Infusion of Alloreactive nk Cells for Mrd-positive Aml Patients

Infusion of Alloreactive nk Cells for Acute Myeloid Leukemia Patients, Eligible for Allogeneic Stem Cell Transplantiation, With Persistent Minimal Residual Disease After Conventional Chemotherapy

This is a interventional, transplantation study. The procedure under study is the infusion of alloreactive NK cells in adult AML patients, eligible for ASCT, who achieved CR after conventional chemotherapy, but harbor MRD-positivity.

Haploidentical KIR-L mismatched donors will be included if present at least one allele mismatch at a class I locus among the following ones: HLA-C alleles with Asn77-Lys80, HLA-C alleles with Ser77-Asn80, HLA-Bw4 alleles. KIR-L mismatched donor alloreactive NK cell repertoire will be evaluated in order to determine the functional cell dose to be used for NK cell collection. Phenotypical analysis of KIRs will be correlated to functional tests. NK cells will be selected from a steady-state large volume leukapheresis product from a suitable haploidentical KIR-ligand incompatible donor. NK cell purification will be performed if the donor leukapheresis product contains at least 10x106 NK cells/Kg.

Immunomagnetic enrichment of NK cells will follow two subsequent steps: 1) depletion of CD3+ T cells followed by 2) positive selection of CD56+ NK cells.

Patients will receive immunosuppressive chemotherapy, fludarabine (Flu) 25 mg/mq/ from day -5 to -3 and cyclophosphamide (Cy) 2 g/mq on day -2 (Flu/Cy). Two days after Cy administration, patients will be infused intravenously with a single dose of cryopreserved NK cells (day 0), which will be followed by subcutaneous administration of IL-2 (10 x 106 IU/day, 3 times weekly) for 2 weeks (6 doses total). PB samples will also be collected for biological studies. In particular, PB samples will be collected for molecular assessment of microchimerism and tracking of haploidentical NK cells for 30 days, immunophenotype studies, alloreactive NK cells cloning and functional assays (cytotoxicity). Enrolled patients will be followed up for at least 12 months after NK cell infusion.

Study Overview

• Status: Recruiting
• Conditions: Acute Myeloid Leukemia; Minimal Residual Disease; Natural Killer Cell
• Intervention / Treatment: Biological: Infusion of alloreactive NK cells

• Study Type: Interventional
• Enrollment (Estimated): 22
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Antonio Curti; Phone Number: +390512144074; Email: antonio.curti2@unibo.it

Study Locations

• Italy
  • BO
    • Bologna, BO, Italy, 40138
      • Recruiting
      • Antonio Curti
      • Contact: Antonio Curti; Phone Number: +390512144074; Email: antonio.curti2@unibo.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosis of de novo or secondary AML
• Age ≥ 18 years
• Morphologic CR
• Eligibility for ASCT
• MRD-positivity after induction chemotherapy
• Availability of a KIR-L incompatible haploidentical donor
• Performance Status ≥ 70% (Karnofsky score) or ≤ 2 (WHO).
• Adequate renal (serum creatinine < 2 mg/dl), pulmonary (Sat O2 ≥ 96%) and hepatic (ALT/AST < 2.5 x N) function.
• Left Ventricular Ejection Fraction (LVEF) of >50% as determined by Echocardiogram (ECHO).
• Signed informed consent.

Exclusion Criteria:

• Diagnosis of AML FAB M3
• HIV positivity.
• HCV positivity with high viral load.
• Pregnant or nursing females.
• Current uncontrolled infection.
• Signs or symptoms of fluid retention (e.g. pleural effusion).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Infusion of alloreactive NK cells; Infusion of alloreactive NK cells for acute leukemia patients, eligible for allogeneic stem cell transplantation, with persistent minimal residual disease after conventional chemotherapy	Biological: Infusion of alloreactive NK cells; Infusion of alloreactive NK cells for acute leukemia patients harboring minimal residual disease after conventional chemotherapy and prior to allogeneic stem cell transplantation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety of infusing a functional target cell dose of 2x105 alloreactive NK cells/kg in AML patients,eligible for ASCT, with persistent MRD after conventional chemotherapy	Safety of infusing a functional target cell dose of 2x105 alloreactive NK cells/kg in AML patients,eligible for ASCT, with persistent MRD after conventional (number of adverse events and severe adverse events)	48 months
Feasibility of collecting a functional target cell dose of 2x105 alloreactive NK cells/kg in at least 70% of patients entering the study	Feasibility of collecting a functional target cell dose of 2x105 alloreactive NK cells/kg in at least 70% of patients entering the study as evaluated by in vitro cytotoxicity assay.	48 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients who achieve and maintain MRD negativity after infusion of alloreactive NK cells	Number of patients who achieve and maintain MRD negativity after infusion of alloreactive	48 months
Number of patients who enter ASCT in MRD-negativity	Number of patients who enter ASCT in MRD-negativity	48 months
Relapse-free survival (RFS) of patients infused with alloreactive NK cells	Relapse-free survival (RFS)of patients infused with alloreactive NK cells	48 months
overall survival (OS) of patients infused with alloreactive NK cells	overall survival (OS) of patients infused with alloreactive NK cells	48 months
Assess the predictive impact of donor NK cell repertoire on overall survival	Assess the predictive impact of donor NK cell repertoire as evaluated as the number of alloreactive NK cells/kg, in terms of overall survival	48 months
Assess the predictive impact of donor NK cell repertoire on relapse-free survival	Assess the predictive impact of donor NK cell repertoire as evaluated as the number of alloreactive NK cells/kg, in terms of relapse-free survival	48 months
Evaluate the microchimerism of patients receiving human NK cells	Evaluate the microchimerism of patients receiving human NK cells, as evaluated as percent of donor's cells into recipients	48 months
Functionally evaluate, in vitro and ex vivo, the antitumor activity of infused NK cells	Functionally evaluate, in vitro and ex vivo, the antitumor activity of infused NK cells, as evaluated by in vitro cytotoxicity assay (percent of lysis by donor NK cells of recipients cells).	48 months
Assess the molecular features of infused NK cells	Assess the molecular features of infused NK cells, qualitative gene expression profile.	48 months

Collaborators and Investigators

• Sponsor: IRCCS Azienda Ospedaliero-Universitaria di Bologna
• Investigators: Principal Investigator: Antonio Curti, Istituto di Ematologia Seràgnoli, Azienda Ospedaliero-Universitaria di Bologna (IRCCS)

Study record dates

Study Major Dates

• Study Start (Actual): January 22, 2021
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: January 22, 2021
• First Submitted That Met QC Criteria: March 18, 2025
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 18, 2025
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Neoplasms by Histologic Type; Hematologic Diseases; Neoplastic Processes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Neoplasm, Residual
• Other Study ID Numbers: MRD-NK

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