This is an area where I was very grateful to Nick Kroeger and John Gribben for being given an opportunity to talk about the importance of prospective randomized studies in stem cell transplantation. We need to be thoughtful that in our routine clinical practice in hemato-oncology new therapeutic interventions are almost without exception evaluated in prospective randomized trials, and they’re not adopted really until the results of those trials are available...
This is an area where I was very grateful to Nick Kroeger and John Gribben for being given an opportunity to talk about the importance of prospective randomized studies in stem cell transplantation. We need to be thoughtful that in our routine clinical practice in hemato-oncology new therapeutic interventions are almost without exception evaluated in prospective randomized trials, and they’re not adopted really until the results of those trials are available. And yet in stem cell transplantation, despite the fact that more than 50% of patients are destined to have poor outcomes either because of transplant toxicity or disease relapse, the number of patients going into prospective randomized studies aimed at asking how we deliver the transplant more effectively is less than 10%, possibly less than 5%. And that’s a really big gap. That means that we are adopting changes in transplant practice which have profound implications for patients without prospective data, which was otherwise being viewed as the gold standard. And also, I think it means that patients’ outcomes are not being informed by the high-quality integrated genomics and MRD studies that you can only deliver in a prospective study.
So if we’re trying to drive forward improvements in transplant, there was a consensus pretty much in the UK about 10 years ago that we needed to set up a transplant trial platform. And thanks to the generous support of Anthony Nolan, NHSBT, and LUCA, we’ve done that. And in the last four years, using the 3.4 million grant, we’ve opened 21 centers. 11 of these centers have funded research nurses. We’ve funded a trials delivery infrastructure, and we’ve been able to open seven studies. So those seven studies are asking pivotal questions prospectively in a randomized format, about the benefit of prophylactic DLI in patients with mixed T-cell chimerism after an allograft AML. PRO-DLI is led by Victoria Potter. And a randomized study of reduced-intensity condition regimens in ALL RIC, led by my colleague David Marks. Looking at two different strategies for GvHD prophylaxis including an evaluation of post-transplant cyclophosphamide, MOTD led by my colleague Ron Chakraverty. And a couple of studies that are looking at optimizing transplant interventions in AML, that COSI study looking at the benefit of addition of CyTBI, and AMADEUS, which is a randomized study of CC-486 maintenance. And then finally, a really important study led by my colleague Adrian Bloor in Manchester, which is looking at a treatment now, randomization. He used lenzilumab, a study called RATinG.
So these studies are actually defying the conventional wisdom that transplant studies don’t accrue. These studies are accruing, and they’re accruing rapidly, and we’ve now got 1,004 patients randomized to these potentially practice-informing centers. At the same time, they’ve got integrated MRD and genomic studies led by a number of gifted scientific colleagues, including Sylvie Freeman and Paresh Vyas across the UK. So I think taking together the impact initiative shows that providing you create an infrastructure and you overcome the blocks, typically research nurses but also a facilitator infrastructure for trial development by gifted investigators, there’s a great appetite among transplant physicians and also patients to enter such studies. They drive transformational studies on prospective cohorts in terms of scientific output. And I hope that they’ll be able to inform clinical practice, not only the UK, but worldwide.
I think the challenge now is to create a sustainable infrastructure, and we’ve created the model using a trials delivery vehicle called Accelerating Clinical Trials which is now open, which we believe will be sustainable delivering a mixed portfolio of industry-sponsored trials and academic ITs. And I think also invest further in the research nurse network in the UK, and thinking about opening up more centers with dedicated research nurses. And then finally thinking about how we can do this across Europe, or how we can do this linking with other countries. And I think also saying to governments, “It’s pivotally important we deliver these studies. Please, can we look at removing the barriers that there are in terms of regulatory holdup, regulatory obfuscation? And also, please, can we prioritize funding for research nurse networks such as the USCTN, so that across Europe we can be driving pivotal studies that are broader, bigger, to improve outcomes for patients having a transplant? It’s just unacceptable that, having invested trillions into basic science, now we come up with plausible interventions with the potential to transform outcomes, that clinical trials are so challenging to set up and accrue to. But, nonetheless, we’re really heartened by our experience with the IMPACT Consortium and the platform. We believe that ACT going forward will be a model to deliver prospective studies using a similar model in transplant and cellular therapy. And we’re immensely grateful to our supporters, which include Anthony Nolan, LUCA, NHSBT, and CureLeukemia. The future must be, as well as doing retrospective studies, in delivering prospective randomized studies with enhanced pharmacovigilance. And I think our experience in the UK has given us some insight into how that may be deliverable.
