In the treatment of relapsed/refractory (R/R) large B-cell lymphoma (LBCL), a disease that refers to several subtypes of non-Hodgkin lymphoma (NHL), with diffuse large B-cell lymphoma (DLCBL) being the most common and aggressive form of the disease, Chimeric Antigen Receptors or CAR T-cell immunotherapy, including axicabtagene ciloleucel (axi-cel; Yescarta®; Kite/Gilead), tisagenlecleucel (tisa-cel; Kymriah®; Novartis), and lisocabtagene maraleucel (liso-cel; Breyanzi®; Juno Therapeutics, a Bristol Myers Squibb/BMS) have been approved by the US Food and Drug Administration (FDA).

Chimeric antigen receptor T-cell therapy, engineered synthetic receptors designed to redirect lymphocytes, most commonly T-cells, to recognize and eliminate cells expressing a specific target antigen, have produced remarkably effective and durable clinical responses in patients treated relapsed and/or refractory tumors, particularly for hematological malignancies.[1][2]

Now, a study led by researchers at Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine suggests that CAR T-cell therapy immunotherapy remains a viable option for patients who have lymphoma that goes into remission before the cell therapy begins.

While the study doesn’t directly answer the question whether cell therapy in remission is the right choice, it confirms that it’s not the wrong choice.

“I don’t think it answers the question of: Should we give these patients cell therapy? But I think it answers the question that we can – that it’s safe and that it’s a reasonable strategy when you’re in that spot,” said Trent Wang, D.O., a Sylvester hematologist and cellular therapy specialist who presented study findings in an oral presentation [3] at the 65th ASH Annual Meeting and Exposition, the American Society of Hematology’s conference taking place in San Diego, California, December 9-12, 2023.

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Most patients receiving cell therapy, a form of immunotherapy that uses immune cells engineered to recognize and attack the patient’s cancer, desperately need it. For some, it comes after many other treatments have failed. But Wang noticed an odd phenomenon in the past few years when treating lymphoma patients with this form of therapy: Some of his patients went into complete remission before the cells ever touched their bodies.

A study led by researchers at Sylvester Comprehensive Cancer Center and presented by hematologist Trent Wang, D.O., at annual meeting of the American Society of Hematology (ASH) suggests that CAR-T immunotherapy remains a viable option for patients who have lymphoma that goes into remission before the cell therapy begins. Photo courtesy: 2023 Clutch Content Partners. Used with permission.

Uncommon scenario
This uncommon scenario occurs during the process of getting to cell therapy, which in the case of Wang’s study uses a kind of engineered immune cell known as CAR-T cells. When a patient starts the process, there’s a waiting period of three to five weeks before they get the treatment. Insurance approval is needed, and the cells themselves need to be manufactured from the patient’s own cells. But many of these patients are very sick with their cancer, so physicians will often treat them with a short course of chemotherapy or other drugs to tamp down the symptoms.

A small handful of these patients end up in remission during this waiting period treatment, the clinicians have found.

“That prompted this dilemma: Now what are we supposed to do?” Wang asked. “Should we change the plan or give the therapy anyway? We just didn’t have a lot of information on this scenario.” he added.

Wang noted that more often than not his team would proceed with the cell therapy in these cases, mainly to prevent yet another stretch of time where the patients’ cancer might come back again.

But it didn’t feel like a very informed decision.

Better after infusion
Wang and his colleagues noticed that their patients who received the cells while in remission tended to fare well after their infusion. But they didn’t know if those results would hold up in an analysis of a larger group. They proposed a research study to the Center for International Blood & Marrow Transplant Research (CIBMTR), a nationwide registry that tracks patients who have received transplants and/or cell therapies.

The study included data from 134 patients diagnosed with LBCL who were included in the registry and who had gone into complete remission (CR) in the waiting period prior to receiving their cell therapy. To find that group, the scientists screened the records for more than 5,000 cell therapy patients treated in 53 different centers.

They found that this group of patients had a 43% probability of progression-free survival (PFS) over the two years following their treatment, about the same percentage as patients in the registry who were not in remission when they received their CAR-T therapy. However, the patients in remission had very low levels of toxicities related to their cell therapies, such as an immune overreaction known as cytokine release syndrome or CRC* and neurotoxicity, two side effects that can sometimes accompany CAR-T cell therapy.

Median follow-up was 24.3 months (range 0.9-49.4).  Following CAR T-cell infusion, 7 out of 134 patients (5.2%) proceeded to subsequent transplant (6 allogeneic, 1 autologous). At two years post-infusion, the investigators noted a probability of progression-free survival (PFS) and Overall Survival (OS) to be 43.5% (95% CI 34.4-52.8) and 63.8% (95% CI 54.4-72.6), respectively. They also noted a cumulative incidence of non-relapse mortality (NRM) at two years was 9% (95% CI 4.5-15.4), and the incidence of relapse/progression to be 47.3% (95% CI 38.2-56.6).

The rate of grade 3 or higher CRS was 2.2% or 3 out of 134 patients, with median time to onset of 3 days (range 1-16). Grade 3 or higher immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 11/134 (8.2%) with a median time to onset of 6 days (range 2-15). On univariate analyses, PFS was worse in patients with 5 or more lines of prior therapy before CAR T cell infusion (hazard ratios [HR] 2.39, 95% CI 1.18-484).

The investigators observed the most common cause of death to be relapse or disease progression, accounting for 26 of 46 patients deaths (56.5%), followed by infection in 8 of 46 patients (17.4%; including 4 (8.7%) from COVID-19), ICANS (2 out of 46 or 4.3%), and other causes.

“The study used data from patients treated with CAR-T cell therapy between 2015 to 2021, and current frequencies of specific cell therapy use are slightly different from those that were used in practice just a few years ago,” Wang concluded.

Next, the investigators want to explore the data paralleling more recent treatment trends.

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Note: * Cytokine Release Syndrome (CRS) occurs when the immune system responds to infection or immunotherapy, including CAR T-cell therapy, more aggressively than it should. Symptoms of CRS generally include fever, nausea, fatigue and body aches. Immediate treatment is needed to reduce the immune response.

Highlights or prescription information
Axicabtagene ciloleucel (axi-cel; Yescarta®; Kite/Gilead)[Prescribing Information]
Tisagenlecleucel (tisa-cel; Kymriah®; Novartis)[Prescribing Information]
Lisocabtagene maraleucel (liso-cel; Breyanzi®; Juno Therapeutics, a Bristol Myers Squibb/BMS)[Prescribing Information]

Reference
[1 ] June CH, O’Connor RS, Kawalekar OU, Ghassemi S, Milone MC. CAR T cell immunotherapy for human cancer. Science. 2018 Mar 23;359(6382):1361-1365. doi: 10.1126/science.aar6711. PMID: 29567707.
[2] Liu D. CAR-T “the living drugs”, immune checkpoint inhibitors, and precision medicine: a new era of cancer therapy. J Hematol Oncol. 2019 Nov 8;12(1):113. doi: 10.1186/s13045-019-0819-1. PMID: 31703740; PMCID: PMC6842223.
[3] Wang T, Wooahn K, Kaur M, Shadman M, Herrera AF, Sauter CS, Hamadani M, Jimenez Jimenez. Chimeric Antigen Receptor (CAR) T Cell Infusion for Large B Cell Lymphoma in Complete Remission: A Center for International Blood & Marrow Transplant Research (CIBMTR) Analysis. 4:30 PM – 6:00 PM Presentation: 5:00 PM Session: 627 [Abstract]

Featured image:  American Society of Hematology 61th Annual Meeting at the Orange County Convention Center, Florida (2019). Photo Courtesy: 2019 – 2023 © ASH/Nick Agro. Used with permission.

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