Reduced Intensity Conditioning for Non-Malignant Disorders Undergoing UCBT, BMT or PBSCT

Study Overview
=================
Brief Summary
-----------------
The objective of this study is to evaluate the efficacy of using a reduced-intensity condition (RIC) regimen with umbilical cord blood transplant (UCBT), double cord UCBT, matched unrelated donor (MUD) bone marrow transplant (BMT) or peripheral blood stem cell transplant (PBSCT) in patients with non-malignant disorders that are amenable to treatment with hematopoietic stem cell transplant (HSCT). After transplant, subjects will be followed for late effects and for ongoing graft success.

Detailed 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.

Official Title
-----------------
A Phase II Study of Reduced Intensity Conditioning in Pediatric Patients and Young Adults ≤55 Years of Age With Non-Malignant Disorders Undergoing Umbilical Cord Blood, Bone Marrow, or Peripheral Blood Stem Cell Transplantation

Conditions
-----------------
Primary Immunodeficiency (PID), Congenital Bone Marrow Failure Syndromes, Inherited Metabolic Disorders (IMD), Hereditary Anemias, Inflammatory Conditions, Systemic Juvenile Idiopathic Arthritis (sJIA)

Intervention / Treatment
-----------------
* Drug: Hydroxyurea
* Drug: Alemtuzumab
* Drug: Fludarabine
* Drug: Melphalan
* Drug: Thiotepa


Participation Criteria
=================
Eligibility Criteria
-----------------
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: 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.

Ages Eligible for Study
-----------------
Minimum Age: 2 Months
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: UCBT:transfusion dependent anemias or increased rejection risk<br>Day -21 to -19: Alemtuzumab + Hydroxyurea; Day -18 to -10: Hydroxyurea; Day -9 to -5: Fludarabine + Hydroxyurea; Day -4 to -3: Melphalan; Day -2: Thiotepa; Day -1: Rest; Day 0: Transplant | Drug: Hydroxyurea<br>* Oral administration at 30 mg/kg/day.<br>* Other names: Droxia;Drug: Alemtuzumab<br>* Intravenous (IV) administration. The first dose for each arm will be a test dose (0.2 mg/kg max 5 mg). The treatment doses of alemtuzumab will be based on the patients' assigned stratum as determined by their age, lymphocyte count and presence of infection. Stratum 1: 1 mg/kg (max dose of 30 mg); Stratum 2: 0.5 mg/kg (max dose of 30 mg); Stratum 3: No treatment dose, test dose only.<br>* Other names: Campath;Drug: Fludarabine<br>* IV administration at 30 mg/m2/day or 1 mg/kg/dose, whichever is lower.<br>* Other names: Fludara;Drug: Melphalan<br>* IV administration at 70 mg/m2/dose.<br>* Other names: Alkeran;Drug: Thiotepa<br>* IV administration at 200 mg/m2/dose<br>|
| Experimental: BMT, PBSCT and not transfusion dependent UCBT<br>Start of conditioning to Day -15: Hydroxyurea; Day -14 to -13: Alemtuzumab + Hydroxyurea; Day -12 to -10: Hydroxyurea; Day -9 to -5: Fludarabine + Hydroxyurea; Day -4 to -3: Melphalan; Day -2: Thiotepa; Day -1: Rest; Day 0: Transplant | Drug: Hydroxyurea<br>* Oral administration at 30 mg/kg/day.<br>* Other names: Droxia;Drug: Alemtuzumab<br>* Intravenous (IV) administration. The first dose for each arm will be a test dose (0.2 mg/kg max 5 mg). The treatment doses of alemtuzumab will be based on the patients' assigned stratum as determined by their age, lymphocyte count and presence of infection. Stratum 1: 1 mg/kg (max dose of 30 mg); Stratum 2: 0.5 mg/kg (max dose of 30 mg); Stratum 3: No treatment dose, test dose only.<br>* Other names: Campath;Drug: Fludarabine<br>* IV administration at 30 mg/m2/day or 1 mg/kg/dose, whichever is lower.<br>* Other names: Fludara;Drug: Melphalan<br>* IV administration at 70 mg/m2/dose.<br>* Other names: Alkeran;Drug: Thiotepa<br>* IV administration at 200 mg/m2/dose<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Donor cell engraftment | Determination of the feasibility of attaining robust donor cell engraftment (>50% donor chimerism at 6 months) following reduced-intensity conditioning (RIC) regimens prior to HSCT in the target population(s). | 6 months post-transplant | 
| Normal enzyme level | Determination of the feasibility of attaining and sustaining normal enzyme levels in the target population(s). | 1 year post-transplant | 
| Neutrophil recovery | Determination of the pace of neutrophil recovery. | 1 year post-transplant | 
| Platelet recovery | Determination of the pace of platelet recovery. | 1 year post-transplant | 
| Grade 3-4 organ toxicity | The number of grade 3-4 organ adverse events. | 1 year post-transplant | 
| Late graft failure | Evaluation of the incidence of late graft failure. | 1 year post-transplant | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Severe Combined Immune Deficiency (SCID), 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, Dyskeratosis Congenita (DC), Congenital Amegakaryocytic Thrombocytopenia (CAMT), Osteopetrosis, Mucopolysaccharidoses, Hurler syndrome (MPS I), Hunter syndrome (MPS II), Leukodystrophies, Krabbe Disease, Metachromatic leukodystrophy (MLD), X-linked adrenoleukodystrophy (ALD), Alpha mannosidosis, Gaucher Disease, Thalassemia major, Sickle cell disease (SCD), Diamond Blackfan Anemia (DBA), Crohn's Disease, Inflammatory Bowel Disease, Hematopoietic Stem Cell Transplant (HSCT), Congenital transfusion dependent anemias, Globoid cell leukodystrophy, Hereditary diffuse leukoencephalopathy with spheroids (HDLS), Systemic Juvenile Idiopathic Arthritis (sJIA)