start date: February 4, 2014
estimated completion: November 2022
last updated: May 5, 2021
phase of development:
Phase 2
size / enrollment: 100
study description: For some non-malignant diseases (NMD; i.e., thalassemia, sickle cell disease, most immune deficiencies) a hematopoietic stem cell transplant may be curative by healthy donor stem cell engraftment alone. HSCT in patients with NMD differs from that in malignant disorders for two important reasons: 1) these patients are typically naïve to chemotherapy and immunosuppression. This may potentially lead to difficulties with engraftment. And 2) RIC with subsequent bone marrow chimerism may be beneficial even in mixed chimerism and result in decreased transplant-related mortality (TRM). Nevertheless, any previous organ damage, as a result of the underlying disease, may remain present after the HSCT.
For other diseases (metabolic disorders, some immunodeficiencies, etc.), a transplant is not curative. For these diseases, the main intent of the transplant is to slow down, or stop, the progress of the disease. In select few cases/diseases, the presence of healthy bone marrow derived cells may even prevent progression and prevent neurological decline.
In this research study, instead of using the standard myeloablative conditioning, the study doctor is using RIC, in which significantly lower doses of chemotherapy will be used. The lower doses may not eradicate every stem cell in the patient's bone marrow, however, in the presented combination, the intention is to eliminate already formed immune cells and provide maximum growth advantage to healthy donor stem cells. This paves the way to successful engraftment of donor stem cells. Engrafting donor stem cells can outcompete, and donor lymphocytes could suppress, the patients' surviving stem cells. With RIC, the side effects on the brain, heart, lung, liver, and other organ functions are less severe and late toxic effects should also be reduced.
The purpose of this study is to collect data from the patients undergoing reduced-intensity conditioning before HSCT, and compare it to the standard myeloablative conditioning. It is expected there will be therapeutic benefits, paired with better survival rate, less organ toxicity and improved quality of life, following the RIC compared to the myeloablative regimen.
primary outcomes:
- Post-transplant treatment-related mortality (TRM)
The number of deaths related to the research intervention at day 100, 6 months, and 1 year post-transplant.
- 1 year post-transplant
Neurodevelopmental milestones
Evaluation of the pace of attaining neurodevelopmental milestones after reduced-intensity conditioning as compared to myeloablative conditioning historical controls from the target population(s).
- 1 year post-transplant
Immune Reconstitution
Evaluation of the pace of immune reconstitution.
- 1 year post-transplant
Severe opportunistic infections
Evaluation of the incidence of severe opportunistic infections.
- 1 year post-transplant
GVHD occurrence
Description of the incidence of acute graft versus host disease (GVHD) (II-IV) and chronic extensive GVHD.
- 1 year post-transplant
secondary outcomes:
- Donor cell engraftment
6 months post-transplant
- Normal enzyme level
1 year post-transplant
- Neutrophil recovery
1 year post-transplant
- Platelet recovery
1 year post-transplant
- Grade 3-4 organ toxicity
1 year post-transplant
- Long-term complications
1 year post-transplant
- Late graft failure
1 year post-transplant
inclusion criteria:
• Eligible Ages: 2 - 55
• Eligible Sexes: all
Inclusion:
A 4/6, 5/6 or 6/6 HLA matched related or unrelated UCB unit available that will deliver a pre-cryopreservation total nucleated cell dose of ≥ 3 x 10e7 cells/kg, or double unit grafts, each cord blood unit delivering at least 2 x 10e7 cells/kg OR an 8 of 8 or 7 of 8 HLA allele level matched unrelated donor bone marrow or peripheral blood progenitor graft.
Adequate organ function as measured by:
Creatinine ≤ 2.0 mg/dL and creatinine clearance ≥ 50 mL/min/1.73 m2.
Hepatic transaminases (ALT/AST) ≤ 4 x upper limit of normal (ULN).
Adequate cardiac function by echocardiogram or radionuclide scan (shortening fraction > 26% or ejection fraction > 40% or > 80% of normal value for age).
Pulmonary evaluation testing demonstrating CVC or FEV1/FVC of ≥ 50% of predicted for age and/or resting pulse oximeter ≥ 92% on room air or clearance by the pediatric or adult pulmonologist. For adult patients DLCO (corrected for hemoglobin) should be ≥ 50% of predicted if the DLCO can be obtained.
Written informed consent and/or assent according to FDA guidelines.
Negative pregnancy test if pubertal and/or menstruating.
HIV negative.
A non-malignant disorder amenable to treatment by stem cell transplantation, including but not limited to:
Primary Immunodeficiency syndromes including but not limited to:
Severe Combined Immune Deficiency (SCID) with NK cell activity
Omenn Syndrome
Bare Lymphocyte Syndrome (BLS)
Combined Immune Deficiency (CID) syndromes
Combined Variable Immune Deficiency (CVID) syndrome
Wiskott-Aldrich Syndrome
Leukocyte adhesion deficiency
Chronic granulomatous disease (CGD)
X-linked Hyper IgM (XHIM) syndrome
IPEX syndrome
Chediak - Higashi Syndrome
Autoimmune Lymphoproliferative Syndrome (ALPS)
Hemophagocytic Lymphohistiocytosis (HLH) syndromes
Lymphocyte Signaling defects
Other primary immune defects where hematopoietic stem cell transplantation may be beneficial
Congenital bone marrow failure syndromes including but not limited to:
Dyskeratosis Congenita (DC)
Congenital Amegakaryocytic Thrombocytopenia (CAMT)
Osteopetrosis
Inherited Metabolic Disorders (IMD) including but not limited to:
Mucopolysaccharidoses
Hurler syndrome (MPS I)
Hunter syndrome (MPS II)
Leukodystrophies
Krabbe Disease, also known as globoid cell leukodystrophy
Metachromatic leukodystrophy (MLD)
X-linked adrenoleukodystrophy (ALD)
Hereditary diffuse leukoencephalopathy with spheroids (HDLS)
Other inherited metabolic disorders
alpha mannosidosis
Gaucher Disease
Other inheritable metabolic diseases where hematopoietic stem cell transplantation may be beneficial.
Hereditary anemias
Thalassemia major
Sickle cell disease (SCD) - patients with sickle disease must have one or more of the following:
Overt or silent stroke
Pain crises ≥ 2 episodes per year for past year
One or more episodes of acute chest syndrome
Osteonecrosis involving ≥ 1 joints
Priapism
Diamond Blackfan Anemia (DBA)
Other congenital transfusion dependent anemias
Inflammatory Conditions
Crohn's Disease/Inflammatory Bowel Disease
exclusion criteria: :
Allogeneic hematopoietic stem cell transplant within the previous 6 months.
Any active malignancy or MDS.
Severe acquired aplastic anemia.
Uncontrolled bacterial, viral or fungal infection (currently taking medication and with progression of clinical symptoms).
Pregnancy or nursing mother.
Poorly controlled pulmonary hypertension.
Any condition that precludes serial follow-up.
