Doctors Debate: Do CAR T Cells and Transplantation Both Have a Place in Aggressive B-Cell Lymphoma Treatment?

Mehdi Hamadani, MD

Treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL) now includes FDA-approved chimeric antigen receptor (CAR) T-cell therapies. The emergence of this new treatment strategy over the past 2 years has brought into question the role of allogeneic hematopoietic stem cell transplant (allo-HCT) in treating this disease.

Two oncologists debated the question during the European Hematology Association (EHA) 2021 Virtual Congress. Mehdi Hamadani, MD, professor of medicine at the Medical College of Wisconsin in Wauwatosa, Wisconsin, argued in favor of CAR T-cell therapy and Bertram Glass, MD, chief physician of hematology and cell therapy at Helios Klinikum Berlin-Buch in Berlin, Germany, argued that there is still a role for allo-HCT in the treatment of patients with relapsed/refractory DLBCL.¹

“With patients in the United States, you have to ask the question of which clinical setting was typically allogeneic transplant considered. While that’s not the case for every single patient, allogeneic transplant was commonly considered in [patients with] aggressive lymphoma who relapsed after an autologous transplant and happened to then respond to the next line of therapy, and if they happen to be fit enough and young enough whenever a donor became available. That’s where allogeneic transplant was historically offered. During the debate, we asked if the historical option of allogeneic transplant is better than one option we have now, CAR T-cell therapies, and we looked at the pros and cons of both approaches,” Hamadani told Targeted Therapies in Oncology™ in an interview.

CAR T-Cell Therapy for Relapsed/Refractory DLBCL

The presentation in favor of CAR T cells began with an explanation of how oncologists are currently using the agents in their practices.

“As of right now, patients who have failed 2 prior lines of therapy, and that includes patients with diffuse large B-cell lymphoma not otherwise specified, or patients with aggressive B-cell lymphoma with high-grade features, and diffuse large B-cell lymphoma transforming from indolent histology, CAR T-cell therapy using 1 of the 3 commercially available platforms directed against the CD19 antigen is currently a standard of care.”

The key question to evoke regarding the argument, according to Hamadani, is whether allo-HCT can outperform CAR T-cell use in any relevant clinical scenario.

In research co-authored by Hamadani and published in the British Journal of Haematology, investigators utilized a prognostic tool to determine survival outcomes of patients who undergo allo-HCT alone. It was concluded from the study that adding novel cellular therapies to transplants can help reduce non-relapse mortality (NRM) and augment the graft-vs-lymphoma effect observed in patients with DLBCL.²

Among adverse prognostic factors in 503 patients who underwent allo-HCT after disease progression/relapse following a prior autologous HCT (auto-HCT), 4 points were scored for having a Karnofsky performance score of <80, 5 points were given for chemoresistance, and 2 points were given to patients who went from auto-HCT to allo-HCT in less than 1 year.

Looking at the 3-year overall survival (OS) rate, the OS was 43% in patients with low-risk disease (0 points), 39% in those with intermediate-risk disease (2-5 points), 19% in those with high-risk disease (6-9 points), and 11% in the very high-risk population (11 points). Further, a comparison of CAR T-cell therapy to allo-HCT using the prognostic tool showed that the probability of progression-free survival (PFS) improvement was higher for CAR T-cell therapy vs allo-HCT. The probability of disease progression or relapse at 3 years was 38% (95% CI, 34%-43%).

A multivariate evaluation of chemoresistance before transplant and its impact on outcomes showed that patients with chemo-resistant disease had a higher risk of NRM (HR, 1.44; 95% CI, 1.04-2.00; P = .03). Those with chemo-resistant disease also had a higher risk of progression or relapse after allo-HCT (HR, 2.25; 95% CI, 1.51-3.36; P < .0001). Patients with a Karnofsky performance status <80 and chemo-resistant disease also had inferior OS outcomes compared with those without these features (HR, 1.86; 95% CI, 1.33-2.60; P = .0003).

Based on this research, Hamadani explained a scenario in which CAR T-cell therapy would be more optimal for a patient than allo-HCT: “I’m not saying that every single 70- or 80-year-old can get CAR T-cell therapy. But it is a more feasible treatment for elderly patients. You can arguably give CAR T-cell therapy to less-fit patients, obviously not to a patient who is in active cardiac failure, but you have more wiggle room in terms of cardiac reserve, lung reserve, and hepatic reserve to give CAR T-cell therapies,” he explained. “There is no donor requirement for commercially available CAR T cells, so you don’t have to wait for a donor to be available. Today, these are some practical differences which make CAR T-cell therapy logistically easier.”

During his presentation, Hamadani further explained that looking at outcomes in patients with DLBCL over a 10-year period, allo-HCT has always been less active than auto-HCT, and better activity was shown once CAR T cells were introduced in 2017.

According to clinical trial results, axicabtagene ciloleucel (axi-cel; Yescarta), tisagenlecleucel (tisa-cel; Kymriah), and lisocabtagene maraleucel (liso-cel; Breyanzi) can all produce higher objective response rates (ORRs) in patients with relapsed/refractory aggressive non-Hodgkin lymphoma, including DLBCL. The ORR observed with axi-cel in the phase 2 ZUMA-1 trial (NCT02348216) of 101 patients was 82%, with a 54% complete response (CR) rate.³ With tisa-cel in the phase 2 JULIET trial (NCT02445248) of 111 patients, the ORR was 52%, with a CR rate of 40%.⁴ Finally, liso-cel achieved an ORR of 73%, with a CR rate of 53% in the phase 1 TRANSCEND-NHL-001 trial (NCT02631044) of 269 patients.⁵

Toxicity with CAR T cells and allo-HCT can be of concern, Hamadani explained during the interview.

“The adverse event [AE] profile of CAR T-cell therapy and transplantation is different but there is obviously some overlap. The overlap is where you see common toxicities because of either transplant conditioning or lymphodepletion before CAR T-cell therapy. Both treatments can cause a patient’s blood counts to go down. So cytopenias happened with both, and the need for blood transfusions, nausea, vomiting, fatigue, and risk of infections exists with both therapies, but there are some toxicities that are very distinct. Reversible toxicities with CAR T-cell therapies are things like cytokine release syndrome where a patient develops fevers, trouble breathing, or hypotension,” Hamadani said.

Explaining that there is no one-size-fits-all approach to the treatment of DLBCL, Hamadani said: “These treatments are not mutually exclusive. In our experience, we have seen patients who got allo transplants, relapsed, and then were cured with CAR T-cell therapies. We have also seen patients who don’t benefit from either therapy. Finally, we have seen patients who have gotten CAR T-cell therapies, relapsed, and then went on to get an allo transplant and we’re long-term survivors following allo transplant.

Transplant for Relapsed/Refractory DLBCL

Bertram Glass, MD

The early years of utilizing allo-HCT showed that the strategy could achieve disease control, even in patients with very advanced disease.6 During the EHA presentation, Glass explained that the high remission rate observed with allo-HCT and its use in addition to CAR T-cell therapy could lead to optimal responses in patients.

“In one larger trial that has been run by my own group some years ago and published in The Lancet Oncology, we applied allogeneic stem cell transplantation to patients with relapsed and refractory B- and T-cell lymphoma and the remission-free survival [rate] was in the range of 40%. There are also some analyses as well from the Center for International Blood and Marrow Transplant Research that show more or less the same thing,” Glass told Targeted Therapies in Oncology™ in an interview.

In the randomized, open-label, phase 2 study (NCT00785330) conducted in Germany, 84 patients were randomized evenly to receive rituximab (Rituxan) or lymphoma-directed myeloablative conditioning with allo-HCT. The primary end points of the study were OS at 1 year after transplantation in all patients and the incidence of grade 2 to 4 acute graft-vs-host disease (GVHD) at 100 days in the rituximab and no rituximab groups, as reported by the treating physician. Secondary end points explored in the study included PFS in all patients, as well as time to progression, non-relapse mortality, the incidence of infectious complications, and the incidence and severity of chronic GVHD for rituximab compared with no rituximab in the intention-to-treat population.⁶

At a median follow-up of 4.0 years (interquartile range, 2.5-5.6), the cumulative incidence of acute GVHD with lymphoma-directed myeloablative conditioning and allo-HCT was 42% (95% CI, 29%-59%), compared with 46% (95% CI, 32%-62%) in the rituximab arm (HR, 0.91; 95% CI, 0.52-1.60; P = .74). In all patients, the 1-year OS rate was 52% (95% CI, 41%-62%).

“Although we now have CAR T cells, my central argument would be that for the first allogeneic stem cell transplantation, it has been proven to be quite dangerous, but on the other hand, [it is] a very efficient method to treat relapse and chemorefractory aggressive B-cell lymphoma. The relapse rates in refractory and in relapsed patients is around 30 to 40 in many analyses, which included both retrospective and prospective studies,” Glass stated.

Glass explained that although allo-HCT is very effective at getting patients into remission, and although CAR T cells are an effective treatment option, their efficacy falls behind allo-HCT in this regard.

“On the other hand, the competitors, the CAR T cells, are also effective. However, if you look at the relapse rates, they are quite less effective towards the lymphoma. And then allogeneic stem cell transplant in context with high-dose chemotherapy can be because relapse rates or progression rates in most analyses of CAR T cells is around 60%. They are far less dangerous than allogeneic stem cell transplantation. So the treatment-related mortality with allo transplant is around 30% and with CAR T cells it is less than 5%. So the natural result in the end is not so far away from each other. Both can produce long-term remission-free survival in the range of 30% to 40%,” Glass said.

Another important factor that sets these treatment strategies apart is toxicity, as Glass noted, and although both strategies have their risks, one may be easier for oncologists to manage than the other. “The difference is that in one situation with CAR T cells, you don’t have to pay a high price in terms of toxicity, either acute or long term,” Glass said.

Further, considering the lower number of AEs that occur with CAR T cells, one strategy may be to use CAR T cells ahead of allo-HCT in patients with relapsed/refractory DLBCL.

“CAR T cells don’t solve the whole problem, and if patients fail from CAR T cells, it is one of the most valuable methods to apply allo-HCT to obtain long-term remissions in patients,” Glass said. “And therefore, I would say at the moment, before we have better CAR T cells and other methods like bispecific antibodies, allogeneic stem cell transplantation will keep its place for treatment of relapsed and refractory aggressive lymphoma.”

Bringing into thought Hamadani’s point of no one-size-fit- all approach, the use of both allo-HCT and CAR T-cell therapy in different treatment lines was a point he agreed with. “We don’t have data out to 3 years, 4 years, 5 years, but you can sequence these therapies,” he said. “And that was one of the messages that Dr Glass said, and I completely agree with it.”

_References:

_{1. Hamadani M, Glass B. CAR-T or allogeneic transplant for relapsed/refractory DLBCL? Presented at: European Society of Hematology 2021 Congress; June 9-17, 2021; virtual. Accessed June 11, 2021.}

_{2. Fenske TS, Ahn KW, Graff TM, et al. Allogeneic transplantation provides durable remission in a subset of DLBCL patients relapsing after autologous transplantation. Br J Haematol. 2016;174(2):235-248. doi:10.1111/bjh.14046}

_{3. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377(26):2531-2544. doi:10.1056/NEJMoa17074474}

_{4. Schuster SJ, Bishop MR, Tam CS, et al; JULIET Investigators. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380(1):45-56. doi:10.1056/NEJMoa1804980}

_{5. Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet. 2020;396(10254):839-852. doi:10.1016/S0140-6736(20)31366-0}

_{6. Glass B, Hasenkamp J, Wulf G, et al; German High-Grade Lymphoma Study Group. Rituximab after lymphoma-directed conditioning and allogeneic stem-cell transplantation for relapsed and refractory aggressive non-Hodgkin lymphoma (DSHNHL R3): an open-label, randomised, phase 2 trial. Lancet Oncol. 2014;15(6):757-766. doi:10.1016/S1470-2045(14)70161-5}