Abstract
We have been using a combination of fludarabine/busulfan plus low-dose total body irradiation (TBI) as the reduced-intensity conditioning (RIC) regimen for patients age ≥ 60 years undergoing allogeneic hematopoietic cell transplantation (HCT) for myeloid malignancies. We retrospectively analyzed outcomes of 116 older patients (median age 64 years) who underwent HCT from 2006 to 2015 for myeloid malignancies, including acute myeloid leukemia (AML) in first complete remission (CR1). On univariate analysis, overall survival (OS) for the cohort at 3 years was 33% (95% CI 25–42). Cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) at 3 years were 24% (95% CI 16–32) and 43% (95% CI 34–52), respectively. Multivariable analysis for OS demonstrated AML patients to have superior outcome (HR 1.60 for other myeloid, 95% CI 1.01–2.54, p = 0.045), as well as related donors (HR 1.92 for unrelated, 95% CI 1.22–3.03, p = 0.005). For NRM, AML patients had superior outcome (HR 1.76 for other myeloid, 95% CI 1.03–3.01, p = 0.038), as well as patients with related donors (HR 1.81 for unrelated, 95% CI 1.07–3.07, p = 0.028). We then demonstrated that AML patients with related donors (n = 45) had superior 3-year OS of 51% (95% CI 36–65), compared to 21% (95% CI 12–32) for all other patients (p = 0.0003). We conclude that the RIC regimen used is effective for older patients, particularly AML patients in CR1 with matched related donors.
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The annual Surveillance, Epidemiology, and End Results (SEER) data, SEER Cancer Statistics Review (CSR) 1975–2014, by the Surveillance Research Program of the NCI. April 14, 2017. https://surveillance.cancer.gov/statistics/new_data.html
Ma X, Does M, Raza A, Mayne ST (2007) Myelodysplastic syndromes: incidence and survival in the United States. Cancer 109:1536–1542
Appelbaum FR (1997) Allogeneic hematopoietic stem cell transplantation for acute leukemia. Semin Oncol 24:114–123
Yanada M, Matsuo K, Emi N, Naoe T (2005) Efficacy of allogeneic hematopoietic stem cell transplantation depends on cytogenetic risk for acute myeloid leukemia in first disease remission: a metaanalysis. Cancer 103:1652–1658
Oliansky DM, Appelbaum F, Cassileth PA, Keating A, Kerr J, Nieto Y, Stewart S, Stone RM, Tallman MS, McCarthy PL Jr, Hahn T (2008) The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute myelogenous leukemia in adults: an evidence-based review. Biol Blood Marrow Transplant 14:137–180
Koreth J, Schlenk R, Kopecky KJ, Honda S, Sierra J, Djulbegovic BJ, Wadleigh M, DeAngelo DJ, Stone RM, Sakamaki H, Appelbaum FR, Döhner H, Antin JH, Soiffer RJ, Cutler C (2009) Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission: systematic review and meta-analysis of prospective clinical trials. JAMA 301:2349–2361
Wallen H, Gooley TA, Deeg HJ, Pagel JM, Press OW, Appelbaum FR, Storb R, Gopal AK (2005) Ablative allogeneic hematopoietic cell transplantation in adults 60 years of age and older. J Clin Oncol 23:3439–3446
Bacigalupo A, Ballen K, Rizzo D, Giralt S, Lazarus H, Ho V, Apperley J, Slavin S, Pasquini M, Sandmaier BM, Barrett J, Blaise D, Lowski R, Horowitz M (2009) Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transplant 15:1628–1633
Terenzi A, Aristei C, Aversa F et al (1996) Efficacy of fludarabine as an immunosuppressor for bone marrow transplantation conditioning: preliminary results. Transplant Proc 28:3101
Giralt S, Thall PF, Khouri I, Wang X, Braunschweig I, Ippolitti C, Claxton D, Donato M, Bruton J, Cohen A, Davis M, Andersson BS, Anderlini P, Gajewski J, Kornblau S, Andreeff M, Przepiorka D, Ueno NT, Molldrem J, Champlin R (2001) Melphalan and purine analog-containing preparative regimens: reduced-intensity conditioning for patients with hematologic malignancies undergoing allogeneic progenitor cell transplantation. Blood 97:631–637
Shimoni A, Nagler A (2011) Optimizing the conditioning regimen for allogeneic stem-cell transplantation in acute myeloid leukemia; dose intensity is still in need. Best Pract Res Clin Haematol 24:369–379
Slavin S, Nagler A, Naparstek E, Kapelushnik Y, Aker M, Cividalli G, Varadi G, Kirschbaum M, Ackerstein A, Samuel S, Amar A, Brautbar C, Ben-Tal O, Eldor A, Or R (1998) 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 91:756–763
Tauro S, Craddock C, Peggs K, Begum G, Mahendra P, Cook G, Marsh J, Milligan D, Goldstone A, Hunter A, Khwaja A, Chopra R, Littlewood T, Peniket A, Parker A, Jackson G, Hale G, Cook M, Russell N, Mackinnon S (2005) Allogeneic stem-cell transplantation using a reduced-intensity conditioning regimen has the capacity to produce durable remissions and long-term disease-free survival in patients with high-risk acute myeloid leukemia and myelodysplasia. J Clin Oncol 23:9387–9393
Corradini P, Zallio F, Mariotti J, Farina L, Bregni M, Valagussa P, Ciceri F, Bacigalupo A, Dodero A, Lucesole M, Patriarca F, Rambaldi A, Scimè R, Locasciulli A, Bandini G, Gianni AM, Tarella C, Olivieri A (2005) Effect of age and previous autologous transplantation on nonrelapse mortality and survival in patients treated with reduced-intensity conditioning and allografting for advanced hematologic malignancies. J Clin Oncol 23:6690–6698
Schmid C, Schleuning M, Schwerdtfeger R, Hertenstein B, Mischak-Weissinger E, Bunjes D, Harsdorf SV, Scheid C, Holtick U, Greinix H, Keil F, Schneider B, Sandherr M, Bug G, Tischer J, Ledderose G, Hallek M, Hiddemann W, Kolb HJ (2006) Long-term survival in refractory acute myeloid leukemia after sequential treatment with chemotherapy and reduced-intensity conditioning for allogeneic stem cell transplantation. Blood 108:1092–1099
Giralt S, Estey E, Albitar M, van Besien K, Rondón G, Anderlini P, O'Brien S, Khouri I, Gajewski J, Mehra R, Claxton D, Andersson B, Beran M, Przepiorka D, Koller C, Kornblau S, Kørbling M, Keating M, Kantarjian H, Champlin R (1997) Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: harnessing graft-versus-leukemia without myeloablative therapy. Blood 89:4531–4536
Valcárcel D, Martino R, Caballero D, Martin J, Ferra C, Nieto JB, Sampol A, Bernal MT, Piñana JL, Vazquez L, Ribera JM, Besalduch J, Moraleda JM, Carrera D, Brunet MS, Perez-Simón JA, Sierra J (2008) 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 26:577–584
de Lima M, Anagnostopoulos A, Munsell M, Shahjahan M, Ueno N, Ippoliti C, Andersson BS, Gajewski J, Couriel D, Cortes J, Donato M, Neumann J, Champlin R, Giralt S (2004) Nonablative versus reduced-intensity conditioning regimens in the treatment of acute myeloid leukemia and high-risk myelodysplastic syndrome: dose is relevant for long-term disease control after allogeneic hematopoietic stem cell transplantation. Blood 104:865–872
Taussig DC, Davies AJ, Cavenagh JD, Oakervee H, Syndercombe-Court D, Kelsey S, Amess JAL, Rohatiner AZS, Lister TA, Barnett MJ (2003) Durable remissions of myelodysplastic syndrome and acute myeloid leukemia after reduced-intensity allografting. J Clin Oncol 21:3060–3065
Martino R, Caballero MD, Pérez-Simón JA, Canals C, Solano C, Urbano-Ispízua A, Bargay J, Léon A, Sarrá J, Sanz GF, Moraleda JM, Brunet S, San Miguel J, Sierra J, AML and alloPBSCT Subcommittees of the Spanish Group for Hematopoietic Transplantation (2002) Evidence for a graft-versus-leukemia effect after allogeneic peripheral blood stem cell transplantation with reduced-intensity conditioning in acute myelogenous leukemia and myelodysplastic syndromes. Blood 100:2243–2245
Giebel S, Labopin M, Mohty M, Mufti GJ, Niederwieser D, Cornelissen JJ, Janssen JJWM, Milpied N, Vindelov L, Petersen E, Arnold R, Bacigalupo A, Blaise D, Craddock C, Nagler A, Frassoni F, Sadus-Wojciechowska M, Rocha V (2013) The impact of center experience on results of reduced intensity: allogeneic hematopoietic SCT for AML. An analysis from the acute leukemia working party of the EBMT. Bone Marrow Transplant 48:238–242
Sorror ML, Maris MB, Storb R, Baron F, Sandmaier BM, Maloney DG, Storer B (2005) Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood 106:2912–2919
Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, Harrison G, Rees J, Hann I, Stevens R, Burnett A, Goldstone A (1998) The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council adult and Children's Leukaemia working parties. Blood 92:2322–2333
Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, Sanz M, Vallespi T, Hamblin T, Oscier D, Ohyashiki K, Toyama K, Aul C, Mufti G, Bennett J (1997) International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89:2079–2088
Such E, Cervera J, Costa D, Sole F, Vallespi T, Luno E, Collado R, Calasanz MJ, Hernandez-Rivas JM, Cigudosa JC, Nomdedeu B, Mallo M, Carbonell F, Bueno J, Ardanaz MT, Ramos F, Tormo M, Sancho-Tello R, Canizo C, Gomez V, Marco V, Xicoy B, Bonanad S, Pedro C, Bernal T, Sanz GF (2011) Cytogenetic risk stratification in chronic myelomonocytic leukemia. Haematologica 96:375–383
Glucksberg H, Storb R, Fefer A et al (1974) Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation 18:295–304
hulman HM, Sullivan KM, Weiden PL et al (1980) Chronic graft-versus-host syndrome in man. A long-term clinicopathologic study of 20 Seattle patients. Am J Med 69:204–217
Kanda Y (2013) Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transplant 48:452–458
Shimoni A, Kröger N, Zabelina T, Ayuk F, Hardan I, Yeshurun M, Shem-Tov N, Avigdor A, Ben-Bassat I, Zander AR, Nagler A (2005) 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 19:7–12
McClune BL, Weisdorf DJ, Pedersen TL et al (2010) Effect of age on outcome of reduced-intensity hematopoietic cell transplantation for older patients with acute myeloid leukemia in first complete remission or with myelodysplastic syndrome. J Clin Oncol 28:1878–1887
Federmann B, Faul C, Meisner C, Vogel W, Kanz L, Bethge WA (2015) Influence of age on outcome after allogeneic hematopoietic cell transplantation: a single center study in patients aged ⩾60. Bone Marrow Transplant 50:427–431
Estey E, de Lima M, Tibes R, Pierce S, Kantarjian H, Champlin R, Giralt S (2007) Prospective feasibility analysis of reduced-intensity conditioning (RIC) regimens for hematopoietic stem cell transplantation (HSCT) in elderly patients with acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS). Blood 109:1395–1400
Devine SM, Owzar K, Blum W, Mulkey F, Stone RM, Hsu JW, Champlin RE, Chen YB, Vij R, Slack J, Soiffer RJ, Larson RA, Shea TC, Hars V, Sibley AB, Giralt S, Carter S, Horowitz MM, Linker C, Alyea EP (2015) Phase II study of allogeneic transplantation for older patients with acute myeloid leukemia in first complete remission using a reduced-intensity conditioning regimen: results from Cancer and leukemia group B 100103 (alliance for clinical trials in oncology)/blood and marrow transplant clinical trial network 0502. J Clin Oncol 33:4167–4175
Farag SS, Maharry K, Zhang MJ, Pérez WS, George SL, Mrózek K, DiPersio J, Bunjes DW, Marcucci G, Baer MR, Cairo M, Copelan E, Cutler CS, Isola L, Lazarus HM, Litzow MR, Marks DI, Ringdén O, Rizzieri DA, Soiffer R, Larson RA, Tallman MS, Bloomfield CD, Weisdorf DJ, Acute Leukemia Committee of the Center for International Blood and Marrow Transplant Research and Cancer and Leukemia Group B (2011) Comparison of reduced-intensity hematopoietic cell transplantation with chemotherapy in patients age 60-70 years with acute myelogenous leukemia in first remission. Biol Blood Marrow Transplant 17:1796–1803
Versluis J, Hazenberg CL, Passweg JR, van Putten W, Maertens J, Biemond BJ, Theobald M, Graux C, Kuball J, Schouten HC, Pabst T, Löwenberg B, Ossenkoppele G, Vellenga E, Cornelissen JJ, HOVON and SAKK Leukemia Groups (2015) Post-remission treatment with allogeneic stem cell transplantation in patients aged 60 years and older with acute myeloid leukaemia: a time-dependent analysis. Lancet Haematol 2:e427–e436
Aoudjhane M, Labopin M, Gorin NC, Shimoni A, Ruutu T, Kolb HJ, Frassoni F, Boiron JM, Yin JL, Finke J, Shouten H, Blaise D, Falda M, Fauser AA, Esteve J, Polge E, Slavin S, Niederwieser D, Nagler A, Rocha V, Acute Leukemia Working Party (ALWP) of the European group for Blood and Marrow Transplantation (EBMT) (2005) 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 19:2304–2312
Martino R, Iacobelli S, Brand R, Jansen T, van Biezen A, Finke J, Bacigalupo A, Beelen D, Reiffers J, Devergie A, Alessandrino E, Mufti GJ, Barge R, Sierra J, Ruutu T, Boogaerts M, Falda M, Jouet JP, Niederwieser D, de Witte T, Myelodysplastic Syndrome subcommittee of the Chronic Leukemia Working Party of the European Blood and Marrow Transplantation Group (2006) Retrospective comparison of reduced-intensity conditioning and conventional high-dose conditioning for allogeneic hematopoietic stem cell transplantation using HLA-identical sibling donors in myelodysplastic syndromes. Blood 108:836–846
Martino R, Valcárcel D, Brunet S, Sureda A, Sierra J (2008) Comparable non-relapse mortality and survival after HLA-identical sibling blood stem cell transplantation with reduced or conventional-intensity preparative regimens for high-risk myelodysplasia or acute myeloid leukemia in first remission. Bone Marrow Transplant 41:33–38
Giralt S, Ballen K, Rizzo D, Bacigalupo A, Horowitz M, Pasquini M, Sandmaier B (2009) Reduced-intensity conditioning regimen workshop: defining the dose spectrum. Report of a workshop convened by the center for international blood and marrow transplant research. Biol Blood Marrow Transplant 15:367–369
Servais S, Baron F, Beguin Y (2011) Allogeneic hematopoietic stem cell transplantation (HSCT) after reduced intensity conditioning. Transfus Apher Sci 44:205–210
Russell JA, Savoie ML, Balogh A, Turner AR, Larratt L, Chaudhry MA, Storek J, Bahlis NJ, Brown CB, Quinlan D, Geddes M, Stewart DA (2007) Allogeneic transplantation for adult acute leukemia in first and second remission with a novel regimen incorporating daily intravenous busulfan, fludarabine, 400 CGY total-body irradiation, and thymoglobulin. Biol Blood Marrow Transplant 13:814–821
Russell JA, Irish W, Balogh A, Chaudhry MA, Savoie ML, Turner AR, Larratt L, Storek J, Bahlis NJ, Brown CB, Quinlan D, Geddes M, Zacarias N, Daly A, Duggan P, Stewart DA (2010) The addition of 400 cGY total body irradiation to a regimen incorporating once-daily intravenous busulfan, fludarabine, and antithymocyte globulin reduces relapse without affecting nonrelapse mortality in acute myelogenous leukemia. Biol Blood Marrow Transplant 16:509–514
Daly A, Savoie ML, Geddes M, Chaudhry A, Stewart D, Duggan P, Bahlis N, Storek J, Brown C, Shafey M, Turner AR, Russell J (2012) Fludarabine, busulfan, antithymocyte globulin, and total body irradiation for pretransplantation conditioning in acute lymphoblastic leukemia: excellent outcomes in all but older patients with comorbidities. Biol Blood Marrow Transplant 18:1921–1926
Flynn CM, Hirsch B, Defor T et al (2007) Reduced intensity compared with high dose conditioning for allotransplantation in acute myeloid leukemia and myelodysplastic syndrome: a comparative clinical analysis. Am J Hematol 82:867–872
Alousi AM, Le-Rademacher J, Saliba RM et al (2013) Who is the better donor for older hematopoietic transplant recipients: an older-aged sibling or a young, matched unrelated volunteer? Blood 121:2567–2573
Späth C, Busemann C, Krüger WH (2014) Allogeneic stem cell transplantation in patients above 55: suggestion for a further stratification of the HCT-CI. J Cancer Res Clin Oncol 140:1981–1988
Rubio MT, Savani BN, Labopin M, Piemontese S, Polge E, Ciceri F, Bacigalupo A, Arcese W, Koc Y, Beelen D, Gülbas Z, Wu D, Santarone S, Tischer J, Afanasyev B, Schmid C, Giebel S, Mohty M, Nagler A (2016) Impact of conditioning intensity in T-replete haplo-identical stem cell transplantation for acute leukemia: a report from the acute leukemia working party of the EBMT. J Hematol Oncol 9:25
Robin M, Porcher R, Adès L, Boissel N, Raffoux E, Xhaard A, Larghero J, Gardin C, Himberlin C, Delmer A, Fenaux P, Dombret H, Socié G, Peffault de Latour R (2013) Matched unrelated or matched sibling donors result in comparable outcomes after non-myeloablative HSCT in patients with AML or MDS. Bone Marrow Transplant 48:1296–1301
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Khalil, M.M.I., Messner, H.A., Lipton, J.H. et al. Fludarabine and busulfan plus low-dose TBI as reduced intensity conditioning in older patients undergoing allogeneic hematopoietic cell transplant for myeloid malignancies. Ann Hematol 97, 1975–1985 (2018). https://doi.org/10.1007/s00277-018-3391-9
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DOI: https://doi.org/10.1007/s00277-018-3391-9