Long term data from JULIET trial, using tisagenlecleucel for patients with relapsed or treatment-resistant DLBCL

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Published: 2 Dec 2018
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Dr Richard Maziarz - Oregon Health & Science Knight Cancer Institute, Portland, USA

Dr Richard Maziarz speaks to ecancer at ASH 2018 about follow-up results from the JULIET trial for patients with relapsed or treatment-resistant diffuse large B-cell lymphoma (DLBCL).

He reports that 18 months after treatment with product tisagenlecleucel, patients with relapsed or treatment-resistant diffuse large B-cell lymphoma continue to show a high response rates.

Dr Richard Maziarz also explains the adverse effects of the treatment, as well as the potential implications - which he describes as changing the natural history of the disease.

What his press conference here.

Read the article here.

ecancer's filming has been kindly supported by Amgen through the ecancer Global Foundation. ecancer is editorially independent and there is no influence over content. 

We’re developing the immune therapies. A lot of immune therapy historically has been antibody based and the problem with an antibody is they can be very, very effective, they’re very specific but there’s a half-life. What everyone has been excited about over the last decade is the ability to capture and utilise living cells, the immune cells where you can actually genetically modify an immune cell, infuse them back in and where you’d be able to get a therapeutic benefit. But in this case the cell is a viable cell that can be sustained in the body so the half-life, potentially, is not just days or even weeks but there have been some studies now showing that years later you can find a genetically modified immune cell that’s still functional in the person’s body.

So in this case they’ve identified a series of diseases that have very, very low likelihood of any meaningful survival and also they have to have a common antigen. It doesn’t make sense if you have a very specific cancer antigen to that specific cancer, that becomes a specific product for that patient. What has been the focus of attention is can you identify a specific molecule commonly shown across all cancers that could then be a target for immune destruction; that’s the basis of chimeric antigen receptor T-cell therapy – they’ll take your own lymphocytes, genetically modify it by inserting a gene that will express a new receptor that will redirect that immune effector cell to the actual cancer itself to destroy the cancer.
So the methodology of the study is it’s identified a patient population which is of large cell lymphoma, 75,000 cases of lymphoma a year, one-third of them are large cell lymphoma. 60% will be cured, potentially, by chemotherapy and antibody therapy, 10,000 patients a year in the United States will go on to need further therapy and a lot of them will die of their disease. This particular study was focussed as a group of patients that have multiply relapsed or have been proven to be resistant to primary therapy. In this case these patients we would have predicted are probably in the average of about 15%, maybe 20%, two year survival. The ability of getting to complete remission again in this group with the standard chemotherapy and antibody therapy is less than 10%. It was felt that, recognising it’s a high death rate, it’s a common disease and that there’s a common target antigen that we can address and develop or redirect the immune system towards, that this may be an opportunity to change the natural history of that disease. That’s our study, there have been other similar studies using similar constructs and similar molecules, but I will point out that if you look across the landscape of chimeric antigen receptor T-cells they are different drugs. Ours is using the molecule tisagenlecleucel, or the cell product tisagenlecleucel, and we ran a clinical trial sponsored by Novartis that came out of the work from the University of Pennsylvania. The data showed that you can achieve a much higher response rate than would have been anticipated in this group and a higher complete remission rate than would have been otherwise expected. It’s exciting that our data, like others, is now showing a year and a half out from the administration that half the patients are remaining free of progression when you would have predicted, based on any other prior chemotherapy or antibody-based therapy that there would have been much more early relapses and most of the patients would have died by that time.

What were the differences?

In our study, of the patients that were infused, 40% of patients were able to gain a complete remission, 14% had a partial remission, so a total response rate of 54%. What was intriguing, and it goes again to the biology of the cells, over half the patients with partial remission actually proceeded to a complete remission. So this shows that you can actually get a biologic activity over time. The survival rate, if you take the entire group, approximates between 35-40% but for the patients who had a remission status, there’s over 50% survival ongoing currently as of now. The study continues to accrue, I believe the data that we presented was based on approximately 100 patients.

Any therapy will have its own adverse events; there are some unique adverse events of interest. The first is what’s called cytokine release syndrome and that’s an inflammatory event that occurs when the T-cell encounters its target. The inflammatory event will be associated with sometimes extreme haemodynamic instability or sometimes it can be very minor – low grade fevers, a little heart-rates that go faster, sometimes people have had difficulty, oxygenation required and intensive care unit support. In general the cytokine release syndrome was able to be managed; it’s also unique in our study, approximately 20-25% of the patients were able to be treated in an outpatient setting without a significant toxicity of CRS. There’s also a lot of attention that there’s a relatively not understood well toxicity of a neurologic toxicity of delirium and encephalopathy; again, that was seen but in about 10% of patients. When you look across studies it’s sometimes hard to draw good comparisons because there are different grading systems have been used and we’re moving as a community to a consensus grading system so what we report today will be different than what we report tomorrow. So there’s the cytokine release, the inflammatory system and encephalopathy, then there are some patients who have a prolonged, what we call, cytopenia. There’s a bone marrow toxicity that we typically predict after chemotherapy that marrow will recover function within days or maybe one or two weeks and there are a small number of patients that have a profound persistent low blood count, often requiring transfusion and setting them up for infection.

The implications are, in some ways, obvious. You have a therapy that has changed the natural history of disease – when we would have predicted 15-20% survival at two years now we’re predicting approximately 40% survival at two years. The implications are it’s a first step. At the end of the day that means, to me, 50-60% of patients still aren’t surviving and what we need to do is to figure ways to build upon this platform. It’s a first step, it’s not a final step.