Tanya Siddiqi, MD, Discusses the TRANSCEND CLL-004 Trial

Targeted therapies like CAR T-cells have dramatically shifted the standard of care for patients with certain hematologic malignancies, and new research continues to advance this cancer treatment type.

Only 2 CAR T-cell therapies have been approved by the FDA: tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta). Researchers like Tanya Siddiqi, MD, from City of Hope National Medical Center, are currently working to expand the available CAR T-cell treatments. Siddiqi will be presenting on her work thus far in the TRANSCEND CLL-004 study at the 61st American Society of Hematology (ASH) Annual Meeting & Exposition, to be held December 7-10, in Orlando, Florida.

In an interview with CancerNetwork^®, Siddiqi discussed the TRANSCEND CLL-004 trial for patients with chronic lymphocytic leukemia, a type of low-grade B-cell non-Hodgkin lymphoma, and what she thinks lies ahead for CAR T-cell therapy.

CancerNetwork^®: What are you most looking forward to at ASH this year?Siddiqi: Of course, you know, I’m excited to share our data on the Juno CAR T-cell trial that we’ve been doing. But other than that, there are a number of novel agent trials that are going to be reported or updated at ASH this year, for instance the ELEVATE trial with acalabrutinib (Calquence) for instance in previously untreated CLL (chronic lymphocytic leukemia). Some of the others are ibrutinib (Imbruvica) plus cirmtuzumab combinations, vanubrutinib (a newer BTK inhibitor) data, and venetoclax (Venclexta) updates. A lot of useful information will come out of this conference, and this will help us clinically in how to manage patients in the real world as we get to know these patients better and better.

Is there anything you’d be willing to share about your own presentation?
So, in the Juno CAR T-cell trial called the TRANSCEND CLL-004 study, it’s a phase I/II study, we have treated 23 patients with liso-cel across 2 dose levels of cells. We took T-cells from each individual patient, and then Juno in their lab modified these T-cells to make CAR T-cells so that instead of looking for infections to tackle, these T-cells are now going to look for the B-cell lymphoma cells and kill those hopefully. This process of CAR T development takes about a month in the Juno lab. Patients needed to have progressed on or be intolerant of ibrutinib (Imbruvica) or ibrutinib-type BTK inhibitors to be eligible for this CAR T-cell trial. In addition, they needed to have failed a total of 2 or 3 prior lines of therapy. All of them had actually been exposed to ibrutinib in the past and probably 95% of them had actually progressed on ibrutinib, maybe 5% of them had been intolerant of ibrutinib. Several had progressed on venetoclax as well before enrolling in this trial, and so these patients have pretty aggressive CLL. We noted that liso-cel has very little grade 3 or grade 4 toxicity to speak of and no one died from complications of this CAR-T cell therapy. Specifically, when you talk about CAR T therapy, you talk about these toxicities being the most common, but so far 2 had grade 3 cytokine release syndrome and nobody had grade 4 or 5. As far as neurotoxicity is concerned, 5 patients had grade 3 or 4 neurotoxicity and none had grade 5.

The side effects resolve, they’re manageable, and in terms of efficacy we’ve seen up to almost 80% approximately of patients have an objective response on the study, as early as the day 30 assessment time point. Minimal residual disease undetectable responses in the bone marrow or blood was seen in 65-70% of patients early as well. And then over time, about 25% of patients went on to improve their responses. So very early we’ve seen very good, deep remissions, and in the people who didn’t achieve complete remission we’ve seen improvement in their responses over many months. Thus far, we’ve followed the earliest patients treated for two years and they are still in excellent remission with no recurrent MRD positivity, if they had achieved an MRD-negative response. They are doing well and trying to live a normal life with minimal follow-up in clinic. So, the results are very encouraging. Of course, we need to go longer to be able to see is this really a cure for these patients, we don’t know that exactly yet, because when you have a low-grade low growing disease like CLL you have to follow them for at least 10 years. So, there’s a long follow up ahead that is needed, but the early data looks extremely good.

Where are we now in the field of CAR T-cell therapy, and where do you think we’re headed?
So, in CLL specifically, I think there are so many novel agents, oral agents that patients can cycle through to control their disease over many years before they are referred to CAR T-cell therapy. Some doctors and patients think they would want to wait before they take on CAR T-cells, given there is a small chance of cytokine release syndrome neurotoxicity which is all reversible, but of course that first month is a little bit tenuous. And so, right now where it’s being studied is more in the relapsed/refractory setting. For people who have failed a couple of novel agents, I usually put them right into CAR T-cell therapy because I feel like they will not do well with pills and immune therapies over time, just because their disease can aggressively relapse more easily. The biggest challenge is that I would like to see it come more in the first- or second-line setting so that we don’t wait until people have failed 2 or 3 lines of novel therapy and are much sicker before we give them CAR T-cells. So over time, I hope we can show that we are curing people with relapsed CLL, historically an incurable disease, and ultimately earlier lines of therapy can be investigated as well.