Introduction: Children with Down syndrome have increased risk of developing leukemia. Pediatric patients with Down syndrome-associated acute lymphoblastic leukemia (DS-ALL) are known to have significant toxicities with reinduction chemotherapy and historically poor outcomes with stem cell transplant (SCT) compared to those without Down syndrome. Alternate therapies are urgently needed for this patient population. The anti-CD19 chimeric antigen receptor (CAR) T-cell therapy CTL019 has demonstrated high rates of durable complete remission and a manageable safety profile in children with r/r B-ALL treated in the multicenter ELIANA and ENSIGN trials.

Methods: Pooled data from 2 single-arm, multicenter phase 2 trials of CTL019 in pediatric/young adult patients with r/r B-ALL (ELIANA, NCT02435849 and ENSIGN, NCT02228096) were used to characterize efficacy and safety of CTL019 therapy in children with DS-ALL.

Results: Eight patients with DS-ALL were enrolled (data cutoff: ELIANA, 23 November 2016; ENSIGN, 1 February 2016). 7 DS-ALL patients were infused with CTL019; 1 patient died prior to infusion due to ALL progression and intracranial hemorrhage. No manufacturing issues occurred during the production of CTL019 for DS-ALL patients. 5/7 infused patients were male, 2/7 had prior SCT, and the patients' ages ranged from 6-16 years.

Complete remission (CR) or CR with incomplete blood count recovery (CRi) occurred in 6/7 patients by day 28 (CR+CRi rate, 86%); the 7th patient died (cerebral hemorrhage) prior to day 28 and was not evaluable for response. Multiparameter flow cytometry was negative in bone marrow for minimal residual disease in all responding patients. Two patients have relapsed at 5 and 8 months after infusion (both CD19 negative relapses). Ongoing remissions in the 4 patients without relapse ranges from 2 to 11 months.

The safety profile of CTL019 in DS-ALL (n=7) appears similar to that for patients without Down syndrome treated in the same trials (n=90). Grade 3 or 4 cytokine release syndrome occurred in 3/7 patients (43%) with Down syndrome and 44% of patients without Down syndrome. Rates of other grade 3 or 4 adverse events of special interest did not appear to favor a consistent trend between patients with and without Down syndrome (febrile neutropenia: 43% vs 36%; neurological events: 14% vs 11%; tumor lysis syndrome: 14% vs 2%). Importantly, grade 3 or 4 infections were not observed in patients with Down syndrome (0% vs 23%). One patient died after infusion due to intracranial parenchymal hemorrhage on day 15 associated with ongoing coagulopathy. Extent and timing of CTL019 expansion as well as long-term persistence of CTL019 was similar in patients with and without Down syndrome.

Conclusions: This is the first analysis of CAR T-cell therapy in pediatric patients with r/r B-ALL and Down syndrome. Although experience in these patients is limited, these data suggest that toxicities appear similar to B-ALL patients without Down syndrome, rates of remission in DS-ALL are high and long-term outcomes of CTL019 therapy with sustained persistence appear promising. Further exploration of CTL019 therapy as an alternative to SCT in children with r/r DS-ALL is warranted.


Laetsch: Novartis Pharmaceuticals Corporation: Consultancy. Maude: Novartis Pharmaceuticals: Consultancy, Other: Medical Advisory Boards. Grupp: Novartis Pharmaceuticals Corporation: Consultancy, Other: grant; Adaptimmune: Consultancy; University of Pennsylvania: Patents & Royalties; Jazz Pharmaceuticals: Consultancy. Boyer: Novartis Pharmaceuticals Corporation: Honoraria. Phillips: Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees. Pulsipher: Chimerix: Other: Advisory board Dec 2015; Jazz Pharmaceuticals: Other: advisory board, education; CSL Behring: Other: advisory board Feb 2017; Adaptive: Other: Advisory board 6/17; Novartis Pharmaceuticals Corporation: Consultancy, Other: Phase II steering committee. Bittencourt: Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Travel Grant; Amgen Inc.: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy. Wood: Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Mueller: Novartis Pharmaceuticals Corporation: Employment. Weng: Novartis Pharmaceuticals Corporation: Employment. June: Immune Design: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Celldex: Honoraria, Membership on an entity's Board of Directors or advisory committees; WIRB/Copernicus Group: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Patents & Royalties, Research Funding; Tmunity Therapeutics: Equity Ownership, Research Funding. Levine: Tmunity Therapeutics: Equity Ownership, Research Funding; Novartis Pharmaceuticals Corporation: Patents & Royalties, Research Funding; Brammer Bio: Consultancy; GE Healthcare: Consultancy. Hiramatsu: Novartis Pharmaceuticals Corporation: Other: Clinical trials .

Author notes


Asterisk with author names denotes non-ASH members.