Clinical trial NCT00075816: Peripheral Blood Stem Cell Transplant vs Bone Marrow Transplant in Individuals With Hematologic Cancers (BMT CTN 0201)
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Leukemia
Myeloproliferative Disorders
Myelodysplastic-Myeloproliferative Diseases
Lead sponsor: Medical College of Wisconsin
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
name: Blood and Marrow Transplant Clinical Trials Network
name: National Cancer Institute (NCI)
name: National Marrow Donor Program
First posted: 2004-01-13
Enrollment: 551
Sex: ALL
Maximum age (years): 66
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

  1. One antigen mismatch at HLA-A, B, or DRB1 is acceptable with or without mismatch at HLA-C
  2. 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

Primary outcomes:
measure: Two-year Overall Survival
timeFrame: Measured at 2 years
Secondary outcomes:
measure: Neutrophil Engraftment
timeFrame: Measured at Day 28
measure: Platelet Engraftment
timeFrame: Measured at Day 180
measure: Graft Failure
timeFrame: Measured at 28 and 100 days
measure: Extensive Chronic Graft-versus-host Disease (GVHD)
timeFrame: Measured at 730 days
measure: Chronic GVHD
timeFrame: Measured at 2 years
measure: Relapse
timeFrame: Measured at 2 years
measure: Infections
timeFrame: Measured at 1 and 2 years
measure: Grades III-V Unexpected Adverse Events
timeFrame: Measured by 2 years
measure: Acute GVHD Grade II-IV
timeFrame: 100 days, 180 days
measure: Acute GVHD Grade III-IV
timeFrame: 100 days, 180 days
measure: Current Immunosuppressive (IS) Free Survival
timeFrame: Measured at 2 years
measure: Immune Reconstitution
timeFrame: Measured at 100 days, 6 months, and 1 and 2 years
measure: Donor Recovery of Baseline Complete Blood Count (CBC) and White Blood Cell Count (WBC) Differential
timeFrame: Measured at 1, 6, and 12 months
measure: Donor Recovery to Baseline Toxicity Scores
timeFrame: Measured at 1, 6, and 12 months
measure: Donor Quality of Life
timeFrame: Measured at 1, 6, and 12 months
measure: Patient Quality of Life
timeFrame: Measured at baseline, 6 months, and 1, 2, and 5 years
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Duarte
country: United States
facility: City of Hope National Medical Center
state: California
city: La Jolla
country: United States
facility: UCSD Cancer Center
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Stanford
country: United States
facility: Stanford Hospital and Clinics
state: California
city: Gainesville
country: United States
facility: University of Florida College of Medicine (Shands)
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Maywood
country: United States
facility: Loyola University
state: Illinois
city: Indianapolis
country: United States
facility: IBMT (Indiana Blood and Marrow Transplant) at St Francis Franciscan Health
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics
state: Iowa
city: Kansas City
country: United States
facility: University of Kansas Hospital
state: Kansas
city: Baltimore
country: United States
facility: University of Maryland
state: Maryland
city: Boston
country: United States
facility: DFCI/Brigham & Women's
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Medical Center
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic Cancer Center
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University/Barnes Jewish Hospital
state: Missouri
city: Saint Louis
country: United States
facility: Washington University/St. Louis Children's Hospital
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Hackensack
country: United States
facility: Hackensack University Medical Center Cancer Center
state: New Jersey
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New Hyde Park
country: United States
facility: Cohen Children's Hospital
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Health Sciences
state: North Carolina
city: Columbus
country: United States
facility: Ohio State/Arthur G. James Cancer Hospital
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Medical Center
state: Oklahoma
city: Portland
country: United States
facility: Oregon Health & Science University (Peds)
state: Oregon
city: Portland
country: United States
facility: Oregon Health Sciences University
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania Cancer Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Cancer Institute
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
city: Dallas
country: United States
facility: Baylor University Medical Center
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine/The Methodist Hospital
state: Texas
city: Houston
country: United States
facility: University of Texas/MD Anderson CRC
state: Texas
city: San Antonio
country: United States
facility: Texas Transplant Institute
state: Texas
city: Salt Lake City
country: United States
facility: Utah BMT/Primary Children's Medical Center
state: Utah
city: Salt Lake City
country: United States
facility: Utah BMT/University of Utah Medical School
state: Utah
city: Richmond
country: United States
facility: Virginia Commonwealth University MCV Hospitals
state: Virginia
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
city: Calgary
country: Canada
facility: Tom Baker Cancer Centre, Calgary
state: Alberta
city: Vancouver
country: Canada
facility: Vancouver General Hospital
state: British Columbia
city: Hamilton
country: Canada
facility: Hamilton Health Sciences - McMaster Site
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Hospital
state: Ontario
city: Toronto
country: Canada
facility: University of Toronto, Princess Margaret Hospital
state: Ontario
city: Halifax
country: Canada
facility: Queen Elizabeth II Health Sciences Centre - Halifax
Study officials:
affiliation: Center for International Blood and Marrow Transplant Research
name: Mary Horowitz, MD
role: STUDY_DIRECTOR
References:
citation: Anasetti C, Logan BR, Lee SJ, Waller EK, Weisdorf DJ, Wingard JR, Cutler CS, Westervelt P, Woolfrey A, Couban S, Ehninger G, Johnston L, Maziarz RT, Pulsipher MA, Porter DL, Mineishi S, McCarty JM, Khan SP, Anderlini P, Bensinger WI, Leitman SF, Rowley SD, Bredeson C, Carter SL, Horowitz MM, Confer DL; Blood and Marrow Transplant Clinical Trials Network. Peripheral-blood stem cells versus bone marrow from unrelated donors. N Engl J Med. 2012 Oct 18;367(16):1487-96. doi: 10.1056/NEJMoa1203517.
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citation: Switzer GE, Bruce JG, Harrington D, Haagenson M, Drexler R, Foley A, Confer D, Bishop M, Anderlini P, Rowley S, Leitman SF, Anasetti C, Wingard JR. Health-related quality of life of bone marrow versus peripheral blood stem cell donors: a prespecified subgroup analysis from a phase III RCT-BMTCTN protocol 0201. Biol Blood Marrow Transplant. 2014 Jan;20(1):118-27. doi: 10.1016/j.bbmt.2013.10.024. Epub 2013 Nov 1.
citation: Waller EK, Logan BR, Harris WA, Devine SM, Porter DL, Mineishi S, McCarty JM, Gonzalez CE, Spitzer TR, Krijanovski OI, Linenberger ML, Woolfrey A, Howard A, Wu J, Confer DL, Anasetti C. Improved survival after transplantation of more donor plasmacytoid dendritic or naive T cells from unrelated-donor marrow grafts: results from BMTCTN 0201. J Clin Oncol. 2014 Aug 1;32(22):2365-72. doi: 10.1200/JCO.2013.54.4577. Epub 2014 Jun 30.
citation: Khera N, Majhail NS, Brazauskas R, Wang Z, He N, Aljurf MD, Akpek G, Atsuta Y, Beattie S, Bredeson CN, Burns LJ, Dalal JD, Freytes CO, Gupta V, Inamoto Y, Lazarus HM, LeMaistre CF, Steinberg A, Szwajcer D, Wingard JR, Wirk B, Wood WA, Joffe S, Hahn TE, Loberiza FR, Anasetti C, Horowitz MM, Lee SJ. Comparison of Characteristics and Outcomes of Trial Participants and Nonparticipants: Example of Blood and Marrow Transplant Clinical Trials Network 0201 Trial. Biol Blood Marrow Transplant. 2015 Oct;21(10):1815-22. doi: 10.1016/j.bbmt.2015.06.004. Epub 2015 Jun 11.
citation: Young JH, Logan BR, Wu J, Wingard JR, Weisdorf DJ, Mudrick C, Knust K, Horowitz MM, Confer DL, Dubberke ER, Pergam SA, Marty FM, Strasfeld LM, Brown JWM, Langston AA, Schuster MG, Kaul DR, Martin SI, Anasetti C; Blood and Marrow Transplant Clinical Trials Network Trial 0201. Infections after Transplantation of Bone Marrow or Peripheral Blood Stem Cells from Unrelated Donors. Biol Blood Marrow Transplant. 2016 Feb;22(2):359-370. doi: 10.1016/j.bbmt.2015.09.013. Epub 2015 Sep 25.
citation: Burns LJ, Logan BR, Chitphakdithai P, Miller JP, Drexler R, Spellman S, Switzer GE, Wingard JR, Anasetti C, Confer DL; Blood and Marrow Transplant Clinical Trials Network. Recovery of Unrelated Donors of Peripheral Blood Stem Cells versus Recovery of Unrelated Donors of Bone Marrow: A Prespecified Analysis from the Phase III Blood and Marrow Transplant Clinical Trials Network Protocol 0201. Biol Blood Marrow Transplant. 2016 Jun;22(6):1108-1116. doi: 10.1016/j.bbmt.2016.02.018. Epub 2016 Mar 21.
citation: Lee SJ, Logan B, Westervelt P, Cutler C, Woolfrey A, Khan SP, Waller EK, Maziarz RT, Wu J, Shaw BE, Confer D, Horowitz MM, Anasetti C. Comparison of Patient-Reported Outcomes in 5-Year Survivors Who Received Bone Marrow vs Peripheral Blood Unrelated Donor Transplantation: Long-term Follow-up of a Randomized Clinical Trial. JAMA Oncol. 2016 Dec 1;2(12):1583-1589. doi: 10.1001/jamaoncol.2016.2520.