"Phase I / II Study on Infusion of Natural Killer Cells After Haploidentical Transplantation in Pediatric Patients"

Phase I / II Study on Infusion of Alloreactive or Stimulated Natural Killer Cells With IL-15 ex Vivo After Haploidentical Transplantation of Hematopoietic Progenitors in Pediatric Patients With Hematological Neoplasms

Phase I / II study on infusion of alloreactive or stimulated Natural Killer cells with IL-15 ex vivo after haploidentical transplantation of hematopoietic progenitors in pediatric patients with hematologic malignancies (PHINK

Haploidentical hematopoietic stem cell transplantation (haploTPH) constitutes a highly complex but effective procedure for some hematologic malignancies high-risk pediatric patients in the absence of an identical HLA donor. Relapse Post-transplant leukemia is the main problem for survival. Just like reported different expert groups on haploTPH in adults and children, there is a determining role of Natural Killer (NK) cells in haploTPH as inducers powerful graft-versus-leukemia (EIcL) effect. The presence of NK cells allo-reactive is correlated with a lower relapse rate, in addition to favoring the graft, decrease graft versus recipient disease (GVHD) and decrease viral infections. This only occurs in half of the donor-recipient pairs, so that, in its absence, it is necessary to develop other strategies for activating the NK cells. In this sense, the investigational group has extensive experience in research translational with NK cells and is a pioneer in infusing ex vivo activated NK cells with IL-15.

The investigators propose a phase I / II clinical trial with dose escalation, multicenter, framed in the Spanish Group of Hematopoietic Transplantation / Marrow Transplant Bone in Children (GETH / GETMON), to determine the safety and efficacy of a post-haploTPH IL-15 alloreactive / stimulated NK cell infusion in children with malignant blood diseases. The investigators will monitor immune reconstitution, chimerism, Post-transplantation NK cell expansion, phenotype, and function.

Secondarily evaluate the effectiveness of therapy on the incidence of graft failure; EICR; viral reactivations; transplant-related mortality; and relapse of leukemia.

Inclusion Criteria:

• Patients of both sexes with age ≤ 21 years.
• Not having an identical HLA donor (family or non-family) available in the time needed for the donation of hematopoietic parents.
• Having a haploidenic donor available
• Diagnosis of high-risk hematological malignancy. This includes:
• i. High risk ALL in first complete remission (RC1);
• ii. ALL in second complete remission (RC2);
• iii. ALL in third complete remission (RC3) or later;
• iv. High risk AML in RC1;
• v. AML in RC2 or later;
• vi. Relapsed AML with <25% blasts in bone marrow;
• vii. AML related to previous treatments in CR> 12 months;
• viii. Primary or secondary myelodysplastic syndrome
• ix. NK cell leukemia, biphenotypic or undifferentiated in RC1 or later,
• x. Chronic myeloid leukemia (CML) in accelerated phase, in chronic phase with persistent molecular positivity, or with intolerance to tyrosine kinase inhibitors
• xi. Hodgkin's lymphoma in RC2 or later after failure of autologous TPH, or unable to mobilize hematopoietic progenitors for autologous TPH
• xii. Non-Hodgkin's lymphoma in RC2 or later after failure of autologous TPH, or unable to mobilize hematopoietic progenitors for autologous TPH
• xiii. Myelomonocytic juvenile leukemia.
• Positive pre-transplant evaluation
• i. Left ventricular ejection fraction > 40% or shortening fraction ≥ 25%;
• ii. Creatinine clearance (ACr) or glomerular filtration rate (TFG) ≥ 50 ml/min/1.73 m2
• iii. Forced Vital Capacity (FVC) ≥ 50% of predicted value or pulse-oximetry ≥ 92% if the patient cannot perform the pulmonary function tests;
• iv. Karnofsky or Lansky Index (depending on the patient's age) ≥ 50;
• v. Bilirubin ≤ 3 times the upper limit of normal for age
• vi. Alanine aminotransferase (ALT) ≤ 5 times the upper limit of normal for age
• vii. Women who are not breastfeeding.
• viii. No uncontrolled bacterial, fungal, or viral infections at the time of inclusion.
• Women of childbearing potential must have a negative serum or urine pregnancy test performed within 14 days prior to trial inclusion and must agree to use highly effective contraceptive methods (diaphragms plus spermicide or male condom plus spermicide, oral contraceptive combined with a second method of contraceptive implant, injectable contraceptive, permanent intrauterine device, sexual abstinence, or partner with vasectomy) during study participation and for six months after the last trial visit. In the case of male patients with reproductive capacity, they must commit to using an appropriate barrier method for the duration of the study and for up to 6 months thereafter

Exclusion Criteria:

• Patients with an active infectious process or other serious underlying medical condition
• Patients who, according to the investigator's criteria, have a history of poor compliance with therapy.
• Patients who after a psycho-social evaluation are advised as not suitable for the procedure:
• i. Social-family situation that makes correct participation in the study impossible.
• ii. Patients with emotional or psychological problems secondary to the illness such as post-traumatic stress disorder, phobias, delusions, psychosis, with the need for support from specialists.
• iii. Evaluation of the involvement of family members in the health of the patient
• Inability to understand the information about the trial
• Received an investigational drug within 30 days prior to the start of therapy or within 5 half-lives of receiving an investigational drug, whichever is longer.