Stem Cell Transplant Holds its Position as Upfront Treatment for Hematologic Malignancies

Robert J. Soiffer, MD

Across hematologic malignancies, transplant is a modality that has been used for more than 40 years, according to Robert J. Soiffer, MD. Today, transplant remains the standard of care for many hematologic malignancies, but in the near future, chimeric antigen receptor (CAR) T-cell therapy may change that.

From non-Hodgkin lymphoma to leukemia and multiple myeloma, CAR T-cell products have been FDA approved, predominantly for treatment in the later-line settings.¹

In multiple myeloma, both idecabtagene vicleucel (ide-cel; Abecma) and ciltacabtagene autoleucel (cilta-cel; Carvykti) are FDA approved for the treatment of relapsed or refractory (R/R) disease after 4 or more prior lines of therapy, which includes an immunomodulatory agent, a proteasome inhibitor, and an antidCD38 monoclonal antibody.

For R/R large B-cell lymphoma after two or more lines of systemic therapy, FDA-approved CAR T-cell therapy options include lisocabtagene maraleucel (liso-cel; Breyanzi) and axicabtagene ciloleucel (axi-cel; Yescarta).

Finally, tisagenlecleucel (tisa-cel; Kymriah) is an FDA-approved CAR T-cell product for both R/R diffuse large B-cell lymphoma and young adult patients up to age 25 with R/R acute lymphoblastic leukemia (ALL). Brexucabtagene autoleucel (brexu-cel;Tecartuc) is FDA-approved for the treatment of patients with R/R mantle cell lymphoma and with R/RB-cell precursor ALL.

Even with all the available CAR T-cell therapies that have shown efficacy across hematologic malignancies, autologous and allogeneic stem cell transplant remains the sole curative treatment used in the frontline setting. Next-generation agents like CD19- and B-cell maturation antigen-directed CAR T cells could change the golden standard.

In an interview with Targeted Oncology™, Soiffer, the chair, Executive Committee for Clinical Programs, vice chair, Department of Medical Oncology, chief, Division of Hematologic Malignancies and institute physician at Dana-Farber Cancer Institute, as well as the Worthington and Margaret Collette Professor of Medicine in the Field of Hematologic Oncology, Harvard Medical School, discussed the evolving role of stem cell transplant in hematologic malignancies as CAR T-cell therapies begin to reshape treatment landscapes.

TARGETED ONCOLOGY: What was the role of stem cell transplant in the treatment of hematologic malignancies prior to the availability of CAR T-cell products?

Soiffer: We've been doing transplantation now for close to 40 years. There are 2 types of transplants. There is autologous transplantation which is someone who uses their own stem cells. Stem cells are taken out prior to the transplant, and they're usually frozen. And then we give the patient high doses of chemotherapy or chemotherapy and radiation and then infuse those stem cells back, like sort of a stem cell rescue. These transplants are typically done for diseases like non-Hodgkin lymphoma and multiple myeloma.

In terms of allogeneic transplant where we use someone else's cells, usually for a disorder where the bone marrow is heavily involved with a malignancy, that includes acute myelogenous leukemia and other stem cell disorders like myelodysplastic syndrome, and myelofibrosis.

The allogeneic transplants are more toxic than autologous transplants, they run the risk of causing graft versus host disease. But they play an important role in the treatment of patients with blood cancers. They have become part of standard of care for patients with hematologic malignancies over the past 3 decades, and their use has increased year after year. They've increased it to some extent, because we are now able to offer allogeneic transplant to patients who are quite older, up to their late 70s. Individuals who are relatively fit in the late 70s can undergo successful transplant. That’s opened opportunities which weren't open many years ago.

In addition, in terms of allogeneic transplant when we’re using a donor. When I started 40 years ago, we were limited to young patients who had siblings, brothers and sisters, who are identical. Over my career, we've been able to extend that to use alternative sources of stem cells, either unrelated donor stem cells as volunteers from around the world, who are selflessly willing to donate their metabolic stem cells to a stranger, or haploidentical transplant which is half-match transplants, using brothers or sisters, parents, or children. That’s due to some of the great work that’s been piloted out of Johns Hopkins and other institutions.

Transplant is still the only upfront therapy and therapy to achieve remission for many hematologic malignancies. Can you explain which diseases this is true for?

I’ll put it in the context of different settings. Let’s talk about a non-Hodgkin lymphoma. It is now considered, or it has been considered standard of care for patients with non-Hodgkin lymphoma who’ve relapsed after their initial therapy, particularly patients with large-cell lymphoma, to once they achieve a second remission move into an autologous transplant. And that's been able to result in cures anywhere between 40% and 60% of patients who are able to successfully undergo a transplant, and that's in the lymphoma setting.

In the world of multiple myeloma, autologous transplant again, using your own stem cells, is often used upfront. It may or may not really be a curative therapy, but it's certainly something that extends progression-free survival and allows patients to live for a long period of time without intervention.

On the acute leukemia side, and let's say marrow disorders like MDS, allogeneic transplant can be curative for a variety of these disorders. The likelihood of cure depends a lot on the molecular and genetic composition of leukemia itself. So, individuals with very high-risk leukemias will do poorly with standard therapy. They'll do somewhat better with allogeneic transplant. In patients with let's say intermediate-risk leukemias who do modestly well with chemotherapy alone, do even better with an allogeneic transplant.

What role does transplant play in the post CAR-T setting?

This is an evolving area, and I think that if we were to have this discussion last year, the answer would have been different. And if we were to have this discussion again next year, the answer will be different again, so, this is a snapshot in time.

CAR T cells were approved for treatment in lymphoma and acute leukemia about 3 or 4 years ago, and these work for patients who either didn't have a transplant and were refractory, or who had relapsed after their transplant. CAR T cells are commonly used for patients who had an autologous transplant, say for lymphoma, or now for multiple myeloma, they relapsed after that and they may have had other therapies subsequent to that, but they can be treated with CAR T cells. There are a number of products out there that can that they can be treated with successfully, to induce remissions, and in many patients, long term remissions. That is for patients with recurrent disease after an auto or an allo transplant.

There were 3 exciting presentations at ASH, several of which were just published, which looked at the question of whether CAR T-cell therapy could replace 1 of these transplants, particularly autologous transplant, and the studies were designed, there were 3 of them, with the 3 different CAR T-cell products. The studies were designed to take patients who were at high risk, who had relapsed with large-cell lymphoma within the first year of diagnosis, either they had relapsed, or they never actually got into remission in the first place.

What they did with those patients is they randomized patients to receive CAR T cells straight off, perhaps with some bridging chemotherapy, versus what's considered standard of care therapy. Standard of care therapy would be chemotherapy to decrease the amount of residual lymphoma present, followed by an autologous transplant. It was CAR T-cell therapy on 1 side versus standard of care, which was cytoreduction with chemotherapy plus an auto transplant. What 2 of the 3 studies demonstrated, 1 with a product called axi-cel and 1 with a product called liso-cel, was an improved response rate for patients who got the CAR T-cell approach compared to the standard of care. Not only was it improved response rate, it was also improved complete response rate and improved event-free survival, which is extraordinarily exciting.

With a paradigm shifting approach to patients who have who have refractory disease who have early relapse after initial therapy, it should be noted that 1 of the 3 trials using tisa-cel, did not actually show an improvement. We really have to drill down and understand why it is that 2 of the studies were positive and 1 was negative. That's work that we need to do over the next year to try to understand the differences between these 3 studies.

How has the success of CAR T cells impacted the transplant overall for these hematologic malignancies?

I think at the present time, in terms of AML and MDS for which we often do allogeneic transplants, CAR T cells have not yet had an impact. I think there are some challenges with CAR T-cell therapy for AML as to determining what the correct target is for AML. There's also challenges in terms of concern for the consequences of a successful CAR T-cell eradication in leukemia, because those CAR T cells may actually target normal hematopoietic stem cells and result in prolonged aplasia and low blood counts. It may be that we're going to have to combine if we will get to the point where we have a successful CAR T cells for AML. We may have to combine that with allogeneic transplant integrated so that we have a sequential approach where we either first eliminate the tumor with CAR T cells and then go on to perform an allogeneic transplant or conceivably vice versa in the opposite direction.

So, that's the future. For the present, I think that we will need to decide as a community, how we're going to integrate CAR T-cell therapy in for patients with non-Hodgkin lymphoma, high-risk large cell lymphoma, specifically. These are patients who will be either primary refractory, or who have had an early relapse after their initial therapy, the data right now at least for 2 of the products are very suggestive that straight CAR T-cell therapy may be the best approach that is not going to assign a reductive chemotherapy and auto transplant. And 1 of those products was just as FDA approved for that very indication.

You mentioned that this conversation could be different next year. If you could make a prediction, where is the field heading?

I think what we'll be seeing in the next 5 years are more studies trying to evaluate the place a CAR T-cell therapy in a variety of different diseases. It's an extraordinarily exciting time and fast-changing. As I said, I believe that is we have this conversation in a year or 2, it'll be different discussion.

_REFERENCES

_{Young RM, Engel NW, Uslu U, et al. Next-generation CAR T-cell therapies. Cancer Discov. 2022. Published online ahead of print. doi: 10.1158/2159-8290.CD-21-1683.}