cd19-car immunotherapy for childhood acute lymphoblastic leukemia (all)

Conditions: Acute Lymphoblastic Leukemia

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 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 mrd positive (bcr-abl/abl ratio \> 0.01%) after hr3 block of esphall or pre-hsct or * infant all age \ 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 \ 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

Keywords: immunotherapy gene therapy paediatric b cell acute lymphoblastic leukaemia