reduced intensity conditioning for non-malignant disorders undergoing ucbt, bmt or pbsct

Conditions: Primary Immunodeficiency (PID); Congenital Bone Marrow Failure Syndromes; Inherited Metabolic Disorders (IMD); Hereditary Anemias; Inflammatory Conditions; Systemic Juvenile Idiopathic Arthritis (sJIA); Juvenile Rheumatoid Arthritis (JRA)

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.

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. research funds are not available to assist with enrollment on this trial. 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.

Eligibility criteria:
inclusion: 1. 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. 2. adequate organ function as measured by: 1. creatinine ≤ 2.0 mg/dl and creatinine clearance ≥ 50 ml/min/1.73 m2. 2. hepatic transaminases (alt/ast) ≤ 4 x upper limit of normal (uln). 3. adequate cardiac function by echocardiogram or radionuclide scan (shortening fraction \> 26% or ejection fraction \> 40% or \> 80% of normal value for age). 4. 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. 3. written informed consent and/or assent according to fda guidelines. 4. negative pregnancy test if pubertal and/or menstruating. 5. hiv negative. 6. a non-malignant disorder amenable to treatment by stem cell transplantation, including but not limited to: 1. 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 2. congenital bone marrow failure syndromes including but not limited to: * dyskeratosis congenita (dc) * congenital amegakaryocytic thrombocytopenia (camt) * osteopetrosis 3. 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. 4. 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 5. inflammatory conditions * crohn's disease/inflammatory bowel disease exclusion: 1. allogeneic hematopoietic stem cell transplant within the previous 6 months. 2. any active malignancy or mds. 3. severe acquired aplastic anemia. 4. uncontrolled bacterial, viral or fungal infection (currently taking medication and with progression of clinical symptoms). 5. pregnancy or nursing mother. 6. poorly controlled pulmonary hypertension. 7. any condition that precludes serial follow-up.

Keywords: 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) juvenile rheumatoid arthritis (jra)