Liso-Cel CAR T-Cell Therapy May Significantly Reduce Relapse, Recurrence of Lymphoma


Asking patients to “give us a month of [their] life” for autologous chimeric antigen receptor therapy may reduce relapse or recurrence for 4 years or more, according to expert.

Tanya Siddiqi, MD, an assistant professor at the Department of Hematology and Hematopoietic Cell Transplantation at City of Hope National Medical Center in Duarte, CA, discusses novel data about lisocabtagene maraleucel (liso-cel) chimeric antigen receptor (CAR) T cells for relapsed or refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) with Pharmacy Times at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois.

PT Staff:Why is it significant that the study population in TRANSCEND CLL 004 (NCT03331198) was heavily pretreated before starting liso-cel?

Tanya Siddiqi, MD: So CLL is basically a disease, which is considered to be an incurable, low grade, sort of chronic type of a non-Hodgkin lymphoma (NHL). And people technically live with it all their lives. But we are starting to see this population emerge, which, where the patients are progressing after a couple of our best treatment options out there now Bruton’s tyrosine Kinase inhibitors (BTKi) and venetoclax (Venclexta; AbbVie, Genentech) therapy. And we felt like trying this new modality of treatment, and CLL, which is CART-cell therapy, we wanted to focus on that patient population first before anyone else or before trying to use it in earlier lines of therapy. We wanted to make sure that we could help the patients who are now failing, more and more of the standard novel agents that are routinely used in the real world. And therefore, the patient population that's on this trial has technically failed 2 or 3 prior lines of therapy already per protocol. And the median number of lines of therapy now are 4 or 5 that they have gone through before coming to CART cells.

PT Staff: What are the primary drivers of treatment-resistance to current lines of therapy for CLL/SLL?

Tanya Siddiqi, MD: Well, it’s a bit paradoxical, right? Because we've moved away from chemotherapy entirely in CLL, at least in my practice, and a lot of practices. I know people have moved away entirely from chemo- immunotherapy. Because data has shown many studies have shown that BTKI patients do better venetoclax combinations— patients do better. So why go to chemotherapy? In the past, when we used a lot of chemotherapy, resistance and relapses built up faster. So now patients are living much longer with the newer treatment modality, which is why I'm saying that we're just now starting to see emergence of this patient population, which is now progressing on the BTKIs and the venetoclax. So it's actually a slow emergence of this population of patients, but it is coming, because cancer is smart and it learns to find a way around the best treatments we throw at it, right? So therefore, there's always a need to find better and better treatments to fight the cancer with over time. We've made a lot of progress in CLL, but now we need even more.

PT Staff:What are key highlights of the TRANSCEND CLL 004 (NCT03331198) study?

Tanya Siddiqi, MD: The TRANSCEND CLL 004 study is a phase 1/2, open-label, multicenter clinical trial using lyso-cel CART cells, or Lisocabtagene maraleucel (the full name) CART cells that attack B-lymphocyte antigen CD19 (CD 19) and are manufactured differently from other CART cells. They are manufactured separately as CD 4 and CD 8+ CAR T cells and given to patients in a 1:1 fashion. And so we use this product, which is already FDA-approved for aggressive lymphoma because we did all those trials first, and now the TRANSCEND CLL 004 study is studying this product in CLL and relapsed refractory CLL.

So patients who've definitely failed prior BTKi therapy, but also 2 or 3 prior lines of therapy was what trial needed for patients to be eligible. We enrolled 137 patients, and we were able to treat (with liso-cel) 117 patients. We found that the treatment was safe and tolerable in that the rates of cytokine release syndrome (CRS) and neurotoxicity which are the main side effects of CART cells we talked about. Those were very low. There was only 1 grade 4 for neurotoxicity. And there was no grade 4 CRS events and very few grade 3s, even maybe just 3 or 4. So most of the toxicities were grade 1 or 2—manageable, reversible, and we know how to deal with that. There were no grade 5 CRS or neurotoxicity events.

And what we found very positively in this patient population is that out of the 117 patients, there were 49 patients at our dose level 2 (which is the dose we're taking forward) [who] had had failed both BTKi therapy and venetoclax. And so those are the more difficult to treat patient population. And in all 117 patients— or I should say in all the efficacy evaluable patients, including those 49 patients I mentioned the double refractory ones— we found that the complete remission rate was 18%, which is statistically and clinically significant. and for this patient population is clinically very meaningful and beneficial. And that was the primary endpoint of the study and the primary endpoint was met, which is a big deal for study. We also found that the overall response rate (ORR), which is the complete plus the partial remissions, was about 43%. And very encouragingly, the undetectable minimal residual disease rates (which means that we can't even catch a little bit of CLL in the blood or the marrow) was as high as 63% in this very difficult to treat and heavily pretreated patient population. So it's just 1 dose of CART cells, you follow them for a month to make sure you get them over their immediate toxicities, and then no more treatment after that. And there's still a lot of patients going a long time who have never needed treatment again, after failing so many lines of therapies. So median follow up is only about 21 months so we need to follow patients even longer to see what the durability will be. But already, we have a bunch of patients who are just 3 or 4 years out without relapsing, which is very nice and encouraging.

I think it is a step towards improved treatment options. And having patients live like a good quality of life (QoL), normal life doing normal things without taking a pill every day, or without going to the doctor every week or every month, I think that's, that's a win for sure. I know that my patients are very, very grateful. We still need to do better, but my patients are very grateful to have gone 3, 4 years without needing treatment at all after being on continuous treatment up till that point.

PT Staff: Based on what you were just discussing, could you dive deeper into the important of QoL during treatment?

Tanya Siddiqi, MD: Absolutely. I mean, during treatment, I tell patients you're going to have to give us a month of your life. So we're going to give you CART cells, and then we're going to watch you very closely for a full month and get you over the immediate side effects. And then after a month or 6 weeks, people start getting back to normal, seeing the doctor less and less. Ultimately I'll see patients every 3 months, then every 6 months. And we still need to see them every 6 months, even once a year after they've hit 5 years, we have we haven't reached that. But seeing doctors less and less, not needing transfusions not needing continuous treatment, maintenance therapy, like the CLL is in remission. It's not every single patient, but it's such a large group of patients that who have benefited that it is highly encouraging. And we can only build more positively from this, I feel.

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