Clinical trialPhase 2Blood cancers (leukaemia, lymphoma and myeloma)Leukaemia

Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia

N Engl J Med · 201875 infused and evaluable patients

Maude SL, Laetsch TW, Buechner J, et al. N Engl J Med. 2018. 378:439-448

Study type: Clinical trial
Study name: ELIANA
Phase: Phase 2
Design: Single-arm, global study in 25 centres
Sample size: 75 infused and evaluable patients
Source: N Engl J Med · 2018
Trial registration: NCT02435849

In plain words

In CAR-T therapy, the patient's own immune cells (T lymphocytes) are collected and engineered in the laboratory to recognise and destroy leukaemia cells, and are then given back to the patient as a single infusion. In this study of children and young people whose leukaemia had come back after other treatments, more than 8 out of 10 went into remission. Important side effects include high fever and low blood pressure (cytokine release syndrome) and sometimes confusion, so the treatment must be given in a well-equipped centre with close monitoring.

Key results

81%

Overall remission within 3 months

All responders MRD-negative by flow cytometry

50%

12-month event-free survival

95% CI 35 to 64

76%

12-month overall survival

95% CI 63 to 86

Drugs in this study:Cyclophosphamide (Endoxan)

Dose and schedule cards

Tisagenlecleucel (CAR T-cell therapy; ELIANA)

B-ALL that is refractory or in second or later relapse, in patients up to 25 years of ageCycle length: One-timeOn the page “Leukaemia” · Regimens and dosing in relapsed or refractory B-ALL

B-ALL that is refractory or in second or later relapse, in patients up to 25 years of age

Drug	Dose	Route	Schedule
Lymphodepletion
Fludarabine	30 mg/m² per day	IV	4 days
Cyclophosphamide	500 mg/m² per day	IV	2 days (starting on the first day of fludarabine)
One-time infusion
Tisagenlecleucel	50 kg or less: 0.2 to 5.0 × 10⁶ CAR-positive viable T cells/kg; more than 50 kg: 0.1 to 2.5 × 10⁸ cells	IV	2 to 14 days after completion of lymphodepletion

Cycle length: One-time
Duration: One-time

Do not use a leukocyte-depleting filter; do not infuse in the presence of active infection.

On the page “Leukaemia” · Regimens and dosing in relapsed or refractory B-ALL

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Tisagenlecleucel (anti-CD19 CAR-T)

Lymphodepletion: 72 of 75 patients (96%) received lymphodepleting chemotherapy (71 fludarabine + cyclophosphamide and 1 cytarabine + etoposide); FDA label regimen: fludarabine 30 mg/m² IV daily for 4 days + cyclophosphamide 500 mg/m² IV daily for 2 days (starting on the first day of fludarabine), with infusion 2 to 14 days after its completion. 87% of patients received bridging chemotherapy before infusion.

Tisagenlecleucel as a single IV infusion: 2.0 to 5.0 × 10⁶ cells per kg for body weight 50 kg or less, or 1.0 to 2.5 × 10⁸ cells for body weight over 50 kg (protocol); median dose received 3.1 × 10⁶ viable transduced T cells/kg (range 0.2 to 5.4 × 10⁶). Label dose: 0.2 to 5.0 × 10⁶ CAR-positive cells/kg (50 kg or less) or 0.1 to 2.5 × 10⁸ cells (over 50 kg).

Source of the regimen details: ClinicalTrials.gov NCT02435849 (protocol dose), full text of the paper in PMC (PMC5996391; dose received and lymphodepletion) and the FDA label for tisagenlecleucel (DailyMed)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Children and young adults (at least 3 years old at screening and no more than 21 years at diagnosis) with relapsed or refractory CD19-positive B-cell acute lymphoblastic leukaemia (including relapse after stem cell transplantation), with at least 5% lymphoblasts in the bone marrow at screening.

Endpoints

Primary endpoint: overall remission rate (complete remission or complete remission with incomplete blood count recovery) within 3 months.

Secondary endpoints: MRD, duration of remission, event-free survival, overall survival and cellular persistence.

Safety and side effects

Grade 3 or 4 adverse events suspected to be related to treatment in 73%. Cytokine release syndrome (CRS) in 77% of patients (58 of 75), with a median onset of 3 days; 47% were admitted to the ICU for management of CRS and 37% were treated with tocilizumab. Neurological events occurred in 40% of patients; grade 3 neurological events in 13%, with no grade 4 events or cerebral oedema.

Clinical significance and place in guidelines

This study was the basis for the world's first approval of a CAR-T therapy: in August 2017 the FDA approved tisagenlecleucel (Kymriah) for patients up to 25 years of age with B-cell ALL that is refractory or in second or later relapse, followed by EMA approval. Anti-CD19 CAR-T is now a standard option for relapsed or refractory ALL in children and young adults.

Limitations

The study was single-arm with no comparator group. Patients who were enrolled but did not receive an infusion because of disease progression, death or cell manufacturing problems were not included in the efficacy analysis. Follow-up in this report was limited, and half of the patients had an event by 12 months.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.