Issues in allogeneic HSCT: Therapeutic options for post-transplant relapse

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Published: 24 May 2019
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Prof David Marks - University Hospital Bristol, Bristol, UK

Prof David Marks talks to ecancer at the European School of Haematology (ESH) meeting: International Conference on Acute Lymphoblastic Leukaemia about the main problems clinicians and patients face after a haematopoietic stem cell transplant (HSCT) is given and the options available to treat this.

Prof Marks reviews data about the therapeutic options available in the post-relapse setting - which includes administering a second transplant and CAR T-cell therapy.

He also describes the risk factors that are associated with an increased risk of relapse in these patients and the role of maintenance therapy to reduce this risk.

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.

I was given a quite challenging topic of post-allograft relapse of acute lymphoblastic leukaemia. First of all what I did was talk about the extent of the problem. It occurs in about somewhere between 10% and up to 60% of patients and we know it has quite a poor outcome. I then went through the data from UKALL14, our recently completed national ALL trial and, in essence, there were about 350 patients had allografts, two-thirds reduced intensity, one-third myeloablative. Of those 359 patients 73 had relapsed and I looked at their outcomes. It occurs about nine months post-transplant and essentially about 40 of them had intensive therapy and half of those patients achieved a further remission but the average survival from relapse was 6.7 months, so quite bad.

Then I, with broad brushstrokes, said that there were two goals you might have in a person you’re aiming to treat intensively. The first is if you are trying to get them to CAR T-cells, what you are aiming to do is obviously keep them reasonably well. You don’t have to get them into remission and you need to preserve their T-cells. Or, alternatively, if you’re going for a second transplant you do need to give them therapy to get a deep remission but also keep them well.
So that brought me on to talking about one of the therapeutic options – a second transplant. I looked at the data and really there isn’t a lot of data out there. There’s some recent data from Anthony Stein just out in Biology of Blood and Marrow Transplantation that has about 30% survival with fairly short follow-up. There’s some data from Italy where the survival is really poor, less than 5%. So with that uncertainty in data what I suggested is there be some minimum requirements for doing a second transplant – that the patient be fit, that they be in a very deep remission, the relapse not be very early and then having an excellent quality donor.

Then the other alternative, if you like, the new kid on the block, is CAR T-cells. We have some good data in children and young adults but much less data in adults. It’s a more toxic therapy, it’s probably a slightly less effective therapy but with limited data we perhaps have about 30% two year survival. So we need a randomised trial, we need a trial that shows, hopefully, that CAR T-cells are better than the alternative therapies. Novartis are hoping to do a trial called OBERON but it’s run into some regulatory issues and the detail of the trial is still up for debate. But we must do that study and we’ll learn so much from it.

Then, finally, I reviewed all the CAR T-cell data, especially the paper from Jae Park of Memorial Sloan Kettering. But the issue with that CAR T-cell study is that it wasn’t a persistent CAR T-cell, it lasted for only 14 days and then they had to do a transplant in many of the patients. That’s not satisfactory and it isn’t really applicable to most of our practices because using, really, our two most effective therapies and then only having a moderate success rate, that’s not really where we should be aiming.

Finally, and although it’s a slightly grim thing to say, I talked about the patients who relapse after an allograft, the possibility of them having palliative care should be discussed because intensive therapy is not for everybody. There are some subgroups of patients that probably won’t benefit from intensive therapy.

Are there any other risk factors associated with an increased risk of relapse in these patients?

There are quite a lot. All the risk factors that predict relapse with chemotherapy also predict relapse after a transplant, so high white cell count, adverse cytogenetics, being minimal residual disease positive, they all predict. But with the transplant what we now know, and it was something I discussed, is that the graft versus leukaemia effect is very powerful and very important in preventing relapse. A recent paper out in Blood Advances by Moshe Yeshurun, just out earlier this year, shows very clearly that if you get mild acute graft versus host disease you have better survival, you have less relapse. So that’s a goal for all of us – to do a transplant where there’s mild graft versus host disease.

Is there a role for maintenance therapy to try and reduce the risk of relapse?

The only maintenance therapy that there’s good evidence for now is using tyrosine kinase inhibitors after transplant for Philadelphia positive ALL. Standard use of imatinib, although it’s hard to get in, it probably does reduce the chance of relapse.