Expert Discusses Potential for CAR T-Cell Therapy to Replace ASCT in DLBCL

The treatment landscape of diffuse large B-cell lymphoma (DLBCL) is shifting, as investigators are beginning to recognize that high-risk patients who relapse after standard therapy or are refractory to salvage chemotherapy can be treated with CAR T cells, said Paul J. Shaughnessy, MD.

“In the next 5 to 10 years, one of the biggest things will be CAR T-cell therapy and will that actually supplant the use of high-dose chemotherapy in autologous stem cell transplant in DLBCL,” he said.

In an interview withTargeted Oncologyduring the 2019Transplantation and Cellular Therapy Meetings,Shaughnessy, medical director of adult blood and marrow transplant at the Texas Transplant Institute, discussed updates in stem cell mobilization and transplant for DLBCL. In addition, he underscored the importance of clinical research in this space and accruing patients in the community to clinical trials.

TARGETED ONCOLOGY: What does the current treatment landscape look like for DLBCL?

Shaughnessy: For non-Hodgkin lymphoma, the most common lymphoma we treat would be DLBCL, and when DLBCL relapses, we would treat with salvage chemotherapy. Most patients are sensitive to salvage chemotherapy, so we would mobilize autologous stem cells and go into high-dose chemotherapy and autologous stem cell transplant to provide a better chance for long-term disease-free and overall survival compared to non-transplant therapy.

The landscape is changing, however, because we are recognizing that the high-risk DLBCL patients that relapse quickly after standard therapy or are refractory to salvage chemotherapy can be treated with CAR T-cell therapy. With these powerful immunologic therapies that we have, we are able to salvage more patients than we could previously. I do think CAR T-cell therapy may actually start to supplant autologous stem cell transplant for DLBCL.

TARGETED ONCOLOGY: What are the main points oncologists should take away from you talk?

Shaughnessy: The main points of my talk are we now see a variety of different chemotherapy agents being used to treat different types of lymphoma, and we can still mobilize adequate stem cells, even with these new chemotherapy regimens that we are using. We do need to be conscious of the risk of toxicity to underlying hematopoietic stem cells and not being able to collect adequate stem cells. I also talked about the need to do more studies to better understand graft content as well as the number of stem cells we are giving to see if this can make an impact in the future and if can we do even better in treating some of these patients.

I hope that what oncologists see is that it is still very important to refer patients for a timely assessment of transplant needs in DLBCL. Even some high-risk patients, seeing them upfront and then of course, certainly at first relapse, we do want to see these patients early so that we can assess for proper stem cell mobilization, can we get enough stem cells, or in some patients with high-risk disease, are they better served by CAR T cell therapies, different salvage regimens, or other research protocols that we have. Early referral and involving us in their salvage therapy so that we better get the patients to transplant really does help.

TARGETED ONCOLOGY: What are some of the unanswered questions that still need to be addressed in this space?

Shaughnessy: One challenge is in really just treating these relapsed/chemotherapy-sensitive DLBCL patients, so can we use better regimens to get more people to respond with less toxicity? Then, can we still mobilize adequate stem cells? Do we need chemotherapy to mobilize the stem cells, or can we use cytokine-alone mobilization techniques to spare some patients toxicity? I think those are some of the major challenges. Then also, can we optimize what we do with peripheral blood stem cell transplantation, better preoperative regimens, or can we use higher graft numbers to get quicker outcomes? Also, can we manipulate the autologous stem cell graft with higher lymphocyte counts to get better outcomes as well and quicker immune reconstitution? These are all things that need to be answered in future prospective studies.

TARGETED ONCOLOGY: Is there any ongoing research looking into this?

Shaughnessy: I think there is. We have seen our colleagues at Mayo Clinic show that with higher lymphocyte counts, they are seeing better outcomes in autologous stem cell transplant for DLBCL. We’ve seen prior retrospective studies show that higher CD34 counts are associated with quicker engraftment, quicker time out of the hospital, and maybe, a suggestion towards better outcomes in some of these patients, but once again, we need more prospective studies to look at this and at how we optimize these autologous stem cell grafts in lymphoma.

TARGETED ONCOLOGY: Where is the field headed in the next decade or so?

Shaughnessy: In the next 5 to 10 years, one of the biggest things will be the CAR T-cell therapy and will that actually supplantthe use of high-dose chemotherapy in autologous stem cell transplant in DLBCL. We already see research studies moving CAR T-cell therapy sooner into the therapy of relapsed lymphoma and even in some patients with high-risk lymphoma and replacing stem cell transplant therapy, so that’s a big change. I also think doing autologous stem cell transplant, we will hopefully have more information on higher CD34 counts improving outcomes, as well as the lymphocyte subsets and some autologous graft engineering, may help us do better in those patients. I think those are the major changes for the next 5 years.

TARGETED ONCOLOGY: What is important for a community oncologist to know right now about treating DLBCL and other lymphomas?

Shaughnessy: The best thing to tell the community oncologist is call us early and call us often. We want to hear about lymphoma patients, even newly diagnosed lymphoma patients. There are some patients we might consider for studies upfront, and then there are many different types of lymphoid malignancies. For instance, with mantle cell lymphoma, we want to hear about those patients at diagnosis because I do believe consolidating these patients in first remission is beneficial. Certainly, in any relapsed lymphomas, follicular lymphomas, DLBCL, the sooner we hear about them, the better we can accrue them to research studies, the better we can treat them with salvage therapy, and to try and cure more of more of these patients with different therapies, through either high-dose chemotherapy and transplant or with immunologic maneuvers such as CAR T-cell therapy.