risk-adapted allogeneic stem cell transplantation for mixed donor chimerism in patients with non-malignant diseases

Conditions: Bone Marrow Failure; Osteopetrosis; Fanconi Anemia; Severe Combined Immunodeficiency

Summary: this study proposes the use of a reduced intensity chemotherapy/radiation therapy regimen followed by stem cell transplantation, as compared to standard ablative chemotherapy regimens associated with stem cell transplantation, in a population of patients with non-malignant diseases (non-cancer). eligible patients will have a non-malignant disease in one of the following four strata: bone marrow failure syndromes, immunodeﬁciencies, inborn errors of metabolism, or histiocytoses. patients will be assigned to therapy according to diagnosis. patients will be stratiﬁed by disease into one of four strata and treatment regimens will be based on speciﬁc disease criteria and conditions. although these diseases are non-malignant in name, they are often malignant by nature of the disease progression, treatment and associated complications.

this treatment program proposes the use of a reduced intensity chemotherapy regimen, which has been shown to be effective for inducing remission and cure in these diseases. studies have shown that the use of non-myeloablative chemotherapy regimens have resulted in 75-100% engraftment (replacement of the recipient bone marrow with the donor bone marrow), and signiﬁcantly reduced transplant related complications as compared to the standard myeloablative chemotherapy regimens.

Eligibility criteria:
inclusion criteria patients must meet the eligibility criteria for organ function regardless of diagnosis: * age \< 30 or = 30 years of age * adequate renal function defined as serum creatinine \ or =40 ml/min/m2 or \>60 ml/min/1.73 m2 or an equivalent gfr as determined by the institutional normal range * adequate liver function defined as serum glutamic oxaloacetic transaminase (sgot)(aspartate transaminase (ast)) or serum glutamic-pyruvic transaminase (sgpt) (alanine aminotransferase (alt)) \< 5.0 x normal * adequate cardiac function defined as shortening fraction of \> or = 28% by echocardiogram, or ejection fraction of \> or = 48% by radionuclide angiogram or echocardiogram * adequate pulmonary function defined as asymptomatic or, if symptomatic, carbon monoxide diffusing capacity test (dlco) \>45% of predicted (corrected for hemoglobin level). if unable to obtain pulmonary function test, o2 saturation \>85% in room air. bone marrow failure syndromes patients with the following diagnoses are eligible: severe aplastic anemia: * hypocellular bone marrow biopsy (\<25% cellularity) and 2/3 of the following (at diagnosis or nadir): * absolute neutrophil count (anc) \<200/mm3, * platelets \<20,000/mm3 * reticulocyte count \<60,000/mm3 fanconi anemia: * abnormal clastogenic studies (all patients) severe congenital neutropenia (kostmann's syndrome) amegakaryocytic thrombocytopenia * severe thrombocytopenia (\< or =20,000/mm3) at diagnosis * severe depletion of megakaryocytes on bone marrow aspirate (\< or =25% normal) diamond-blackfan anemia: * corticosteroid dependent for \> 6 months or transfusion dependent or refractory acquired pure red cell aplasia. infantile osteopetrosis schwachman-diamond syndrome dyskeratosis congenita other bone marrow failure syndromes at discretion of co-principal investigators all bm failure patients must have bm bx within 2 weeks prior to starting therapy to confirm disease status immunodeficiencies: * scids, all subtypes * combined immunodeficiency syndrome * wiskott-aldrich syndrome * chronic granulomatous disease * chediak-higashi syndrome * leukocyte adhesion deficiency * other immunodeficiencies at discretion of co-principal investigators inborn errors of metabolism (ieom): transplant is recommended for the following disorders: * hurler syndrome (alpha-l-iduronidase deficiency, mps-i), preferably before age 24 months * maroteaux-lamy syndrome (galactosamine-4-sulfatase deficiency,mpsvi) * sly syndrome (beta-glucuronidase deficiency, mps-vii) * globoid cell leukodystrophy (galactocerebrosidase deficiency), with careful attention to neurologic status in the infantile form * metachromatic leukodystrophy (arylsulfatase a deficiency),juvenile or adult onset form; late infantile mld only if pre-symptomatic * childhood-onset x-linked adrenoleukodystrophy (x-ald), at initial signs of neuropsychological deterioration, with dietary modification prior to transplant * fucosidosis (fucosidase deficiency) * mannosidosis * aspartylglucosaminuria * niemann-pick disease type b (acid sphingomyelinase deficiency) * other diagnoses may be considered at the discretion of the co-principal investigators transplant is not recommended for hunter syndrome (iduronate sulfatase deficiency), sanfilippo syndrome type a (heparan n-sulfatase deficiency), sanfilippo syndrome type b (-n-acetyl-transferase deficiency), sanfilippo syndrome type c (-acetyltransferase deficiency), sanfilippo syndrome type d (-acetylglucosamine-6-sulfatase deficiency), morquio syndrome (galactose-6-sulfatase deficiency); or niemann-pick disease type a or c. for x-ald patients greater than 5 years of age, iq \>80 is required. for other patients greater than 5 years of age, iq \> 70 is required. for patients less than 5 years of age, the developmental quotient or clinical neurodevelopmental examination should demonstrate potential for stabilization at a level of functioning where continuous life support (e.g. mechanical ventilation) would not be predicted to be required in the year following transplantation. for gaucher disease (glucocerebrosidase deficiency) type i (non-neuropathic), the primary therapy is enzyme replacement, but allogeneic stem cell transplant has been used effectively. histiocytoses: * hemophagocytic lymphohistiocytosis (hlh) * familial erythrophagocytic lymphohistiocytosis * langerhans cell histiocytosis * patients with multi-system disease whose initial disease is stable or progressive after minimum 6 weeks of appropriate therapy, or patients with recurrent multi-system disease. * malignant histiocytosis * all histiocytic patients must have bm bx within 2 weeks prior to starting therapy to confirm disease status other non-malignant diseases not listed above may be eligible if deemed appropriate by the co-principal investigators.

Keywords: bone marrow failure fanconi anemia severe combined immunodeficiency osteopetrosis allogeneic stem cell transplantation chemotherapy radiation therapy