In this study, participants with high-risk hematologic malignancies undergoing hematopoietic
cell transplantation (HCT), who do not have a suitable human leukocyte antigen (HLA)-matched
related/sibling donor (MSD), matched unrelated donor (MURD) or killer-immunoglobulin
receptors (KIR) ligand mismatched haploidentical donor identified, will receive a combined T
cell depleted (TCD) haploidentical peripheral blood stem cell (PBSC) and unrelated umbilical
cord blood transplantation (UCBT) using a total lymphoid irradiation (TLI) based preparative
regimen.
Primary objective:
- To estimate the incidence of donor derived neutrophil engraftment by day +42
post-transplant for participants with high-risk hematologic malignancies undergoing a
total lymphoid irradiation (TLI)-based hematopoietic cell transplantation (HCT) using a
T cell depleted (TCI) haploidentical donor peripheral blood stem cell (PBSC) donor
combined with an unrelated umbilical cord blood (UCB) donor.
Secondary objectives:
- Estimate the incidence of malignant relapse, event-free survival (EFS), and overall
survival (OS) at one-year post-transplantation.
- Estimate the incidence and severity of acute and chronic graft versus host disease
(GVHD) in the first 100 days after transplantation.
- Estimate the incidence of secondary graft failure transplant related mortality (TRM) and
transplant related morbidity in the first 100 days after HCT.
Prior to stem cell infusion, participants will receive a preparative regimen of total
lymphoid irradiation (TLI), fludarabine, cyclophosphamide, melphalan, and thiotepa to prepare
their bone marrow. Thereafter, they will receive a hematopoietic cell graft from a
haploidentical donor and an unrelated umbilical cord blood donor. Post-transplantation
immunosuppressive treatment will include tacrolimus and mycophenolate mofetil.
Inclusion Criteria-Transplant Recipient:
- Age less than or equal to 21 years old.
- Does not have a suitable matched related/sibling donor (MSD) or volunteer matched
unrelated donor (MUD) available in the necessary time for stem cell donation.
- Has a suitable partially human leukocyte antigen (HLA)-matched (≥ 3 of 6) family
member donor.
- Has a partially HLA-matched single umbilical cord blood (UCB) unit (≥ 4 of 6) with
adequate cell dose. UCB units must fulfill eligibility as outlined in 21 CFR 1271 and
agency guidance.
- High-risk hematologic malignancy.
- High risk acute lymphocytic leukemia (ALL) in complete remission-1 (CR)1.
[Examples include, but not limited to t(9;22), hypodiploid,, M2 or greater marrow
at the end of induction, infants with mixed lineage leukemia (MLL) fusion or
t(4;11)].
- ALL in High risk CR2. [Examples include but not limited to t(9;22), bone marrow
(BM) relapse <36 mo CR1, T-ALL, very early (< 6mo CR1) isolated central nervous
system (CNS) relapse.]
- ALL in CR3 or subsequent.
- Acute myeloid leukemia (AML) in high risk CR1. [Examples include but not limited
to preceding MDS, 5q-, -5, -7, FAB M6, FAB M7 not t(1;22), minimal residual
disease (MRD) ≥ 5% on day 22 (AML08), M3 marrow after induction 1, M2 marrow
after two cycles of induction, FLT3-ITD.]
- AML in CR2 or subsequent.
- Therapy related AML, with prior malignancy in CR > 12mo
- Myelodysplastic syndrome (MDS), primary or secondary
- Natural killer (NK) cell, biphenotypic, or undifferentiated leukemia in CR1 or
subsequent.
- Chronic myeloid leukemia (CML) in accelerated phase, or in chronic phase with
persistent molecular positivity or intolerance to tyrosine kinase inhibitor.
- Hodgkin lymphoma in CR2 or subsequent after failure of prior autologous
hematopoietic cell transplantation (HCT), or unable to mobilize stem cells for
autologous HCT.
- Non-Hodgkin lymphoma in CR2 or subsequent.
- Juvenile myelomonocytic leukemia (JMML).
- Refractory hematologic malignancies [ALL, AML, chronic myeloid leukemia (CML) in
blast crisis, Hodgkin or non-Hodgkin lymphoma] due to chemoresistant relapse or
primary induction failure.
- All patients with evidence of CNS leukemia must be treated and be in CNS CR to be
eligible for study.
- Patient must fulfill pre-transplant evaluation:
- Cardiac Function: Left ventricular ejection fraction (LVEF) ≥ 40% or shortening
fraction (SF) ≥ 25%.
- Creatinine clearance (CrCL) or glomerular filtration rate (GFR) ≥ 50
ml/min/1.73m2.
- Forced vital capacity (FVC) ≥ 50% of predicted value or pulse oximetry (Pox) ≥
92% on room air.
- Karnofsky or Lansky performance score ≥ 50.
- Bilirubin ≤ 3 times the upper limit of normal for age.
- Alanine aminotransferase (ALT) ≤ 5x the upper limit of normal for age.
- Aspartate aminotransferase (AST) ≤ 5x the upper limit of normal for age.
Exclusion Criteria - Transplant Recipient:
- Patient has a suitable MSD, volunteer matched unrelated donor (MURD), or
killer-immunoglobulin receptors (KIR) mismatched haploidentical donor available in the
necessary time for stem cell donation.
- Patient has any other active malignancy other than the one for which HCT is indicated.
- Patient is pregnant as confirmed by positive serum or urine pregnancy test within 14
days prior to enrollment.
- Patient is breast feeding.
- Patient has Down Syndrome.
- Patient has a current uncontrolled bacterial, fungal, or viral infection per the
judgment of the principal investigator.
Inclusion criteria - haploidentical donor
- At least single haplotype matched (≥ 3 of 6) family member
- At least 18 years of age.
- Human immunodeficiency virus (HIV) negative.
- Not pregnant as confirmed by negative serum or urine pregnancy test within 14 days
prior to enrollment (if female).
- Not breast feeding.
- Regarding eligibility, is identified as either:
- Completed the process of donor eligibility determination as outlined in 21 CFR
1271 and agency guidance; OR
- Does not meet 21 CFR 1271 eligibility requirements, but has a declaration of
urgent medical need completed by the principal investigator or physician
sub-investigator per 21 CFR 1271.
