Pilot Study of Co-Infusion of Donor Lymphocytes Enriched With Regulatory T Lymphocytes With Ex-vivo CD3-Depleted Hematopoietic Stem Cell Graft for the Prevention of Graft-versus-Host Disease in Children With Hematopoietic and Lymphoid Tissue Neoplasms
Overview
- Phase
- Phase 2
- Status
- Recruiting
- Enrollment
- 64
- Locations
- 1
- Primary Endpoint
- Feasibility- Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Overview
Brief Summary
Two key methods of GVHD prevention in allogeneic HSCT have a number of limitations: ex vivo T depletion is associated with an excess of infectious complications, and pharmacological immunosuppression with insufficient efficacy of GVHD prevention. Modern graft engineering technologies make it possible to create a graft with a balanced cell composition, reducing the risk of adverse events, in particular, severe forms of acute and chronic GVHD, while preserving the immunological function of the graft. In the proposed concept, enrichment of the T graft with regulatory cells will reduce the risk of GVHD and preserve a sufficient number of T lymphocytes in the graft for the formation of protective anti-infective immunity in the early stages after HSCT. The combination of partial T depletion and pharmacological immunosuppression minimized in volume and duration will combine the advantages of T depletion (early engraftment, low risk of GVHD, low risk of organ complications) and pharmacological prophylaxis (restoration of anti-infective immunity).
Detailed Description
- Infusion of ex-vivo T-depleted peripheral blood hematopoietic stem cells (CD3 depletion product)
- Infusion of donor lymphocytes enriched with T regulatory lymphocytes (CD25 selective product)
- Drug therapy (pharmacological prophylaxis of GVHD)
- Cyclosporine A
- Sirolimus o Ruxolitinib o Abatacept
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Sequential
- Primary Purpose
- Treatment
- Masking
- Single (Care Provider)
Eligibility Criteria
- Ages
- 1 Year to 25 Years (Child, Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Informed consent signed by the patient (age 14 to 25 years) and/or his/her legal representative (age 0 to 18 years).
- •The patient has an indication for allogeneic hematopoietic stem cell transplantation (HSCT) established in accordance with the current regulatory framework
- •Planned HSCT from a haploidentical donor
- •The Karnofsky or Lansky score is more than 70%
- •Life expectancy of at least 8 weeks
- •Heart function: ejection fraction of at least 40%
- •Consent to continue follow-up for 3 years
Exclusion Criteria
- •Acute viral hepatitis or acute HIV infection
- •Hypoxemia with SaO2 \<90%
- •Bilirubin \>3 normal
- •Creatinine \>3 norms
- •Pregnancy and lactation
- •Life-threatening infection
- •Severe (\>?) pathology of the central nervous system (epilepsy, dementia, organic damage to the central nervous system)
- •Karnofsky score or Lansky score \<70%
Arms & Interventions
Cyclosporine A
Four groups corresponding to the pharmacological prophylaxis of GVHD: 1) Cyclosporine A
Intervention: Cyclosporine A (CsA) (Drug)
Sirolimus
Drug therapy (pharmacological prophylaxis of GVHD) 2) Sirolimus
Intervention: Sirolimus (Drug)
Ruxolitinib
Drug therapy (pharmacological prophylaxis of GVHD) Ruxolitinib
Intervention: Ruxolitinib (JAKAVI®) (Drug)
Abatacept
Drug therapy (pharmacological prophylaxis of GVHD) Abatacept
Intervention: Abatacept (Drug)
Outcomes
Primary Outcomes
Feasibility- Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Time Frame: day 30
proportion of patients who received an infusion of the planned dose of regulatory T lymphocytes (at least 80%)
Safety- Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Time Frame: 120 days after HSCT
Cumulative risk of GVHD Grade III-IV (target \< 5%)
Secondary Outcomes
- Cumulative probability of engraftment(up to 100 day)
- Time to engraftment of neutrophils and platelets(100 day after HSCT)
- Cumulative risk of acute GVHD Grade II-IV(up to 100 days after HSCT)
- Cumulative risk of viral(at 120 day after HSCT)
- cumulative risk of developing severe chronic GVHD(at 2 years)
- Cumulative risk of leukemia relapse(at 2 years)
- Cumulative risk of non-relapse mortality(at 100 days and 2 years)
- Overall survival(at 3 years)
- Event-free survival(at 3 years)
- GVHD- and relapse-free survival(at 3 years)