Risk-Adapted Allogeneic Stem Cell Transplantation For Mixed Donor Chimerism In Patients With Non-Malignant Diseases

Risk-Adapted Allogeneic Stem Cell Transplantation For Mixed Donor Chimerism In Patients With Selected Non-Malignant Diseases

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.

Study Overview

• Status: Completed
• Conditions: Severe Combined Immunodeficiency; Fanconi Anemia; Bone Marrow Failure; Osteopetrosis
• Intervention / Treatment: Drug: Cyclophosphamide; Drug: Fludarabine; Drug: Alemtuzumab; Drug: Busulfan; Drug: Rabbit Anti-thymocyte Globulin; Drug: Horse Anti-thymocyte Globulin

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 38
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 30 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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 = 1.5 x normal, or creatinine clearance or radioisotope glomerular filtration rate (GFR) > 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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Regimen A - Standard Conditioning Regimen; Standard conditioning regimen for all diseases except those diseases or conditions noted in Regimen B, C and D: Fludarabine (180 mg/m2 total dose); Busulfan (16 mg/kg less than or equal to 4 yrs and 12.8 mg/ kg >4 yrs total dose); Alemtuzumab (2mg/m2 x 1day, 6mg/m2 x 2 days, 20mg/m2 x 2days)	Drug: Fludarabine; Other Names: Fludara®; Drug: Alemtuzumab; Other Names: Campath®; Drug: Busulfan; Other Names: Busulfex®
Experimental: Regimen B; Includes patients with a diagnosis of: Osteopetrosis and Severe Aplastic Anemia with a history of >10 blood transfusions, or Blackfan-Diamond's anemia, or Chronic Granulomatous Disease, or Wiskott Aldrich Syndrome: Cyclophosphamide (200 mg/kg total dose); Fludabarine (180 mg/m2 total dose); Rabbit Anti-thymocyte Globulin (8mg/kg total dose)	Drug: Cyclophosphamide; Other Names: Cytoxan®; Drug: Fludarabine; Other Names: Fludara®; Drug: Rabbit Anti-thymocyte Globulin; Other Names: Thymoglobulin; TMG
Experimental: Regimen C; Includes patients with any one of the following specific diagnosis: Fanconi Anemia, Dyskeratosis Congenita or Schwachman Diamond Syndrome; Cyclophosphamide (40 mg/kg total dose); Fludarabine (140 mg/m2 total dose); Anti-Thymocyte Globulin (horse) (150mg/kg total dose)/TBI 450 cGy	Drug: Cyclophosphamide; Other Names: Cytoxan®; Drug: Fludarabine; Other Names: Fludara®; Drug: Horse Anti-thymocyte Globulin; Other Names: ATG; Lymphocyte Immune Globulin
Experimental: Regimen D; Includes patients with the following specific diagnosis of: Severe Combined Immune Deficiency Syndrome with no evidence of host NK function (will receive Regimen A) and matched related donor; Cyclophosphamide (30 mg/kg total dose); Fludarabine (90 mg/m2 total dose); Rabbit anti-thymocyte globulin (Thymoglobulin)(TMG)**(8 mg/kg total dose) TMG only in family haploidentical and unrelated donors	Drug: Cyclophosphamide; Other Names: Cytoxan®; Drug: Fludarabine; Other Names: Fludara®; Drug: Rabbit Anti-thymocyte Globulin; Other Names: Thymoglobulin; TMG

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with Adverse Events	The number of participants with adverse events as assessed by National Cancer Institute (NCI) Common Terminology Criteria Adverse Events (CTCAE - Version 4.0)	Up to 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Risk of disease progression	To determine the risk of disease progression (including neuropsychological deterioration in patients with metabolic non-malignant diseases) following a Flu/CY or Bu/Flu based conditioning regimen.	Up to 1 year
Immune reconstitution	Titers of immune cells (T cells, B cells, and NK cells) from peripheral blood will be measured following a Flu/CY or Bu/Flu based conditioning regimen and AlloSCT in patients with selected non-malignant diseases.	Up to 1 year
Incidence of graft versus host disease (GVHD)	Incidence of GVHD in participants following a Flu/Cy or Bu/Flu based conditioning regimen.	Up to 1 year
Metabolic/Immune reconstitution	To determine metabolic/immune (gene/protein) reconstitution by standard biochemical/PCR assays in patients.	Up to 1 year

Collaborators and Investigators

• Sponsor: Columbia University
• Investigators: Principal Investigator: James Garvin, MD, PhD, Columbia University

Publications and helpful links

Helpful Links

• Click on "Morgan Stanley Children's Hospital" and then "Clinical Services" and then "Blood & Marrow Transplantation"

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2002
• Primary Completion (Actual): September 7, 2021
• Study Completion (Actual): September 7, 2021

Study Registration Dates

• First Submitted: November 23, 2009
• First Submitted That Met QC Criteria: November 23, 2009
• First Posted (Estimated): November 25, 2009

Study Record Updates

• Last Update Posted (Actual): October 31, 2024
• Last Update Submitted That Met QC Criteria: October 28, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: Severe Combined Immunodeficiency; Chemotherapy; Allogeneic Stem Cell Transplantation; Radiation Therapy; Fanconi Anemia; Osteopetrosis; Bone marrow Failure
• Additional Relevant MeSH Terms: Congenital Bone Marrow Failure Syndromes; Primary Immunodeficiency Diseases; Urogenital Diseases; Cytopenia; Bone Diseases; Musculoskeletal Diseases; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Genetic Diseases, Inborn; Metabolic Diseases; Immune System Diseases; Infant, Newborn, Diseases; Hematologic Diseases; Bone Marrow Diseases; Anemia; DNA Repair-Deficiency Disorders; Osteosclerosis; Osteochondrodysplasias; Bone Diseases, Developmental; Renal Tubular Transport, Inborn Errors; Anemia, Hypoplastic, Congenital; Anemia, Aplastic; Bone Marrow Failure Disorders; Immunologic Deficiency Syndromes; Severe Combined Immunodeficiency; Osteopetrosis; Fanconi Syndrome; Fanconi Anemia; Pancytopenia; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Alemtuzumab; Cyclophosphamide; Fludarabine; Immunoglobulins; Busulfan; Antilymphocyte Serum; Thymoglobulin
• Other Study ID Numbers: AAAB0170; CHNY-01-509 (Other Identifier: CU)