Intrabone Infusion of Cord Blood in Adults With Hematological Malignancies

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the engraftment of donor hemopoiesis (proportion of transplanted patients with successful engraftment at day +42) in adult patients affected by high risk hematological malignancies after intrabone infusion of cord blood.

Detailed Description
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For many hematological malignancies, hemopoietic stem cell (HSC) transplant is the only possible treatment. The source of HSC is often bone marrow (BM) or, in the past 10 years, peripheral blood cell (PBSC) mobilized by granulocyte growth factor. Transplant needs a HLA compatible (related or unrelated) donor. Around 10-30% of patients with indication for allogeneic HSC transplant are not able to undergo the procedure because of the lack of a HLA compatible donor. Cord blood (CB) cells represent another possible source, which needs a lower degree of HLA compatibility, this type of transplant, however, offers a lower number of HSC. For this reason, adult patients, until now, could not use this source, because of the not suitable number of cell per kg, of recipient body weight. Recently, in experimental animal models it was observed that intrabone HSC transplant allows, in the recipient, engraftment of donor hemopoiesis by using a 1Log (10-1) lower number of cells compared to the intravenous way (Yahata 2003, Castello 2004). Safety and feasibility of intrabone infusion was verified by two clinical studies on humans: the first was conducted by Ringden O. et al. in 18 patients without any evidence of collateral effects and with complete engraftment of donor hemopoiesis with BM as a source of HSC (Hagglund 1998); the second one was conducted by Frassoni et al. (Frassoni 2008) with CB as the source of HSC. The aim of this study is to evaluate the intrabone infusion instead of the intravenous one, for the HSC transplant from CB in patients with haematological malignancies when it is not possible to find a HLA matched donor. We will perform: evaluation of the engraftment kinetics; evaluation of the chimerism degree at 30, 60, 100 days, 6 months and 1 year after transplant; studies on immunological reconstitution and the role of the NK compartment.

Official Title
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Intrabone Infusion of Cord Blood Hemopoietic Stem Cells in Adult Patients With High Risk Haematological Malignancies.

Conditions
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Hematological Malignancies

Intervention / Treatment
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* Procedure: Intrabone cord blood infusion


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age between 18 and 65 years. Patients affected by hematological malignancies without a HLA identical sibling donor or unrelated donor. Informed consent. Exclusion Criteria: Patients with ECOG < 2. Patients with blood creatine > 2 mg/dl or with transaminase or cholestase index > 5 times compared to normality upper limits. Patients with Cardiac Fraction Ejection < 40%. Patients with DLCO < 60% or Diffusing Lung Capacity of carbon monoxide attesting a severe pulmonary insufficiency. Patients with peripheral blast cell count over 10%. Second neoplasia diagnosed no more than 2 years before. Patients with active or suspected infection by fungi for which a therapeutic treatment is ongoing. HIV positive patients. HCV-RNA and HBV-RNA positive patients (it is possible to enrol them after discussion with the Principal Investigator). Pregnant or lactating women. Severe mental diseases.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Intrabone cord blood infusion<br>All adults patients with hematological malignancies, lacking a HLA matched donor but with a HLA compatible CB unit, fulfilling the inclusion criteria, will undergo to intrabone HSC infusion of CB. | Procedure: Intrabone cord blood infusion<br>* Myeloablative conditioning regimen (MAC): i.v. Busulfan 12.8 mg/kg, Cyclophosphamide 120 mg/kg, ATG-Fresenius 30 mg/kg Reduced intensity conditioning regimen (RIC): Tiothepa 10 mg/kg, Fludarabine 100 mg/kg, Cyclophosphamide 100 mg/kg, ATG-Fresenius 30 mg/kg GVHD prophylaxis: Cyclosporine 1 mg/kg since day -7 to +120, Mycophenolate 15 mg kg x 2 since day +1 to +27<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of transplanted patients with successful engraftment at day +42 |  | Within the first 42 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical response with the analysis of global survival, survival without relapse, relapse incidence |  | 1 year | 
| Acute and chronic GVHD incidence |  | For acute GVHD 100 days; for chronic GVHD 1 year | 
| Infection incidence |  | 1 year | 
| Chimerism study on selected populations (myeloid, lymphoid, NK) |  | 30, 60, 100 days, 6 months and 1 year | 
| Studies on immunological reconstitution |  | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anti-thymocyte globulin Fresenius, Busulfan, Cord blood, Cyclophosphamide, Fludarabine, Human Leucocyte Antigen, Hematopoietic Stem Cell, Hematopoietic Stem Cell Transplant, Graft-versus-Host-Disease, Graft-versus-Host-Disease prophylaxis, Intrabone infusion, Thiotepa