CD34+ Cell Enriched and T Cell Depleted Allogeneic Stem Cell Transplantation for Patients With Mismatched Related Donors or Borderline Organ Function

Study Overview
=================
Brief Summary
-----------------
The purpose of this protocol is to provide access to the CliniMACS® System to hematopoietic cell transplant (HSCT) patients who do not have a matched related donor. The CliniMACS system is currently approved for use in patients who have AML, and a genetically matched sibling donor. Through this protocol, the investigators will be able to offer potentially life-saving transplants to patients who have genetically mis-matched donor, who have no other options for treatment.

Official Title
-----------------
An Expanded Access Study Using the CliniMACS System to Offer Therapeutic Manipulated Grafts That Are CD34 Cell Enriched and T Cell Depleted for Allogeneic Stem Cell Recipients With Mismatched Related Donors or Borderline Organ Function

Conditions
-----------------
Malignant Diseases, Non-malignant Diseases

Intervention / Treatment
-----------------
* Device: CliniMACS CD34+ cell enrichment and T-cell depletion


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Participant age is 0 (newborn) to 35 years-old. Participant has a disorder affecting the hematopoietic system that are inherited, acquired, or a result from the myeloablative treatment that can benefit from alternative stem cell transplantation according to standard practice guidelines for including patients for transplant. Participant's medical screening clears s/he for allogeneic transplantation as per current institutional SOP based on standards of foundation for accreditation of cellular therapy and stem cell transplantation (FACT); Participant must lack a healthy, HLA-identical related or unrelated donor unless s/he has a borderline organ function that will preclude the recipient from receiving a curative therapy due to the need of post-HSCT immunosuppressive therapy. Participant must have a matched or mismatched-related donor who is: Able to receive granulocyte colony-stimulating factor (G-CSF) and undergo apheresis either through placement of catheters in antecubital veins or a temporary central venous catheter OR agrees on a bone marrow harvest; Healthy as per donor selection screening (following current SOP based on standards of foundation for accreditation of cellular therapy and stem cell transplantation - FACT); Willing to participate and sign consent. Participant or Legal Authorized Representative is able to sign informed consent (and signed assent, if applicable) for transplant. Exclusion Criteria: Participant does not qualify for an allogeneic transplant due to medical screening, underlying disease, or lack of alternative donors. Any condition that compromises compliance with the procedures of this protocol, as judged by the principal investigator.

Ages Eligible for Study
-----------------
Maximum Age: 35 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ARM A Malignant TBI<br>Malignant diseases Conditioning including total body irradiation and chemotherapy | Device: CliniMACS CD34+ cell enrichment and T-cell depletion<br> <br> |
| Experimental: ARM B Malignant Non-TBI<br>Malignant diseases chemotherapy based conditioning | Device: CliniMACS CD34+ cell enrichment and T-cell depletion<br> <br> |
| Experimental: ARM C Non-malignant<br>Non-malignant diseases Chemotherapy based conditioning | Device: CliniMACS CD34+ cell enrichment and T-cell depletion<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Severe (Grade III/IV) Acute Graft vs Host Disease (GVHD) | GVHD is a condition that occurs when donor bone marrow or stem cells attack the recipient. | Day +100 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Graft Failure | Failure of donor stem cells to make neutrophils | Up to Day +42 after stem cell transplant | 
| Length of Time to Engraftment | Absolute neutrophil count (ANC) >500 for 3 consecutive days and >80% donor cells in blood. | up to +1 year post-transplant | 
| Chimerism of Donor Cells | The percentage of donor cells for all evaluable (without disease progression) patients | Day +100 post-transplant | 
| Immune Recovery (CD4) | The time to CD4 count >100 | up to +1 year post-transplant | 
| Number of Participants With Immune Recovery (CD4 >200) by Year 1 |  | up to +1 year post-transplant | 
| Immune Recovery Shown as Phytohemagglutin (PHA) | Immune recovery defined as achieving normal levels of PHA (53,000-200,000 CPM) | 6 months and 1 year post-transplant | 
| Number of Patients With Post-transplant Lymphoproliferative Disease (PTLD) | Post-transplant lymphoproliferative disorder (PTLD) is a well-known, life-threatening complication of organ transplantation, predominantly occurring after solid organ transplantation (SOT) and hematopoietic stem cell transplantation (HSCT). | up to +1 year post-transplant | 
| Number of Patients With Severe Toxicities | Incidence of transplant-related toxicities | up to +1 year post-transplant | 
| Number of Participants Experiencing Post-transplant Infections | Post-transplant infections will be described by incidence and type. Participants may have had more than one type of infection. | up to +1 year post-transplant | 
| Transplant-related Mortality (TRM) | Death related to transplant | at Day +100 and +1 year post-transplant | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Haplocompatible, Stem cell transplant, Borderline organ function, Alternative donor stem cell transplant