Acute Myeloid Leukemia, Relapsed, Acute Lymphoblastic Leukemia, High Risk, Acute Myeloid Leukemia, High Risk, Acute Lymphoblastic Leukemia, Relapse
Conditions
Keywords
Acute myeloid leukemia, Acute lymphoblastic leukemia, relapse, T regulatory, CD3 depletion, allogeneic HSCT
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
1. Infusion of ex-vivo T-depleted peripheral blood hematopoietic stem cells (CD3 depletion product) 2. Infusion of donor lymphocytes enriched with T regulatory lymphocytes (CD25 selective product) 3. Drug therapy (pharmacological prophylaxis of GVHD) * Cyclosporine A * Sirolimus o Ruxolitinib o Abatacept
Interventions
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).
DRUGSirolimus
Pharmacological prophylaxis of GVHD is one of the key subjects of evaluation in the current study. Since the optimal pharmacological approach is not known, the allocation of the patients to study groups will be by randomization procedure, although not for the purpose of direct comparison, but for unbiased descriptive analysis. There will be four main groups and an additional group to be open for allocation based on the main group closing for fitting the stopping rules. The details of pharmacological GVHD prevention are Sirolimus 1 mg -3 till +30 4-8 ng/ml
Pharmacological prophylaxis of GVHD is one of the key subjects of evaluation in the current study. Since the optimal pharmacological approach is not known, the allocation of the patients to study groups will be by randomization procedure, although not for the purpose of direct comparison, but for unbiased descriptive analysis. There will be four main groups and an additional group to be open for allocation based on the main group closing for fitting the stopping rules. The details of pharmacological GVHD prevention regimens are Ruxolitinib 5 mg -2 till +30
DRUGAbatacept
Pharmacological prophylaxis of GVHD is one of the key subjects of evaluation in the current study. Since the optimal pharmacological approach is not known, the allocation of the patients to study groups will be by randomization procedure, although not for the purpose of direct comparison, but for unbiased descriptive analysis. There will be four main groups and an additional group to be open for allocation based on the main group closing for fitting the stopping rules. Abatacept 10 mg/kg -1, +7, +14, +28
Sponsors
Federal Research Institute of Pediatric Hematology, Oncology and Immunology
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
SINGLE (Caregiver)
Eligibility
Sex/Gender
ALL
Age
1 Years to 25 Years
Healthy volunteers
No
Inclusion criteria
1. Informed consent signed by the patient (age 14 to 25 years) and/or his/her legal representative (age 0 to 18 years). 2. The patient has an indication for allogeneic hematopoietic stem cell transplantation (HSCT) established in accordance with the current regulatory framework 3. Planned HSCT from a haploidentical donor 4. The Karnofsky or Lansky score is more than 70% 5. Life expectancy of at least 8 weeks 6. Heart function: ejection fraction of at least 40% 7. Consent to continue follow-up for 3 years
Exclusion criteria
1. Acute viral hepatitis or acute HIV infection 2. Hypoxemia with SaO2 \<90% 3. Bilirubin \>3 normal 4. Creatinine \>3 norms 5. Pregnancy and lactation 6. Life-threatening infection 7. Severe (\>?) pathology of the central nervous system (epilepsy, dementia, organic damage to the central nervous system) 8. Karnofsky score or Lansky score \<70%
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Feasibility- Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | 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 | 120 days after HSCT | Cumulative risk of GVHD Grade III-IV (target \< 5%) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | — |
| 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 developing severe chronic GVHD | at 2 years | Severity of chronic GVHD |
| Cumulative risk of viral | at 120 day after HSCT | (CMV, ADV, EBV, HHV-6) DNA detection in blood, peak viral DNA load and the duration of detectable viral DNA (each virus separately) |
| Cumulative risk of leukemia relapse | at 2 years | — |
Countries
Russia
Contacts
CONTACTMichael Maschan, Prof
Outcome results
None listed