Consultant Haematologist, Director of Adult Stem Cell Transplant Unit
Manchester Royal Infirmary UK
Eleni can share an expertise that covers a wide range of haemato-oncological malignancies (leukaemia, myeloma, lymphoma) and non-malignant disorders (bone marrow failures, aplastic anaemia). She is a member of the Haemato-Oncology Pathway Board at Manchester Cancer and national bodies such as the AML Working group and BMT Clinical Reference Group. She has authored and co-authored many publications around topics of haematopoietic stem cell transplantation including manuscripts book chapters and presented at several scientific congresses on the matter.
Section 1: Current SCT Therapy
1.1. How would you describe the current SCT patient journey?
So pre-COVID, there has been an increasing trend to actually do transplants in the ambulatory. The pathway of the patient would be, they need some pre-transplant investigations to be assessed to make sure that they are physically fit enough to actually undergo the transplant so they wouldn’t experience severe organ failure straight away.
The patients need to have an assessment of their key organs, to see if they’re deemed fit enough and they then proceed for the transplant. The transplant, pre-COVID would a week roughly of chemotherapy plus minus radiotherapy and then STEM cell infusion. On average, patients stay between three and four weeks in hospital, but we’ve been increasingly introducing ambulatory services.
This means doing the transplants ambulatory either through from their own home if they live nearby or close enough to the hospital to be representing in a quicker way. If they become poorly or if they are at home or if they’re too far away and they can’t stay at home, we do have for example, studio apartments or sometimes other hospitals commission hotels nearby. So, there you’ve got a very big ambulatory service where patients come and go on a daily or every other day basis and provided, they’ve got the care, they can stay near the hospital and receive their treatment and close monitoring. Increasingly we’ve probably been doing the ambulatory side, but COVID has put a bit of a halt to it. People do less ambulatory at the moment with COVID just because of the frequency, in and out of the hospital is challenging. When you need readmission at the moment, it’s a bit chaotic.
1.2. What indications is SCT currently used for?
They differ in terms of indications or the diseases you’re trying to treat. So, an autologous stem cell transplant would be indicated in multiple myeloma. It’s not curative there and it’s also indicated in relapsed lymphoma and it’s curative there. For myeloma for example, it’s not curative, so the disease will relapse. You can do a second transplant at some later point and for the lymphomas, it would be a one-off treatment and curative intent. For that process, you need to collect the stem cells of the patient first, freeze them and then the patient comes in, undergoes chemotherapy, and then gets their own stem cells given back.
The mortality is low or relatively low for the autologous transplants and they’ve got less complications. It’s really a bit similar to high-dose chemotherapy for a month. Then you actually recover after that. Whereas for the allogeneic transplant, it’s quite a big undertaking. It doesn’t quite finish at the time of discharge after engraftment you need to come quite regular back to the hospital. It’s more intense for the patient and the mortality is higher.
An autologous transplant has got a mortality at one year of less than 2%, whereas an allogeneic transplant, the lowest would be 10%, but it ranges up to 30 to 40%, so it’s a big difference The aftermath, so the aftercare is a lot more intense. After the transplant, you need to return back to the treating center once to twice weekly for a significant period before you can be followed up less frequent and there is often complications occurring. You get readmissions because of a type of infection for graft versus host disease or other post-transplant complications. It’s a lot more intense and it’s indicated primarily for acute leukemias for example, and in some lymphoma, some myelomas it’s very rare, but it’s primarily used for acute leukemias or aplastic anemia.
There is also syngeneic transplantation that can be done. It means you’ve got an identical twin and again, it depends on the diagnosis because in some diseases and if it runs in the family, there may be difficulties. You can’t use them for example, for a myeloid condition, you can’t use the syngeneic donor because, and it’s only possible if it was the identical twin. So, they need to have an identical twin first of all, and you need to confirm that they are identical twins and not just ordinary siblings. In myeloma it’s particularly good because it would be the reason why myeloma often relapses, there’s a theory that you’ve got contamination of the cells, with the underlying disease.
If you give them clean stem cells from somebody who is identical to them, that means you don’t have the risks of the allogeneic transplant, but the cells you give them are absolutely squeaky clean the chances of a cure or long-term remission are a lot higher. It’s very much done if there’s an identical twin present in myeloma for example, but you never would use it in myeloid conditions or aplasia or something, because they could be a link within that identical twin because they are identical twins. Something in the genome is faulty somewhere deep down in that sense. Whereas plasma cell disorders or myeloma are usually a defect at a later maturation stage of the lymphocyte for example, not at an early stem cell stage.
1.3. What are the main bottlenecks in the SCT patient journey?
I think the bottlenecks are to get first of all, through the inpatient stay, the intensive treatment because that’s obviously the worst period where there are the ills, because they get low blood counts, they get severe infections, they get a sore mouth, diarrhea and they’re out of their own comfort zone; they are in hospital it’s quite intensive treatment. So that’s probably the first bottleneck to get through, their inpatient stay and engraft. That means the stem cell transplant sets in and it’s working and it’s producing healthy bone marrow and blood, so they don’t need any more blood transfusions. So, the first hurdle is to get to the engraftment stage and be well enough to go home. Then the next hurdle will probably be six months, a year, two years, and then five years.
For the allogeneic, it’s a six-month period because that’s the time when you stop the anti-rejection drugs. Typically, the patients following a donor transplant are on an anti-rejection drug to stop the extreme reactions between the donor and the recipient. So, they engraft, and they don’t develop graft vs source disease. The issue there is that quite often around the time when it’s coming to reducing the immune suppression, either they can get graft versus host disease, or they can get early signs of disease relapse. In terms of disease relapse, usually the disease relapses within the first, for those who relapse, the majority of them will relapse within year one. That is why it’s the next hurdle to get over year one, when they get over the highest risk of relapse. Then the other thing is they come off the immune suppression and they’ve not developed graft versus host disease; that’s a big plus.
Section 2: Future of SCT Therapy
2.1. How will the patient journey for SCT change in the future?
I think for the next five years, we may be reducing the autologous transplants in myeloma. Certainly, we will probably be reducing the second autologous transplants in myeloma, just because they’re non-curative and there are new drugs coming on the market. There are CAR T therapies coming on the market, and so we will probably see a reduction in the myeloma autologous transplants. Whether they’ll be completely replaced I doubt it.
It was one of the breakthrough treatments, but things have moved on since. We’ve got novel drugs and in light of the novel treatments, including the cellular therapies, which seems very promising and third-line, and possibly will be even more promising and second line, it may just be that the treatment algorithm will change a little bit; that’s what I anticipate. I can’t see a cure with acute myeloid leukemia, other than anything like a transplant in the next five years; I think that will stay. The allogeneic donor transplants they will primarily stay, because there isn’t anything else which is competing at the moment with them. Maybe in 10 years’ time, there will be a shift but not in the next three to five years.
So, we use autologous transplants in lymphomas at first relapse at second line. If CAR Ts get licensed or approved to be used in second line over the next five years, again, we will probably see a difference there. We will probably move towards CAR T rather than the autologous transplants, if the data adds up to it, just because it’s less toxic. The autologous transplants are very toxic for lymphomas. In terms of the side effects, in terms of the chemotherapy and the experience of the patient and the time in hospital spend, it’s a lot more intense than the myeloma transplants or the CAR T cell therapies.
2.2. What oncology indications will see future SCT treatment?
You can do autologous transplants for non-malignant conditions. You can do it for severe crones, multiple sclerosis, scleroderma, some rheumatological conditions, chronic inflammatory bowel conditions and neurological inflammatory conditions. The indications are but the challenge is in terms of it’s a difficult one, you do need to get and work together with your colleagues in the other specialties. If they are not keen or particularly interested in involving you or referring them to you, that’s the challenge. It’s about convincing the other guys who are not involved it usually with a stem cell transplant. The indications are there, we can use them, but we don’t often get the referrals. Some centers have sort of a refined referral pathway, but quite often we don’t get that.
Regarding the manufacturing capability for autologous transplantation I can imagine I the future it being on major hospital sites for example, rather than it going to what is a central lab that then distributes these stem cells out for all the individual hospitals.
I think we’ve got the staff because we collect them, and we freeze them. You don’t produce the stem cells so it’s a more established service. No, we could easily set up the manufacturer of CAR Ts. It’s just it’s a new field and somebody needs to have time to look at it, plan it and concentrate on it. Once it’s done, it’s done and then the processes are rolling. That wouldn’t be a problem. It’s just every beginning, but obviously I’ve come into the transplant unit here whilst it was all already set up, so I didn’t need to start from scratch. The processes are a little bit more simplified you don’t play around with viral vectors.
There are some new clinical trials on the horizon as well. We were doing a lot more haploidentical transplants which are easy. We have had the NiCord study where we used its cord blood transplants where you do an expansion of one of the cord blood units gets expanded in vitro and then infused into the patient. We’ve done that for example, and I think that’s getting on the market somehow or it’s trying to get into the markets. I think at the moment, it’s possible to find a donor. When we are talking about donor transplants, in the majority of cases, we are able to identify a donor. I have not had a case where we couldn’t find a donor, or we didn’t have a donor between haplo and cord blood. If we are failing to get an unrelated or sibling donor, we always have found a donor than resulting to haplo and cord blood transplant.
2.3. Is there an emphasis on outpatient vs. inpatient SCT therapy?
I would be quite keen to do a lot more in outpatient. I don’t think everything could be moved, but I think a significant proportion can be moved ambulatory once we’ve got a handle on this COVID pandemic and I think it is possible. I think that’s a move everybody’s driving towards actually in the UK particularly because we’re getting a lot more new therapies. Gene therapy coming on the market, some complicated cellular therapies that you want to actually have your inpatient sections only for those very complex cases who can’t be done or those who get readmitted with complications or with some infections. So, I think that is possible and there is a move and a drive to do that. It’s just how each center structures, it might be slightly different and may depend also again on the kind of investment they get from the trust let’s say.