Role of allogeneic HSCT fading in lymphoma management
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As targeted therapies and novel treatments emerge, allogeneic hematopoietic cell transplantation has taken a backseat to immunotherapy in the treatment of lymphoma.
Healio spoke with Courtney Bellomo, MD, a hematologist and stem cell transplant specialist with New York Oncology Hematology, a private, community-based oncology practice in the Albany region of New York, and a HemOnc Today Next Gen Innovator, about the history of the use of allogeneic HSCT, where the treatment fits into the current treatment landscape for lymphoma and more.
Healio: How has allogeneic HSCT been used historically in the management of lymphoma?
Bellomo: Allogeneic HSCT is truly for patients with relapsed/refractory lymphoma. Patients who do not respond to conventional chemotherapy and who also do not respond to autologous HSCT are the patients who have typically been treated with allogeneic HSCT in the past. The exception to that are the patients with T-cell lymphomas, which can be aggressive right from the get-go and for which we sometimes bypass autologous transplant. The chemotherapy-resistant group of patients have been the ones to undergo allogeneic HSCT, typically in the third-line setting. We have also done this for our patients with lymphoma when autologous transplant was not effective as well as sometimes for those with mature leukemias.
Healio: Where does allogeneic HSCT fit into the current treatment landscape for lymphoma?
Bellomo: Chimeric antigen receptor T-cell therapy is changing the treatment paradigm. Follicular lymphoma is a great example of this. The patient who is on third-line treatment for follicular lymphoma probably would be considered for allogeneic HSCT. We know that most follicular lymphomas are indolent, but about 20% have frequent relapses and behave aggressively and those patients would have been treated with autologous HSCT which would still happen. But now, instead of an allogeneic HSCT, we are looking at CAR T-cell therapy for these patients and the side effect profile of those two treatments are very different. CAR T-cell therapy may leave a patient with long-term pancytopenia or hypogammaglobulinemia, which are much more manageable than graft-versus-host disease, which may arise with HSCT. There is a role here to “shuttle” people away from that. CAR T-cell therapy is also going to change the paradigm of when we use autologous HSCT. For a third-line follicular lymphoma patient who has undergone a lot of treatment, maybe we would have thought about an autologous transplant for them in the past, but now they are eligible for CAR T-cell therapy. This is how the paradigm is changing in the indolent lymphomas. In the aggressive lymphomas, we were always kind of doing allogeneic HSCT in hopes that it worked, but we knew for a lot of people that did not work. So now we have a good option for them. CAR T-cell therapy is changing not only utilization but also how we discuss prognosis with patients.
Healio: Immunotherapy has significantly altered treatment for lymphoma, particularly diffuse large B-cell lymphoma. Does allogeneic HSCT still have a role in DLBCL?
Bellomo: I am honestly not sure that it does — it is an unanswered question at this point. In general, we are treating these patients with CAR T-cell therapy and if they relapse after CAR T-cell therapy, then we do have more options, including targeted monoclonal antibodies or bispecific antibodies on the market now. A lot of people are hopeful that we could get these patients to allogeneic HSCT, but most do not make it that far. Patients who are ineligible for CAR T-cell therapy are ineligible for allogeneic HSCT. For those who relapse after CAR T-cell therapy, getting them to remission is difficult because allogeneic HSCT only really works for the patient who is in remission. From a science perspective, there is still the question of whether it would even work. If we manipulate a patient’s T-cell immunity and that does not treat their cancer, would someone else’s T-cell immunity still be effective? Our suspicion is yes, but we do not have an answer yet.
Healio: For which patients with T-cell lymphoma would allogeneic HSCT be a good option?
Bellomo: I do not think the treatment paradigm is changing for these patients because we do not have a targeted CAR T-cell therapy against T-cell lymphomas. For most systemic T-cell lymphomas, excluding cutaneous T-cell lymphomas, we are looking at a consolidative autologous HSCT upfront. For anyone who relapses, allogeneic HSCT is the path to go down if they are physically fit to do so and can get into remission.
For most T-cell lymphoma patients, treatment across the board in the front-line setting is only 40% effective and then only 20% to 30% at best effective for all other lines of therapy. This means that there is a 70% to 80% chance that we are not getting someone into remission. But that is still the pathway right now if someone relapses or they are not responding to chemotherapy — we get them to autologous HSCT. We can take them to allogeneic HSCT with a small burden of disease, but it will not work if they are disease significant amount of disease. It is a matter of how well they are doing on their disease course.
Healio: What strategies have been used to improve outcomes with allogeneic HSCT over time?
Bellomo: This is a tough question. We are constantly getting better at managing graft-versus-host disease from the newer therapies that are on the market, but in the way of the conditioning regimens and those changes, I am not sure.
Healio: What role do you think allogeneic HSCT will play in the future?
Bellomo: We will continue to use allogeneic HSCT, certainly for our leukemias, and more than likely for our T-cell lymphomas. We may continue to use it for chronic lymphocytic leukemia or Richter’s transformation because we know in the Richter’s transformation population that CAR T-cell therapy is not as useful.
The hard part will be determining its use once off-the-shelf CAR T-cell products become available. Right now, we are using the patient’s own immune system, but what happens when CAR T-cell therapy or other variations are allogeneic? Then, we may have minimal graft-versus-host disease but a different immune system and so we may be almost combining those two technologies. This is where I think it is going to be a bigger and tougher question for allogeneic HSCT. I would suspect that for leukemia, a full new reboot to the immune system with an allogeneic HSCT is probably going to be useful, but will the allogeneic CAR T-cells overcome an allogeneic HSCT in lymphoma? Maybe, but we do not have the science yet to have any idea what that is going to look like.
Healio: Is there anything else that you would like to mention for our readers?
Bellomo: It is going to be fascinating to see where all of this ends up. For example, for patients with myeloma, where is autologous HSCT going to fall vs. CAR T-cell therapy? What is CAR T going to look like regarding maintenance therapy for patients? Where is allogeneic HSCT going to fall if CAR T-cell therapy works well for leukemia at second relapse? Where are all these things going to be placed in a treatment discussion and how is that going to impact the timing of these treatments?
In general, a lot of the trials that have looked at cellular therapy have excluded people who have had an allogeneic HSCT — not all of them, but most of them. This is because there is a real concern about risk: If we turn on the T-cell immunity, will we create graft-versus-host disease in patients who had an allogeneic HSCT? It will not only be about use, but it will also be about timing because we do not want to activate the immune system and cause debility from graft-versus-host disease. Timing is going to be important as well as cost and utilization. All these questions remain.
Just recently, I asked a colleague from Dana-Farber Cancer Institute about a patient of mine, for whom we once administered an allogeneic HSCT, whether we are now taking them for CAR T-cell therapy. He said 100% CAR T-cell therapy. When CAR T-cell therapy is proving to be effective in myeloma and follicular lymphoma, for example, allogeneic HSCT will fall to the wayside. In places where CAR T-cell therapy may not be as effective, we may be still thinking about allogeneic HSCT, but then which should come first? This is still something that we are trying to figure out.
For more information:
Courtney Bellomo, MD, can be reached at courtney.bellomo@usoncology.com.
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