Reduced Intensity Conditioning for Non-Malignant Disorders Undergoing UCBT, BMT or PBSCT (HSCT+RIC)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Congenital Bone Marrow Failure Syndromes; Inflammatory Conditions; Primary Immunodeficiency (PID); Inherited Metabolic Disorders (IMD); Hereditary Anemias; Systemic Juvenile Idiopathic Arthritis (sJIA); Juvenile Rheumatoid Arthritis (JRA)
• Intervention / Treatment: Drug: Hydroxyurea; Drug: Alemtuzumab; Drug: Fludarabine; Drug: Melphalan; Drug: Thiotepa

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.

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.

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Shawna McIntyre, RN; Phone Number: 412-692-5552; Email: mcintyresm@upmc.edu
• Study Contact Backup: Name: Paul Szabolcs, MD; Phone Number: 412-692-5427; Email: paul.szabolcs@chp.edu

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15224
      • Recruiting
      • UPMC Children's Hospital of Pittsburgh
      • Sub-Investigator: Paulina Horvei, MD
      • Contact: Shawna McIntyre, RN; Phone Number: 412-692-5552; Email: mcintyresm@upmc.edu
      • Sub-Investigator: Randy Windreich, MD
      • Sub-Investigator: Archana Ramgopal, DO

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 months to 55 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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.

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

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: UCBT:transfusion dependent anemias or increased rejection risk; Alemtuzumab, Hydroxyurea, Fludarabine, Melphalan, and Thiotepa conditioning regimen prior to allogenic HSCT.	Drug: Hydroxyurea; Oral administration; Other Names: Hydrea; hydroxycarbamide; Droxia; Drug: Alemtuzumab; Intravenous (IV) administration.; Other Names: Campath; Drug: Fludarabine; IV administration; Other Names: Fludara; Drug: Melphalan; IV administration; Other Names: Alkeran; Melphalan hydrochloride; Drug: Thiotepa; IV administration
Experimental: BMT, PBSCT and not transfusion dependent UCBT; Alemtuzumab, Hydroxyurea, Fludarabine, Melphalan, and Thiotepa conditioning regimen prior to allogenic HSCT.	Drug: Hydroxyurea; Oral administration; Other Names: Hydrea; hydroxycarbamide; Droxia; Drug: Alemtuzumab; Intravenous (IV) administration.; Other Names: Campath; Drug: Fludarabine; IV administration; Other Names: Fludara; Drug: Melphalan; IV administration; Other Names: Alkeran; Melphalan hydrochloride; Drug: Thiotepa; IV administration

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

Collaborators and Investigators

• Sponsor: Paul Szabolcs
• Investigators: Principal Investigator: Paul Szabolcs, MD, University of Pittsburgh

Publications and helpful links

General Publications

• Vander Lugt MT, Chen X, Escolar ML, et al. Reduced-intensity single-unit unrelated cord blood transplant with optional immune boost for nonmalignant disorders. Blood Adv. 2020;4(13):3041-3052. Blood Adv. 2020 Aug 11;4(15):3508. doi: 10.1182/bloodadvances.2020002967. No abstract available.
• Vander Lugt MT, Chen X, Escolar ML, Carella BA, Barnum JL, Windreich RM, Hill MJ, Poe M, Marsh RA, Stanczak H, Stenger EO, Szabolcs P. Reduced-intensity single-unit unrelated cord blood transplant with optional immune boost for nonmalignant disorders. Blood Adv. 2020 Jul 14;4(13):3041-3052. doi: 10.1182/bloodadvances.2020001940.

Helpful Links

• Reduced-intensity single-unit unrelated cord blood transplant with optional immune boost for nonmalignant disorders

Study record dates

Study Major Dates

• Study Start (Actual): February 4, 2014
• Primary Completion (Estimated): November 1, 2026
• Study Completion (Estimated): November 1, 2027

Study Registration Dates

• First Submitted: October 10, 2013
• First Submitted That Met QC Criteria: October 10, 2013
• First Posted (Estimated): October 14, 2013

Study Record Updates

• Last Update Posted (Estimated): December 15, 2025
• Last Update Submitted That Met QC Criteria: December 8, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: Inflammatory Bowel Disease; Crohn's Disease; Gaucher Disease; Leukodystrophies; Hematopoietic Stem Cell Transplant (HSCT); Osteopetrosis; 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); Mucopolysaccharidoses; Hurler syndrome (MPS I); Hunter syndrome (MPS II); Krabbe Disease; Metachromatic leukodystrophy (MLD); X-linked adrenoleukodystrophy (ALD); Alpha mannosidosis; Thalassemia major; Sickle cell disease (SCD); Diamond Blackfan Anemia (DBA); Congenital transfusion dependent anemias; Globoid cell leukodystrophy; Hereditary diffuse leukoencephalopathy with spheroids (HDLS); Systemic Juvenile Idiopathic Arthritis (sJIA); Juvenile Rheumatoid Arthritis (JRA)
• Additional Relevant MeSH Terms: Bone Marrow Failure Disorders; Cytopenia; Neurologic Manifestations; Endocrine System Diseases; Bone Diseases; Musculoskeletal Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Pathologic Processes; Chronic Disease; Disease Attributes; Arthritis; Joint Diseases; Rheumatic Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Intestinal Diseases; Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Disease; Digestive System Diseases; Gastrointestinal Diseases; Neurobehavioral Manifestations; Infant, Newborn, Diseases; Death; Eye Diseases; Leukocyte Disorders; Hematologic Diseases; Demyelinating Diseases; Immunologic Deficiency Syndromes; Skin Diseases; Gastroenteritis; Eye Diseases, Hereditary; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Congenital Abnormalities; Blood Coagulation Disorders; Bone Marrow Diseases; Heredodegenerative Disorders, Nervous System; Lipid Metabolism Disorders; Adrenal Gland Diseases; Hemorrhagic Disorders; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hemoglobinopathies; Skin Diseases, Genetic; Intellectual Disability; Genetic Diseases, X-Linked; Carbohydrate Metabolism, Inborn Errors; Lysosomal Storage Diseases; Mucinoses; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Skin Abnormalities; Blood Coagulation Disorders, Inherited; Leukopenia; Hereditary Central Nervous System Demyelinating Diseases; Leukoencephalopathies; Lipid Metabolism, Inborn Errors; DNA Repair-Deficiency Disorders; Phagocyte Bactericidal Dysfunction; Death, Sudden; Osteosclerosis; Osteochondrodysplasias; Bone Diseases, Developmental; Lysosomal Storage Diseases, Nervous System; Histiocytosis, Non-Langerhans-Cell; Histiocytosis; Albinism; Anemia, Hypoplastic, Congenital; Red-Cell Aplasia, Pure; Sphingolipidoses; Lipidoses; Anemia, Aplastic; Adrenal Insufficiency; Sulfatidosis; Thalassemia; Lymphopenia; Peroxisomal Disorders; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Skin and Connective Tissue Diseases; Hemic and Lymphatic Diseases; X-Linked Intellectual Disability; Mannosidase Deficiency Diseases; Infant Death; Primary Immunodeficiency Diseases; Congenital Bone Marrow Failure Syndromes; Arthritis, Juvenile; Syndrome; Anemia, Sickle Cell; Mucopolysaccharidoses; Crohn Disease; beta-Thalassemia; Severe Combined Immunodeficiency; Granulomatous Disease, Chronic; Mucopolysaccharidosis II; Mucopolysaccharidosis I; Osteopetrosis; Inflammatory Bowel Diseases; Anemia, Diamond-Blackfan; Dyskeratosis Congenita; Lymphohistiocytosis, Hemophagocytic; Gaucher Disease; Adrenoleukodystrophy; Leukodystrophy, Metachromatic; Leukodystrophy, Globoid Cell; alpha-Mannosidosis; Chediak-Higashi Syndrome; Wiskott-Aldrich Syndrome; Autoimmune Lymphoproliferative Syndrome; Sudden Infant Death; Congenital amegakaryocytic thrombocytopenia; Hereditary Diffuse Leukoencephalopathy with Spheroids; Leukocyte adhesion deficiency type 1; Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked Syndrome; Amino Acids, Peptides, and Proteins; Proteins; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Hydrocarbons; Amides; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Amino Acids; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Phenylalanine; Amino Acids, Aromatic; Amino Acids, Cyclic; Triethylenephosphoramide; Aziridines; Azirines; Urea; Alemtuzumab; Melphalan; Thiotepa; Hydroxyurea; fludarabine; fludarabine phosphate
• Other Study ID Numbers: STUDY19060337

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No