Chimeric antigen receptor (CAR) T-cell therapies have quickly shifted the treatment paradigm for many people with several types of aggressive blood cancers, in whom treatment options have been limited. Studies presented at the 60th American Society of Hematology (ASH) Annual Meeting and Exposition spotlight the long-term effectiveness of these therapies in some patients.

CAR T-cell therapies are designed by harvesting a patient's own T cells, reengineering them to target specific proteins on the surface of cancer cells, and reintroducing the modified T cells back into the patient's immune system.

"These are transformative therapies and we're seeing their expanding value in terms of giving patients who essentially ran out of options an opportunity to live," said Joseph Alvarnas, MD, of the City of Hope in California. "At the same time, we're identifying the limitations of these therapies. For example, CAR T cells may stop working in some patients for various reasons, which has prompted researchers to ask what combination therapies could be used to extend the benefits of treatment."

An updated analysis of the efficacy and safety of tisagenlecleucel in pediatric and young adult patients with relapsed/refractory acute lymphoblastic leukemia (ALL) showed that a single infusion of tisagenlecleucel continues to be highly effective in fighting cancer in most people, without the need for additional therapies. This latest analysis of the ELIANA trial results includes four additional patients and another year of follow up.

"These are patients who weren't eligible for transplant, or who had relapsed after transplant; none were in remission and no other treatments were available at the time they entered the trial," said lead study author Stephan A. Grupp, MD, PhD, of the Children's Hospital of Philadelphia. "We've shown that not only can we get these patients into remission, but they're also going into remission with durable responses with CAR-T alone – most patients without any subsequent therapies, and with no minimal residual disease when we tested for evidence of leukemia."

These most recent data continue to validate the benefits of using this new treatment paradigm in this patient population, Dr. Grupp added.

Ninety-seven patients were enrolled in this single arm, open-label phase II study, which was conducted in 25 centers in 11 countries across North America, Europe, Australia, and Asia. Patients ranged in age from 3-24 and received a median of three prior lines of therapy (e.g., chemotherapy, radiation, or targeted therapy). A majority had undergone a previous hematopoietic stem cell transplant.

Among the 79 patients who were followed for three or more months after being infused with their reprogrammed CAR-T product, 82 percent achieved a complete remission. Researchers also reported that 66 percent of patients who had a complete response to CAR-T were still in remission at 18 months. Additionally, the majority of the infused patients were still alive (overall survival of 70 percent) at 18 months post-infusion. Even in this updated analysis, median overall survival has not been reached. Another success, according to researchers, is that the many centers in the study have been able to safely and consistently administer CAR T-cell therapy.

"We see relatively similar results across study sites — even with centers with no prior experience administering CAR T-cell therapy — so we've shown we can roll this out, do it safely, and promulgate appropriate approaches to toxicity management as well," said Dr. Grupp.

Seventy-seven percent of patients experienced grade 3 or 4 cytokine release syndrome (CRS), which is triggered by an over-reactive immune response. Nearly half of these patients required treatment in the intensive care unit for a median of seven days. All cases were ultimately reversed using the management algorithm developed for this study. Most key adverse events occurred in the first eight weeks after infusion and included infection, low white blood cell and platelet counts, and neurological events. No cases of cerebral edema were reported. Twenty-five deaths were reported after CAR-T infusion, mostly due to disease progression and other causes unrelated to CAR T-cell therapy.

Dr. Grupp said the prevalence of adverse events remains unchanged from previous analyses and there is ongoing evidence that CAR-T is benefiting patients well after a year.

Further follow-up of patients is ongoing in the ELIANA trial.  This study was supported by Novartis. 

Another study was a follow-up analysis of the international JULIET trial.  More than 18 months after patients with relapsed or treatment-resistant diffuse large B-cell lymphoma (DLBCL) were treated with a single dose of tisagenlecleucel, high response rates persist, further demonstrating that this therapy is beneficial for many patients who otherwise wouldn't have a viable option for treatment.

In this latest follow-up analysis, 19-month results show the overall response rate was 54 percent among 99 patients who were followed for at least three months or discontinued therapy early, with 40 percent achieving a complete response and 16 percent achieving a partial response. Moreover, 64 percent of patients who achieved a complete response earlier in the trial are currently still in remission with no detectable evidence of cancer. Median duration of response and median overall survival in responding patients was not reached. Response rates were consistent across subgroups of patients, including the elderly and those with particularly aggressive lymphoma (double-/triple-hit) or prior stem cell transplantation.

"We're seeing that the responses are sustained. There are a significant number of patients who are staying free of disease, and none of the patients in remission have proceeded on to transplantation," said lead study author Richard Thomas Maziarz, MD, of the Oregon Health & Science Knight Cancer Institute, in Portland, Oregon.

DLBCL is the most common form of lymphoma, accounting for roughly one-third of all non-Hodgkin lymphoma cases. While current treatment options are successful for many people with this disease, primary therapy often fails in about one-third of people with DLBCL, and half of these patients won't be eligible for stem cell transplantation, which is considered the best second-line treatment approach. Such patients would be candidates for this type of therapy.

This single-arm, open-label Phase II trial is among the largest studies to examine a CAR T-cell therapy exclusively in people with DLBCL. It was conducted at 27 treatment sites spanning 10 countries across North America, Europe, Australia, and Asia. Enrollees had to receive two or more previous treatments with documented disease progression, or failed to respond or were otherwise ineligible for autologous stem cell transplant. A total of 115 patients were successfully infused. Patients ranged in age from 22-76 years old with a median age of 56.

Of note, 54 percent of patients who initially had a partial response ended up having a complete response, which suggests that the cell product persists viably and remains active in vivo over time, according to Dr. Maziarz.

Consistent with previous reports on safety, most of the severe adverse events were seen shortly after infusion and included drop in mature blood cells (34% of patients), CRS (23% of patients), infection (19% of patients), and neurological events (11% of patients). There were no deaths that investigators attributed to the therapy.

Patients in the JULIET trial who responded to therapy will continue to be followed. Dr. Maziarz said that as research evolves, the focus will need to be on approaches for optimizing the outcomes of therapy, such as combination therapy with checkpoint inhibitors or other targeted therapy to enhance, maintain, or stimulate their responses.

"We're changing the natural history of the disease, and identifying subpopulations of patients who may need therapies in addition to CAR-T will be an important next step," he said. "This research is really the foundation for the next wave of studies to assess combination therapies."

Funding for this study was provided by Novartis.