Hemoglobinopathies, Immunodeficiencies, Non Malignant Diseases
Conditions
Keywords
Non-malignant diseases, Immune deficiencies, Hemoglobinopathies, Reduced Intensity Conditioning(RIC)
Brief summary
This Phase II pilot study evaluates the safety and effectiveness of reduced-intensity conditioning (RIC) regimens prior to allogeneic hematopoietic stem cell transplantation (HSCT) in pediatric and young adult patients with non-malignant disorders, including immunodeficiencies and hemoglobinopathies. The study examines different conditioning approaches that vary in the timing and dosing of alemtuzumab (Campath), as well as disease-specific modifications for beta thalassemia major and infants. The primary objective is to assess donor engraftment and event-free survival at one year following transplant. The study aims to determine whether RIC regimens can reduce toxicity while maintaining successful engraftment and disease control.
Detailed description
This Phase II, single-institution, investigator-initiated pilot study evaluates reduced-intensity conditioning (RIC) strategies in the setting of allogeneic hematopoietic stem cell transplantation (HSCT) for non-malignant disorders. The study focuses on optimizing conditioning approaches to balance adequate immunosuppression for donor engraftment with minimization of regimen-related toxicity. RIC regimens are designed to reduce the organ toxicity and late effects associated with traditional myeloablative conditioning while maintaining sufficient host immune suppression to allow durable donor cell engraftment. This approach is particularly relevant in patients with pre-existing organ dysfunction or increased vulnerability to treatment-related complications. In non-malignant diseases, full donor chimerism may not be required for therapeutic benefit, and stable mixed chimerism may be sufficient for disease correction. The conditioning strategies evaluated in this protocol primarily differ in the timing and administration of alemtuzumab, an anti-CD52 monoclonal antibody used to deplete host lymphocytes and reduce the risk of graft rejection and graft-versus-host disease. Earlier ("distal") administration is intended to reduce prolonged exposure at the time of stem cell infusion, thereby preserving donor immune function, while more proximal administration provides more immediate immunosuppression but may increase the risk of delayed immune recovery. Disease-specific modifications to conditioning intensity are incorporated for select populations. Patients with beta thalassemia major receive additional cytoreductive and immunosuppressive agents to address the higher risk of graft rejection associated with intact immunity and expanded marrow space. Infants with immunodeficiencies are treated with modified regimens designed to reduce toxicity while maintaining engraftment potential. Following conditioning, patients undergo stem cell transplantation using donor sources that may include related or unrelated donors as well as cord blood or alternative donor options based on clinical circumstances. Standard supportive care and post-transplant immunosuppression are administered according to institutional guidelines. Patients are monitored longitudinally for engraftment, donor chimerism, immune recovery, and transplant-related complications. The study also evaluates clinical management strategies such as donor lymphocyte infusions or second transplantation in cases of declining chimerism or graft failure. This study is intended to inform optimal conditioning approaches for patients with non-malignant disorders undergoing HSCT, with the goal of improving transplant tolerability while maintaining effective and durable engraftment.
Interventions
DRUGReduced-Intensity Conditioning
A pre-transplant conditioning approach designed to provide sufficient immunosuppression to enable donor cell engraftment while minimizing regimen-related toxicity compared to myeloablative conditioning. Regimens are adapted based on patient age and underlying disease characteristics using the following agents: Campath, Fludarabine, Melphalan, Cyclosporine, Cellcept (MMF).
Sponsors
Children's Hospital of Philadelphia
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is a single-group assignment study in which all enrolled participants receive reduced-intensity conditioning prior to allogeneic hematopoietic stem cell transplantation. The study evaluates multiple conditioning approaches that vary in the timing and components of the regimen (including alemtuzumab-based strategies and disease-specific modifications), without randomization or comparison to a separate control group. Outcomes are assessed across the entire cohort to evaluate engraftment, tolerability, and feasibility of the RIC approaches.
Eligibility
Sex/Gender
ALL
Age
6 Months to 25 Years
Healthy volunteers
No
Inclusion criteria
1. Age \>6 months- 25 years 2. Diseases eligible for Distal Alemtuzumab: * Immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome * Sickle cell disease (Neurologic: history of stroke or any neurologic defect lasting \>24 hours accompanied by infarct on MRI; or abnormal transcranial Doppler, or abnormal MRI with cerebral vasculature stenosis. OR minimum 2 episodes of acute chest syndrome in preceding 2 year period OR history 3 or more severe pain events/year in the 2 years prior to transplant.) * Thalassemia major * Bone marrow failure, including Kostmann's, amegakaryocytic thrombocytopenia, Blackfan-Diamond syndrome 3. Diseases eligible for Intermediate Alemtuzumab * Hemophagocytic lymphohistiocytosis other macrophage activation syndromes, severe Langerhans histiocytosis * Severe combined immune deficiency, adenosine deaminase deficiency, common variable immunodeficiency * Wiskott-Aldrich syndrome 4. Organ criteria: * Cardiac: Echocardiogram shortening fraction \>27% * Pulmonary: for those with pulmonary function tests: DLCO/VA \>40% If DLCO/VA is not reported this is considered inability to perform the test. In this case Pulse Ox and Respiratory Exam will be used as evaluation criteria. * Renal: Serum creatinine \<1.5 x upper limit of normal for age * Hepatic:; ALT and AST \<5 x upper limit of normal * Infection: No active infections.
Exclusion criteria
1. Uncontrolled bacterial, fungal or viral infections. 2. Bare lymphocyte syndrome (MHC class II deficiency)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Engraftment | Post Transplant -100 days | engraftment of patients with non-malignant disorders will be evaluated using a reduced-intensity conditioning regimen |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Event-free Survival | 1 year post transplant | Event-free survival is defined as the time interval to either primary or late graft failure, disease recurrence, or death. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORTimothy J Olson, MD
Children's Hospital of Philadelphia
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 7.87 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 49 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants |
| HLH vs Non-HLH HLH | 6 Participants |
| HLH vs Non-HLH Non-HLH | 48 Participants |
| Sex: Female, Male Female | 25 Participants |
| Sex: Female, Male Male | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 4 / 54 |
| other Total, other adverse events | 0 / 54 |
| serious Total, serious adverse events | 4 / 54 |
Outcome results
None listed