for a particular patient? What is the most important factor to consider?
I think for large B-cell lymphoma, a really important thing is cell processing time. So when I talk to fellows about this when they're out in the real world and they're prescribing CAR T-cells, really communicate with your commercial entity that's providing the CAR T-cells and the insurance plans, and see what the turnaround is going to be for the particular product.
In clinical trials it seemed that axi-cell was the fastest, then liso-cel [lisocabtagene maraleucel], and then tisa-cel [tisagenlecleucel]. So think about your patient and the cell processing time. Is this a patient who is very chemo-refractory, where you suspect that they will not respond to bridging therapy? Then you want really fast cell processing times. That's very high priority.
And then also think about your patient in terms of toxicity profiles, of course. I think for patients with underlying neurologic disorders, perhaps you're a little bit more concerned about the axi-cel product. Patients who are elderly and maybe have imperfect renal function, I think the liso-cel clinical trial tried to incorporate those patients, so you could consider that product for them.
And if your patient is just very chemosensitive, and you feel very confident about your bridging therapy, then financial considerations and logistical considerations are also really important, and perhaps you can wait for that longer cell processing time. So that is broadly how I think about that problem.
What are some of the most important questions being explored in CAR T-cell therapy for hematologic malignancies?
One question is whether patients can be re-treated with CAR T-cells after failure of the first infusion. Patients re-treated with axicabtagene after relapse on ZUMA-1 (aggressive B-cell non-Hodgkin lymphoma) who had evidence of response to the first infusion and no evidence of CD19 loss had limited response to re-treatment.
In contrast, patients enrolled in ZUMA-5 (indolent B-cell non-Hodgkin lymphoma) who were re-treated according to similar criteria appeared to benefit from re-treatment. These observations are preliminary and based on a small group of patients and therefore must be viewed with caution.
Another question is when should patients with non-Hodgkin lymphoma be referred for CAR T-cell therapy. Retrospective data suggest a trend to better outcomes if patients receive CAR T- cells earlier (i.e., after two lines of chemotherapy or after autologous stem cell transplant that followed two lines of chemotherapy) rather than later (i.e., after at least three lines of chemotherapy or after receipt of additional treatment after autologous stem cell transplant).
In a similar vein, an intent-to-treat retrospective comparison of CAR T-cells or allogeneic hematopoietic cell transplant for multiply relapsed diffuse large B-cell lymphoma showed, at 12 months, a significantly lower non-relapse mortality (3% vs 21%, in favor of CAR T-cells; P=0.04), whereas differences in relapse rates, progression-free survival, and overall survival were not statistically significant.
What requirements must doctors and treatment centers meet in order to provide CAR T-cell therapy?
To prescribe CAR T-cells in the United States, the treating center must be accredited by the Foundation for Accreditation of Cellular Therapy, and the individual physician must have been trained according to a Risk Evaluation and Mitigation Strategy drug safety program that is mandated by the FDA.
Patients must remain within proximity (typically interpreted as up to a 2-hour drive) of the treatment center for at least 4 weeks after administration of the product because of toxicities such as cytokine release syndrome and immune cellassociated neurotoxicity syndrome, which require specific awareness, monitoring, and management. All products other than tisagenlecleucel must be administered in an inpatient setting, and the patient must be monitored at least daily for 7 days.
Read the study here and expert commentary about the clinical implications here.
Brudno reported no potential conflicts of interest; Gill reported relationships with Carisma Therapeutics, Interius Biotherapeutics, Magellan, Asher Bio, and Novartis.
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