Peripheral Blood Stem Cell Transplant vs Bone Marrow Transplant in Individuals With Hematologic Cancers (BMT CTN 0201)

Study Overview
=================
Brief Summary
-----------------
The study is designed as a Phase III, randomized, open label, multicenter, prospective, comparative trial of granulocyte colony stimulating factor (G-CSF)-mobilized peripheral blood stem cells (PBSC) versus marrow from unrelated donors for transplantation in patients with hematologic malignancies. Recipients will be stratified by transplant center and disease risk and will be randomized to either the PBSC or marrow arm in a 1:1 ratio.

Detailed Description
-----------------
BACKGROUND: Many studies of allogeneic marrow transplantation have shown that a higher dose of marrow cells correlates with more robust hematopoietic engraftment and lower mortality from infectious complications. Peripheral blood stem cells (PBSC) collected after mobilization with granulocyte colony stimulating factor (G-CSF) contain a larger number of CD34-positive (CD34) progenitors and total cells than bone marrow. These observations led to the hypothesis that transplantation of PBSC would lead to lower mortality compared to transplantation of marrow. In addition, PBSC grafts have a higher T cell content, predicting a possibly more powerful anti-leukemia effect. However, the higher T cell content of PBSC may also lead to increased incidence and severity of acute and chronic graft-versus-host disease (GVHD). This concern is especially serious when the donor is unrelated to the recipient. This prospective, randomized, multicenter clinical trial of unrelated donor transplantation will test the hypothesis that transplantation of PBSC leads to similar patient survival compared to transplantation of marrow. DESIGN NARRATIVE: This is a Phase III randomized, open label, multicenter clinical trial sponsored by the National Marrow Donor Program (NMDP) and the National Institutes of Health (NIH). The objective of the trial is to test the null hypothesis that there is no difference in overall survival after PBSC versus marrow transplants from HLA compatible unrelated donors. The study will compare G-CSF-mobilized PBSC transplantation with bone marrow transplantation from HLA-compatible unrelated donors for patients with leukemia, myelodysplastic or myeloproliferative syndromes. Conditioning and GVHD prophylaxis regimens will vary by center and within centers, however, the center must declare before randomization what regimens will be used for each patient. The primary endpoint of this trial is 2-year survival following randomization. Secondary analyses will consider neutrophil and platelet recovery, acute and chronic GVHD, time off all immunosuppressive therapy, relapse, infections, adverse events and immune reconstitution. The trial will include evaluation of patient and donor quality of life, composition of the graft, and immune reconstitution. Accrual is anticipated for 3 years with a follow-up period of 3 years.

Official Title
-----------------
A Phase III Randomized, Multicenter Trial Comparing G-CSF Mobilized Peripheral Blood Stem Cell With Marrow Transplantation From Human Leukocyte Antigen (HLA) Compatible Unrelated Donors (BMT CTN #0201)

Conditions
-----------------
Leukemia, Myeloproliferative Disorders, Myelodysplastic-Myeloproliferative Diseases

Intervention / Treatment
-----------------
* Biological: Allogeneic bone marrow transplantation
* Biological: Peripheral blood stem cell transplantation


Participation Criteria
=================
Eligibility Criteria
-----------------
Patient Inclusion Criteria: One of the following diagnoses: Acute myelogenous leukemia at the following stages: first remission, second remission, third or subsequent remission, or not in remission Acute lymphoblastic leukemia at the following stages: first remission, second remission, third or subsequent remission, or not in remission Chronic myelogenous leukemia at the following stages: chronic phase, accelerated phase, or blast phase Myelodysplastic syndromes (MDS) at the following stages: refractory anemia; refractory anemia with ringed sideroblasts; refractory cytopenia with multilineage dysplasia; refractory cytopenia with multilineage dysplasia and ringed sideroblasts; refractory anemia with excess blasts-1 (5-10% blasts); refractory anemia with excess blasts-2 (10-20% blasts); myelodysplastic syndrome, unclassified; or MDS associated with isolated del (5q) Myeloproliferative diseases: chronic myelomonocytic leukemia; agnogenic myeloid metaplasia with myelofibrosis (idiopathic myelofibrosis); juvenile myelomonocytic leukemia Therapy-related acute myelogenous leukemia (AML) or MDS with prior malignancy that has been in remission for at least 12 months. If the remission is less than 12 months, Medical Monitor or Protocol Chair approval is required for eligibility Patient Exclusion Criteria: Prior allogeneic or autologous transplants using any hematopoietic stem cell source; patients with secondary malignancies who have had a prior autologous transplant will be eligible; the prior autologous transplant must have been performed for the primary malignancy (such as lymphoma) and must have occurred 12 or more months prior to enrollment Lymphoma (11% of 2001 NMDP transplants), other malignant disorders (6%), and non-malignant disorders (9%) Donor Inclusion Criteria: Matched for HLA-A, B, and DRB1 antigens One antigen mismatch at HLA-A, B, or DRB1 is acceptable with or without mismatch at HLA-C Typing is by DNA techniques: intermediate resolution for A, B, and C, and high resolution for DRB1. HLA-C typing is mandatory but will not count in the match. Willing to undergo both bone marrow harvest and G-CSF administration with apheresis Willing to be randomly assigned to either marrow or PBSC collection Adequate peripheral venous access for leukapheresis or willing to undergo placement of a central catheter Donor center affiliation with NMDP Additional donor inclusion criteria can be found in the Donor Companion Manual Donor Exclusion Criteria: Pregnant (positive serum β-HCG) or uninterruptible breastfeeding Known allergy to G-CSF or to E. Coli-derived recombinant protein products History of autoimmune disorders History of deep vein thrombosis or venous thromboembolism History of iritis or episcleritis History of serious adverse reaction to anesthesia Thrombocytopenia (platelets less than 150,000 per mcL) at baseline evaluation Current treatment with lithium Presence of sickle hemoglobin as demonstrated by appropriate testing such as hemoglobin electrophoresis Receiving experimental therapy or investigational agents

Ages Eligible for Study
-----------------
Maximum Age: 66 Years

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

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

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

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Bone Marrow Transplant<br>Allogeneic bone marrow transplantation | Biological: Allogeneic bone marrow transplantation<br>* Bone marrow transplant from HLA compatible unrelated donors.<br>|
| Active Comparator: Blood Stem Cell Transplant<br>Peripheral blood stem cell transplantation | Biological: Peripheral blood stem cell transplantation<br>* Peripheral blood transplant from HLA compatible unrelated donors.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Two-year Overall Survival | Overall survival rate at 2 years according to an intention-to-treat analysis. | Measured at 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neutrophil Engraftment |  | Measured at Day 28 | 
| Platelet Engraftment |  | Measured at Day 180 | 
| Graft Failure |  | Measured at 28 and 100 days | 
| Extensive Chronic Graft-versus-host Disease (GVHD) |  | Measured at 730 days | 
| Chronic GVHD |  | Measured at 2 years | 
| Relapse | Analysis restricted to patients who received the transplant. | Measured at 2 years | 
| Infections | Number of infection reports per patient. | Measured at 1 and 2 years | 
| Grades III-V Unexpected Adverse Events |  | Measured by 2 years | 
| Acute GVHD Grade II-IV |  | 100 days, 180 days | 
| Acute GVHD Grade III-IV |  | 100 days, 180 days | 
| Current Immunosuppressive (IS) Free Survival | This outcome measure takes into account subsequent immunosuppressive therapy that may occur following discontinuation of initial immunosuppressive therapy. | Measured at 2 years | 
| Immune Reconstitution |  | Measured at 100 days, 6 months, and 1 and 2 years | 
| Donor Recovery of Baseline Complete Blood Count (CBC) and White Blood Cell Count (WBC) Differential |  | Measured at 1, 6, and 12 months | 
| Donor Recovery to Baseline Toxicity Scores |  | Measured at 1, 6, and 12 months | 
| Donor Quality of Life |  | Measured at 1, 6, and 12 months | 
| Patient Quality of Life |  | Measured at baseline, 6 months, and 1, 2, and 5 years |