Family-mismatched/Haploidentical Donors Versus Matched Unrelated Donors

Study Overview
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Brief Summary
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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 Primary objectives: Overall survival of FMT may be similar to that of MUT 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

Detailed Description
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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.

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

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Transplants from 8/8-matched Unrelated donors
* Drug: Transplants from family-mismatched/haploidentical donors


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 17 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Transplants from 8/8-matched unrelated<br>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<br>* 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<br>|
| Experimental: Transplants from family-mismatched/haploidentical donors<br>Participants will receive FMT using a reduced intensity conditioning regimens. | Drug: Transplants from family-mismatched/haploidentical donors<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | 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 | 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 | 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 | 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 | 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 | 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) | 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) | 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 | 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 | 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 | 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 | WT1 MRD assessment | before and 1 month after transplantation, then every 3 months through 3 years | 
| BAALC MRD assessment | BAALC MRD assessment | before and 1 month after transplantation, then every 3 months through 3 years | 
| NGS-based MRD assessment | NGS-based MRD assessment | before and 1 month after transplantation, then every 3 months through 3 year | 
| T cells reconstitution | T cell subsets | before and 2 weeks and 1 month after transplantation, then every 3 months through 1 year | 
| NK cells reconstitution | NK cell subsets | before and 2 weeks and 1 month after transplantation, then every 3 months through 1 year | 
| B cells reconstitution | B cells | before and 2 weeks and 1 month after transplantation, then every 3 months through 1 year |