Top

Published in:

Open Access 01-12-2016 | Research

The impact of HLA-matching on reduced intensity conditioning regimen unrelated donor allogeneic stem cell transplantation for acute myeloid leukemia in patients above 50 years—a report from the EBMT acute leukemia working party

Authors: Marie T. Rubio, Bipin N. Savani, Myriam Labopin, Emmanuelle Polge, Dietger Niederwieser, Arnold Ganser, Rainer Schwerdtfeger, Gerhard Ehninger, Jürgen Finke, Arnold Renate, Charles Craddock, Nicolaus Kröger, Michael Hallek, Pavel Jindra, Mohamad Mohty, Arnon Nagler

Published in: Journal of Hematology & Oncology | Issue 1/2016

Abstract

Background

Data comparing fully matched and mismatched-unrelated-donor (M- and mM-URD) allogeneic hematopoietic stem cell transplant (allo-SCT) following reduced intensity conditioning regimens for acute myeloid leukemia are limited.

Methods

We retrospectively compared the outcome of 3398 patients above the age of 50 years who underwent 10/10 M-URD (n = 2567), 9/10 (n = 723), or 8/10 (n = 108) mM-URD allo-SCT for acute myeloid leukemia after reduced intensity conditioning regimen between 2000 and 2013. The Kaplan-Meier estimator, the cumulative incidence function, and Cox proportional hazards regression models were used where appropriate.

Results

HLA matching had no impact on engraftment (p = 0.31). In univariate analysis, in comparison to 10/10 M-URD, mM-URD was associated with higher incidence of grade II–IV acute graft-versus-host disease (GVHD) (p = 0.0002), similar rates of chronic GVHD (p = 0.138) but increased incidence of its extensive form (p = 0.047). Compared to 10/10 M-URD, patients transplanted in the first complete remission (CR1) with a 9 or an 8/10 mM-URD had decreased 2-year leukemia free (LFS) (p = 0.005) and overall survivals (OS) (56.7, 46.1, and 50.2 %, respectively, p = 0.005), while outcomes were comparable between all groups for patients transplanted beyond CR1. In multivariate analysis, 9/10 versus 10/10 URD was associated with higher non-relapse mortality (HR 1.34, p = 0.001), similar risk of relapse and chronic GVHD and inferior LFS (HR 1.25, p = 0.0001), and OS (HR 1.27, p = 0.0001). There was no difference in adjusted transplant outcomes between 9/10 and 8/10 mM-URD.

Conclusions

Reduced intensity conditioned allo-SCT with a 10/10 M-URD remains the preferable option for AML patients above the age of 50 years. The use of a 9/10 or an 8/10 mM-URD in patients not having a fully matched donor represents an alternative therapeutic option that should be compared to other alternative donor transplant strategies.

Available only for authorised users

Slavin S, Nagler A, Naparstek E, Kapelushnik Y, Aker M, Cividalli G, et al. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood. 1998;91(3):756–63.PubMed

McSweeney PA, Niederwieser D, Shizuru JA, Sandmaier BM, Molina AJ, Maloney DG, et al. Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood. 2001;97(11):3390–400.CrossRefPubMed

Shimoni A, Kroger N, Zabelina T, Ayuk F, Hardan I, Yeshurun M, et al. Hematopoietic stem-cell transplantation from unrelated donors in elderly patients (age >55 years) with hematologic malignancies: older age is no longer a contraindication when using reduced intensity conditioning. Leukemia. 2005;19(1):7–12.PubMed

Valcarcel D, Martino R, Caballero D, Martin J, Ferra C, Nieto JB, et al. Sustained remissions of high-risk acute myeloid leukemia and myelodysplastic syndrome after reduced-intensity conditioning allogeneic hematopoietic transplantation: chronic graft-versus-host disease is the strongest factor improving survival. J Clin Oncol. 2008;26(4):577–84.CrossRefPubMed

Ringden O, Labopin M, Ehninger G, Niederwieser D, Olsson R, Basara N, et al. Reduced intensity conditioning compared with myeloablative conditioning using unrelated donor transplants in patients with acute myeloid leukemia. J Clin Oncol. 2009;27(27):4570–7.CrossRefPubMed

Gyurkocza B, Storb R, Storer BE, Chauncey TR, Lange T, Shizuru JA, et al. Nonmyeloablative allogeneic hematopoietic cell transplantation in patients with acute myeloid leukemia. J Clin Oncol. 2010;28(17):2859–67.CrossRefPubMedPubMedCentral

Chevallier P, Szydlo RM, Blaise D, Tabrizi R, Michallet M, Uzunov M, et al. Reduced-intensity conditioning before allogeneic hematopoietic stem cell transplantation in patients over 60 years: a report from the SFGM-TC. Biol Blood Marrow Transplant. 2012;18(2):289–94.CrossRefPubMed

Sengsayadeth S, Savani BN, Blaise D, Malard F, Nagler A, Mohty M. Reduced intensity conditioning allogeneic hematopoietic cell transplantation for adult acute myeloid leukemia in complete remission-a review from the Acute Leukemia Working Party of the EBMT. Haematologica. 2015;100(7):859–69.CrossRefPubMedPubMedCentral

Mohty M, de Lavallade H, Ladaique P, Faucher C, Vey N, Coso D, et al. The role of reduced intensity conditioning allogeneic stem cell transplantation in patients with acute myeloid leukemia: a donor vs no donor comparison. Leukemia. 2005;19(6):916–20.CrossRefPubMed

10.

Kurosawa S, Yamaguchi T, Uchida N, Miyawaki S, Usuki K, Watanabe M, et al. Comparison of allogeneic hematopoietic cell transplantation and chemotherapy in elderly patients with non-M3 acute myelogenous leukemia in first complete remission. Biol Blood Marrow Transplant. 2011;17(3):401–11.CrossRefPubMed

11.

Russell NH, Kjeldsen L, Craddock C, Pagliuca A, Yin JA, Clark RE, et al. A comparative assessment of the curative potential of reduced intensity allografts in acute myeloid leukaemia. Leukemia. 2015;29(7):1478–84.CrossRefPubMed

12.

Aoudjhane M, Labopin M, Gorin NC, Shimoni A, Ruutu T, Kolb HJ, et al. Comparative outcome of reduced intensity and myeloablative conditioning regimen in HLA identical sibling allogeneic haematopoietic stem cell transplantation for patients older than 50 years of age with acute myeloblastic leukaemia: a retrospective survey from the Acute Leukemia Working Party (ALWP) of the European group for Blood and Marrow Transplantation (EBMT). Leukemia. 2005;19(12):2304–12.CrossRefPubMed

13.

Champlin R. Reduced intensity allogeneic hematopoietic transplantation is an established standard of care for treatment of older patients with acute myeloid leukemia. Best Pract Res Clin Haematol. 2013;26(3):297–300.CrossRefPubMed

14.

Hahn T, McCarthy Jr PL, Hassebroek A, Bredeson C, Gajewski JL, Hale GA, et al. Significant improvement in survival after allogeneic hematopoietic cell transplantation during a period of significantly increased use, older recipient age, and use of unrelated donors. J Clin Oncol. 2013;31(19):2437–49.CrossRefPubMedPubMedCentral

15.

Passweg JR, Baldomero H, Bader P, Bonini C, Cesaro S, Dreger P, et al. Hematopoietic SCT in Europe 2013: recent trends in the use of alternative donors showing more haploidentical donors but fewer cord blood transplants. Bone Marrow Transplant. 2015;50(4):476–82.CrossRefPubMedPubMedCentral

16.

Sierra J, Martino R, Sanchez B, Pinana JL, Valcarcel D, Brunet S. Hematopoietic transplantation from adult unrelated donors as treatment for acute myeloid leukemia. Bone Marrow Transplant. 2008;41(5):425–37.CrossRefPubMed

17.

Gooley TA, Chien JW, Pergam SA, Hingorani S, Sorror ML, Boeckh M, et al. Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med. 2010;363(22):2091–101.CrossRefPubMedPubMedCentral

18.

Huisman C, Meijer E, Petersen EJ, Lokhorst HM, Verdonck LF. Hematopoietic stem cell transplantation after reduced intensity conditioning in acute myelogenous leukemia patients older than 40 years. Biol Blood Marrow Transplant. 2008;14(2):181–6.CrossRefPubMed

19.

Schetelig J, Bornhauser M, Schmid C, Hertenstein B, Schwerdtfeger R, Martin H, et al. Matched unrelated or matched sibling donors result in comparable survival after allogeneic stem-cell transplantation in elderly patients with acute myeloid leukemia: a report from the cooperative German Transplant Study Group. J Clin Oncol. 2008;26(32):5183–91.CrossRefPubMed

20.

Robin M, Porcher R, Ades L, Boissel N, Raffoux E, Xhaard A, et al. Matched unrelated or matched sibling donors result in comparable outcomes after non-myeloablative HSCT in patients with AML or MDS. Bone Marrow Transplant. 2013;48(10):1296–301.CrossRefPubMed

21.

Appelbaum FR, Gundacker H, Head DR, Slovak ML, Willman CL, Godwin JE, et al. Age and acute myeloid leukemia. Blood. 2006;107(9):3481–5.CrossRefPubMedPubMedCentral

22.

Kantarjian H, O’Brien S, Cortes J, Giles F, Faderl S, Jabbour E, et al. Results of intensive chemotherapy in 998 patients age 65 years or older with acute myeloid leukemia or high-risk myelodysplastic syndrome: predictive prognostic models for outcome. Cancer. 2006;106(5):1090–8.CrossRefPubMed

23.

Shimoni A, Nagler A. Non-myeloablative hematopoietic stem cell transplantation (NST) in the treatment of human malignancies: from animal models to clinical practice. Cancer Treat Res. 2002;110:113–36.CrossRefPubMed

24.

Petersen SL. Alloreactivity as therapeutic principle in the treatment of hematologic malignancies. Studies of clinical and immunologic aspects of allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning. Dan Med Bull. 2007;54(2):112–39.PubMed

25.

Ho VT, Kim HT, Aldridge J, Liney D, Kao G, Armand P, et al. Use of matched unrelated donors compared with matched related donors is associated with lower relapse and superior progression-free survival after reduced-intensity conditioning hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2011;17(8):1196–204.CrossRefPubMed

26.

Bacigalupo A, Ballen K, Rizzo D, Giralt S, Lazarus H, Ho V, et al. Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transplant. 2009;15(12):1628–33.CrossRefPubMedPubMedCentral

27.

Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995;15(6):825–8.PubMed

28.

Shulman HM, Sullivan KM, Weiden PL, McDonald GB, Striker GE, Sale GE, et al. Chronic graft-versus-host syndrome in man. A long-term clinicopathologic study of 20 Seattle patients. Am J Med. 1980;69(2):204–17.CrossRefPubMed

29.

Saber W, Opie S, Rizzo JD, Zhang MJ, Horowitz MM, Schriber J. Outcomes after matched unrelated donor versus identical sibling hematopoietic cell transplantation in adults with acute myelogenous leukemia. Blood. 2012;119(17):3908–16.CrossRefPubMedPubMedCentral

30.

Luger SM, Ringden O, Zhang MJ, Perez WS, Bishop MR, Bornhauser M, et al. Similar outcomes using myeloablative vs reduced-intensity allogeneic transplant preparative regimens for AML or MDS. Bone Marrow Transplant. 2012;47(2):203–11.CrossRefPubMed

31.

Yakoub-Agha I, Mesnil F, Kuentz M, Boiron JM, Ifrah N, Milpied N, et al. 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;24(36):5695–702.CrossRefPubMed

32.

Huang XJ, Liu DH, Liu KY, Xu LP, Chen H, Han W, et al. Treatment of acute leukemia with unmanipulated HLA-mismatched/haploidentical blood and bone marrow transplantation. Biol Blood Marrow Transplant. 2009;15(2):257–65.CrossRefPubMed

33.

Luznik L, O’Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M, et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. 2008;14(6):641–50.CrossRefPubMedPubMedCentral

34.

Yu S, Fan Q, Sun J, Fan Z, Zhang Y, Jiang Q, et al. Haploidentical transplantation without in vitro T-cell depletion results in outcomes equivalent to those of contemporaneous matched sibling and unrelated donor transplantation for acute leukemia. Medicine (Baltimore). 2016;95(11), e2973.CrossRef

35.

Luo Y, Xiao H, Lai X, Shi J, Tan Y, He J, et al. T-cell-replete haploidentical HSCT with low-dose anti-T-lymphocyte globulin compared with matched sibling HSCT and unrelated HSCT. Blood. 2014;124(17):2735–43.CrossRefPubMedPubMedCentral

36.

Chen Y, Wang Y, Xu LP, Liu KY, Chen H, Chen YH, et al. Haploidentical stem cell transplantation in patients aged 50 yr and older with leukemia: similar outcomes compared to younger adults. Clin Transplant. 2015;29(6):523–30.CrossRefPubMed

37.

Blaise D, Furst S, Crocchiolo R, El-Cheikh J, Granata A, Harbi S, et al. Haploidentical T cell-replete transplantation with post-transplantation cyclophosphamide for patients in or above the sixth decade of age compared with allogeneic hematopoietic stem cell transplantation from an human leukocyte antigen-matched related or unrelated donor. Biol Blood Marrow Transplant. 2016;22(1):119–24.CrossRefPubMed

38.

Bashey A, Zhang X, Jackson K, Brown S, Ridgeway M, Solh M, et al. Comparison of outcomes of hematopoietic cell transplants from T-replete haploidentical donors using post-transplantation cyclophosphamide with 10 of 10 HLA-A, −B, −C, −DRB1, and −DQB1 allele-matched unrelated donors and HLA-identical sibling donors: a multivariable analysis including Disease Risk Index. Biol Blood Marrow Transplant. 2016;22(1):125–33.CrossRefPubMed

39.

Raiola AM, Dominietto A, di Grazia C, Lamparelli T, Gualandi F, Ibatici A, et al. Unmanipulated haploidentical transplants compared with other alternative donors and matched sibling grafts. Biol Blood Marrow Transplant. 2014;20(10):1573–9.CrossRefPubMed

40.

Ciurea SO, Zhang MJ, Bacigalupo AA, Bashey A, Appelbaum FR, Aljitawi OS, et al. Haploidentical transplant with posttransplant cyclophosphamide vs matched unrelated donor transplant for acute myeloid leukemia. Blood. 2015;126(8):1033–40.CrossRefPubMed

41.

Kanate AS, Mussetti A, Kharfan-Dabaja MA, Ahn KW, DiGilio A, Beitinjaneh A, et al. Reduced-intensity transplantation for lymphomas using haploidentical related donors vs HLA-matched unrelated donors. Blood. 2016;127(7):938–47.CrossRefPubMed

Title: The impact of HLA-matching on reduced intensity conditioning regimen unrelated donor allogeneic stem cell transplantation for acute myeloid leukemia in patients above 50 years—a report from the EBMT acute leukemia working party
Authors: Marie T. Rubio
Bipin N. Savani
Myriam Labopin
Emmanuelle Polge
Dietger Niederwieser
Arnold Ganser
Rainer Schwerdtfeger
Gerhard Ehninger
Jürgen Finke
Arnold Renate
Charles Craddock
Nicolaus Kröger
Michael Hallek
Pavel Jindra
Mohamad Mohty
Arnon Nagler
Publication date: 01-12-2016
Publisher: BioMed Central
Published in: Journal of Hematology & Oncology / Issue 1/2016
Electronic ISSN: 1756-8722
DOI: https://doi.org/10.1186/s13045-016-0295-9

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2016

Interleukin-15 enhances the proliferation, stimulatory phenotype, and antitumor effector functions of human gamma delta T cells

Integrating a prospective pilot trial and patient-derived xenografts to trace metabolic changes associated with acute myeloid leukemia

Alantolactone selectively ablates acute myeloid leukemia stem and progenitor cells

Improving nelarabine efficacy in T cell acute lymphoblastic leukemia by targeting aberrant PI3K/AKT/mTOR signaling pathway

Metformin sensitizes sorafenib to inhibit postoperative recurrence and metastasis of hepatocellular carcinoma in orthotopic mouse models

Immune phenotypes predict survival in patients with glioblastoma multiforme

Keynote webinar | Spotlight on antibody–drug conjugates in cancer