Professor of Medicine, Bone Marrow Transplantation & Leukaemia
Washington University School of Medicine
Ravi has practised hematologic oncology for 20+ years. His main research interests are in multiple myeloma and AML/myelodysplastic syndromes. He serves on numerous committees including the International Myeloma Working Group (IMWG) the Core Transplant, Myeloma and Leukemia Committees of the CALGB and Steering Committee of the Multiple Myeloma Research Consortium, and the Myeloma Committee of the BMT Clinical Trials Network (CTN).
Section 1: Current SCT Therapy
1.1. How would you describe the current SCT patient journey?
Obviously stem cell transplants are done mainly in tertiary care centers. So very few community hospitals have access to stem cell transplantation facilities. Some that do, do primarily autologous stem cell transplants, which are much less challenging. However, the vast majority of the allogeneic transplants and the autologous transplants take place in tertiary care centers. The fact is that there’re roughly about, the data that we have available from the CIBMTR, which is the repository of transplant information in the United States, suggests that as of 2018, they don’t have data. I think more recent, there were roughly about 14,000 odd autologous transplants and 9,000 odd allogeneic transplants being done in the United States. The fact is that what we have seen is a shift to our older patients, both for autologous and allogeneic transplant. This is primarily driven in autologous transplant by very supportive care and by an allogeneic transplant by the use of reduced intensity conditioning regimens that started getting popular about now nearly 15 to 20 years ago, and now form the transplant conditioning regimen for two-thirds of patients in the United States.
Now, what we have seen also is that there is a growing number of haploidentical transplants being done in the United States. Nearly 20 to 25% of all allogeneic transplants are now haploidentical, that means half matched donor transplants. That is one of the main two sources of alternative donor transplantation.
Cord blood transplantation, which has started growing in number before haploidentical transplants really took off, these have now really come down in number and it’s mainly done in pediatric institutions and few adult institutions that have a research interest in cord blood. Otherwise, even randomized trials published recently have shown that a haploidentical transplant outcomes seem to be better than cord blood transplants in adult patients. I think that the number of haploidentical transplants will continue to grow still and more so will increase total transplant activity worldwide because there in other parts of the world, I know you’re wanting to focus on U.S., but just to say that in other parts of the world, unrelated donor transplantation has been holding back the growth of allogeneic transplant because there aren’t too many minorities in the unrelated donor registries.
With this now, nearly everybody has a parent, any brother or sister or any child could be a transplant candidate. What we’ve also seen is that the use of peripheral blood as a source, which is now responsible for about 85% of related donor and 80% of unrelated donor, and about 70 to 75% of haploidentical transplants. So that bone marrow as a source is not as common. It is more common in children who are metabolic errors of are often the reason to do a stem cell transplant. Whereas it does the vast majority of transplants are done for malignant disorders.
The number one indication in adults used to be, 25 years ago, CML. Now obviously we hardly do any transplants for CML. It’s mainly for acute myeloid leukemia. Number one, by far, the number one indication. Then a distant second, would be myelodysplastic syndrome and acute lymphoblastic leukemia and then those smaller numbers, perhaps for non-Hodgkin’s lymphoma.
In the era of autonomous transplantation, the vast majority, I would say 75% of autologous transplants are now done for myeloma. The number of transplants being done for non-Hodgkin’s lymphoma has decreased as better therapies have become available, and fewer patients are in the need of a transplant. Also, I think in the future, as CAR T-cell therapies show more promise it is possible that those numbers will dip lymphoma even more.
I would say the other trends have been that with the use of reduced intensity conditioning regimens, that the treatments that we use prior to transplant have changed. They’re less total body radiation-based treatment, and the drugs used for conditioning have also changed. For that, Busulfan is probably the most common conditioning regimen today. Whereas in the past it used to be Busulfan and Cytoxan.
I would say the trends have also shown that the outcomes of related donor and unrelated donor transplant are nearly superimposable, and increasingly data is suggesting that haploidentical transplant results are coming close. Though I think that the quality of life for patients who want to go haploidentical transplant is worse, that doesn’t often get captured in the survival curves.
I would say that the big advances for allogeneic transplant were still 10 to 20% of people die due to transplant related causes would be to better manage graft versus host disease, primarily acute, and some extent chronic. I think infections, we can also do a better job at, but I think the major benefit will come if you have very graft versus host disease treatments. But again, both autologous and allogeneic transplant, the number one cause of mortality is still disease relapse and trying to employ strategies to reduce disease relapse is very important.
With reduced intensity transplantation, it is now responsible for two thirds of allogeneic transplants. Reduced intensity transplant just refers to the intensity of the chemotherapy and radiation that is given to allogeneic transplant recipients. So, the fact is that all autologous transplant has to be myeloablative, but reduced intensity transplants and allogeneic transplant recipients reduces the toxicity, the treatment related toxicity at the cost of higher disease relapse. It is as much art as it is science to where to employ reduced intensity trans conditioning regimen and where to use a fully myeloablative regimen. Generally reduced intensity transplants are done, the older you are, the more likely you’re going to do a reduced intensity transplant.
If your disease is in complete remission, then a reduced intensity transplant is probably the way to go. For low grade malignancies where unlike acute leukemia, some of the chronic lymphomas, the chronic leukemias, reduced intensity transplant is probably better because of those diseases, you don’t have often very rapid growth of the cancer. In reduced intensity transplant, what you’re relying more on is the immune system of the donor attacking the cancer in the recipient and less reliant on the conditioning regimen that you’re giving the patient before the transplant. So, if your low-grade malignancies not growing rapidly and the immune system, the donor has time or weeks and months to reallocate the disease. Whereas if you have an acute leukemia patient, who’s especially not in a remission, reduced intensity transplant is not going to be worth it because you really need the power of the chemotherapy and radiation. You’re exposing the patient to be maximized, because if you rely on the immune system in order to do the job, the cancer will probably relapse before the immune system can kick it.
1.2. What are the main bottlenecks in the SCT patient journey?
I think that the bottlenecks, first of all, it would be some patients don’t get referred from community doctors. I think a lot of community doctors assume that a patient is not a candidate for transplant because of their age and don’t refer patients. Also, community doctors have, some also have a bias against stem cell transplant, perceiving it to be a harsh therapy.
I would say that after that, obviously you need to have a patient in good performance status and lack of comorbidity. So, some of those patients fall off because they don’t have a good performance status. They have got other health related issues.
Then you need to have insurance to do transplant, and a few patients, fall off because a lack of insurance coverage for transplant. It’s a minority that face that bottleneck. In the case of autologous transplants, some people fall off because their disease doesn’t respond to pre-transplant treatments, which is important because taking a patient with disease is not responding to pre-transplant treatment usually does not help taking the patient to transplant in that condition.
A few patients for autologous transplants, you are able to not collect enough stem cells for the transplant procedure. That’s not as big a problem today as it used to be a couple of decades ago, because you have better growth factors, but still a few people may not be able to collect enough stem cells.
So those are, I think the major bottlenecks. Then, as I said, an allogeneic transplant, one of the major barriers has been the lack of availability of a suitable fully matched donor because only 25% of individuals have a related donor. So, you have to rely solely match to donor. In the past you had to rely totally on unrelated donor registries. They’ll find donors for the rest of the 75%. Now, however, as I said, with the ability of haploidentical transplant, that bottleneck is starting to ease significant.
Section 2: Future of SCT Therapy
2.1. How will the patient journey for SCT change in the future?
Well, I think that the modality has been long enough that I don’t see any dramatic changes in referral patterns or anything. I think that, yes, you continue to educate the community, continue to hold CME programs. But I think, I don’t see any major change in referral patterns. Now, the only thing I would say is that with the increased use of CAR T-cells, which is also something that transplant programs are the ones usually offering now, there may be some more patients that get referred for CAR T-cell or that did not earlier see you. Now, as far as that goes, yes, CAR T-cells are, I think going to take away some patients, especially patients who are having their autologous transplant for lymphoma. If the second line trials of that have been done, but not yet reported of transplant versus CAR T-cells, and second line for diffuse, large B-cell lymphoma readout, and they are positive, then you will see a further dip in the number of autologous transplants for lymphoma.
We’ve already seen nearly a 50% decline in autologous transplants for lymphoma because of better drugs and CAR T-cells could further accelerate that decline. Plus, there are other, better drugs coming along in the pipeline. Now, in myeloma too, there are better drugs coming along, no doubt about it, but most of the drugs in myeloma are not curative therapies. So at least historically, and I think in the immediate future, the thing that will most likely happen is that these new drugs will be incorporated into the transplant paradigm before and after transplant, rather than replacing transplant within the five-year timeframe. Now in the future, you know, 10-year timeframe, would transplants in myeloma decrease, I would say so. I think that again, CAR T-cells by that time may start moving up into earlier lines of treatment in myeloma and reducing the number of patients that go to an autologous transplant for myeloma. That won’t happen in the three- to five-year timeframe, I doubt it.
I think that in the case of allogeneic transplants, certainly again, better drugs are becoming available for patients, especially with acute leukemia, that form the number one indication for allogeneic transplantation. But in AML, at least, none of the treatments that I have seen have the ability to cure. They are better bridges to an allogeneic transplant. So possibly the number of allogeneic transplants may at least transiently increase as you, A, have more people go into remission with better therapies that can then be helped with an allogeneic transplant, and B, as we said, the real increase in availability of haploidentical donors is probably still going to push the number of people going to allogeneic transplant for KML.
Now, ELL, which is the number two indication perhaps in adults, there are certainly some potentially curative therapies that are coming into frontline. Blincyto and Besponsa, that have been approved in later lines, are slowly showing, especially in some of the demographics of patients. Plus the tyrosine kinase inhibitors are also in combination with chemotherapy and these new drugs, showing that fully positive ELL, which is about 25% of adult ELL, and is disproportionately represented among the transplant group because more people historically with fully positive ELL all have gone to transplant may start dropping. Because these early data seem to suggest, it’s not foolproof data yet, but the early data seem to suggest in ELL that we may be able to cure more people with traditional, not traditional but novel agents that we have so far used only later lines of disease.
I don’t see anything curative coming along. It’s going to be, I think we’ll have better bridges to transplant. Plus, I think that in MDS, historically, it’s a disease of older individuals And CMS, which is what the insurance that most of these individuals have historically never covered allogeneic transplant for MDS. Now for the last five to 10 years, they started saying if you are on a trial, that we will cover it. So that’s how most people got transplanted. I think going forward, as the data has suggested from these trials, that CMS wanted us to do, that we can cure patients with MDS, even at older age. Perhaps CMS will start covering allogeneic transfers for MDS, that may then lead to, I wouldn’t say a floodgates opening up, but will probably lead to an increase in transplant activity for MDS as well. Other than that, I don’t see any major trends in disease state, how the disease states are going to be treated, that I can think of.
2.2. What oncology indications will see future SCT treatment?
I think that most of the things that happen in the field of transplantation are incremental rather than transformative, but I think that better treatments for graft versus host disease are probably coming along. I think we’ve made a dent with JAK inhibitors already, but we are going to have greater approval based on some of the recent trials. For now, for JAK inhibitors and other indications and potentially other drugs that are showing promise. I think that people are looking at other technologies to expand stem cells. That is primarily, I think, relevant to cord blood transplantation. I am a little skeptical that these technologies, even though they may be successful, will lead to a surge in cord blood transplants. One of the limitations of cord blood transplantation that prevented its adoption in adults was the limited number of stem cells that you have in a cord. For a child, you find enough stem cells in one cord. For anybody less than 50 kilogram in weight, it’s okay but most adults are over 50 kilograms and historically require two cords to get them through the transplant. New technologies are trying to expand the number of cells in a single cord.
As I said, I think some of them at least will succeed, but again, it may be for pediatric transplanters in the future when, but I doubt seriously that adults will start going back to what blood transplants. They never did adopt in a big way, but there was at least an interest in it 10 years ago that has waned with haploidentical transplants. Then people are going to stick with haploidentical transplantations.
2.3. Is there going to be a shift there in the hospitals that can carry out stem cell transplantations?
I doubt there’s going to be a major shift. Now, the thing is that doing transplant requires you to be accredited by the FACT organization, which is the organization that accredits transplant centers in the United States. Literally no insurance will pay for a transplant in a center that is not accredited by FACT. FACT accreditation is not a simple procedure. It requires a lot of investment in quality assurance and other SOPs. To get FACT accreditation at the beginning, you have to have your institution swallow the cost of doing, like, 10 allogeneic transplants and 10 autologous transplants free of charge, because you got to do it without insurance paying for it and then generate the data to give to FACT, and then they get accredited, and then insurance will start paying for it. So, I don’t think that that is easily going to happen.
Now, one of the things is that CAR T-cells, again, people want to give in the community, and will some centers be motivated to invest for CAR T-cells for FACT accreditation? I seriously doubt that’s going to happen. First of all, even for CAR T-cells, I think that the economics of CAR T-cells for inpatient use at least is not feasible for most organizations. Our CAR T-cell activity shifts in the future to outpatient, CAR T-cells are not going to be something that is going to be feasible in smaller centers. I think a lot of people feel that it’s a good marketing thing, and it’s prestigious to do. It’s what everybody advertises. When the CFOs get behind closed doors, they kind of are really leery about CAR T-cells and its inpatient structure right now.