Cord blood (CB) transplants are an option for patients lacking an HLA identical donor but are hampered by low cell dose, prolonged aplasia and high transplant related mortality. UM171, a novel and potent agonist of hematopoietic stem cell self renewal could solve this major limitation, allowing for CB's important qualities as lower risk of chronic GVHD and relapse to prevail. In previous trials (NCT02668315, NCT03913026, NCT04103879, and NCT03441958), the CB expansion protocol using the ECT-001-CB technology (UM171 molecule) has proven to be technically feasible and safe in adults.

UM171 expanded CB was associated with a prompt (D+17), robust (98%) and durable neutrophil recovery. Amongst patients who received a single UM171 CB transplant with a median follow-up of 18 months, risk of TRM (10%), grade 3-4 acute GVHD (13%) and moderate-severe chronic GVHD (2%) was low at 1 year post-transplant. Incidence of severe viral and bacterial infections was reduced and immunosuppression could be discontinued in 77% of patients at 1 year. Thus, PFS and GRFS were very promising, 72% and 59% at 12 months, 69% and 53% at 24 months, respectively, in particular accounting for a large proportion of very high-risk patients. By a 10-fold increase of CB accessibility, ECT-001-CB allowed access to smaller, better HLA matched CBs.

This new study seeks to test a similar strategy in a group of pediatric and young adult patients with high risk myeloid malignancies. 12 patients will be enrolled in the first stage of this 2-stage design protocol. If intervention is considered promising (<= 3 relapses in the first 12 patients), this study will open multicenter and be extended to a second stage (16 additional patients for a total accrual 28).

Inclusion Criteria:

1. Acute Myeloid Leukemia

   1. Chemo-refractory relapse (MRD+)
   2. Primary induction failure (no CR or CRi after >= 2 courses of intensive induction therapy): < 30% blasts in evaluable marrow.
   3. Relapse after previous allogeneic (or autologous) transplant (>4 months)
   4. Secondary or therapy-related MDS/AML
   5. Poor response to induction (5-30% blasts) or MDR+ after induction

2. Myelodysplastic syndrome (MDS)

   1. Relapse after allogeneic or autologous transplant (>4 months)
   2. ≥10 % blasts within 30 days of start of conditioning regimen
   3. Poor and very poor cytogenetics abnormalities

3. Chronic myelogenous leukemia: Patients who progressed to blast crisis

4. Mixed Phenotype Acute Leukemia: MRD+ or relapse after previous transplant (>4 months).

5. JMML (Juvenile Myelo-Monocytic Leukemia)

6. Availability of 2 ≥ 4/8 HLA matched CBU (allele level: A, B, C and DRB1)

   1. Cord to be expanded: CD34+ cell count ≥ 0.5 x 10^5/kg and TNC ≥ 1.5 x 10^7/kg (pre-cryo)
   2. Back up cord: Pre-freeze TNC ≥ 2 x 10^7/kg with CD34+ cells ≥ 1.5 x 10^5/kg. If a single cord does not meet this criterion 2 back up cords will be an acceptable alternative with a minimum for each of 1.5 x 10^7 TNC/kg with 1.0 x 10^5 CD34+/kg. Another acceptable HSC back up source could be a haploidentical with medical clearance prior to starting conditioning regimen.

7. Lansky / Karnofsky >60%

8. Bilirubin < 2 x upper limit of normal (ULN) unless felt to be related to Gilbert's disease or hemolysis; AST and ALT < 3 x ULN; alkaline phosphatase < 5 x ULN

9. Estimated or measured creatinine clearance ≥ 50ml/min/1.73m2

10. Left ventricular ejection fraction of ≥ 40%

11. FVC, FEV1 and DLCO ≥ 50% of predicted

12. Signed written informed consent

13. Female patients of childbearing potential must have a negative serum pregnancy test within 7 days of enrolment and mush be willing to use an effective contraceptive method while enrolled in the study.

Exclusion Criteria:

1. Previous allogeneic transplantation within 4 months.
2. Uncontrolled infection.
3. Presence of other malignancy other than the one for which the CB transplant is being performed, with an expected survival to be less than 75% at 5 years
4. Seropositive for HIV.
5. Hep B and C infection with measurable viral load.
6. Liver cirrhosis.
7. Active CNS disease.
8. Chloroma > 2cm.
9. >30% blasts in marrow in evaluable marrow sample.
10. Pregnancy, breastfeeding, or unwillingness to use appropriate contraception
11. Participation in a trial with an investigational agent within 30days prior to entry in the study.
12. Any abnormal condition or lab result that is considered by the PI capable or altering patient's condition or study outcome.