UM171 Expanded Cord Blood In Patients With High-Risk Acute Leukemia/Myelodysplasia

Methodology:

This is a multi-center open label phase II clinical trial. Patients with high and very high-risk acute leukemia/myelodysplasia will receive a single 5-7/8 HLA matched ECT-001 (UM171) expanded cord blood after an ablative conditioning regimen. This group of patients would be expected to have poor progression free survival (PFS) after a conventional allogeneic transplant (bone marrow-peripheral blood).

Investigators key primary and secondary objectives include:

• To confirm low Transplant Related Mortality (TRM)
• To evaluate relapse free survival (RFS)
• To analyze kinetics of hematologic engraftment;
• To evaluate the incidence of acute and chronic GVHD
• To evaluate the safety of the procedure
• To evaluate incidence of infectious complications
• To analyze duration of hospitalization
• To evaluate the incidence of pre-engraftment/engraftment syndrome (PES/ES)
• To analyze the effect of cryopreservation of the expanded CD34+ fraction on safety and efficacy endpoints

Inclusion criteria

• Presence of high-risk acute leukemia/myelodysplasia defined as one of the following:

I. Acute Myeloid Leukemia:

• Primary induction failure (no CR or CRi after ≥ 2 courses of induction therapy or after ≥ 1 induction containing high dose Ara-C)
• Chemorefractory relapse (no CR or CRi after 1 chemointensive treatment)
• Relapse after allogeneic or autologous transplant
• High risk AML in CR1: i) any adverse genetic abnormality as defined by European Leukemia Net excluding FLT3 mutation; ii) secondary or therapy related AML excluding good risk genetic abnormalities (as defined by ELN); or iii) any other poor risk feature known to be associated with a PFS or DFS ≤40% at 2 years after conventional transplantation.
• CR2 excluding good risk genetic abnormalities defined by ELN
• ≥CR3

II. Acute Lymphoid Leukemia

• Primary induction failure (≥ 2 inductions)
• Chemorefractory relapse (at least 1 intensive induction chemotherapy; blinatumomab, inotuzumab or CAR-T cells may be considered as an equivalent)
• Relapse after allogeneic or autologous transplant
• High risk ALL in CR1: Ph like ALL or any other poor risk feature known to be associated with an PFS or DFS ≤40% at 2 years after conventional transplantation.
• ≥CR2
• MRD+ within 1 month of start of conditioning regimen.

III. Myelodysplastic syndrome

• Relapse after allogeneic or autologous transplant
• ≥10 % blasts within 1 month of start of conditioning regimen
• Very poor cytogenetics (>3 abnormalities)
• Any poor risk feature known to be associated with a PFS or DFS ≤40% at 2 years after conventional transplantation
• TP53 mutation
• ≥40 years old and RAS or JAK2 mutation
• CMML with HCT-specific CPSS score high or intermediate-2
• Stable disease (absence of CR/PR/HI) after 6 cycles of azacitidine (or another demethylating agent)
• Progressive disease while on azacitidine (or another demethylating agent)
• 18-70 years old
• Availability of 2 CBs ≥ 4/8 HLA match when A, B, C and DRB1 are performed at the allele level.

I. Cord to be expanded:

• CD34+ cell count >0.5 x 105/kg and TNC>1.5 x 107/kg (these numbers are all pre-freeze)
• Needs to be erythrodepleted by bank prior to cryopreservation
• Must come from a cord bank that is FACT (Foundation for the Accreditation of Cellular Therapy) accredited, FDA approved or eligible for NMDP IND.

II. Non-expanded CB/back-up cord:

• Pre-freeze TNC count ≥ 2.0 x 107/kg with CD34+ cells ≥1.5 x 105/kg or TNC count ≥ 1.5 x 107 TNC/kg with CD34+ cells ≥1.7 x 105/kg. If a single cord does not meet these criteria, 2 back up cords will be an acceptable alternative with a minimum for each of 1.5 x 107/kg TNC and 1 x 105/kg CD34+ cells; another acceptable HSC back up source could be a haploidentical donor with medical clearance prior to starting conditioning regimen.
• Must come from a cord bank that is FACT accredited, FDA approved or eligible for NMDP IND
• Karnofsky score ≥ 70%
• Bilirubin < 2 x upper limit of normal (ULN) unless felt to be related to Gilbert's disease or hemolysis; AST and ALT ≤ 2.5 x ULN; alkaline phosphatase ≤ 5 x ULN.
• Estimated or measured creatinine clearance ≥ 60 ml/min/1.73m2.
• Hematopoietic cell transplantation specific comorbidity index (HCT-CI) ≤5 for patients < 60 years old; HCT-CI ≤3 for patients < 60 years old and acute leukemia not in CR/CRi; HCT-CI ≤3 for patients 60-65 years old; HCT-CI ≤1 if 66-70 years old.
• Left ventricular ejection fraction ≥ 40%
• Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1) and diffusing capacity corrected for hemoglobin (DLCOc) ≥ 50% of predicted
• Signed written informed consent
• Female patients of childbearing potential must have a negative serum pregnancy test within 7 days of enrolment and must be willing to use an effective contraceptive method while enrolled in the study.

Exclusion criteria

• Patient never treated with cytotoxic chemotherapy and planned conditioning regimen does not include 12 Gy TBI (exceptions allowed if approved by PI).
• Allogeneic myeloablative transplant within 6 months.
• Autologous hematopoietic stem cell transplant within 6 months.
• Planned use of ATG in conditioning regimen (exceptions allowed if approved by PI in which case ATG must be adjusted for weight/lymphocyte count and given more than 1 week prior to transplant; any patient who receives ATG will have immune recovery studies but will not be counted with rest of patients and will be analyzed separately).
• Planned use of an HLA matched CB (8/8 allele matched)
• Uncontrolled infection.
• Presence of a malignancy other than the one for which the CB transplant is being performed, with an expected survival estimated to be less than 75% at 5 years.
• Seropositivity for HIV.
• Hepatitis B or C infection with measurable viral load. Patients with chronic hepatitis B or C infection regardless of viral load require clear documentation of absence of cirrhosis by either fibroscan or biopsy. If fibroscan is the method used, the test must be unequivocally negative.
• Liver cirrhosis.
• Active central nervous system involvement
• Chloroma > 2 cm
• ≥50% blasts in marrow in an evaluable marrow sample (>25% of normal cellularity for age) collected less than one month prior to start of conditioning regimen.
• Peripheral blasts >1000/mm3
• Pregnancy, breastfeeding or unwillingness to use appropriate contraception.
• Participation in a trial with an investigational agent within 30 days prior to entry in the study.
• Patient unable to give informed consent or unable to comply with the treatment protocol including appropriate supportive care, follow-up, and tests.
• Any abnormal condition or laboratory result that is considered by the PI capable of altering patient's condition or study outcome.