PRWCC: Disease burden impacts outcomes in paediatric and young adult B-Cell ALL after commercial tisagenlecleucel

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Published: 16 Dec 2020
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Dr Liora Schultz - Stanford University School of Medicine, Palo Alto, USA

Dr Schultz talks to ecancer about disease burden impacts outcomes in paediatric and young adult B-cell acute lymphoblastic leukaemia after commercial tisagenlecleucel: Results from the paediatric real world CAR consortium (PRWCC). These results were presented at this year’s ASH 2020 virtual conference.

Dr Schultz initially gives an explanation of what PRWCC was and then moves on to explain what this specific study evaluated and how. She says that in this study retrospective data was collected from 15 PRWCC member institutions and included 200 patients.

She then mentions the key results from this study and talks about the future of this research and how it can change the treatment of B-cell acute lymphoblastic leukaemia.

In conclusion she says that this retrospective, multi-institutional analysis describes real world outcomes using tisagenlecleucel to treat paediatric r/r B-ALL.

PRWCC: Disease burden impacts outcomes in paediatric and young adult B-Cell ALL after commercial tisagenlecleucel

Dr Liora Schultz - Stanford University School of Medicine, Palo Alto, USA


CARs came about and have mediated striking remissions in that really clinical experience. It was really exciting and that led to FDA approval. The FDA approved tisagenlecleucel, a CD19 targeting CAR T-cell therapy, in August 2017. Since then with commercialisation it has been phenomenal, in that there is increased access across many different centres and more patients can get treated. However, one of the challenges is delivering CARs out of the context of the tightly regulated clinical trials. There is a lot of heterogeneity in practice, in clinical practice, and we haven’t been standardised in the way that we have been collecting patient data. So the consortium came about because we asked the question of how do these CARs function in the real world setting and what are some of the clinical gaps and how can we address and improve them.

So because the individual institutional data is not powered to answer a lot of these questions, we said, ‘Okay, let’s form collaborations across centres delivering commercial tisagenlecleucel.’ So we created, we established, a consortium that to date has about twenty participating sites. Our goal was really to establish and facilitate communication and create a forum for shared data and analysis to interrogate how these CARs are performing in the real world setting and allow us to ask some very basic questions and try to answer how we can improve CAR therapy for our patients and patient outcomes.

What did this study evaluate and what was the methodology used in this study?

It was a retrospective study, our first study. It was a retrospective study and it was geared towards establishing outcomes, both overall survival and event free survival outcomes in the real world setting, looking at relapse rates and patterns of antigen expression at relapse; looking at toxicities. One of our major focuses was to interrogate how baseline features from patient disease and prior treatment before receiving the CAR impact outcomes of CAR T-cell therapy. CAR T-cells are a therapy that rely on the patient’s individualised T-cell pool and we know every patient’s T-cell pool is different which means it’s really an individualised therapy which makes it very hard to study. So since commercialisation we have about 200 patients that we have been able to study and question using multivariate analyses to question how these baseline features impact outcomes.

One of the really interesting findings that surfaced is that the baseline disease burden really impacts outcome. So, patients who come in with a higher disease burden actually have inferior overall survival and event free survival at six months and a year. This is interesting because looking at the prior patient data in clinical trials, it really restricted or defined which patients were treated. With the commercialisation a broader patient sampling can be treated and this includes patients with high disease burden and patients that were previously excluded from trials with very low disease burden. These were outcomes that haven’t been looked at stratified across disease burden. So that was one of our interesting initial findings.

Are there any other key results that you would like to talk about from the study?

One of the really wonderful things is the forging of collaboration. Along with our initial retrospective study, what we have done is establish multiple working groups to simultaneously ask many questions. Because CAR therapy is still somewhat in its infancy, there are very basic questions that we don’t understand. How does transplant affect outcomes? Patients receiving transplants post-CAR, does that improve outcomes or not? How do high risk populations perform such as infant ALL or patients that have prior CD19 therapy or patients with high risk cytogenetics? What does their infection and immune reconstitution look like post-CAR T-cell therapy? What is the fate of patients after they relapse post-CAR T-cell therapy? These are all somewhat basic questions that we don’t have answers to.
So what we’ve done is we’ve forged working collaborations, working groups, to attack some of these specific questions. Those efforts are ongoing so I look forward to seeing what data comes from that.

How do these results impact the future treatment of B-cell lymphoblastic leukaemia?

Currently we don’t really know the ideal disease burden that patients should have at the start of CAR T-cell therapy. It has been something that we have grappled with. Data shows different things, so there is data that supports that you need some baseline antigen expression, some baseline CD19 expression to allow the CARs to function, and that’s across both physiologic and leukemic B-cells. There has also been data in the adult world and some in the paediatric clinical trial setting that demonstrates that in the leukaemia setting CARs function worse in patients that have high burden. So we looked at this in the commercial setting and see that really high burden outcomes are quite inferior to those patients who are treated with low burden. For example, in our entire patient cohort at one year the event free survival is 50% but in that high burden disease cohort the event free survival is only 34%. So, to us, that begs the question of should patients be infused with a lower disease burden. We don’t know yet if debulking will actually improve outcomes or if high burden is just a surrogate for a worse biology. These are things that we are going to study. But clinically that may impact what our target disease burden is at the infusion of CAR T-cell therapy.

CARs have been commercialised for about three years now, so longitudinal data is really only starting to become available. It is really a missed opportunity to not look at the prior patient experience that has amassed to date to help us understand how to improve these outcomes. Again, I mentioned that at one year the outcome is only 50% for patients to be alive and in a relapse-free setting and we don’t have good predictors of outcomes. We can’t risk stratify and say, ‘Yes, this patient is at high risk of relapse and this patient is likely to achieve a durable remission.’ One of our real aims is to try to understand which patients achieve the durable remission and which patient may be at high risk of relapse and warrant a further consolidative therapy to help enhance the CAR outcomes. I look forward to seeing what we find and what evolves within the field to help us really achieve more durable outcomes for our patients, for paediatric patients receiving CAR therapy.