Patient case: 4-year-old female with leukemia; genetic feature: ABL1

Clinical trial: CD19-CAR Immunotherapy for Childhood Acute Lymphoblastic Leukemia (ALL)

Summary: The aim of this clinical trial is to evaluate the feasibility, safety and biological effect of adoptive transfer of CD19ζ chimaeric receptor transduced donor-derived EBV-specific cytotoxic T-lymphocytes (EBV-CTL) in patients with high-risk or relapsed B cell precursor ALL after allogeneic Haematopoietic Stem Cell Transplantation (HSCT).


Eligibility: 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 MRD positive (BCR-ABL/ABL ratio > 0.01%) after HR3 block of EsPhALL or pre-HSCT or
  -  Infant ALL age < 6 months at diagnosis with MLL gene rearrangement and either presenting wcc >300 x 10^9/L or poor steroid early response (i.e circulating blast count >1x10^9/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 UKALL2011
  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)or
  -  Any relapse of infant or Philadelphia-positive ALL in morphological complete remission
  -  Any patient being transplanted in 3rd or greater CR
  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 (or BCR-ABL/ABL ratio 0.05% in Ph+ve ALL patients with no IgH MRD marker) 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 (8/8 HLA A,B,C and DR at medium resolution typing) or a single antigenic/allelic (7/8) mismatch with the recipient
  -  A life expectancy of at least 12 weeks
  -  Karnofsky score of >60% if >10 years old or Lansky performance score of >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 criteria
  -  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
  -  Patients with CD19 negative precursor B cell ALL
  -  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 criteria
  -  Serologically positive for Hepatitis B, C or HIV pre-HSCT
  -  Females of childbearing age with a positive pregnancy test
  -  Known allergy to DMSO

Relevance to patient case: definitely relevant