Risk-adapted Donor Lymphocyte Infusion After Allo-HSCT in Children With Hematologic Malignancy

Study of the Efficacy and Safety of Risk-adapted Donor Lymphocyte Infusions for the Prophylaxis and Prevention of Relapses After Allogeneic Hematopoietic Stem Cell Transplantation in Children and Adolescent With Hematologic Malignancy

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.

Study Overview

• Status: Completed
• Conditions: Hematologic Malignancy
• Intervention / Treatment: Biological: Prophylactic Donor lymphocytes infusions; Biological: Preventive Donor lymphocytes infusions

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Russian Federation
  • Saint Petersburg, Russian Federation, 197022
    • RM Gorbacheva Research Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 months to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Prophylactic; The patients with high risk of relapse of disease and full donor chimerism after allo-HSCT without signs of the disease will be include in this group.	Biological: Prophylactic 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.
Experimental: Preventive; The patients with persisted minimal residual disease or cytogenetic relapse after allo-HSCT will be include in this group.	Biological: Preventive 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relapse - free survival	Estimate time to morphological relapse by Kaplan Mayer	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival analysis	Estimate time to death by Kaplan Mayer	24 months
Relapse rate analysis	Cumulative incidence of patients with relapse by Gray's test	24 months
Non-relapse mortality analysis	Cumulative incidence of patients with mortality without hematological relapse of malignancy	24 months
Incidence of acute GVHD grade II-IV	Cumulative incidence of patients with acute GVHD II-IV grade by Gray's test	125 days
Incidence of moderate and severe chronic GVHD	Cumulative incidence of patients with moderate and severe chronic GVHD according to NIH 2015 criteria by Gray's test	24 months
Incidence of achievement MRD negative status	Cumulative incidence of patients with MRD positive status, who had responds to therapy Gray's test	24 months
Relapse - free survival	Estimate time to appearing of MRD or morphological relapse by Kaplan Mayer	24 months
Graft - versus -host-disease free/relapse free survival	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	24 months

Collaborators and Investigators

• Sponsor: St. Petersburg State Pavlov Medical University

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2021
• Primary Completion (Actual): April 1, 2023
• Study Completion (Actual): April 1, 2024

Study Registration Dates

• First Submitted: August 16, 2021
• First Submitted That Met QC Criteria: August 16, 2021
• First Posted (Actual): August 17, 2021

Study Record Updates

• Last Update Posted (Actual): June 25, 2024
• Last Update Submitted That Met QC Criteria: June 23, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Keywords: children; allo-HSCT; Donor LymphocyteI Infusion
• Additional Relevant MeSH Terms: Neoplasms by Site; Hematologic Diseases; Neoplasms; Hematologic Neoplasms
• Other Study ID Numbers: hsct/dli

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No