Tisagenlecleucel Safety, Efficacy Promising in Pediatric Down Syndrome and ALL

Theodore W. Laetsch, MD

A first-time study of chimeric antigen receptor (CAR) T-cell therapy in youths with Down syndrome-associated relapsed/refractory (r/r) acute lymphoblastic leukemia (DS-ALL) produced high remission rates and toxicity results that were similar to those observed in patients with r/r ALL, according to results presented at the 2018 American Society of Pediatric Hematology/Oncology Conference.

In DS-ALL patients (n = 8), two relapsed at 5 and 8 months after infusion, both being CD19-negative relapses, and ongoing remissions in 4 patients without relapse ranged from 2 to 11 months.

The results are promising, because patients with Down syndrome have historically experienced more toxicity and had poorer outcomes and are typically excluded from clinical trials of novel therapies for ALL, said lead author Theodore W. Laetsch, MD, of the Department of Pediatrics at the University of Texas Southwestern Medical Center, in a poster presentation.

“Of the evaluable patients, there was an 86% response rate in children and young adults with Down syndrome, which is very similar to the 81% response rate reported for similarly aged patients without Down syndrome,” Laetsh said. “What this means to me is that this therapy appears to work as well in patients with Down syndrome as patients without, which is very different than other therapies for children and young adults with relapsed leukemia like stem cell transplant, where there is much higher reported toxicity and less survival.

“This is a good option for kids with relapsed Down syndrome ALL.”

Based on the results, investigators anticipate long-term outcomes with sustained persistence and concluded further exploration of tisagenlecleucel therapy as an alternative to stem cell transplantation in this patient population is warranted.

Investigators conducted a pooled analysis of 8 patients with Down syndrome and 90 without who were treated for ALL in the ELIANA and ENSIGN trials. Both were multicenter, single-arm, phase II trials evaluating tisagenlecleucel in children and young adults.

Patients with Down syndrome were aged a median of 8 years (range, 6-16) compared with 12 years (range 3-25) for other patients. The Down syndrome cohort was mostly male (71.4%) and had high tumor burden; median blast count in bone marrow prior to enrollment was 80%. Six patients in this cohort were classified as CNS-1 at enrollment, meaning no central nervous system disease, and 1 was classified as CNS-2, meaning mild disease. All patients had refractory ALL, and the median time from most recent relapse to CAR T-cell infusion was 3.1 months.

Among patients without Down syndrome, 50.5% were male and had a median blast count in bone marrow of 73% prior to enrollment. The majority (85.5%) were classified as CNS-1 and 12.2% were CNS-2. Nearly all (91.1%) had relapsed disease, and the remainder had primary refractory ALL. Median time from most recent relapse to infusion was 3.2 months.

On day 15, 1 patient with Down syndrome died due to intracranial parenchymal hemorrhage associated with ongoing coagulopathy and was not evaluable for response.

Two (28.6%) patients with Down syndrome had undergone prior stem cell transplantation compared with 48 (53.3%) among non-Down syndrome patients.

By day 28 after infusion, 6 of 7 (85.7%) patients with Down syndrome had complete remission or complete remission with incomplete blood count recovery (CR/CRi). All responding patients had minimal residual disease according to multiparameter flow cytometry of bone marrow.

All patients in both groups experienced adverse events (AEs) at any point post-infusion. Laetsch said that incidence and severity of AEs were similar in both groups and declined after 8 weeks. Up to 8 weeks, the rate of any-grade AEs was 100% in the Down syndrome cohort and 97.8% in the non-Down syndrome cohort. After 8 weeks, those rates dropped to 83.3% and 82.4%, respectively.

The rates of grade 3/4 AEs were similar between the groups up to 8 weeks (85.7% vs 82.2%). The rate subsequently declined to 66.7% in the Down syndrome group compared with 39.2% in the non-Down syndrome group.

“The side effects with this therapy were very similar in patients with Down syndrome and those without Down syndrome, in terms of cytokine release syndrome [CRS], the incidence of neurologic toxicities, and the incidence of infections,” Laetsch said. “Even looking specifically within patients who had CRS, incidence of severe CRS was similar across the groups.”

Rates of grade 3/4 CRS were 42.9% in the Down syndrome group compared with 44.4% of the non-Down syndrome group.

Investigators characterized exposure to tisagenlecleucel in both groups to assess the relationship between transgene expansion and safety in patients with Down syndrome. Laetsch et al found that exposure and time to reach peak tisagenlecleucel concentration in peripheral blood was comparable between the 2 groups.

Laetsch said the study is ongoing and investigators do not yet have duration of response data. He plans to update the data for publication.

In August 2017, the FDA approved tisagenlecleucel for patients aged up to 25 years with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse, making it the first CAR T-cell therapy approved in the United States. Earlier this week, tisagenlecleucel won FDA approval for use in adult patients with relapsed/refractory large B-cell lymphoma—including diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma and DLBCL arising from follicular lymphoma—after 2 or more lines of systemic therapy.

Laetsch T, Maude SL, Grupp SA, et al. Tisagenlecleucel (CTL019) therapy appears safe and effective in pediatric patients with down syndrome with relapsed/refractory acute lymphoblastic leukemia. Presented at: 2018 ASPHO Conference; May 2-5, 2018; Pittsburgh, PA. Poster 703.

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