Family-mismatched/Haploidentical Donors Versus Matched Unrelated Donors

This study is currently recruiting participants. (see Contacts and Locations)
Verified January 2013 by Seoul St. Mary's Hospital
Sponsor:
Information provided by (Responsible Party):
Byung-Sik Cho, Seoul St. Mary's Hospital
ClinicalTrials.gov Identifier:
NCT01751997
First received: December 14, 2012
Last updated: January 9, 2013
Last verified: January 2013
  Purpose

This study will compare the clinical outcomes of transplants from family-mismatched/haploidentical donors (FMT) with transplants from 8/8-matched unrelated donor (MUT), which is a current gold standard donors when lacking of HLA-matched-siblings

  1. Primary objectives: Overall survival of FMT may be similar to that of MUT
  2. Secondary objectives:

    i. Comparison of disease-free survival, relapse, non-relapse mortality, immune reconstitution cytomegalovirus infection, and acute or chronic graft-versus-host disease between FMT and MUT.

    ii. Investigation of possible biomarkers related with above events after transplantation


Condition Intervention Phase
Acute Myeloid Leukemia
Drug: Transplants from 8/8-matched Unrelated donors
Drug: Transplants from family-mismatched/haploidentical donors
Phase 3

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: The Comparison of Transplantation From Family-mismatched/Haploidentical Donors With Matched Unrelated Donors in Adult Patients With Acute Myeloid Leukemia

Resource links provided by NLM:


Further study details as provided by Seoul St. Mary's Hospital:

Primary Outcome Measures:
  • Overall survival [ Time Frame: annually through 3 years ] [ Designated as safety issue: No ]
    Overall survival is defined as the time interval between date of enrollment and death from any cause or for surviving patients, to last follow-up


Secondary Outcome Measures:
  • Neutrophil recovery [ Time Frame: 56 days ] [ Designated as safety issue: No ]
    defined as achieving an absolute neutrophil count greater than or equal to 500/mm^3 for three consecutive measurements on three difference days. The first of the 3 days will be designated the day of neutrophil recovery.

  • Primary Graft failure [ Time Frame: 56 days ] [ Designated as safety issue: Yes ]
    defined as failure to achieve a neutrophil count greater than 500/mm^3 for 3 consecutive days at any time after transplantation.

  • Secondary Graft failure [ Time Frame: 100 days ] [ Designated as safety issue: Yes ]
    defined as the development of an absolute neutrophil count less than 500/mm^3 after achievement of initial engraftment in the absence of recurrent disease.

  • Platelet recovery [ Time Frame: 100 days and 180 days ] [ Designated as safety issue: No ]
    defined as the first day of a sustained platelet count greater than 20,000/mm^3 without platelet transfusions in preceding 7 days. The first day of the sustained platelet count will be designated the day of platelet engraftment.

  • Donor cell engraftment [ Time Frame: 56 days ] [ Designated as safety issue: No ]
    Donor cell engraftment is defined as donor chimerism greater than or equal 5% on Day 56 after transplantation. Chimerism may be evaluated in whole blood or blood cell fractions, including cluster of differentiation (CD) 3 and CD33 or CD15 fractions. The actual measurement dates may be within +/- 7 days of the above recommended time points.

  • Acute graft-versus-host disease (aGVHD) [ Time Frame: every 3 months through 3 years ] [ Designated as safety issue: No ]
    The cumulative incidence of aGVHD (grade II-IV and III-IV) will be determined. The time to onset of aGVHD will be recorded, as well as the maximum grade achieved.

  • Chronic graft-versus-host disease (cGVHD) [ Time Frame: every 3 months through 3 years ] [ Designated as safety issue: No ]
    The cumulative incidence of cGVHD will be determined. Data will be collected directly from providers and chart review according to the recommendations of the NIH Consensus Conference. The NIH global severity scores of mild, moderate, and severe cGVHD will be assessed.

  • Disease free survival [ Time Frame: annually through year 3 ] [ Designated as safety issue: No ]
    defined as the time interval from date of enrollment and time to relapse/progression, to death or to last follow-up

  • Non-relapse mortality [ Time Frame: annually through year 3 ] [ Designated as safety issue: Yes ]
    The cumulative incidence of non-relapse mortality will be estimated at Days 100, 180, and at 1 and 2 years after transplantation. An event for this endpoint is death without evidence of disease progression or recurrence

  • Infection [ Time Frame: annually through year 3 ] [ Designated as safety issue: No ]
    All grade 2 and 3 infections will be reported. Grade 1 cytomegalovirus infections through Day 56 will also be reported.


Estimated Enrollment: 116
Study Start Date: January 2013
Estimated Study Completion Date: December 2017
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Transplants from 8/8-matched unrelated
Participants will receive transplants from 8/8-matched unrelated donors using myeloablative or reduced-intensity conditioning according to age or comorbidity.
Drug: Transplants from 8/8-matched Unrelated donors
  • Myeloablative conditioning

    1. Total body irradiation; 165 cGy, every 12 hours, 8 doses, days -7 to -4 (total 1320 cGy)
    2. Cyclophosphamide; 60 mg/kg/day, IV for 30 minutes, days -3 to -2 (total 120 mg/kg)
    3. Antithymocyte globulin (ATG); 1.25 mg/kg/day, IV for 6 hours, days -3 to -2, (total 2.5 mg/kg)
  • Reduced-intensity conditioning; older patients (age > 55 years) and/or patients with comorbidities

    1. Fludarabine; 30 mg/m^2/day, IV for 1 hour, days -8 to -4 (total 150 mg/m^2)
    2. Busulfex; 3.2 mg/kg/day, IV for 3 hours, days -3 to -2 (total 6.4 mg/kg)
    3. Total body irradiation; 200 cGy, every 12 hours 2 doses, days -1 (total 400 cGy)
    4. ATG; 1.25 mg/kg/day, IV for 6 hours, days -3 to -2, (total 2.5 mg/kg)
  • GVHD prophylaxis

    1. Tacrolimus; 0.03 mg/kg/day, IV for 24 hours from day -1 (0.12 mg/kg/day, PO, if tolerable)
    2. Methotrexate; 5 mg/m^2/day, IV push, days +1, +3, +6, +11
Experimental: Transplants from family-mismatched/haploidentical donors
Participants will receive FMT using a reduced intensity conditioning regimens.
Drug: Transplants from family-mismatched/haploidentical donors
  • Reduced-intensity conditioning

    1. Total body irradiation; 200 cGy, every 12 hours, 4 doses, days -9 to -8 (total 800 cGy)
    2. Fludarabine; 30 mg/m^2/day, IV for 1 hour, days -7 to -3 (total 150 mg/m^2)
    3. Busulfex; 3.2 mg/kg/day, IV for 3 hours, days -6 to -5 (total 6.4 mg/kg)
    4. ATG; 1.25 mg/kg/day, IV for 6 hours, days -4 to -1 (total 5.0 mg/kg)
  • GVHD prophylaxis

    1. Tacrolimus; 0.03 mg/kg/day, IV for 24 hours from day -1 (0.12 mg/kg/day, PO, if tolerable)
    2. Methotrexate; 5 mg/m^2/day, IV push, days +1, +3, +6, +11

Detailed Description:

For patients lacking an HLA-identical sibling, 8/8-matched unrelated donors are currently the "gold standard" for a donor, since outcomes after HLA-identical sibling have been compared to 8/8-matched unrelated donors. Currently, there are three alternative graft sources, including mismatched unrelated donors, familial mismatch/haploidentical donors, and umbilical cord bloods. Compared with other sources, transplants from familial mismatch/haploidentical donors (FMT) have the benefit of an immediate availability of a donor, particularly for those patients who urgently need transplantation. Initial reports had characterized FMT to a poor engraftment and a high incidence of graft-versus-host disease. However, outcomes of FMT have significantly improved over the past decade in the optimization of conditioning regimen and graft selection to allow a stable engraftment across major HLA barriers, with promising leukemia-free survival in adults with acute leukemia. Despite the encouraging results and potential benefit of FMT, there have been few studies comparing clinical outcomes of FMT with other donor types, particularly in acute myeloid leukemia (AML) as a single disease. Since August 2008, we have been continuously performing FMT using unmanipulated donor cells and a less aggressive conditioning regimen in high-risk AML lacking an HLA-identical sibling, 8/8 or 7/8-matched unrelated donors. We reported the feasibility of FMT using our novel reduced-intensity regimen without ex vivo T-cell depletion, showing early results similar to outcomes of transplant from 8/8-matched unrelated donors (MUT). This study will test the hypothesis that overall survival at 3 years after FMT is similar to overall survival after MUT.

  Eligibility

Ages Eligible for Study:   17 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

  • Patients with AML aged from 18 to 65 years
  • Eastern Cooperative Oncology Group (ECOG) performance < 2
  • High risk group for relapse

    1. Complete remission (CR) 1 with unfavorable prognostic factor; presenting white blood cell > 100,000/microliter or prior myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN) or MDS/MPN or cytogenetics & molecular features (intermediate and adverse)
    2. CR2 or CR3 at transplantation
  • No HLA-matched sibling and unrelated donor (HLA-A, -B, -C, and -DRB1)
  • Acceptable organ function defined as serum creatinine < 2 mg/dl, unless considered due to leukemia and serum bilirubin < 3 mg/dl, unless considered due to leukemia
  • Written informed consent form

Exclusion Criteria

  • Active uncontrolled infections
  • Corrected pulmonary diffusion capacity of <40%
  • Cardiac ejection fraction of <35%
  • ECOG performance status :2, 3, 4
  • Active central nervous system involvement of disease
  • Serological evidence of infection with HIV
  • Pregnancy or breastfeeding
  • Patient who are not suitable for the trial in accordance with principal investigator's decision
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01751997

Contacts
Contact: Hee-Je Kim, MD, PhD 82-2-2258-6054 cumckim@catholic.ac.kr
Contact: Byung-Sik Cho, MD, PhD 82-2-2258-6072 cbscho@catholic.ac.kr

Locations
Korea, Republic of
Catholic Blood and Marrow Transplantation Center, Seoul St. Mary's Hospital Recruiting
Seoul, Korea, Republic of, 137-701
Sponsors and Collaborators
Seoul St. Mary's Hospital
Investigators
Principal Investigator: Hee-Je Kim, MD, PhD Catholic Blood and Marrow Transplantation Center, Seoul St. Mary's Hospital, The Catholic University of Korea
  More Information

Publications:

Responsible Party: Byung-Sik Cho, Assistant Professor, Seoul St. Mary's Hospital
ClinicalTrials.gov Identifier: NCT01751997     History of Changes
Other Study ID Numbers: CBMTC-AML-1
Study First Received: December 14, 2012
Last Updated: January 9, 2013
Health Authority: Korea: Food and Drug Administration
Korea: Institutional Review Board
Korea: Ministry for Health, Welfare and Family Affairs
Korea: Ministry of Education, Science, and Technology

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms
Neoplasms by Histologic Type

ClinicalTrials.gov processed this record on October 23, 2014