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

Primary Immunodeficiency (PID) Clinical Trial

— HSCT+RIC  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01962415
• Other study ID #: PRO13100018
• Status: Recruiting
• Phase: Phase 2
• Start date: February 4, 2014
• Est. completion date: November 2024

Study information

• Verified date: March 2024
• Source: University of Pittsburgh
• Contact: Paul Szabolcs, MD
• Phone: 412-692-5427
• Email: paul.szabolcs[@]chp.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 100
• Est. completion date: November 2024
• Est. primary completion date: November 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Months to 55 Years

Eligibility

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.

Related Conditions & MeSH terms

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

Intervention

Drug:
• Hydroxyurea
Oral administration at 30 mg/kg/day.
• Alemtuzumab
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.
• Fludarabine
IV administration at 30 mg/m2/day or 1 mg/kg/dose, whichever is lower.
• Melphalan
IV administration at 70 mg/m2/dose.
• Thiotepa
IV administration at 200 mg/m2/dose

Locations

Country	Name	City	State
United States	UPMC Children's Hospital of Pittsburgh	Pittsburgh	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
Paul Szabolcs

Country where clinical trial is conducted

United States, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	Immune Reconstitution	Evaluation of the pace of immune reconstitution.	1 year post-transplant
Primary	Severe opportunistic infections	Evaluation of the incidence of severe opportunistic infections.	1 year post-transplant
Primary	GVHD occurrence	Description of the incidence of acute graft versus host disease (GVHD) (II-IV) and chronic extensive GVHD.	1 year post-transplant
Secondary	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
Secondary	Normal enzyme level	Determination of the feasibility of attaining and sustaining normal enzyme levels in the target population(s).	1 year post-transplant
Secondary	Neutrophil recovery	Determination of the pace of neutrophil recovery.	1 year post-transplant
Secondary	Platelet recovery	Determination of the pace of platelet recovery.	1 year post-transplant
Secondary	Grade 3-4 organ toxicity	The number of grade 3-4 organ adverse events.	1 year post-transplant
Secondary	Late graft failure	Evaluation of the incidence of late graft failure.	1 year post-transplant

External Links

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