Donor-derived NK-cell infusions to prevent leukemia relapse after stem cell transplant

Phase I/II Clinical Trial of mbIL21 ex Vivo-expanded Donor-derived NK-cell Infusions With Hematopoietic Stem Cell Transplantation for Disease Relapse Prophylaxis in Pediatric and Young Adult Patients With Chemorefractory or Minimal Residual Disease Positive Acute Leukemia

This trial tests donor-derived, mbIL21-expanded natural killer (NK) cell infusions given before and after matched-related or haploidentical stem cell transplants to try to prevent relapse in children and young adults (about 1–25 years) with chemorefractory or MRD-positive acute leukemia.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 15 (estimated)
• Ages: 1 Month to 25 Years
• Sex: All
• Sponsor: Federal Research Institute of Pediatric Hematology, Oncology and Immunology (Academic / other)
• Drugs / interventions: tocilizumab, cyclophosphamide, fludarabine, prednisone
• Locations: 1 site (Moscow)
• Trial ID: NCT07256210 on ClinicalTrials.gov

What this trial studies

This is a phase I/II program that begins with a 3+3 dose-escalation (phase I) to identify the maximum tolerated dose of mbIL21-expanded donor NK cells and proceeds to a phase II cohort. Donor-derived NK cells are expanded ex vivo with mbIL21 and infused around the time of allogeneic hematopoietic stem cell transplantation (split conditioning regimen) with two planned NK-cell infusions. The trial enrolls pediatric and young adult patients with chemorefractory or pre-transplant MRD-positive acute myeloid leukemia, T-lymphoblastic leukemia, or mixed phenotype acute leukemia who receive haploidentical or matched-related grafts. Primary endpoints are feasibility, safety, and MTD; secondary endpoints include short-term disease response, lymphocyte subset reconstitution, and transplant outcomes.

Who should consider this trial

Good fit: Children and young adults roughly 1–25 years old with chemorefractory or pre-transplant MRD-positive acute myeloid leukemia, T-lymphoblastic leukemia, or mixed phenotype acute leukemia who are planned for matched-related or haploidentical allogeneic stem cell transplantation and have an available donor.

Not a fit: Patients in durable complete remission without MRD, those not proceeding to allo-HSCT, adults outside the eligible age range, or patients with uncontrolled infections or severe organ dysfunction are unlikely to benefit from this intervention.

Why it matters

Potential benefit: If successful, this approach could reduce relapse after transplant and improve long-term outcomes for high-risk pediatric and young adult acute leukemia patients.

How similar studies have performed: Early-phase trials of donor NK-cell infusions and ex vivo-expanded NK products have shown acceptable safety and some anti-leukemia signals, but the specific mbIL21-expanded peri-transplant strategy is relatively novel and not yet proven.

Eligibility criteria

Inclusion Criteria:

1. Patient (age from 14 to 25 years) and/or patient's legal representative (age from 0 to 18 years) should provide written informed consent.
2. Patients with one of the following disease:

   * Acute myeloid leukemia: a. primary refractory disease (absence of complete remission (CR) after two induction regimens), b. refractory relapse (absence of CR after one salvage regimen), c. MRD-persistence before conditioning (presence of residual leukemic population more than 0,01% of bone marrow nucleated cells by flow cytometry);
   * Acute T-lymphoblastic leukemia: a. primary refractory disease (absence of complete remission (CR) after two induction regimens), b. refractory relapse (absence of CR after one salvage regimen), c. MRD-persistence before conditioning (presence of residual leukemic population more than 0,1% of bone marrow nucleated cells by flow cytometry);
   * Acute mixed phenotype leukemia: a. primary refractory disease (absence of complete remission (CR) after two induction regimens), b. refractory relapse (absence of CR after one salvage regimen), c. MRD-persistence before conditioning (presence of residual leukemic population more than 0,01% of bone marrow nucleated cells by flow cytometry).
3. Patient is indicated to receive allo-HSCT according to actual clinical practice.
4. Haploidentical or matched related donor was chosen and is available for allo-HSCT (and NK-cell therapy).
5. Patient's clinical status: Lansky/Karnowski index ≥50%.
6. Kidney function: clearance of endogenous creatinine or glomerular filtration rate according to Schwarz equation ≥50 ml/min/1,73 m2.
7. Liver function: total bilirubin ≤3 ULN except for Gilbert's disease, ALT/AST ≤3 ULN.
8. Heart function: left ventricular ejection fraction ≥40%.
9. Lung function: lung capacity ≥50%, for children who cannot carry out of respiratory function - oxygen saturation during pulse oximetry ≥92% (without supplemental oxygen).
10. Life expectancy ≥8 weeks.
11. Patients who agree to long-term follow up for up to 2 years.

Exclusion Criteria:

1. Inability to provide or withdrawal of written informed consent.
2. Cellular therapy including allo-HSCT within prior 4 months period, absence of active signs of GVHD, sinusoidal obstruction syndrome, cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome.
3. Active hepatitis B, C or HIV infection.
4. Pregnant or lactating women.
5. Uncontrolled infection; principal investigator is the final arbiter of this criterion.
6. Clinical signs of grade ≥3 CNS disorders (seizure disorder, paresis, aphasia, cerebrovascular ischemia/hemorrhage, severe brain injuries, dementia, organic brain syndrome, psychosis, coordination or movement disorder).
7. Mental illness of the patient or caregivers, making it impossible to realize the essence of the study and compromising compliance with medical appointments and sanitary and hygienic regime.

Where this trial is running

Moscow

• Dmitry Rogachev Federal Research and Clinical Centre of Paediatric Haematology, Oncology and Immunology — Moscow, Russia (Recruiting)

Study contacts

• Study coordinator: Timofei Y Zavidnyi, MD

Conditions Acute Myeloid Leukemia; Acute Lymphoblastic T-cell Leukemia; Mixed Phenotype Acute Leukemia; Natural killer cell therapy; Hematopoietic stem cell transplantation; Leukemia, Acute; Refractory Leukemias; Pre-transplantation MRD-positivity