Clinical trial NCT01751997: Family-mismatched/Haploidentical Donors Versus Matched Unrelated Donors
Official title: The Comparison of Transplantation From Family-mismatched/Haploidentical Donors With Matched Unrelated Donors in Adult Patients With Acute Myeloid Leukemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Acute Myeloid Leukemia
Lead sponsor: Seoul St. Mary's Hospital
Sponsor class: OTHER
First posted: 2012-12-18
Enrollment: 116
Sex: ALL
Minimum age (years): 17
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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

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 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

Primary outcomes:
measure: Overall survival
timeFrame: annually through 3 years
Secondary outcomes:
measure: Neutrophil recovery
timeFrame: 56 days
measure: Primary Graft failure
timeFrame: 56 days
measure: Secondary Graft failure
timeFrame: 100 days
measure: Platelet recovery
timeFrame: 100 days and 180 days
measure: Donor cell engraftment
timeFrame: 56 days
measure: Acute graft-versus-host disease (aGVHD)
timeFrame: every 3 months through 3 years
measure: Chronic graft-versus-host disease (cGVHD)
timeFrame: every 3 months through 3 years
measure: Disease free survival
timeFrame: annually through year 3
measure: Non-relapse mortality
timeFrame: annually through year 3
measure: Infection
timeFrame: annually through year 3
measure: WT1 MRD assessment
timeFrame: before and 1 month after transplantation, then every 3 months through 3 years
measure: BAALC MRD assessment
timeFrame: before and 1 month after transplantation, then every 3 months through 3 years
measure: NGS-based MRD assessment
timeFrame: before and 1 month after transplantation, then every 3 months through 3 year
measure: T cells reconstitution
timeFrame: before and 2 weeks and 1 month after transplantation, then every 3 months through 1 year
measure: NK cells reconstitution
timeFrame: before and 2 weeks and 1 month after transplantation, then every 3 months through 1 year
measure: B cells reconstitution
timeFrame: before and 2 weeks and 1 month after transplantation, then every 3 months through 1 year
Other outcomes:
Locations:
city: Seoul
country: Korea, Republic of
facility: Catholic Blood and Marrow Transplantation Center, Seoul St. Mary's Hospital
Study officials:
affiliation: Seoul St. Mary's Hematology Hospital
name: Hee-Je Kim, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Aversa F. Haploidentical haematopoietic stem cell transplantation for acute leukaemia in adults: experience in Europe and the United States. Bone Marrow Transplant. 2008 Mar;41(5):473-81. doi: 10.1038/sj.bmt.1705966. Epub 2008 Jan 7.
citation: Ruggeri A, Ciceri F, Gluckman E, Labopin M, Rocha V; Eurocord and Acute Leukemia Working Party of the European Blood and Marrow Transplant Group. Alternative donors hematopoietic stem cells transplantation for adults with acute myeloid leukemia: Umbilical cord blood or haploidentical donors? Best Pract Res Clin Haematol. 2010 Jun;23(2):207-16. doi: 10.1016/j.beha.2010.06.002.
citation: Yakoub-Agha I, Mesnil F, Kuentz M, Boiron JM, Ifrah N, Milpied N, Chehata S, Esperou H, Vernant JP, Michallet M, Buzyn A, Gratecos N, Cahn JY, Bourhis JH, Chir Z, Raffoux C, Socie G, Golmard JL, Jouet JP; French Society of Bone Marrow Transplantation and Cell Therapy. Allogeneic marrow stem-cell transplantation from human leukocyte antigen-identical siblings versus human leukocyte antigen-allelic-matched unrelated donors (10/10) in patients with standard-risk hematologic malignancy: a prospective study from the French Society of Bone Marrow Transplantation and Cell Therapy. J Clin Oncol. 2006 Dec 20;24(36):5695-702. doi: 10.1200/JCO.2006.08.0952. Epub 2006 Nov 20.
citation: Beatty PG, Clift RA, Mickelson EM, Nisperos BB, Flournoy N, Martin PJ, Sanders JE, Stewart P, Buckner CD, Storb R, et al. Marrow transplantation from related donors other than HLA-identical siblings. N Engl J Med. 1985 Sep 26;313(13):765-71. doi: 10.1056/NEJM198509263131301.
citation: Anasetti C, Hansen JA. Effect of HLA incompatibility in marrow transplantation from unrelated and HLA-mismatched related donors. Transfus Sci. 1994 Sep;15(3):221-30. doi: 10.1016/0955-3886(94)90134-1.
citation: Henslee-Downey PJ, Abhyankar SH, Parrish RS, Pati AR, Godder KT, Neglia WJ, Goon-Johnson KS, Geier SS, Lee CG, Gee AP. Use of partially mismatched related donors extends access to allogeneic marrow transplant. Blood. 1997 May 15;89(10):3864-72.
citation: Aversa F, Terenzi A, Tabilio A, Falzetti F, Carotti A, Ballanti S, Felicini R, Falcinelli F, Velardi A, Ruggeri L, Aloisi T, Saab JP, Santucci A, Perruccio K, Martelli MP, Mecucci C, Reisner Y, Martelli MF. Full haplotype-mismatched hematopoietic stem-cell transplantation: a phase II study in patients with acute leukemia at high risk of relapse. J Clin Oncol. 2005 May 20;23(15):3447-54. doi: 10.1200/JCO.2005.09.117. Epub 2005 Mar 7.
citation: Ruggeri L, Mancusi A, Capanni M, Urbani E, Carotti A, Aloisi T, Stern M, Pende D, Perruccio K, Burchielli E, Topini F, Bianchi E, Aversa F, Martelli MF, Velardi A. Donor natural killer cell allorecognition of missing self in haploidentical hematopoietic transplantation for acute myeloid leukemia: challenging its predictive value. Blood. 2007 Jul 1;110(1):433-40. doi: 10.1182/blood-2006-07-038687. Epub 2007 Mar 19.
citation: Ciceri F, Labopin M, Aversa F, Rowe JM, Bunjes D, Lewalle P, Nagler A, Di Bartolomeo P, Lacerda JF, Lupo Stanghellini MT, Polge E, Frassoni F, Martelli MF, Rocha V; Acute Leukemia Working Party (ALWP) of European Blood and Marrow Transplant (EBMT) Group. A survey of fully haploidentical hematopoietic stem cell transplantation in adults with high-risk acute leukemia: a risk factor analysis of outcomes for patients in remission at transplantation. Blood. 2008 Nov 1;112(9):3574-81. doi: 10.1182/blood-2008-02-140095. Epub 2008 Jul 7.
citation: Huang XJ, Liu DH, Liu KY, Xu LP, Chen H, Han W, Chen YH, Zhang XH, Lu DP. Treatment of acute leukemia with unmanipulated HLA-mismatched/haploidentical blood and bone marrow transplantation. Biol Blood Marrow Transplant. 2009 Feb;15(2):257-65. doi: 10.1016/j.bbmt.2008.11.025.
citation: Cho BS, Yoon JH, Shin SH, Yahng SA, Lee SE, Eom KS, Kim YJ, Lee S, Min CK, Cho SG, Kim DW, Lee JW, Min WS, Park CW, Kim HJ. Comparison of allogeneic stem cell transplantation from familial-mismatched/haploidentical donors and from unrelated donors in adults with high-risk acute myelogenous leukemia. Biol Blood Marrow Transplant. 2012 Oct;18(10):1552-63. doi: 10.1016/j.bbmt.2012.04.008. Epub 2012 Apr 16.
citation: Cho BS, Min GJ, Park S, Park SS, Shin SH, Yahng SA, Jeon YW, Yoon JH, Lee SE, Eom KS, Kim YJ, Lee S, Min CK, Cho SG, Kim DW, Lee JW, Kim M, Kim Y, Kim HJ. Haploidentical vs matched unrelated donor transplantation for acute myeloid leukemia in remission: A prospective comparative study. Am J Hematol. 2021 Jan;96(1):98-109. doi: 10.1002/ajh.25993. Epub 2020 Nov 24.