Single tisagenlecleucel infusion yields durable response in acute lymphoblastic leukemia

Stephan A. Grupp

SAN DIEGO — An updated analysis of the phase 2 ELIANA trial confirmed the efficacy of a single infusion of the chimeric antigen receptor T-cell therapy tisagenlecleucel among children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia, according to a presentation at ASH Annual Meeting and Exposition.

Perspective from James K. McCloskey, MD

“[The] longer-term follow-up is very exciting to us and indicates that there are a group of patients for whom this therapy [works],” Stephan A. Grupp, MD, PhD, lead investigator of the ELIANA trial and director of the Cancer Immunotherapy Program at Children’s Hospital of Philadelphia, said in a press conference. “This is a therapy that has potential for long-term disease control.”

The global, 25-center ELIANA trial included 97 patients (median age, 11 years; range 3-24) with CD19-positive relapsed or refractory B-cell ALL. Ten patients were not infused because of adverse events or death.

The majority of patients (61%) underwent prior hematopoietic stem cell transplantation.

Among the 79 patients infused with tisagenlecleucel (Kymriah, Novartis), nearly all (n = 75) received the single infusion (median dose, 3 x 10⁶ CAR-positive viable T cells/kg; range, 0.2-5.4 x10⁶) following lymphodepleting chemotherapy.

Median time from infusion to data cutoff was 24 months (range 4.5-35 months), which represented an additional 11 months of follow-up from previous reports.

Overall remission rate — which included complete remission plus complete remission with incomplete blood count recovery — within 3 months and maintained for 28 or more days served as the study’s primary endpoint. Secondary endpoints included duration of remission, OS, safety and cellular kinetics.

The study met its primary objective, with an overall remission rate of 82% (95% CI, 72-90).

Among 65 patients who achieved complete remission or complete remission with incomplete blood count recovery, all but one (98%) were minimal residual disease negative in their bone marrow within 3 months.

Patients with no minimal residual disease detected in bone marrow at day 28 by next-generation sequencing had superior outcomes and may represent a subgroup of patients eligible for no further therapy, such as bone marrow transplant, Grupp said.

Median duration of remission was not reached, but responses were ongoing in 29 patients at 29 months.

Nineteen patients relapsed before receiving additional anticancer treatment, and 13 subsequently died. Eight patients underwent stem cell transplants while in remission, eight received other anticancer therapy and one discontinued therapy while in remission.

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Relapsed tended to occur early — within the first year — and most were CD19 negative, Grupp said. Also, all CD19-negative relapses occurred in the context of persistent B-cell aplasia.

The probability of RFS was 66% (95% CI, 52-77) at 18 months and 62% (95% CI, 47-75) at 24 months.

Median OS was not reached. OS probability at 18 months was 70% (95% CI, 58-79).

Grade 3 or grade 4 cytokine release syndrome occurred in 77% of the patients. Of those, 39% received tocilizumab (Actemra, Genentech) with or without other anticytokine therapies. Forty-eight percent required ICU-level treatment, with a median ICU stay of 7 days. All cases were reversible.

Other grade 3 or grade 4 nonhematologic adverse events included neutropenia with a body temperature above 38.3 degrees Celsius (62% within 8 weeks of infusion), hypoxia (20%) and hypotension (20%). Most cases of grade 3 or grade 4 thrombocytopenia and neutropenia resolved to grade 2 or less by 3 months.

Grade 3 neurological events occurred among 13% of patients. There were no cases of cerebral edema.

Researchers reported 25 postinfusion deaths, including two within 30 days of infusion and 23 after 30 days (range, 53-859 days). Most of the deaths (n = 19) were due to disease progression.

Tisagenlecleucel expansion correlated with severity of cytokine release syndrome. Researchers observed persistence of tisagenlecleucel with B-cell aplasia in peripheral blood for 2.5 years in some patients.

“We think the efficacy is sustained and excellent,” Grupp said. “I think this is clearly an opportunity for us to treat our patients both in America and now across the world.” – by John DeRosier

Reference:

Grupp S, et al. Abstract 895. Presented at: ASH Annual Meeting and Exposition; Dec. 1-4, 2018; San Diego.

Disclosures : Novartis funded this study. Grupp reports consultant roles with Adaptimmune Therapeutics, Jazz Pharmaceuticals and Novartis. Please see the abstract for all other authors’ relevant financial disclosures.

Perspective

James K. McCloskey, MD

This represents additional follow-up of patients treated on the trial that led to the approval of the first of what is likely to be many CAR T-cell therapies in patients with hematologic malignancies and other cancers. What we saw in this particular clinical update was that, within 11 months of additional observation, many people maintained an enduring response to treatment.

The initial results showed over an 80% complete response rate. With that, many of us were skeptical or curious on how durable that remission would be, but with this clinical trial we saw that many patients retained that remission. Maintaining that kind of duration of response certainly lends promise that they will continue to respond and eventually do well in the long-term.

There are several abstracts [at ASH Annual Meeting and Exposition detailing] how we might salvage patients who start to lose their response. In general, a loss of response or relapse can usually be characterized as loss of CD19 expression or loss of effectiveness of the CAR T-cell product.

There also are abstracts dealing with whether we can use other immunotherapy to re-engage those CAR T-cell products and allow for expansion of the initial product. Others look at the infusion of the product to boost CAR T-cell clonal populations in circulation and improve response rates. Where we go with CAR T-cell failure is still a little bit up in the air, and those clinical trials are still early in development but offer a lot of promising options in the future.

Toxicities of cell therapy in general are improving over time. With this longer period of observation, there was not an increase in toxicities related to cytokine release syndrome, or neurologic toxicities.

That being said, 50% of patients can have some serious cytokine release syndrome-related toxicities. One thing that’s important to remember is that these trials were performed at centers with a lot of experience with these products. It takes a lot of exposure to get used to managing these toxicities. Newer products in development, however, do offer potential better ways of managing those toxicities in the future. It’s certainly always our goal to move forward with products that are going to be less toxic.

A great question is whether we would see similar results in older patients. Those of us who treat adults have borrowed from our pediatric colleagues who often push the boundaries before us in terms of treatment of the disease, monitoring the disease and risk-stratification techniques. We are trying to apply some of these therapies to adolescent and young adult patients and even adults. We have struggled to produce similar efficacy rates and have seen increased toxicities. The biology of B-cell ALL in adults is different than that in children. There are some important similarities that we can often borrow from, but some of the differences are important and we need to address some of those to overcome the refractoriness that we see in those patients.

James K. McCloskey, MD

Hackensack University Medical Center

Disclosures: McCloskey reports no relevant financial disclosures.

ASH Annual Meeting and Exposition

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Single tisagenlecleucel infusion yields durable response in acute lymphoblastic leukemia

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