CAR T-Cell Therapy Impacts Role of Stem Cell Transplant in B-Cell ALL

Partow Kebriaei, MD

Partow Kebriaei, MD

The need for stem cell transplantation in patients with acute lymphoblastic leukemia (ALL) may decrease as chimeric antigen receptor (CAR) T-cell therapies continue to evolve and develop in this space. According to Partow Kebriaei, MD, some patients may benefit from receiving CAR T-cell therapy prior to undergoing transplant.

Patients with B-cell ALL, in particular, appear to have benefit with CAR T-cell therapy. Response rates up to 90% have been demonstrated in this patient population before proceeding to transplant, according to Kebriaei inher presentation at the 7th Annual Society of Hematologic Oncology Meeting.¹

Fifty-three patients with relapsed B-cell ALL were treated with 19—28z CAR T cells targeting CD19 and CD28 in a study evaluating the CAR T-cell product. This treatment induced a complete response (CR) rate of 83%, and those patients with a disease burden below 5% in bone marrow blasts prior to treatment had a greater duration of remission and survival. Additionally, 32 patients achieved minimal residual disease (MRD) negativity.²

Following the CAR T-cell therapy treatment, some of the patients who had MRD-negative CR underwent transplantation. However, there was no statistically significant benefit from transplant in terms of event-free survival (P= .64) or overall survival (P= .89), according to study findings.²

Although the CAR T-cell therapies appear promising in this patient population, the next question to be addressed revolves around the consolidation treatment following CAR T-cell therapy. For some patients, they should be moved to transplant, but not all patients should undergo transplant following CAR T-cell therapy.

“With CAR T-cell therapy, I think we need to be smarter about looking for persistence of the CAR or surrogates of persistence of CAR,” explained Kebriaei, a stem cell transplant physician at The University of Texas MD Anderson Cancer Center. “In the group that appears to have persistence and therefore potential cure with the CAR, we should wait [before proceeding to transplant]. In the group that doesn’t show those signs, those patients should be transplanted.”

In an interview withTargeted Oncology, Kebriaei discussed the role of transplantation in patients with ALL following treatment with targeted cellular therapies, such as CAR T-cell therapy. She highlights the patient population that receives the most benefit from the use of CAR T-cell therapy and when transplant should be considered for these patients.

TARGETED ONCOLOGY: Could you provide us with an overview of your debate on whether transplant plays a role now in targeted cellular therapy for patients with ALL?

Kebriaei:The debate this morning was looking at the role of transplant in the setting of these new novel targeted cellular therapies. As we talked about, these are highly effective agents with now very high response rates in a very refractory disease setting. The question is once we achieve a response, what should we do next? The durability of response is different for each of these products, so we talk about them broadly, but when we talk about cellular therapy, we are talking about live cells, so we have adoptive CAR T-cell therapy in that space or natural killer (NK) cell subsets. These are using gene-modified or non—gene-modified T-cell products. The biggest examples are the CAR T cells. We have the bispecific T-cell engagers, so I spoke about blinatumomab (Blincyto) in this study. We then have antibody-mediated drugs, like inotuzumab ozogamicin (Besponsa), which is also very highly effective.

For the first time in the setting of B-cell ALL, because they are mainly targeting CD19, these drugs are highly efficacious, and we are seeing response rates of 60% to 80%. The question then is once we have treated them, how should we consolidate? I am for consolidating with transplant because now as we have continued follow-up with these agents and the immunotherapies like blinatumomab and inotuzumab, we already knew that we are using these drugs to get patients into remission and to then take them to transplant. With CAR T-cell therapy, it’s not so clear because you’ve infused this living cell that you hope will continue to eradicate disease and provide cure. However, with 2-year follow-up now in the majority of the trials, we are seeing about half of these patients relapsing.

One can either think of transplant across the board for all patients, or we can use algorithms to try to determine that population that still needs to be transplanted. That is the smarter approach, so I actually advocate moving towards that. With CAR T-cell therapy, I think we need to be smarter about looking for persistence of the CAR or surrogates of persistence of CAR. In the group that appears to have persistence and therefore potential cure with the CAR, we should wait [before proceeding to transplant]. In the group that doesn’t show those signs, those patients should be transplanted.

Again, with immunotherapies such as blinatumomab and inotuzumab, I believe that we are using these drugs in combination with chemotherapy to get a group of very refractory patients who beforehand would not have been able to even be considered for curative therapy and use transplant as a form of consolidation to effect cure.

TARGETED ONCOLOGY: What are the considerations for adults versus pediatric patients with ALL?

Kebriaei:It is not a one-size-fits-all, so we do have to talk about whether it is pediatric or adults and the frailty of the person because the toxicity profile matters. At the end of the day, survival is a combination of toxicity and benefit. That should also be taken into account. When we are talking about CAR T-cell therapy, we have to remember that each CAR construct is different, so we have to think about and be cognoscente of the CAR that is being used when we then have expectations for cure.

TARGETED ONCOLOGY: As you said, CAR T-cell therapy would come first, followed by transplant. How does sequencing work with other agents as well in ALL?

Kebriaei:We don’t have any studies that are looking at sequential versus combination therapies. There are pros and cons to both. One can consider combining the drugs up front. The idea behind that is you use everything you have at once to really eradicate the disease to the lowest level possible. One can see how that may affect a higher rate of cure. The other approach is to take 1 drug, use it as long as we can, and then look for surrogates or early markers of relapse. If we start to see those, then we start to go on the next drug. That approach is reasonable too, but the concern is when using such targeted therapies is are you going to drive resistance or emergence of a clone that doesn’t have the target antigen that you’re targeting. My particular bias, especially with very targeted therapy, is I worry about resistance if we use sequential therapy.

I do believe, and I think we all agree, that combining standard cytotoxic chemotherapy with a targeted immunotherapy is the way forward and in earlier [settings]. That was 1 of my points, using them earlier in the relapse setting, so as salvage therapy rather than waiting.

TARGETED ONCOLOGY: How do you determine if patients are eligible for transplant?

Kebriaei:The best patient to go forward with transplant is that patient who is MRD negative. As you go beyond first remission, the likelihood of achieving MRD negativity goes down. In general, we would say if a patient has a remission—morphologic is adequate—and they are fit to undergo transplant, those are the criteria that need to be met in order to move forward.

What is happening now is we are taking patients who may be on their third, fourth, or fifth line of treatment who in the past would not have been expected to maintain response, and now these patients are retaining response. We will take them to transplant. It doesn’t matter that they have maintained response after the fifth line of therapy.

TARGETED ONCOLOGY: What does future of transplantation look like in the treatment landscape of ALL?

Kebriaei:I think what we are going to see is more precise transplantation. We all agree that transplant has long-term complications and long-term morbidity. It’s not something that we want to apply to everyone, so the best outcome for ALL as a field is if we could be very precise about who needs that transplant.

On the flip side, as transplanters, are working to improve the overall tolerance of transplant. That work is ongoing, but I think the best combination is about being precise about who you are going to give the transplant to, then also improving the transplant in general so it is more tolerable. That will give us an improved overall survival for the whole ALL field.

TARGETED ONCOLOGY: What are some of the challenges found with transplant in ALL? How are these challenges being addressed?

Kebriaei:The biggest challenge is that the ALL blasts are rapidly dividing. It’s a very aggressive disease, and traditionally we’ve been very aggressive with our treatment up front. We’ve given very aggressive dose-intense cytotoxic chemotherapy, and with transplant, more and more studies, mostly in a retrospective fashion, show that you need a myeloablative total body irradiation—containing regimen. The biggest challenge is now that we are using these drugs where some have toxicities, such as hepatic toxicity with inotuzumab, we worry about complications such as veno-occlusive disease. You want to modify your preferably regimen to lower the risk of treatment-related mortality, but that may also lower the efficacy of the transplant. In ALL in particular, the challenge is the data would suggest that we need an intense myeloablative regimen to successfully treat the patient, but often when we get a patient that has been heavily pretreated, they may not be fit enough for a myeloablative transplant. That is really the challenge.

TARGETED ONCOLOGY: What is your key takeaway message on transplantation in ALL?

Kebriaei:In the era of targeted therapies, we now have patients who are able to get a transplant. For the first time, it’s gratifying to see that 50% to 70% of refractory patients are now transplant-eligible because they are showing response to these novel therapies. These patients should be very quickly and rapidly identified and sent to transplant centers. As transplanters, we need to be smart about selecting the correct patients to go forward and to be mindful of the regimens that they have previously had and potentially modify the regimen to lower the transplant-related mortality.

From the session, I think another point that was brought up is that we need to continue to work on are our elderly patients with ALL. We talk a lot about pediatric and young kids with ALL being essentially cured. Adolescent patients or young adult patients being treated with pediatric-inspired regimens are having survival rates in an upwards of 50% without transplant. The group that remains are those patients over the age of 55, that second peak in the incidence of ALL. This is the elderly ALL population where expected survival rates are consistently less than 30%. This is a group that we can think about using these immunotherapies in a smart way combined with very low intensity chemotherapy to treat that group and hopefully improve the survival rates. That is the next group of patients that I hope will start to see some better responses.

References

1. Kebriaei P, Pulsipher M. Is transplant still necessary in the era of targeted cellular therapy for ALL? Presented at: 2019 Society of Hematologic Oncology Annual Meeting; September 11-14, 2019; Houston, TX.
2. Park JH, Rivière I, Gonen M, et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia.N Engl J Med.2018;378(5):449-459. doi: 10.1056/NEJMoa1709919.