Haploidentical Allogeneic Hematopoietic Stem Cell Transplantation in Children and Adolescents

Study Overview
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Brief Summary
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Purpose of study: This phase I/II trial is to evaluate the safety and feasibility of TCRαβ-depleted graft from haploidentical family donors in treating children and adolescents with malignant or non-malignant diseases.

Official Title
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Haploidentical Allogeneic Hematopoietic Stem Cell Transplantation in Children and Adolescents

Conditions
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Haploidentical Hematopoietic Stem Cell Transplantation, Malignant Disease, Non-malignant Disease

Intervention / Treatment
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* Drug: Fludarabine
* Drug: Cyclophosphamide
* Biological: anti-thymocyte globulin
* Biological: filgrastim
* Radiation: Total body irradiation
* Procedure: TCRαβ-depleted hematopoietic cell transplantation
* Device: CliniMACS


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A. Disease inclusions Hematologic malignancy: Acute lymphoblastic leukemia including induction failure, CR1 (Ph+, t(4:11), hypodiploid and other very high risk features), ≥ CR2, infant ALL with MLL or other unfavorable features Acute myeloid leukemia excluding CR1 with t(8:21), inv(16), t(15:17), and Down syndrome Myelodysplastic syndrome: RCC with -7 or RCC in need of transfusion Chronic myeloid leukemia in AP Juvenile myelomonocytic leukemia Malignant lymphoma, NHL or HD, after failed autologous HSCT Other Non-hematologic malignancy Relapsed or refractory solid tumors including neuroblastoma, rhabdomyosarcoma and so on Non-malignant hematologic disease Acquired severe and very severe aplastic anemia Fanconi anemia Paroxysmal nocturnal hemoglobinuria Congenital dyserythropoietic anemia Others Inherited or metabolic disease Hemophagocytic lymphohistiocytosis Malignant osteopetrosis Storage diseases Others B. Recipient inclusions 1. Age < 21 years 2. No HLA-identical stem cell donor available 3. Lansky-Play performance score >60 4. No active infection at the time of transplantation Exclusion Criteria: HIV-infection Presence of active and serious infection Cardiac ejection fraction <35% on echocardiography Severe pulmonary dysfunction (DLCO <30%) Liver function abnormalities with bilirubin >4mg/dL and elevation of transaminases > 400U/L Concurrent severe or uncontrolled medical disease Patients who are pregnant Patients unwilling or unable to comply with the protocol or unable to give informed consent

Ages Eligible for Study
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Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HAPLO<br> | Drug: Fludarabine<br>* 40mg/M2 once daily IV on days -7 to -2<br>Drug: Cyclophosphamide<br>* 50 mg/kg IV on day -3 and -2<br>Biological: anti-thymocyte globulin<br> <br> Biological: filgrastim<br>* Beginning on day 4 and continuing until blood counts recover<br>Radiation: Total body irradiation<br>* 200 cGy per day on D-6 to -4 (eligible disease except aplastic anemia) 200 cGy per day on D-5 & -4 (severe aplastic anemia)<br>Procedure: TCRαβ-depleted hematopoietic cell transplantation<br> <br> Device: CliniMACS<br>* Immunogenetic depletion of TCRαβ cells<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate tralsplant-related mortality after haploidentical hematopoietic stem cell transplantation using TCRαβ-depleted graft |  | 1 year posttransplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess engraftment and graft failure |  | 28 days posttransplant | 
| To estimate the risk of acute GVHD |  | 100 days posttransplant | 
| To estimate the incidence of relapse |  | 100 days and 1 year post-transplant | 
| To estimate the incidence and severity of chronic GVHD |  | 1 year posttransplant | 
| To estimate the overall survival |  | 1 year posttransplant | 
| To estimate the incidence of bacterial, fungal and viral infection |  | 100 days and 1 year posttransplant | 
| To estimate the reactivation rate of CMV, EBV |  | 100 days and 1 year posttransplant | 
| To evaluate the immune reconstitution of T, B, and NK cells |  | days 7, 14, 21, 28, 60, 90, 180, 270, and 365 days post-transplant | 
| To evaluate the lineage-specific chimerism using flow cytomery of CD3+, CD19, CD56, TCR αβ, and TCRγδ at pre-transplant |  | days 7, 10, 14, 21, 28, 60, 90, 180, 270 and 365 post-transplant | 
| To assess event free survival |  | 1 year posttransplant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TCRαβ depletion, Children and adolescents, Malignant disease, Non-malignant disease, Haploidentical hematopoietic stem cell transplantation