Partially HLA Mismatched (Haploidentical) Allogeneic Bone Marrow Transplantation
|ClinicalTrials.gov Identifier: NCT01749293|
Recruitment Status : Terminated (The protocol design is being reconfigured in order to open a new study.)
First Posted : December 13, 2012
Last Update Posted : May 27, 2015
Allogeneic stem cell transplantation is a potentially curative treatment for patients with many hematologic malignancies (e.g. leukemia, lymphoma, and myeloma with high risk of relapse). This process requires a suitable donor. The best case scenario involves an Human Leukocyte Antigen (HLA) matched sibling donor. However, this type of donor is not always available. Donor registries can provide another source for matched unrelated donors, but this may take valuable time delaying treatment for the transplant recipient. Donor availability remains a significant barrier to the use of allogeneic (from a donor) stem cell transplant. This issue disproportionately affects patients of minority backgrounds. Novel strategies to improve outcomes using alternative donors are desperately needed.
Haploidentical transplants are an alternative which provides a readily available donor in the form of a partially HLA matched family member. This provides for more potential donors and the donors can be selected based on other factors that can play a role in transplant success (e.g. age, gender, KIR alloreactivity). Recent advances in transplant techniques have greatly improved success rates with haploidentical transplants although disease relapse has remained as issue.
This trial aims to provide an alternative transplant option for patients with hematologic malignancies who require bone marrow transplantation but lack an HLA identical donor. The investigational component of this study is the combination of the Fludarabine/ Busulfan/ Total Body Irradiation conditioning regimen and the HLA Haploidentical Transplant with post-transplant Cyclophosphamide.
|Condition or disease||Intervention/treatment||Phase|
|Hematologic Malignancies||Procedure: Haploidentical Transplant Drug: Fludarabine Drug: Busulfan Radiation: Total Body Irradiation Drug: Cyclophosphamide||Phase 2|
Allogeneic stem cell transplantation is a potentially curative treatment for patients with hematologic malignancies such as leukemia, lymphoma and myeloma who are at high risk of relapse. As well as the potential to deliver high doses of chemotherapy or radiation this procedure affords the benefit of an immunologic weapon against disease in the form of the graft versus tumor effect.
The major variables affecting the outcome of allogeneic transplant include: patient selection (age and comorbidities); disease status at the time of transplantation (remission vs. active disease); type of donor (HLA matched vs. mismatched or related vs. unrelated); type of conditioning regimen; source of stem cells (bone marrow vs. peripheral blood). Recent advances in the field of stem cell transplant have substantially lowered transplant related morbidity and mortality.
The availability of stem cell transplant as a treatment modality is dependent upon the availability of a suitable donor. Best outcomes are thought to occur in HLA matched sibling donors. The chance of a sibling being HLA matched is approximately 25%. Despite the development of large worldwide donor registries the likelihood of finding an HLA matched unrelated donor is 60-70% at best and drops to 10% in some ethnic minorities. In addition the process of identifying, confirming and harvesting an unrelated donor is cumbersome and time consuming at a time when the patient must proceed immediately to transplant (time from initiation of search to identification of an unrelated donor identification takes a median of 49 days). Therefore the development of alternative sources of hematopoietic stem cells is an area of immense interest to many investigators.
Alternative sources include cord blood and HLA haploidentical donors. Cord blood has been an attractive source permitting immediate availability and possibly a lower rate of graft versus host disease (GVHD). However delay in engraftment, particularly after myeloablative conditioning, remains a significant disadvantage. Haploidentical transplants carry some of the same advantages with virtually all patients having immediate access to a suitable and willing donor in the form of a partially HLA matched family member. Furthermore the number of potential donors allows for donor selection based upon factors such as age, gender, KIR alloreactivity. Finally the donor is readily available for future cellular therapies such as donor lymphocyte infusion.
Early attempts at haploidentical transplantation were hampered by high rates of graft failure and severe graft versus host disease. Recent advances in graft versus host disease prophylaxis with post transplant high dose cyclophosphamide (Cy) have overcome these barriers to a large degree. Published studies have shown that HLA-haploidentical bone marrow transplant (BMT) after non-myeloablative conditioning and using 2 doses of post-transplantation Cy followed by tacrolimus and mycophenolate mofetil (MMF) is a well-tolerated procedure. However, the major cause of treatment failure in this high-risk population was early relapse. As conditioning intensity has been clearly linked to rates of relapse in multiple diseases, it is postulated that utilizing conditioning with higher anti-tumor potential will lead to a lower relapse rate.
Given the advances in GVHD prophylaxis with post-transplantation Cy, reduced intensity conditioning with Fludarabine, Busulfan and total body irradiation combined with high-dose post-transplantation Cy is the platform for this study. The toxicities of this reduced intensity conditioning regimen are not expected to differ substantially from previous data incorporating post-transplantation Cy. However, this regimen may have higher anti-tumor potential resulting in a decreased relapse rate.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||2 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Partially HLA Mismatched (Haploidentical) Allogeneic Bone Marrow Transplantation for Patients With Hematologic Malignancies|
|Study Start Date :||August 2012|
|Estimated Primary Completion Date :||June 2017|
|Estimated Study Completion Date :||June 2017|
Experimental: Haploidentical Transplant
All subjects will be dosed with pre-transplant Fludarabine (180mg/m2)and Busulfan total AUC 2400 μmol*min/L or 6.4mg/kg. Subjects will then undergo total body irradiation 2Gy. Subjects will undergo haploidentical allogeneic bone marrow transplant, followed by Cyclophosphamide, Tacrolimus and MMF based GVHD prophylaxis.
Procedure: Haploidentical Transplant
Subjects will be dosed with pre-transplant Fludarabine (180mg/m2)and Busulfan total AUC 2400 μmol*min/L or 6.4mg/kg. Subjects will then undergo total body irradiation 2Gy. Subjects will undergo haploidentical allogeneic bone marrow transplant, followed by Cyclophosphamide, Tacrolimus and MMF based GVHD prophylaxis.
Other Name: Mismatched allogeneic bone marrow transplantDrug: Fludarabine
Subjects in this trial will receive Fludarabine 30 mg/m2 IV QD, adjusted for CrCl from Days -8 through -3.
Other Name: FludaraDrug: Busulfan
Subjects in this trial will receive Busulfan total AUC 2400 μmol*min/L or 6.4mg/kg in 4 doses with seizure prophylaxis from Days -6 through -3.
Other Names:Radiation: Total Body Irradiation
Subjects in this trial will receive total body irradiation (2Gy fractionated) from Day -2 or -1.Drug: Cyclophosphamide
Subjects in this trial will receive Cyclophosphamide 50 mg/kg IV QD on Days 3 and 4 post-transplant.
- Engraftment Rate [ Time Frame: Up to Day 60 post-transplant. ]To estimate engraftment rates and incidence of full donor chimerism at Day 60 in patients undergoing an HLA haploidentical stem cell transplant with post transplant high dose cyclophosphamide.
- Overall & Event-Free Survival [ Time Frame: Up to one year post-transplant. ]To estimate the overall survival (OS), event free-survival (EFS) and incidence of progression or relapse at 1 year post transplant.
- Toxicity [ Time Frame: Up to one year post-transplant. ]To determine the overall toxicity including rate of graft versus host disease.
- HLA Disparity [ Time Frame: Up to one year post-transplant. ]Describe transplantation outcomes according to donor-recipient HLA disparity and models of natural killer cell alloreactivity.
- Immune Reconstitution [ Time Frame: Up to one year post-transplant. ]To assess immune reconstitution after transplant the patient's blood will be drawn and tested at baseline then 1, 3, 6, and 12 month. 10 ml of blood will be drawn for detection of lymphocyte subsets, monocytes, and dendritic cells by flow cytometry.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01749293
|United States, Illinois|
|University of Illinois Cancer Center|
|Chicago, Illinois, United States, 60612|
|Principal Investigator:||Pritesh Patel, MD||University of Illinois at Chicago|