Natural Killer-cell Therapy for Acute Myeloid Leukemia

Infusion of ex Vivo-generated Allogeneic Natural Killer Cells in Combination With Subcutaneous IL-2 in Patients With Acute Myeloid Leukemia: a Phase I/IIa Study

This study investigates an innovative treatment for relapsed or refractory acute myeloid leukemia exploiting administration of ex vivo-generated allogeneic natural killer (NK) cells with preceding non-myeloablative conditioning chemotherapy with or without subsequent in vivo IL-2 cytokine support.

This study investigates an innovative treatment for relapsed or refractory acute myeloid leukemia (AML) exploiting administration of ex vivo-generated allogeneic natural killer (NK) cells with preceding non-myeloablative conditioning chemotherapy with or without subsequent in vivo IL-2 cytokine support.

This is a prospective phase I/IIa study. The first phase is a IL-2 dose-escalating safety study in twelve patients. The second phase of the study is designed as a Simon's optimal two-stage single-arm phase IIa study, comprising seventeen patients. Prior to NK cell infusion, all patients will receive cyclophosphamide and fludarabine (Cy/Flu) based lymphodepleting chemotherapy. On day 0, all patients will receive a fixed dose of 1.0-3.0 x 10^9 allogeneic umbilical cord blood-derived NK cells (UCB-NK cells). These cells are generated ex vivo from CD34+ hematopoietic progenitor cells obtained from an allogeneic UCB unit.

In phase I of the study patients will receive UCB-NK cells without subcutaneous (SC) IL-2, with lower dose SC IL-2 or with higher dose SC IL-2 (n=3 per treatment group, n=6 in the highest tolerable dose). After establishing the safety of UCB-NK cells combined with SC IL-2, we will continue with phase IIa of the study, with ten patients in the first stage (including the six patients from phase I with comparable IL-2 dose) and if clinical efficacy is achieved an additional seven patients in the second stage.

Inclusion Criteria:

• AML patients (de novo and secondary) or patients with MDS excess blasts-2 according to WHO criteria 2016, who have stable disease or non-rapidly progressive disease with or without disease controlling medication who are (at time of inclusion) ineligible for allo-SCT.

• Patients may belong to any of the following categories:

  • Relapsed/refractory disease after treatment with intensive chemotherapy, hypomethylating agents, targeted agents, autologous or allo-SCT (at least 6 months ago) and DLI
  • Newly diagnosed, untreated patients ineligible for allo-SCT

Other inclusion criteria:

• Age ≥ 18 years
• WHO performance 0-2
• Life expectancy of > 4 months
• Written informed consent
• Hydrea is allowed as pre-treatment to control blast count until day -3
• Other disease controlling medication is allowed until day -7

Exclusion Criteria:

• Progressive disease according to ELN criteria in case of previous therapy
• Patients on immunosuppressive drugs or active GvHD
• Patients with active infections (viral, bacterial or fungal); acute anti-infectious therapy must have been completed within 14 days prior to study treatment
• Severe cardiovascular disease (CTCAE III-IV)
• Severe pulmonary dysfunction (CTCAE III-IV)
• Severe renal dysfunction (CTCAE III-IV)
• Severe hepatic dysfunction (CTCAE III-IV)
• Severe neurological or psychiatric dysfunction (CTCAE III-IV)
• Patients on concurrent chemotherapy or interferon-alpha treatment
• Pregnancy or breastfeeding