Hematologic Malignancy
Conditions
Keywords
allo-HSCT, children, Donor LymphocyteI Infusion
Brief summary
Allo-hsct is potentially curative method of treatment for children and adolescent with hematologic malignancy. However, relapses of disease after allo-hsct occur up to 50% of patients and constitute the main cause of mortality after HSCT. Donor lymphocytes infusion (DLI) is a form of immunotherapy based on developement of reaction graft versus from leukemia. This study evaluates the safety and efficacy of risk-adapted srtategy of DLI for prophylaxis and prevention posttransplant relapses in children and adolescent with hematologic malignancy.
Interventions
BIOLOGICALProphylactic Donor lymphocytes infusions
Donor lymphocytes is taken by apheresis or dose of blood from allogeneic donor. After apheresis lymphocytes arel freezed for next using. DLI is transfused to patients IV using central venous access. Donor lymphocytes infusion start from D+60 - D+100 and continue with escalating doses every 1.5-3 months during first year after HSCT up to appearance of GVHD or signs of disease. First dose is 1\*10\*6 CD3+/kg. Subsequent doses increases by 0.5 log for haploidentical and unrelated donor and 1 log for sibling donor up to 1\*10\*8 CD3+/kg.
BIOLOGICALPreventive Donor lymphocytes infusions
Donor lymphocytes is taken by apheresis or dose of blood from allogeneic donor. After apheresis lymphocytes freeze for next using. DLI are transfused to patients IV using central venous access. Donor lymphocytes infusion continue with escalating doses every 1.5-3 months up to achieving MRD negative status or appearance of GVHD or signs of active disease. First dose is 1\*10\*6 CD3+/kg for patients without previous GVHD and 1\*10\*5 CD3+/kg for patients with previous GVHD. Subsequent doses increases by 0.5 log for haploidentical and unrelated donor and 1 log for sibling donor up to 1\*10\*8 CD3+/kg.
Sponsors
St. Petersburg State Pavlov Medical University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Intervention model description
The patients in this study will be divided into 2 groups: prophylactic and preventive depending on indications. Patients without signs of disease with high risk of relapse will be included into prophylactic group. Patients with persistence minimal residual disease or cytogenetic relapse will be included into preventive group. Also, patients will move from the first group to second group, if the clinical status changes.
Eligibility
Sex/Gender
ALL
Age
4 Months to 18 Years
Healthy volunteers
No
Inclusion criteria
* Age 4 months - 18 years old * Diagnosis: acute lymphoblastic leukemia, acute myeloid leukemia, juvenile myelomonocytic leukemia, myelodysplastic syndrome, chronic myeloid leukemia * Signed by legal representatives informed consent * High risk disease ( for ALL - initial hyperleukocytosis\> 50x109 / L, T-cell ALL, hypodiploid karyotype, complex karyotype, MLL gene rearrangement, SIL-TAL deletion, primary resistent of the disease, early/very earle relapse, infant ALL; for AML patients - rearrangement of the MLL gene (except for t (1; 11) and t (9; 11) with M5 morphology), inv (3), t (3; 3), complex karyotype anomalies, t (8; 21 ) with trisomy 4, t (16; 21), monosomy 7, monosomy 5, M7 without t (1; 22), FLT3+, M6, t (7; 12), AML with multilineage dysplasia, p53 gene mutations, NUP98 translocations, primary resistent of the disease, early/very earle relapse infant AML, secondary AML; all juvenile myelomonocytic leukemia and myelodysplastic syndrome; allo-HSCT at 3 or more remission; persistence MRD before alloHSCT; allo-HSCT out of remission; persistence MRD after alloHSCT; cytogenetic relapse after alloHSCT ) * Donor chimerism=\>95% * No poor graft function (haemoglobin concentration \< 100 g/L; neutrophils \< 1.0 × 10E + 9/L; and platelets \< 30 × 10E + 9/L on day ≥ 30 post transplant with complete donor chimerism and no graft-versus-host disease or relapse ) * ECOG 0-2 status * Karnofsky/Lansky status \>30%
Exclusion criteria
* Uncontrolled bacterial or fungal infection at the time of enrollment * Severe organ failure: creatinine more than 2 norms; ALT, AST more than 5 norms; bilirubin more than 1.5 norms * Ejection fraction less than 50% * Requirement for vasopressor support at the time of enrollment * Somatic or psychiatric disorder making the patient unable to sign an informed consent * Acute GVHD grade 3-4 in patient medical history * Severe chronic GVHD in patient medical history
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Relapse - free survival | 24 months | Estimate time to morphological relapse by Kaplan Mayer |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Relapse rate analysis | 24 months | Cumulative incidence of patients with relapse by Gray's test |
| Non-relapse mortality analysis | 24 months | Cumulative incidence of patients with mortality without hematological relapse of malignancy |
| Incidence of acute GVHD grade II-IV | 125 days | Cumulative incidence of patients with acute GVHD II-IV grade by Gray's test |
| Overall survival analysis | 24 months | Estimate time to death by Kaplan Mayer |
| Incidence of achievement MRD negative status | 24 months | Cumulative incidence of patients with MRD positive status, who had responds to therapy Gray's test |
| Relapse - free survival | 24 months | Estimate time to appearing of MRD or morphological relapse by Kaplan Mayer |
| Graft - versus -host-disease free/relapse free survival | 24 months | Estimate time to date of III-IV acute GVHD (aGVHD), chronic GVHD (cGVHD) requiring systemic immunosuppressive treatment, disease relapse or death from any other cause by Kaplan Mayer |
| Incidence of moderate and severe chronic GVHD | 24 months | Cumulative incidence of patients with moderate and severe chronic GVHD according to NIH 2015 criteria by Gray's test |
Countries
Russia
Outcome results
None listed