Family-mismatched/Haploidentical Donors Versus Matched Unrelated Donors

April 17, 2024 updated by: Byung-Sik Cho

The Comparison of Transplantation From Family-mismatched/Haploidentical Donors With Matched Unrelated Donors in Adult Patients With Acute Myeloid Leukemia

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

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

116

Phase

  • Phase 2
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Korea, Republic of
      • Seoul, Korea, Republic of, 137-701
        • Catholic Blood and Marrow Transplantation Center, Seoul St. Mary's Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

17 years to 65 years (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall survival
Time Frame: annually through 3 years
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
annually through 3 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Neutrophil recovery
Time Frame: 56 days
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.
56 days
Primary Graft failure
Time Frame: 56 days
defined as failure to achieve a neutrophil count greater than 500/mm^3 for 3 consecutive days at any time after transplantation.
56 days
Secondary Graft failure
Time Frame: 100 days
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.
100 days
Platelet recovery
Time Frame: 100 days and 180 days
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.
100 days and 180 days
Donor cell engraftment
Time Frame: 56 days
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.
56 days
Acute graft-versus-host disease (aGVHD)
Time Frame: every 3 months through 3 years
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.
every 3 months through 3 years
Chronic graft-versus-host disease (cGVHD)
Time Frame: every 3 months through 3 years
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.
every 3 months through 3 years
Disease free survival
Time Frame: annually through year 3
defined as the time interval from date of enrollment and time to relapse/progression, to death or to last follow-up
annually through year 3
Non-relapse mortality
Time Frame: annually through year 3
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
annually through year 3
Infection
Time Frame: annually through year 3
All grade 2 and 3 infections will be reported. Grade 1 cytomegalovirus infections through Day 56 will also be reported.
annually through year 3
WT1 MRD assessment
Time Frame: before and 1 month after transplantation, then every 3 months through 3 years
WT1 MRD assessment
before and 1 month after transplantation, then every 3 months through 3 years
BAALC MRD assessment
Time Frame: before and 1 month after transplantation, then every 3 months through 3 years
BAALC MRD assessment
before and 1 month after transplantation, then every 3 months through 3 years
NGS-based MRD assessment
Time Frame: before and 1 month after transplantation, then every 3 months through 3 year
NGS-based MRD assessment
before and 1 month after transplantation, then every 3 months through 3 year
T cells reconstitution
Time Frame: before and 2 weeks and 1 month after transplantation, then every 3 months through 1 year
T cell subsets
before and 2 weeks and 1 month after transplantation, then every 3 months through 1 year
NK cells reconstitution
Time Frame: before and 2 weeks and 1 month after transplantation, then every 3 months through 1 year
NK cell subsets
before and 2 weeks and 1 month after transplantation, then every 3 months through 1 year
B cells reconstitution
Time Frame: before and 2 weeks and 1 month after transplantation, then every 3 months through 1 year
B cells
before and 2 weeks and 1 month after transplantation, then every 3 months through 1 year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Byung-Sik Cho

Investigators

  • Principal Investigator: Hee-Je Kim, MD, PhD, Seoul St. Mary's Hematology Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 1, 2013

Primary Completion (Actual)

May 21, 2019

Study Completion (Actual)

December 31, 2019

Study Registration Dates

First Submitted

December 14, 2012

First Submitted That Met QC Criteria

December 14, 2012

First Posted (Estimated)

December 18, 2012

Study Record Updates

Last Update Posted (Actual)

April 19, 2024

Last Update Submitted That Met QC Criteria

April 17, 2024

Last Verified

April 1, 2024

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CBMTC-AML-1

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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