Clinical trial NCT06885476: Infusion of Alloreactive nk Cells for Mrd-positive Aml Patients
Official title: Infusion of Alloreactive nk Cells for Acute Myeloid Leukemia Patients, Eligible for Allogeneic Stem Cell Transplantiation, With Persistent Minimal Residual Disease After Conventional Chemotherapy
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Acute Myeloid Leukemia
Minimal Residual Disease
Natural Killer Cell
Lead sponsor: IRCCS Azienda Ospedaliero-Universitaria di Bologna
Sponsor class: OTHER
First posted: 2025-03-20
Enrollment: 22
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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).

Primary outcomes:
measure: 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
timeFrame: 48 months
measure: Feasibility of collecting a functional target cell dose of 2x105 alloreactive NK cells/kg in at least 70% of patients entering the study
timeFrame: 48 months
Secondary outcomes:
measure: Number of patients who achieve and maintain MRD negativity after infusion of alloreactive NK cells
timeFrame: 48 months
measure: Number of patients who enter ASCT in MRD-negativity
timeFrame: 48 months
measure: Relapse-free survival (RFS) of patients infused with alloreactive NK cells
timeFrame: 48 months
measure: overall survival (OS) of patients infused with alloreactive NK cells
timeFrame: 48 months
measure: Assess the predictive impact of donor NK cell repertoire on overall survival
timeFrame: 48 months
measure: Assess the predictive impact of donor NK cell repertoire on relapse-free survival
timeFrame: 48 months
measure: Evaluate the microchimerism of patients receiving human NK cells
timeFrame: 48 months
measure: Functionally evaluate, in vitro and ex vivo, the antitumor activity of infused NK cells
timeFrame: 48 months
measure: Assess the molecular features of infused NK cells
timeFrame: 48 months
Other outcomes:
Locations:
city: Bologna
country: Italy
facility: Antonio Curti
state: BO
Study officials:
affiliation: Istituto di Ematologia Seràgnoli, Azienda Ospedaliero-Universitaria di Bologna (IRCCS)
name: Antonio Curti
role: PRINCIPAL_INVESTIGATOR
References: