Cranial radiation mostly eliminated in children with T-ALL and bortezomib potentially improves survival in children with T-LL

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Published: 6 Dec 2020
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Prof David Teachey - The University of Pennsylvania, Rutledge, USA

Prof David Teachey speaks to ecancer about the COG trial which was recently presented at ASH 2020.

The topic of this study was ‘Cranial radiation can be eliminated in most children with T-cell acute lymphoblastic leukaemia (T-ALL) and bortezomib potentially improves survival in children with T-cell lymphoblastic lymphoma (T-LL): results of Children’s Oncology Group (COG) Trial'.

He first gives the background of the trial and then talks about how it was carried out. Then Dr Teachey spoke of the key results saying, outcomes for SR and IR patients with T-ALL and T-LL treated with bortezomib were excellent despite the elimination of prophylactic CXRT.

Bortezomib significantly improved 3-year EFS for these groups, comprising ~95% of patients. Outcomes for VHR patients were dismal and worse on the bortezomib arm.

T-LL patients had signitrial backbone. In the end he talks about how this study can impact the future treatment of paediatric T-cell lymphoblastic lymphoma.

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.

The main goal of this trial is to do a number of things. It was, one, to randomise patients with T-cell acute lymphoblastic leukaemia and T-cell acute lymphoblastic lymphoma to receive or not receive the proteasome inhibitor bortezomib on a modified augmented BFM backbone. This was children and young adults. The cure rates for children and young adults with T-cell leukaemia and lymphoma have improved dramatically over the past 70 years but there are still some patients that are not cured and most patients who relapse are not salvageable. So one of our goals in the Children’s Oncology Group has been to move new therapies to the frontline through promising preclinical data, good biologic rationale and data in the ALL07P1 clinical trial in relapsed T-ALL or T-cell lymphoblastic lymphoma suggesting bortezomib was promising.

So the primary role of the study was to move bortezomib to the frontline and randomise patients to receive or not receive four doses of it in two different blocks of therapy. Another major goal of the trial was to try and eliminate cranial radiation in the majority of children. On the predecessor trial to this trial, ALL0434, and a lot of trials throughout the world, children with T-cell leukaemia and lymphoma receive cranial radiation which has a lot of long-term side effects as well as short-term side effects. So we changed the chemotherapy backbone with the goal of eliminating radiation.

How was this trial conducted?

It was a COG initiated clinical trial that was opened at COG sites and centres in the US and then also centres in New Zealand, Australia, Canada and a few places in Europe, over 200 centres.

What were the key results?

A couple of things that we’ve found so far; first, I’d just like to highlight that these are three year results so we need to see how much they hold up with longer time. We found that bortezomib had a trend towards improved survival benefit, both EFS and overall survival, in patients with T-cell lymphoblastic leukaemia and lymphoma. If we looked by disease type, breaking it down to leukaemia and lymphoma, we found there was a survival advantage, both with event free survival and overall survival, in the lymphoblastic lymphoma subjects.

We also found the overall outcomes for patients we defined as standard risk or intermediate risk on the bortezomib arm were extremely good. Patients with very high risk disease did very poorly and that was defined mainly based on having a refractory chemotherapy, defined as in consolidation MRD being positive in the T-cell lymphoblastic leukaemia patients or having a poor radiographic response in the T-cell lymphoblastic lymphoma patients.

We did find if we compared similar patients on that trial to the predecessor trial who received radiation on the predecessor trial and did not receive radiation on the new trial, the one that we presented in ASH, that we were able to successfully eliminate radiation in those patients because outcomes were similar.

The one thing we also saw was that as we intensified therapy overall the overall survival on the current trial comparing all patients to the predecessor trial was a little bit worse. Interestingly, the event free survival was not. So we really need to follow-up a little more time to know which of those will hold true – is it both the event free survival and overall survival were slightly worse on the current trial or with time will it turn out that they’ll be similar – and  we’ll just have to follow that with time.

So the big conclusions were bortezomib is a potentially active agent in T-cell lymphoblastic disease, especially T-cell lymphoblastic lymphoma, and that you can eliminate cranial radiation in most patients with T-cell leukaemia by modifying your backbone.

How can these results impact the future treatment of paediatric T-cell lymphoblastic lymphoma?

We’re going to have to see if they hold up with time. If they do then it may be that we move to a world where bortezomib becomes standard of care for newly diagnosed patients with T-cell lymphoblastic lymphoma. The control arm on the T-cell lymphoblastic lymphoma compared to the prior trial did worse so we need to figure out why the patients who did not receive bortezomib did worse than the predecessor trial. But the difference in survival between the two arms on the AALL1231 trial was pretty striking so if it holds up with time it may change the standard of care.

The only way to have trials like this be successful is through large international cooperative groups that bring centres together to try to ask questions in rare populations.