Abstract
The combination of azacitidine and donor lymphocyte infusions (DLI) as first salvage therapy for relapse after allogeneic transplantation (allo-HSCT) was studied in 30 patients with acute myeloid leukemia (AML; n=28) or myelodysplastic syndromes (MDS; n=2) within a prospective single-arm multicenter phase-II trial. Treatment schedule contained up to eight cycles azacitidine (100 mg/m2/day, days 1–5, every 28 days) followed by DLI (from 1–5 × 106 to 1–5 × 108 CD3+cells/kg) after every second azacitidine cycle. A median of three courses azacitidine (range 1–8) were administered, and 22 patients (73%) received DLI. Overall response rate was 30%, including seven complete remissions (CRs, 23%) and two partial remissions (7%). Five patients remain in CR for a median of 777 days (range 461–888). Patients with MDS or AML with myelodysplasia-related changes were more likely to respond (P=0.011), and a lower blast count (P=0.039) as well as high-risk cytogenetics (P=0.035) correlated with the likelihood to achieve CR. Incidence of acute and chronic graft-versus-host disease was 37% and 17%, respectively. Neutropenia and thrombocytopenia grade III/IV occurred during 65% and 63% of treatment cycles, while infections were the most common grade III/IV non-hematological toxicity. Azacitidine and DLI as salvage therapy is safe, induces long-term remissions and may become an alternative for patients with AML or MDS relapsing after allo-HSCT.
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References
Schlenk RF, Dohner K, Mack S, Stoppel M, Kiraly F, Gotze K et al. Prospective evaluation of allogeneic hematopoietic stem-cell transplantation from matched related and matched unrelated donors in younger adults with high-risk acute myeloid leukemia: German-Austrian trial AMLHD98A. J Clin Oncol 2010; 28: 4642–4648.
Saure C, Schroeder T, Zohren F, Groten A, Bruns I, Czibere A et al. Upfront allogeneic blood stem cell transplantation for patients with high-risk myelodysplastic syndrome or secondary acute myeloid leukemia using a FLAMSA-based high-dose sequential conditioning regimen. Biol Blood Marrow Transplant 2011; 18: 466–472.
Pavletic SZ, Kumar S, Mohty M, de LM, Foran JM, Pasquini M et al. NCI First International Workshop on the Biology, Prevention, and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation: report from the Committee on the Epidemiology and Natural History of Relapse following Allogeneic Cell Transplantation. Biol Blood Marrow Transplant 2010; 16: 871–890.
van den Brink MR, Porter DL, Giralt S, Lu SX, Jenq RR, Hanash A et al. Relapse after allogeneic hematopoietic cell therapy. Biol Blood Marrow Transplant 2010; 16 (1 Suppl): S138–S145.
Porter DL, Alyea EP, Antin JH, DeLima M, Estey E, Falkenburg JH et al. NCI First International Workshop on the Biology, Prevention, and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation: report from the Committee on Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant 2010; 16: 1467–1503.
Kroger N . Approaches to relapse after allogeneic stem cell transplantation. Curr Opin Oncol 2011; 23: 203–208.
Schmid C, Labopin M, Nagler A, Bornhauser M, Finke J, Fassas A et al. Donor lymphocyte infusion in the treatment of first hematological relapse after allogeneic stem-cell transplantation in adults with acute myeloid leukemia: a retrospective risk factors analysis and comparison with other strategies by the EBMT Acute Leukemia Working Party. J Clin Oncol 2007; 25: 4938–4945.
Eapen M, Giralt SA, Horowitz MM, Klein JP, Wagner JE, Zhang MJ et al. Second transplant for acute and chronic leukemia relapsing after first HLA-identical sibling transplant. Bone Marrow Transplant 2004; 34: 721–727.
Bosi A, Laszlo D, Labopin M, Reffeirs J, Michallet M, Gluckman E et al. Second allogeneic bone marrow transplantation in acute leukemia: results of a survey by the European Cooperative Group for Blood and Marrow Transplantation. J Clin Oncol 2001; 19: 3675–3684.
Kuendgen A, Graf T, Zohren F, Hildebrandt B, Hunerliturkoglu A, Gattermann N et al. Induction of complete remission in a patient with acute myeloid leukemia refractory to high-dose chemotherapy through treatment with 5-azacytidine. Leuk Res 2007; 31: 407–409.
Atanackovic D, Luetkens T, Kloth B, Fuchs G, Cao Y, Hildebrandt Y et al. Cancer-testis antigen expression and its epigenetic modulation in acute myeloid leukemia. Am J Hematol 2011; 86: 918–922.
Pinto A, Maio M, Attadia V, Zappacosta S, Cimino R . Modulation of HLA-DR antigens expression in human myeloid leukaemia cells by cytarabine and 5-aza-2′-deoxycytidine. Lancet 1984; 2: 867–868.
Pinto A, Attadia V, Fusco A, Ferrara F, Spada OA, Di Fiore PP . 5-Aza-2′-deoxycytidine induces terminal differentiation of leukemic blasts from patients with acute myeloid leukemias. Blood 1984; 64: 922–929.
Goodyear O, Agathanggelou A, Novitzky-Basso I, Siddique S, McSkeane T, Ryan G et al. Induction of a CD8+ T-cell response to the MAGE cancer testis antigen by combined treatment with azacitidine and sodium valproate in patients with acute myeloid leukemia and myelodysplasia. Blood 2010; 116: 1908–1918.
Sanchez-Abarca LI, Gutierrez-Cosio S, Santamaria C, Caballero-Velazquez T, Blanco B, Herrero-Sanchez C et al. Immunomodulatory effect of 5-azacytidine (5-azaC): potential role in the transplantation setting. Blood 2010; 115: 107–121.
Choi J, Ritchey J, Prior JL, Holt M, Shannon WD, Deych E et al. In vivo administration of hypomethylating agents mitigate graft-versus-host disease without sacrificing graft-versus-leukemia. Blood 2010; 116: 129–139.
Graef T, Kuendgen A, Fenk R, Zohren F, Haas R, Kobbe G . Successful treatment of relapsed AML after allogeneic stem cell transplantation with azacitidine. Leuk Res 2007; 31: 257–259.
Bolanos-Meade J, Smith BD, Gore SD, McDevitt MA, Luznik L, Fuchs EJ et al. 5-Azacytidine as salvage treatment in relapsed myeloid tumors after allogeneic bone marrow transplantation. Biol Blood Marrow Transplant 2011; 17: 754–758.
Czibere A, Bruns I, Kroger N, Platzbecker U, Lind J, Zohren F et al. 5-Azacytidine for the treatment of patients with acute myeloid leukemia or myelodysplastic syndrome who relapse after allo-SCT: a retrospective analysis. Bone Marrow Transplant 2010; 45: 872–876.
Lubbert M, Bertz H, Wasch R, Marks R, Ruter B, Claus R et al. Efficacy of a 3-day, low-dose treatment with 5-azacytidine followed by donor lymphocyte infusions in older patients with acute myeloid leukemia or chronic myelomonocytic leukemia relapsed after allografting. Bone Marrow Transplant 2010; 45: 627–632.
Jabbour E, Giralt S, Kantarjian H, Garcia-Manero G, Jagasia M, Kebriaei P et al. Low-dose azacitidine after allogeneic stem cell transplantation for acute leukemia. Cancer 2009; 115: 1899–1905.
Dohner H, Estey EH, Amadori S, Appelbaum FR, Buchner T, Burnett AK et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 2010; 115: 453–474.
Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD et al. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood 2006; 108: 419–425.
Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant 2005; 11: 945–956.
Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J et al1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant 1995; 15: 825–828.
Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997; 89: 2079–2088.
Schmid C, Labopin M, Nagler A, Niederwieser D, Castagna L, Tabrizi R et al. Treatment, risk factors, and outcome of adults with relapsed AML after reduced intensity conditioning for allogeneic stem cell transplantation. Blood 2012; 119: 1599–1606.
de LM, Giralt S, Thall PF, de Padua SL, Jones RB, Komanduri K et al. Maintenance therapy with low-dose azacitidine after allogeneic hematopoietic stem cell transplantation for recurrent acute myelogenous leukemia or myelodysplastic syndrome: a dose and schedule finding study. Cancer 2010; 116: 5420–5431.
Platzbecker U, Wermke M, Radke J, Oelschlaegel U, Seltmann F, Kiani A et al. Azacitidine for treatment of imminent relapse in MDS or AML patients after allogeneic HSCT: results of the RELAZA trial. Leukemia 2011; 26: 381–389.
Guieze R, Damaj G, Robin M, Mohty M, Michallet M, Tabrizi R et al. Treatment of relapse after allogeneic hematopoietic sem-cell transplantation for myelodysplastic syndrome: a large-scale study on behalf of the Societe Francaise De Greffe De Moelle Et De Therapie Cellulaire (SFGM-TC). ASH Annual Meeting Abstracts 2012; 120: 593.
Lubbert M, Wijermans P, Kunzmann R, Verhoef G, Bosly A, Ravoet C et al. Cytogenetic responses in high-risk myelodysplastic syndrome following low-dose treatment with the DNA methylation inhibitor 5-aza-2′-deoxycytidine. Br J Haematol 2001; 114: 349–357.
Campregher PV, Gooley T, Scott BL, Moravec C, Sandmaier B, Martin PJ et al. Results of donor lymphocyte infusions for relapsed myelodysplastic syndrome after hematopoietic cell transplantation. Bone Marrow Transplant 2007; 40: 965–971.
Arellano ML, Langston A, Winton E, Flowers CR, Waller EK . Treatment of relapsed acute leukemia after allogeneic transplantation: a single center experience. Biol Blood Marrow Transplant 2007; 13: 116–123.
Goodyear OC, Dennis M, Jilani NY, Loke J, Siddique S, Ryan G et al. Azacitidine augments expansion of regulatory T cells after allogeneic stem cell transplantation in patients with acute myeloid leukemia. Blood 2012; 119: 3361–3369.
Blum W, Klisovic RB, Becker H, Yang X, Rozewski DM, Phelps MA et al. Dose escalation of lenalidomide in relapsed or refractory acute leukemias. J Clin Oncol 2010; 28: 4919–4925.
Fehniger TA, Uy GL, Trinkaus K, Nelson AD, Demland J, Abboud CN et al. A phase 2 study of high-dose lenalidomide as initial therapy for older patients with acute myeloid leukemia. Blood 2011; 117: 1828–1833.
Fenaux P, Giagounidis A, Selleslag D, Beyne-Rauzy O, Mufti G, Mittelman M et al. A randomized phase 3 study of lenalidomide versus placebo in RBC transfusion-dependent patients with Low-/Intermediate-1-risk myelodysplastic syndromes with del5q. Blood 2011; 118: 3765–3776.
Lioznov M, El-Cheikh J, Hoffmann F, Hildebrandt Y, Ayuk F, Wolschke C et al. Lenalidomide as salvage therapy after allo-SCT for multiple myeloma is effective and leads to an increase of activated NK (NKp44(+)) and T (HLA-DR(+)) cells. Bone Marrow Transplant 2010; 45: 349–353.
Sekeres MA, List AF, Cuthbertson D, Paquette R, Ganetzky R, Latham D et al. Phase I combination trial of lenalidomide and azacitidine in patients with higher-risk myelodysplastic syndromes. J Clin Oncol 2010; 28: 2253–2258.
Sekeres MA, O’Keefe C, List AF, Paulic K, Afable M, Englehaupt R et al. Demonstration of additional benefit in adding lenalidomide to azacitidine in patients with higher-risk myelodysplastic syndromes. Am J Hematol 2011; 86: 102–103.
Breems DA, Van Putten WL, De Greef GE, Van Zelderen-Bhola SL, Gerssen-Schoorl KB, Mellink CH et al. Monosomal karyotype in acute myeloid leukemia: a better indicator of poor prognosis than a complex karyotype. J Clin Oncol 2008; 26: 4791–4797.
Acknowledgements
This study was supported by research funding of Celgene Corporation, Germany to GK. This work was also supported by the Leukämie Lymphom Liga e. V. Duesseldorf, Germany and the Forschungskommision of the Heinrich-Heine-University, Duesseldorf, Germany. We would like to thank the staff of the transplant unit of the Department of Hematology, Oncology and Clinical Immunology for excellent patient care as well as Julia Fröbel, Ron-Patrick Cadeddu and Annemarie Koch for excellent laboratory work.
Author contributions
Conception and design: GK and AC. Provision of study materials or patients: NK, GB, UP, TL, LU, KR, CW, GK and TS. Collection and assembly of data: TS, GK, NK, GB, UP, TL, LU, KR and CW. Data analysis and interpretation: TS, GK, AC, RF, FZ and IB. Manuscript writing: TS, GK, RH and AC. Final approval of the manuscript: all authors.
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TS received financial travel support and honoraria from Celgene Corporation, Germany. UP received advisory fees, honoraria and research funding from Celgene Corporation, Germany. GB received advisory fees, honoraria, travel grants and research funding from Celgene Corporation, Germany. FZ is employed as medical director Millenium Pharmaceuticals, USA. RF received advisory fees, honoraria, travel grants and research funding from Celgene Corporation, Germany. UG received received honoraria and research funding from Celgene Corporation, Germany. NK received research funding from Celgene Corporation, Germany. The remaining authors declare no conflict of interest.
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Parts of this study have been presented at the 52nd American Society of Hematology (ASH) Annual Meeting, Orlando, FL, 4–7 December 2010, the BMT Tandem Meeting 2011, Honolulu, HI, 17–21 February 2011, the 37th Annual Meeting of the European Group for Bone and Marrow Transplantation (EBMT), Paris, France, 3–7 April 2011 and at the 53rd American Society of Hematology (ASH) Annual Meeting, San Diego, CA, 10–13 December 2011.
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Schroeder, T., Czibere, A., Platzbecker, U. et al. Azacitidine and donor lymphocyte infusions as first salvage therapy for relapse of AML or MDS after allogeneic stem cell transplantation. Leukemia 27, 1229–1235 (2013). https://doi.org/10.1038/leu.2013.7
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DOI: https://doi.org/10.1038/leu.2013.7
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