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Immunotherapy With CD19ζ Gene-modified EBV-specific CTLs After Stem Cell Transplant in Children With High-risk Acute Lymphoblastic Leukaemia

Phase 1/Phase 2
18 Years
Open (Enrolling)
Acute Lymphoblastic Leukemia

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Trial Information

Immunotherapy With CD19ζ Gene-modified EBV-specific CTLs After Stem Cell Transplant in Children With High-risk Acute Lymphoblastic Leukaemia

Inclusion Criteria

Inclusion Criteria Pre-emptive arm

Children (18 years or younger) with CD19+ precursor B cell ALL fulfilling one of the
following criteria who are undergoing an allogeneic stem cell transplant from an
EBV-seropositive donor:

In first remission, if at least one of the following criteria are met:

- t(9;22) and prednisone poor response or not in molecular remission (BCR-ABL/ABL ratio
> 0.02%) pre-HSCT or

- Infant ALL age < 6 months at diagnosis with MLL gene rearrangement and either
presenting wcc >300 x 109/L or poor steroid early response (i.e circulating blast
count >1x109/L following 7 day steroid pre-phase of Interfant 06) or

- Resistant disease (> 30% blasts at end of induction treatment day 28-33) in
subsequent morphological CR or

- High level bone marrow MRD (> 1 in 1000) at week 12 ALL-BFM 2000/AIEOP BFM ALL
2009/EORTC 58951 protocols, week 12-15 of FRALLE A or at week 14 of UKALL2010

Relapsed patients if at least one of the following criteria are met:

- Very early (< 18 months from diagnosis) bone marrow or extramedullary relapse in
second CR or

- Early (within 6 months of finishing therapy) isolated bone marrow relapse with bone
marrow MRD > 1 in 100 at day 35 of reinduction in second CR or

- Early (within 6 months of finishing therapy) bone marrow or combined relapse with
high level bone marrow MRD (> 1 in 1000) at the end of consolidation therapy (week
12-13 UKALL R3/INTREALL and COOPRALL protocols, prior to protocol M in BFM relapse
protocol (ALL-REZ BFM 2002) and after Protocol II-IDA in AIEOP LLA Rec 2003) These
patients have a high (> 50%) risk of relapse and will be monitored for evidence of
MRD in bone marrow aspirates (monthly for months 1-6, 6 weekly months 7.5-12 post
HSCT) for the first year post-transplant. Patients who become MRD +ve in the marrow
at a level minimum 5 x 10-4 but are in morphological remission (<5% blasts in BM)
will be eligible to be treated pre-emptively with CD19ζ transduced CTL

Prophylaxis arm

Additionally, any patient (≤ 18 years) with ALL relapsing in the bone marrow (isolated or
combined) after myeloablative allogeneic HSCT who achieves morphological remission after
re-induction and who is a candidate for second HSCT at one of the participating centres is
eligible to receive CD19ζ transduced CTL prophylactically

- Stem cell donors must be EBV sero-positive and HLA-matched (10/10) or a single
antigenic/allelic (9/10) mismatch with the recipient

- A life expectancy of at least 8 weeks

- Karnofsky score of >60% if >10 years old or Lansky performance score of greater than
60 if ≤ 10 years old

- Patients must have transduced donor-derived EBV-specific CTLs with 15% or higher
expression of CD19ζ determined by flow-cytometry which meet the specified release

- Informed written consent indicating that patients are aware this is a research study
and have been told of its possible benefits and toxic side effects

Exclusion Criteria

- EBV seronegative or > single antigenic/allelic HLA-mismatched donor

- Active acute GVHD overall Grade 2 or higher or significant chronic GVHD requiring
systemic steroids at the time of scheduled infusion of transduced CTL will be
excluded until the patient is GVHD-free and off steroids

- Pre-existing severe lung disease (FEV1 or FVC < 50% predicted) pre-HSCT or an oxygen
requirement of >28% O2 supplementation or active pulmonary infiltrates on chest X-ray
at the time scheduled for transduced CTL infusion

- Serum bilirubin >3 times the upper limit of normal or an AST or ALT > 5 times the
upper limit of normal

- Serum creatinine >3 times upper limit of normal

- Active severe intercurrent infection at the time of transduced CTL infusion (if
present consult with Chief investigator).

- Patients in whom transduced donor-derived EBV-specific CTLs don't meet release

- Serologically positive for Hepatitis B, C or HIV pre-HSCT

- Females of childbearing age with a positive pregnancy test

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Toxicity attributable to transfer of CD19-zeta transduced CTL

Outcome Description:

Incidence of grade 3-5 toxicity attributable to transfer of CD19-zeta transduced CTL within 12 weeks of infusion. Incidence of significant (Grade II-IV) and severe (Grade III-IV) acute GVHD before day 100 and limited/extensive chronic GVHD between day 100-365. Incidence of hypogammaglobulinaemia after CD19-zeta CTL transfer at day 100, 6 months and 1 year post-HSCT

Outcome Time Frame:

1 year

Safety Issue:


Principal Investigator

Persis Amrolia, Professor

Investigator Role:

Study Chair

Investigator Affiliation:

Great Ormond Street Hospital for Children NHS Foundation Trust


United Kingdom: Medicines and Healthcare Products Regulatory Agency

Study ID:




Start Date:

May 2012

Completion Date:

January 2021

Related Keywords:

  • Acute Lymphoblastic Leukemia
  • Immunotherapy
  • Gene Therapy
  • Paediatric
  • B cell Acute Lymphoblastic Leukaemia
  • Leukemia
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma