Robert J. Soiffer, MD

Robert J. Soiffer, MD, 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, discusses the role of transplant in the post chimeric antigen receptor (CAR) setting for patients with hematologic malignancies.

According to Soiffer, transplant is a modality which has been used for over 40 years and remains the standard of care (SOC) for many hematologic malignancies.

However, increasing information and data regarding CAR T-cell therapy may change this SOC as the non-Hodgkin lymphoma, leukemia, and multiple myeloma settings have already had CAR T-cell products approved by the FDA.

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 be treated successfully, to induce remissions, and in many patients, long term remissions and what appears to be a cure. That is for patients with recurrent disease after an auto or an allo transplant.

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Robert J. Soiffer, MD, discusses the role of transplant in the post chimeric antigen receptor setting for patients with hematologic malignancies.

The Use of Transplant in the Post CAR T Setting

Robert J. Soiffer, MD, the chair of the executive committee for clinical programs, vice chair of the department of medical oncology, chief of the division of hematologic malignancies, and institute physician at Dana-Farber Cancer Institute, discusses the approaches to integrating chimeric antigen receptor (CAR) T-cell therapy into the treatment of hematologic malignancies.

Soiffer says that currently CAR T-cell therapies have not had an impact in myeloid malignancies, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), due to the difficulty targeting the cancer. CAR T cells may also target healthy hematopoietic stem cells in these patients, causing significant adverse events. One potential solution would be combining CAR T-cell therapy with allogeneic hematopoietic stem cell transplant (SCT) to introduce healthy stem cells that would not be targeted.

In addition, hematologists need to determine how to introduce CAR T-cell therapies in patients with non-Hodgkin lymphoma, according to Soiffer, now that they have been approved for large B-cell lymphomas. Based on the trials, patients who are refractory to primary therapy or have an early relapse within 12 months after therapy should be considered as candidates for CAR T-cell therapy as an alternative to cytoreductive chemotherapy followed by autologous SCT.

 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 are 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. Integrate it 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, who are either primary refractory, or who have had an early relapse after their initial therapy.

Robert J. Soiffer, MD, discusses the approaches to integrating chimeric antigen receptor T-cell therapy into the treatment of hematologic malignancies.

Impact of CAR T-Cell Therapy on Use of SCT for Hematologic Malignancies

Robert J. Soiffer, MD, 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, discusses the use of transplant in various hematologic malignancies.

Transplant is a modality that has been used for more than 40 years for many patients with hematologic malignancies. However, research is currently evaluating chimeric antigen receptor T-cell therapy as a possible replacement and new standard of care.

Here, Soiffer discusses the role of transplantation for patients with non-Hodgkin lymphoma, the use of autologous transplant for patients with multiple myeloma, and allogeneic transplant for patients with acute leukemia or myelodysplastic syndrome (MDS).

 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. 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.

Robert J. Soiffer, MD, discusses the use of transplant in various hematologic malignancies.

Role of Transplant Across Hematologic Malignancies

Robert J. Soiffer, MD, 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, discusses the use of stem cell transplant in treating hematologic malignancies prior to the availability of chimeric antigen receptor (CAR) T-cell products.

Prior to the development of CAR T-cell therapies, stem cell and allogeneic transplants have been the 2 main approaches for treating patients with hematologic malignancies, according to Soiffer. Transplant has been the standard of care for many hematologic malignancies and has been used for over 40 years.

Stem cell transplants are typically performed in patients with non-Hodgkin lymphoma and multiple myeloma, while allogeneic transplants typically are for patients with acute myelogenous leukemia, myelodysplastic syndrome, myelofibrosis, and more.

However, with developments focused on evolving CAR T-cell therapies, the main treatment approach for this patient population may change.

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.

Robert J. Soiffer, MD, discusses the use of stem cell transplant in treating hematologic malignancies prior to the availability of chimeric antigen receptor T-cell products.

Exploring Transplants Prior to CAR T-Cell Therapy in Hematologic Malignancies

Robert J. Soiffer, MD, 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, discusses how the role of transplantation is evolving with the availability of chimeric antigen receptor (CAR) T-cell agents.

According to Soiffer, who is also the Worthington and Margaret Collette Professor of Medicine in the Field of Hematologic Oncology, Harvard Medical School, transplantation has been done within patients for close to 40 years and consists of 2 types: autologous and allogeneic transplantation. A number of approved therapies for diseases like non-Hodgkin lymphoma, Hodgkin lymphoma and multiple myeloma exists, but there is a need to further understand how to best use them and in what context.

In regard to transplantation in the evolving post CAR T setting, CAR T cells are commonly used for patients who had an autologous transplant and for who may have had other therapies prior. However, the question of whether CAR T-cell therapy could actually replace one of these transplants remains.

 We're not at the beginning of the end, we are at the end of the beginning of a CAR T-cell therapy. It has taken 20 plus years for CAR T cells to evolve to the point where we have therapies that are approved. We still need to figure out how to use them, in what context to use them, whether they're going to be used adjunctively with auto transplant, to follow auto transplant, whether they're going to replace transplant altogether, or whether they're going to be used in other settings.

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

Robert J. Soiffer, MD, discusses how the role of transplantation is evolving with the availability of chimeric antigen receptor T-cell agents.

Robert J. Soiffer, MD | Authors

Articles

The Use of Transplant in the Post CAR T Setting

Impact of CAR T-Cell Therapy on Use of SCT for Hematologic Malignancies

Role of Transplant Across Hematologic Malignancies

Exploring Transplants Prior to CAR T-Cell Therapy in Hematologic Malignancies

The Role of ASCT After CAR T-Cell Therapy