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NCT Number: NCT01751997

Family-mismatched/Haploidentical Donors Versus Matched Unrelated Donors

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

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Key information

Conditions

Acute Myeloid Leukemia Hematologic Diseases Hemic and Lymphatic Diseases Leukemia Leukemia, Myeloid Leukemia, Myeloid, Acute Neoplasms Neoplasms by Histologic Type

Age range

17 year–65 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2 / Phase 3

Primary location

Catholic Blood and Marrow Transplantation Center, Seoul St. Mary's Hospital

Seoul, 137-701, South Korea

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

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

Treatment and study plan

Transplants from 8/8-matched Unrelated donors

Drug
  • Myeloablative conditioning
  • Total body irradiation; 165 cGy, every 12 hours, 8 doses, days -7 to -4 (total 1320 cGy)
  • Cyclophosphamide; 60 mg/kg/day, IV for 30 minutes, days -3 to -2 (total 120 mg/kg)
  • 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
  • Fludarabine; 30 mg/m^2/day, IV for 1 hour, days -8 to -4 (total 150 mg/m^2)
  • Busulfex; 3.2 mg/kg/day, IV for 3 hours, days -3 to -2 (total 6.4 mg/kg)
  • Total body irradiation; 200 cGy, every 12 hours 2 doses, days -1 (total 400 cGy)
  • ATG; 1.25 mg/kg/day, IV for 6 hours, days -3 to -2, (total 2.5 mg/kg)
  • GVHD prophylaxis
  • Tacrolimus; 0.03 mg/kg/day, IV for 24 hours from day -1 (0.12 mg/kg/day, PO, if tolerable)
  • Methotrexate; 5 mg/m^2/day, IV push, days +1, +3, +6, +11

Transplants from family-mismatched/haploidentical donors

Drug
  • Reduced-intensity conditioning
  • Total body irradiation; 200 cGy, every 12 hours, 4 doses, days -9 to -8 (total 800 cGy)
  • Fludarabine; 30 mg/m^2/day, IV for 1 hour, days -7 to -3 (total 150 mg/m^2)
  • Busulfex; 3.2 mg/kg/day, IV for 3 hours, days -6 to -5 (total 6.4 mg/kg)
  • ATG; 1.25 mg/kg/day, IV for 6 hours, days -4 to -1 (total 5.0 mg/kg)
  • GVHD prophylaxis
  • Tacrolimus; 0.03 mg/kg/day, IV for 24 hours from day -1 (0.12 mg/kg/day, PO, if tolerable)
  • Methotrexate; 5 mg/m^2/day, IV push, days +1, +3, +6, +11

Primary outcomes

  1. 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

Secondary outcomes

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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

  9. 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

  10. 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.

  11. WT1 MRD assessment

    Time frame: before and 1 month after transplantation, then every 3 months through 3 years

    WT1 MRD assessment

  12. BAALC MRD assessment

    Time frame: before and 1 month after transplantation, then every 3 months through 3 years

    BAALC MRD assessment

  13. NGS-based MRD assessment

    Time frame: before and 1 month after transplantation, then every 3 months through 3 year

    NGS-based MRD assessment

  14. T cells reconstitution

    Time frame: before and 2 weeks and 1 month after transplantation, then every 3 months through 1 year

    T cell subsets

  15. NK cells reconstitution

    Time frame: before and 2 weeks and 1 month after transplantation, then every 3 months through 1 year

    NK cell subsets

  16. B cells reconstitution

    Time frame: before and 2 weeks and 1 month after transplantation, then every 3 months through 1 year

    B cells

Sponsors and collaborators

Lead sponsor

Byung-Sik Cho

Other

Registry information

Official study title

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

Important dates

Study start
2013
Primary completion
2019
Study completion
2019
First posted
Dec 18, 2012
Registry last updated
Apr 19, 2024

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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