Pooled Unrelated Donor Umbilical Cord Blood Transplant For Hematologic Malignancy Needing Allogeneic Stem Cell Transplant Without Related HLA-Match

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the multi-lineage hematopoietic chimerism for unrelated umbilical cord blood (UCB) grafts pooled from two to three cord blood units. Also to evaluate the toxicity, and antitumor responses of pooled unrelated UCB transplants.

Detailed Description
-----------------
Hematopoietic stem cell (HSC) transplantation, using human HLA-matched sibling or unrelated bone marrow or peripheral blood stem cell donor, has been used successfully to treat patients with high-risk or relapsed hematologic malignancies. However, use of this therapy has been limited by availability of fully HLA-matched donors, despite the increasing size of unrelated donor registries. For those transplanted with unrelated donor marrow stem cells, increased HLA disparity adversely affects survival due to increased risks of severe acute and chronic graft-versus-host disease (GVHD) and opportunistic infection. Only young recipients are able to tolerate a single HLA-A, B, DRB1 mismatch in this setting (1-3). To potentially extend the donor pool, UCB has been used as an alternative source of HSC. Since the first unrelated donor UCB transplant in 1993, UCB transplants have been performed worldwide. It has been found to produce outcome comparable to those from matched unrelated HSC in patients with hematologic malignancies (4). It has been shown that cryopreserved unrelated UCB from 0 to 3 HLA-A, B, DRB1-mismatched donors contains sufficient HSC to engraft most pediatrics and some adult patients (5-10). Unfortunately, the use of UCB transplant is limited by the small number of HSC in each of the cord blood unit. This is particularly a problem for adult patients. It is now possible to pool UBC so that adequate cell numbers are available for adult transplant (11). UBC is rapidly availability and has very low rate of contamination with herpes group viruses. UCB transplant results in a low incidence of both severe acute GVHD and extensive chronic GVHD, despite the use of grafts with substantial donor-recipient HLA disparity (5-10). The following conditioning regimens will be used, depending on the underlying hematologic malignancies. Conditioning regimens with Busulfan/clofarabine and with fludarabine/melphalan will be used for all patients except those with Non-Hodgkin's lymphoma when the conditioning regimen of BCNU, Etoposide, ARA-C and Melphalan will be used. GVHD prophylaxis of oral tacrolimus will be used, depending on the development of GVHD and the clinical conditions of the patients, tacrolimus may be tapered and discontinued by six months after transplant. The hematopoietic stem cells from the donors will be infused within 48-72 hours of completing the chemotherapy. The patients will receive supportive care as indicated including antibiotics, antivirals, antifungals, anti-seizure, anti-emetic medications and other medications as necessary. In addition patients will receive irradiated blood products for support as necessary.CMV negative recipient transplant will receive only CMV- blood products. Neutrophil engraftment will be defined as the day on which the ANC rises to > 500 cells/ml for two consecutive days. Platelet engraftment will be defined as the first day on which the platelet count rises to > 20,000/ml over a 7-day interval without transfusion support.

Official Title
-----------------
A Phase II Study Of Pooled Unrelated Donor Umbilical Cord Blood (UCB) Transplant For Patients With Hematologic Malignancies Needing Allogeneic Stem Cell Transplant But Do Not Have A Related HLA-Matched Donor

Conditions
-----------------
Aplastic Anemia, Acute Myelogenous Leukemia, Acute Lymphocytic Leukemia, Chronic Lymphocytic Leukemia, Chronic Myelogenous Leukemia, Hodgkins Disease, Non-Hodgkins Lymphoma, Multiple Myeloma, Myelodysplastic Syndrome

Intervention / Treatment
-----------------
* Drug: Busulfan
* Drug: Clofarabine
* Drug: Fludarabine
* Drug: Melphalan
* Drug: Carmustine
* Drug: Etoposide
* Drug: Cytarabine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients < 65 years with hematologic malignancies needing stem cell transplant but do not have HLA-matched sibling donor. Patients with the following diagnosis will be included: AML in first or subsequent complete or partial remissions ALL in first or subsequent complete or partial remissions CLL in second remission or more advanced disease CML who has failed tyrosine kinase inhibitors Hodgkin's disease who relapse after autologous transplant Non-Hodgkin's lymphoma who relapse after autologous transplant or NK-cell lymphoma in CR1 Aplastic anemia patients Multiple myeloma in second remission or moer advanced disease, including those who have failed an autologous transplant Myelodysplastic syndrome in first or subsequent complete or partial remission Patients must have 6/6, 5/6 or 4/6 molecular matches from unrelated UCB donors. Matching will be done for A, B, and DR. Matching at DR will be confirmed by molecular typing. Patients must be documented to be HIV negative. Screening must have been performed within previous 6 months. Patients must be able to give written consent. Exclusion Criteria: Patient is excluded if all of the Inclusion criteria above isn't met.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

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

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

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

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Arm<br>The following conditioning regimens will be used, depending on the underlying hematologic malignancies. Conditioning regimens with Busulfan/clofarabine and with fludarabine/melphalan will be used for all patients except those with Non-Hodgkin's lymphoma when the conditioning regimen of BCNU, Etoposide, ARA-C and Melphalan will be used. | Drug: Busulfan<br>* Busulfan 3.2 mg/kg/day intravenously on days -7, -6, -5 and -4(for non-NHL patients patients who get Clofarabine regimen)<br>Drug: Clofarabine<br>* Clofarabine intravenously 40 mg/m2/day on days -7, -6, -5, -4 and -3(for non-NHL patients patients who get Busulfan regimen)<br>Drug: Fludarabine<br>* Fludarabine 30 mg/kg/day intravenously on days -7, -6, -5, -4 and -3 (for non-NHL patients who receive Melphalan containing regimen)<br>Drug: Melphalan<br>* Melphalan intravenously 140 mg/m2/day on day -3 (only for non-NHL patients who receive Fludarabine OR for all NHL regimens)<br>Drug: Carmustine<br>* BCNU(Carmustine)300 mg/m2 intravenously on day -7 (for NHL patients only)<br>Drug: Etoposide<br>* Etoposide 300 mg/m2/day intravenously on days -6, -5, -4 and -3 (for NHL patients only)<br>Drug: Cytarabine<br>* ARA-C(Cytarabine) 100 mg/m2/day on days -6, -5, -4 and -3 (for NHL patients only)<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| evaluate the multi-lineage hematopoietic chimerism for unrelated UCB grafts pooled from two to three cord blood units | Blood will be obtained for DNA preparation for VNTR chimerism study post transplant after time of engraftment, which will happen at an average of 28 days post-trasplant. | Will be tested after granulocyte engraftment - which will happen at an average of 28 days post-transpant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| evaluate the antitumor responses of pooled UCB transplant | Baseline - All patients will have a detailed history and physical examination, CBC, complete biochemical profile and full staging procedure appropriate for the underlying disease. Post Transplant Evaluation- Disease status will be assessed prior to discharge, again at 6 weeks, 3 months, 6 months, 9 months, 12 months and after that every 6 months.The following data will be collected: hematologic recovery, and grade and tumor responses and duration of response. | Disease staged at baseline, then disease status re-assessed at 6 weeks, 3 months, 6 months, 9 months, 12 months and after that every 6 months post-transplant | 
| Number of participants that develop Graft Versus Host Disease after pooled UCB transplant | Baseline - All patients will have a detailed history and physical examination, CBC, complete biochemical profile. Post Transplant Evaluation- Patient will be evaluated prior to discharge,then weekly for first 28 days then re-assessed at 6 weeks, 3 months, 6 months, 9 months, 12 months and after that every 6 months. The following data will be collected: Patient will be assessed for any ongoing adverse events, and CBC's and biochemical profile's will be performed. | Patients will be assessed weekly during first 28 days then re-assessed at 6 weeks, 3 months, 6 months, 9 months, 12 months and after that every 6 months post-transplant. | 
| The Infection rate seen in the participants who received a pooled UCB transplant | Baseline - All patients will have a detailed history and physical examination, CBC, complete biochemical profile. Post Transplant Evaluation- Patient will be evaluated prior to discharge,then weekly for first 28 days then re-assessed at 6 weeks, 3 months, 6 months, 9 months, 12 months and after that every 6 months. The following data will be collected: Patient will be assessed for any ongoing adverse events, and CBC's and biochemical profile's will be performed. | Patients will be assessed weekly during first 28 days then re-assessed at 6 weeks, 3 months, 6 months, 9 months, 12 months and after that every 6 months post-transplant. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Leukemia, Lymphoma, Myeloma, Aplastic Anemia, Myelodysplasia, AML, ALL, CLL, CML