[en] As in younger patients, allogeneic stem cell transplantation (alloHSCT) offers the best chance for durable remission in older patients (≥60 years) with acute myeloid leukemia (AML). However, defining the best treatment strategy (and in particular, whether or not to proceed to alloHSCT) for elderly patients with AML remains a difficult decision for the hematologist, since potential toxicity of conditioning regimens, risks of graft-versus-host disease, impaired immune reconstitution and the need for prolonged immunosuppression may be of major concern in these vulnerable patients with complex needs. Hopefully, significant progress has been made over the past decade in alloHSCT for elderly patients and current evidence suggests that chronological age per se (between 60 and 75) is not a reliable predictor of outcome after alloHSCT. Here, we review the current state of alloHSCT in elderly patients with AML and also discuss the different approaches currently being investigated to improve both accessibility to as well as success of alloHSCT in these patients.
Disciplines :
Hematology
Author, co-author :
SERVAIS, Sophie ; Centre Hospitalier Universitaire de Liège - CHU > > Service d'hématologie clinique
BEGUIN, Yves ; Centre Hospitalier Universitaire de Liège - CHU > > Service d'hématologie clinique
BARON, Frédéric ; Centre Hospitalier Universitaire de Liège - CHU > > Service d'hématologie clinique
Language :
English
Title :
Current Status and Perspectives of Allogeneic Hematopoietic Stem Cell Transplantation in Elderly Patients with Acute Myeloid Leukemia.
Ferrara F, Picardi A. Is outcome of older people with acute myeloid leukemia improving with new therapeutic approaches and stem cell transplantation?. Expert Rev Hematol. 2020;13(2):99-108. https:// doi.org/10.1080/17474086.2020.1715207.
Frisch A, Rowe JM, Ofran Y. How we treat older patients with acute myeloid leukaemia. Br J Haematol. 2020;191(5):682-691. https://doi.org/10.1111/bjh.16701.
Juliusson G, Lazarevic V, Hörstedt A-S, Hagberg O, Höglund M. Acute myeloid leukemia in the real world: why population-based registries are needed. Blood. 2012;119(17):3890-3899. https://doi. org/10.1182/blood-2011-12-379008.
Oran B, Weisdorf DJ. Survival for older patients with acute myeloid leukemia: a population-based study. Haematologica. 2012;97(12):1916-1924. https://doi.org/10.3324/haematol.2012. 066100.
Wetzler M, Mrózek K, Kohlschmidt J, et al. Intensive induction is effective in selected octogenarian acute myeloid leukemia patients: prognostic significance of karyotype and selected molecular markers used in the European LeukemiaNet classification. Haematologica. 2014;99(2):308-313. https://doi.org/10.3324/ haematol.2013.092072.
Juliusson G, Antunovic P, Derolf A, et al. Age and acute myeloid leukemia: real world data on decision to treat and outcomes from the Swedish Acute Leukemia Registry. Blood. 2009;113(18): 4179-4187.
Deeg HJ, Steuten LM. Therapy for hematologic cancers in older patients, quality of life, and health economics: difficult decisions. JAMA Oncol. 2015;1(5):571-572. https://doi.org/10.1001/ jamaoncol.2015.1084.
Thein MS, Ershler WB, Jemal A, Yates JW, Baer MR. Outcome of older patients with acute myeloid leukemia: an analysis of SEER data over 3 decades. Cancer. 2013;119(15):2720-2727.
Smith BD, Smith GL, Hurria A, Hortobagyi GN, Buchholz TA. Future of cancer incidence in the United States: burdens upon an aging, changing nation. J Clin Oncol Off J Am Soc Clin Oncol. 2009;27(17):2758-2765.
Levin-Epstein R, Oliai C, Schiller G. Allogeneic hematopoietic stem cell transplantation for older patients with acute myeloid leukemia. Curr Treat Options Oncol. 2018;19(12):63.
Oran B, Jimenez AM, De Lima M, et al. Age and modified European LeukemiaNet classification to predict transplant outcomes: an integrated approach for acute myelogenous leukemia patients undergoing allogeneic stem cell transplantation. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2015;21(8): 1405-1412.
Jaiswal S, Fontanillas P, Flannick J, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371(26):2488-2498.
Zeng A, Mitchell A, Galkin O, et al. Variation in stem cell driven hierarchies underlies clinical outcome and drug response in AML. Blood (ASH Abstr.) 2020;136(Supplement 1):27-28.
Xie M, Lu C, Wang J, et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med. 2014;20(12):1472-1478.
Prassek VV, Rothenberg-Thurley M, Sauerland MC, et al. Genetics of acute myeloid leukemia in the elderly: mutation spectrum and clinical impact in intensively treated patients aged 75 years or older. Haematologica. 2018;103(11):1853-1861.
Heiblig M, Labussière-Wallet H, Nicolini FE, et al. Prognostic value of genetic alterations in elderly patients with acute myeloid leukemia: a single institution experience. Cancers (Basel). 2019;11(4):170.
Bacher U, Kern W, Schnittger S, et al. Population-based age-specific incidences of cytogenetic subgroups of acute myeloid leukemia. Haematologica. 2005;90(11):1502-1510.
Medeiros BC, Othus M, Fang M, Roulston D, Appelbaum FR. Prognostic impact of monosomal karyotype in young adult and elderly acute myeloid leukemia: the Southwest Oncology Group (SWOG) experience. Blood. 2010;116(13):2224-2228.
Grimwade D, Walker H, Harrison G, et al. The predictive value of hierarchical cytogenetic classification in older adults with acute myeloid leukemia (AML): analysis of 1065 patients entered into the United Kingdom Medical Research Council AML11 trial. Blood 2001;98(5):1312-1320.
Ye X, Chen D, Zheng Y, et al. The incidence, risk factors, and survival of acute myeloid leukemia secondary to myelodysplastic syndrome: a population-based study. Hematol Oncol. 2019;37(4):438-446.
Bertoli S, Tavitian S, Bories P, et al. Outcome of patients aged 60-75 years with newly diagnosed secondary acute myeloid leukemia: a single-institution experience. Cancer Med. 2019;8(8):3846-3854.
Baron F, Efficace F, Cannella L, et al. Impact of the type of anthracycline and of stem cell transplantation in younger patients with acute myeloid leukaemia: long-term follow up of a phase III study. Am J Hematol. 2020;95(7):749-758.
Zhang X-H, Chen J, Han M-Z, et al. The consensus from The Chinese Society of Hematology on indications, conditioning regimens and donor selection for allogeneic hematopoietic stem cell transplantation: 2021 update. J Hematol Oncol. 2021;14(1):145.
Bittencourt MCB, Ciurea SO. Recent advances in allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2020;26(9):e215-e221.
Döhner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):424-447.
Muffly L, Pasquini MC, Martens M, et al. Increasing use of allogeneic hematopoietic cell transplantation in patients aged 70 years and older in the United States. Blood. 2017;130(9):1156-1164.
Rashidi A, Ebadi M, Colditz GA, DiPersio JF. Outcomes of allogeneic stem cell transplantation in elderly patients with acute myeloid leukemia: a systematic review and meta-analysis. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2016;22(4):651-657.
Ringdén O, Boumendil A, Labopin M, et al. Outcome of allogeneic hematopoietic stem cell transplantation in patients age >69 years with acute myelogenous leukemia: on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2019;25(10):1975-1983.
Baron F, Galimard J-E, Labopin M, et al. Allogeneic peripheral blood stem cell transplantation with anti-thymocyte globulin versus allogeneic bone marrow transplantation without anti-thymocyte globulin. Haematologica. 2020;105(4):1138-1146.
Ramadan SM, Suciu S, Stevens-Kroef MJPL, et al. Survival improvement over time of 960 s-AML patients included in 13 EORTCGIMEMA- HOVON trials. Cancers (Basel). 2020;12(11):3334.
Appelbaum FR, Gundacker H, Head DR, et al. Age and acute myeloid leukemia. Blood. 2006;107(9):3481-3485.
Russell NH, Hills RK, Thomas A, et al. Outcomes of older patients aged 60 to 70 years undergoing reduced intensity transplant for acute myeloblastic leukemia: results of the NCRI acute myeloid leukemia 16 trial. Haematologica. 2021. https://doi.org/10.3324/ haematol.2021.279010
Estey E, de Lima M, Tibes R, et al. 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. 2007;109(4):1395-1400.
Versluis J, Hazenberg CLE, Passweg JR, et al. 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. 2015;2(10):e427-e436.
Ustun C, Le-Rademacher J, Wang H-L, et al. Allogeneic hematopoietic cell transplantation compared to chemotherapy consolidation in older acute myeloid leukemia (AML) patients 60-75 years in first complete remission (CR1): an alliance (A151509), SWOG, ECOG-ACRIN, and CIBMTR study. Leukemia. 2019;33(11):2599-2609.
Devine SM, Owzar K, Blum W, et al. 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 Off J Am Soc Clin Oncol. 2015;33(35):4167-4175.
Farag SS, Maharry K, Zhang M-J, et al. Comparison of reducedintensity hematopoietic cell transplantation with chemotherapy in patients age 60-70 years with acute myelogenous leukemia in first remission. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2011;17(12):1796-1803.
Marcucci G, Moser B, Blum W, Stock W, Wetzler M, Kolitz, JE, et al. A phase III randomized trial of intensive induction and consolidation chemotherapy ± oblimersen, a pro-apoptotic Bcl-2 antisense oligonucleotide in untreated acute myeloid leukemia patients >60 years old. J Clin Oncol. 2007;25(18):7012 [abstract].
Baer MR, George SL, Caligiuri MA, et al. Low-dose interleukin-2 immunotherapy does not improve outcome of patients age 60 years and older with acute myeloid leukemia in first complete remission: Cancer and Leukemia Group B Study 9720. J Clin Oncol Off J Am Soc Clin Oncol. 2008;26(30):4934-4939.
Flowers MED, Inamoto Y, Carpenter PA, Lee SJ, Kiem H-P, Petersdorf EW, et al. Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graft-versus-host disease according to National Institutes of Health consensus criteria. Blood. 2011;117(11):3214-3219. Available from: http://www. bloodjournal.org/cgi/doi/10.1182/blood-2010-08-302109
Jagasia M, Arora M, Flowers MED, Chao NJ, McCarthy PL, Cutler CS, et al. Risk factors for acute GVHD and survival after hematopoietic cell transplantation. Blood. 2012;119(1):296-307. Available from: http://www.bloodjournal.org/cgi/doi/10.1182/blood-2011-06-364265
Castermans E, Hannon M, Dutrieux J, Humblet-Baron S, Seidel L, Cheynier R, et al. Thymic recovery after allogeneic hematopoietic cell transplantation with non-myeloablative conditioning is limited to patients younger than 60 years of age. Haematologica [Internet]. 2011 Feb 1 [cited 2019 Sep 5];96(2):298-306. Available from: http:// www.haematologica.org/cgi/doi/10.3324/haematol.2010.029702
Canti L, Humblet-Baron S, Desombere I, et al. Predictors of neutralizing antibody response to BNT162b2 vaccination in allogeneic hematopoietic stem cell transplant recipients. J Hematol Oncol. 2021;14(1):174.
Watson M, Buck G, Wheatley K, et al. Adverse impact of bone marrow transplantation on quality of life in acute myeloid leukaemia patients; analysis of the UK Medical Research Council AML 10 Trial. Eur J Cancer. 2004;40(7):971-978.
Hamilton BK, Rybicki L, Dabney J, et al. Quality of life and outcomes in patients ≥60 years of age after allogeneic hematopoietic cell transplantation. Bone Marrow Transplant. 2014;49(11): 1426-1431.
Bieri S, Roosnek E, Helg C, et al. Quality of life and social integration after allogeneic hematopoietic SCT. Bone Marrow Transplant. 2008;42(12):819-827.
Wong FL, Francisco L, Togawa K, et al. Long-term recovery after hematopoietic cell transplantation: predictors of quality-of-life concerns. Blood. 2010;115(12):2508-2519.
Aoki J, Kanamori H, Tanaka M, et al. Impact of age on outcomes of allogeneic hematopoietic stem cell transplantation with reduced intensity conditioning in elderly patients with acute myeloid leukemia. Am J Hematol. 2016;91(3):302-307.
Schetelig J, Bornhäuser M, Schmid C, 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 Off J Am Soc Clin Oncol. 2008;26(32):5183-5191.
McClune BL, Weisdorf DJ, Pedersen TL, et al. 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 Off J Am Soc Clin Oncol. 2010;28(11):1878-1887.
Sorror ML, Maris MB, Storb R, et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood. 2005;106(8):2912-2919.
Sorror ML, Sandmaier BM, Storer BE, et al. Long-term outcomes among older patients following nonmyeloablative conditioning and allogeneic hematopoietic cell transplantation for advanced hematologic malignancies. JAMA. 2011;306(17):1874-1883.
Sorror ML, Appelbaum FR. Risk assessment before allogeneic hematopoietic cell transplantation for older adults with acute myeloid leukemia. Expert Rev Hematol. 2013;6(5):547-562.
Sorror ML, Storb RF, Sandmaier BM, et al. Comorbidity-age index: a clinical measure of biologic age before allogeneic hematopoietic cell transplantation. J Clin Oncol Off J Am Soc Clin Oncol. 2014;32(29):3249-3256.
Shouval R, Fein JA, Cho C, et al. The Simplified Comorbidity Index (SCI) - a new tool for prediction of non-relapse mortality in allogeneic HCT. Blood Adv. 2022;6(5):1525-1535.
Luft T, Benner A, Terzer T, et al. EASIX and mortality after allogeneic stem cell transplantation. Bone Marrow Transplant. 2020;55(3):553-561.
Kennedy VE, Olin RL. Haematopoietic stem-cell transplantation in older adults: geriatric assessment, donor considerations, and optimisation of care. Lancet Haematol. 2021;8(11):e853-e861.
Wildes TM, Artz AS. Characterize, optimize, and harmonize: caring for older adults with hematologic malignancies. Am Soc Clin Oncol Educ Book Am Soc Clin Oncol Annu Meet. 2021;41:1-9.
Ombres R, des Bordes JKA, Popat UR, et al. Serial frailty assessments following allogeneic stem cell transplant in older adults: a pilot study. J Geriatr Oncol. 2022;13(2):194-199.
Muffly LS, Kocherginsky M, Stock W, et al. Geriatric assessment to predict survival in older allogeneic hematopoietic cell transplantation recipients. Haematologica. 2014;99(8):1373-1379.
Lin RJ, Elko TA, Devlin SM, et al. Impact of geriatric vulnerabilities on allogeneic hematopoietic cell transplantation outcomes in older patients with hematologic malignancies. Bone Marrow Transplant. 2020;55(1):157-164.
Extermann M, Boler I, Reich RR, et al. Predicting the risk of chemotherapy toxicity in older patients: the Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH) score. Cancer. 2012;118(13):3377-3386.
Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374(23):2209-2221.
Fang M, Storer B, Estey E, et al. Outcome of patients with acute myeloid leukemia with monosomal karyotype who undergo hematopoietic cell transplantation. Blood. 2011;118(6):1490-1494.
Whitman SP, Maharry K, Radmacher MD, et al. FLT3 internal tandem duplication associates with adverse outcome and geneand microRNA-expression signatures in patients 60 years of age or older with primary cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. Blood. 2010;116(18):3622-3626.
Perrot A, Luquet I, Pigneux A, et al. Dismal prognostic value of monosomal karyotype in elderly patients with acute myeloid leukemia: a GOELAMS study of 186 patients with unfavorable cytogenetic abnormalities. Blood. 2011;118(3):679-685.
Becker H, Marcucci G, Maharry K, et al. Favorable prognostic impact of NPM1 mutations in older patients with cytogenetically normal de novo acute myeloid leukemia and associated gene- and microRNA-expression signatures: a Cancer and Leukemia Group B study. J Clin Oncol Off J Am Soc Clin Oncol. 2010;28(4):596-604.
Fröhling S, Schlenk RF, Kayser S, et al. Cytogenetics and age are major determinants of outcome in intensively treated acute myeloid leukemia patients older than 60 years: results from AMLSG trial AML HD98-B. Blood. 2006;108(10):3280-3288.
Farag SS, Archer KJ, Mrózek K, et al. Pretreatment cytogenetics add to other prognostic factors predicting complete remission and long-term outcome in patients 60 years of age or older with acute myeloid leukemia: results from Cancer and Leukemia Group B 8461. Blood. 2006;108(1):63-73.
Voso MT, Leone G, Piciocchi A, et al. Feasibility of allogeneic stem-cell transplantation after azacitidine bridge in higher-risk myelodysplastic syndromes and low blast count acute myeloid leukemia: results of the BMT-AZA prospective study. Ann Oncol Off J Eur Soc Med Oncol. 2017;28(7):1547-1553.
Dombret H, Seymour JF, Butrym A, et al. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 2015;126(3):291-299.
Kantarjian HM, Thomas XG, Dmoszynska A, et al. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol Off J Am Soc Clin Oncol. 2012;30(21):2670-2677.
Gao C, Wang J, Li Y, et al. Incidence and risk of hematologic toxicities with hypomethylating agents in the treatment of myelodysplastic syndromes and acute myeloid leukopenia: a systematic review and meta-analysis. Medicine (Baltim). 2018;97(34):e11860.
Bian M-R, Yang H-S, Lin G-Q, et al. Decitabine compared with conventional regimens in older patients with acute myeloid leukemia: a meta-analysis. Clin Lymphoma Myeloma Leuk. 2019;19(12):e636 -e648.
Kröger N. Allogeneic stem cell transplantation for elderly patients with myelodysplastic syndrome. Blood. 2012;119(24):5632-5639.
DiNardo CD, Pratz K, Pullarkat V, et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019;133(1):7-17.
Winters AC, Gutman JA, Purev E, et al. Real-world experience of venetoclax with azacitidine for untreated patients with acute myeloid leukemia. Blood Adv. 2019;3(20):2911-2919.
Feld J, Tremblay D, Dougherty M, et al. Safety and efficacy: clinical experience of venetoclax in combination with hypomethylating agents in both newly diagnosed and relapsed/refractory advanced myeloid malignancies. HemaSphere. 2021;5(4):e549.
Nagler A, Baron F, Labopin M, et al. Measurable residual disease (MRD) testing for acute leukemia in EBMT transplant centers: a survey on behalf of the ALWP of the EBMT. Bone Marrow Transplant. 2021;56(1):218-224.
Ngai LL, Kelder A, Janssen JJWM, Ossenkoppele GJ, Cloos J. MRD tailored therapy in AML: what we have learned so far. Front Oncol. 2020;10:603636.
Schuurhuis GJ, Heuser M, Freeman S, Béné M-C, Buccisano F, Cloos J, et al. Minimal/measurable residual disease in AML: a consensus document from the European LeukemiaNet MRD Working Party. Blood. 2018;131(12):1275-91.
Morsink LM, Sandmaier BM, Othus M, et al. Conditioning intensity, pre-transplant flow cytometric measurable residual disease, and outcome in adults with acute myeloid leukemia undergoing allogeneic hematopoietic cell transplantation. Cancers (Basel). 2020;12(9):2339.
Buccisano F, Maurillo L, Piciocchi A, et al. Minimal residual disease negativity in elderly patients with acute myeloid leukemia may indicate different postremission strategies than in younger patients. Ann Hematol. 2015;94(8):1319-1326.
Hourigan CS, Dillon LW, Gui G, et al. Impact of conditioning intensity of allogeneic transplantation for acute myeloid leukemia with genomic evidence of residual disease. J Clin Oncol Off J Am Soc Clin Oncol. 2020;38(12):1273-1283.
Gilleece MH, Shimoni A, Labopin M, et al. Measurable residual disease status and outcome of transplant in acute myeloid leukemia in second complete remission: a study by the acute leukemia working party of the EBMT. Blood Cancer J. 2021;11(5):88.
Gilleece MH, Labopin M, Yakoub-Agha I, et al. Measurable residual disease, conditioning regimen intensity, and age predict outcome of allogeneic hematopoietic cell transplantation for acute myeloid leukemia in first remission: a registry analysis of 2292 patients by the Acute Leukemia Working Party. Am J Hematol. 2018;93(9):1142-1152.
Milano F, Gooley T, Wood B, et al. Cord-blood transplantation in patients with minimal residual disease. N Engl J Med. 2016;375(10):944-953.
Baron F, Labopin M, Ruggeri A, et al. Impact of detectable measurable residual disease on umbilical cord blood transplantation. Am J Hematol. 2020;95(9):1057-1065.
Sorror ML, Storer BE, Nyland J, Estey EH. Revised acute myeloid leukemia composite model using the 2017 European LeukemiaNet risk classification. JAMA Oncol. 2019;5(7):1062-1064.
Sorror ML, Storer BE, Fathi AT, et al. Development and validation of a novel acute myeloid leukemia-composite model to estimate risks of mortality. JAMA Oncol. 2017;3(12):1675-1682.
Wang H-T, Chang Y-J, Xu L-P, et al. EBMT risk score can predict the outcome of leukaemia after unmanipulated haploidentical blood and marrow transplantation. Bone Marrow Transplant. 2014;49(7):927-933.
Kongtim P, Hasan O, Perez JMR, et al. Novel disease risk model for patients with acute myeloid leukemia receiving allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2020;26(1):197-203.
Kongtim P, Parmar S, Milton DR, et al. Impact of a novel prognostic model, hematopoietic cell transplant-composite risk (HCT-CR), on allogeneic transplant outcomes in patients with acute myeloid leukemia and myelodysplastic syndrome. Bone Marrow Transplant. 2019;54(6):839-848.
Ciurea SO, Kongtim P, Hasan O, et al. Validation of a hematopoietic cell transplant-composite risk (HCT-CR) model for post-transplant survival prediction in patients with hematologic malignancies. Clin Cancer Res Off J Am Assoc Cancer Res. 2020;26(10):2404-2410.
ElSawy M, Storer BE, Sorror ML. "To combine or not to combine": optimizing risk assessment before allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. United States. 2014;20(9):1455-1456.
Gratwohl A, Stern M, Brand R, et al. Risk score for outcome after allogeneic hematopoietic stem cell transplantation: a retrospective analysis. Cancer. 2009;115(20):4715-4726.
Parimon T, Au DH, Martin PJ, Chien JW. A risk score for mortality after allogeneic hematopoietic cell transplantation. Ann Intern Med. 2006;144(6):407-14.
Awada H, Arda D, Gurnari C, et al. The application of machine learning to improve the subclassification and prognostication of acute myeloid leukemia. Blood (ASH Abstr.) 2020;136(Supplement 1):28.
Handschuh L. Not only mutations matter: molecular picture of acute myeloid leukemia emerging from transcriptome studies. J Oncol. 2019;2019:7239206.
Eckardt J-N, Bornhäuser M, Wendt K, Middeke JM. Application of machine learning in the management of acute myeloid leukemia: current practice and future prospects. Blood Adv. 2020;4(23):6077-6085.
Mosquera Orgueira A, Peleteiro Raíndo A, Cid López M, et al. Personalized survival prediction of patients with acute myeloblastic leukemia using gene expression profiling. Front Oncol. 2021;11:657191.
Shouval R, Labopin M, Unger R, et al. Prediction of hematopoietic stem cell transplantation related mortality- lessons learned from the in-silico approach: a European Society for Blood and Marrow Transplantation Acute Leukemia Working Party Data Mining Study. PLoS One. 2016;11(3):e0150637.
Baron F, Labopin M, Ruggeri A, et al. Impact of donor type in patients with AML given allogeneic hematopoietic cell transplantation after low-dose TBI-based regimen. Clin Cancer Res Off J Am Assoc Cancer Res. 2018;24(12):2794-2803.
Fuchs EJ, O'Donnell PV, Eapen M, et al. Double unrelated umbilical cord blood vs HLA-haploidentical bone marrow transplantation: the BMT CTN 1101 trial. Blood. 2021;137(3):420-428.
Majhail NS, Brunstein CG, Shanley R, et al. Reduced-intensity hematopoietic cell transplantation in older patients with AML/ MDS: umbilical cord blood is a feasible option for patients without HLA-matched sibling donors. Bone Marrow Transplant. 2012;47(4):494-498.
Weisdorf D, Eapen M, Ruggeri A, et al. Alternative donor transplantation for older patients with acute myeloid leukemia in first complete remission: a center for international blood and marrow transplant research-eurocord analysis. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2014;20(6):816-822.
Sandhu KS, Brunstein C, DeFor T, et al. Umbilical cord blood transplantation outcomes in acute myelogenous leukemia/ myelodysplastic syndrome patients aged ≥70 years. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2016;22(2):390-393.
Isobe M, Konuma T, Masuko M, et al. Single cord blood transplantation for acute myeloid leukemia patients aged 60 years or older: a retrospective study in Japan. Ann Hematol. 2021;100(7): 1849-1861.
Imus PH, Tsai H-L, Luznik L, et al. Haploidentical transplantation using posttransplant cyclophosphamide as GVHD prophylaxis in patients over age 70. Blood Adv. 2019;3(17):2608-2616.
Ciurea SO, Shah MV, Saliba RM, et al. Haploidentical transplantation for older patients with acute myeloid leukemia and myelodysplastic syndrome. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2018;24(6):1232-1236.
Kasamon YL, Bolaños-Meade J, Prince GT, Tsai H-L, McCurdy SR, Kanakry JA, et al. Outcomes of nonmyeloablative HLAhaploidentical blood or marrow transplantation with high-dose post-transplantation cyclophosphamide in older adults. J Clin Oncol. 2015;33(28):3152-3161. Available from: http://www.ncbi. nlm.nih.gov/pubmed/26261255
Shimoni A, Labopin M, Savani B, et al. Comparable long-term outcome after allogeneic stem cell transplantation from sibling and matched unrelated donors in patients with acute myeloid leukemia older than 50 years: a report on Behalf of the Acute Leukemia Working Party of the European Society. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2019;25(11):2251-2260.
How J, Slade M, Vu K, et al. T cell-replete peripheral blood haploidentical hematopoietic cell transplantation with posttransplantation cyclophosphamide results in outcomes similar to transplantation from traditionally matched donors in active disease acute myeloid leukemia. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2017;23(4):648-653.
Di Stasi A, Milton DR, Poon LM, et al. Similar transplantation outcomes for acute myeloid leukemia and myelodysplastic syndrome patients with haploidentical versus 10/10 human leukocyte antigen-matched unrelated and related donors. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2014;20(12):1975-1981.
Gooptu M, Romee R, St Martin A, et al. HLA haploidentical versus matched unrelated donor transplants with post-transplant cyclophosphamide based prophylaxis. Blood. 2021;138(3): 273-282.
Ciurea SO, Bittencourt MCB, Milton DR, et al. Is a matched unrelated donor search needed for all allogeneic transplant candidates?. Blood Adv. 2018;2(17):2254-2261.
Imus PH, Blackford AL, Bettinotti M, et al. Severe cytokine release syndrome after haploidentical peripheral blood stem cell transplantation. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2019;25(12):2431-2437.
Solán L, Landete E, Bailén R, et al. Cytokine release syndrome after allogeneic stem cell transplantation with posttransplant cyclophosphamide. Hematol Oncol. 2020;38(4):597-603.
Servais S, Baron F, Beguin Y. Allogeneic hematopoietic stem cell transplantation (HSCT) after reduced intensity conditioning. Transfus Apher Sci. 2011;44(2):205-210. Available from: http:// www.ncbi.nlm.nih.gov/pubmed/21345734
Scott BL, Pasquini MC, Logan BR, et al. Myeloablative versus reduced-intensity hematopoietic cell transplantation for acute myeloid leukemia and myelodysplastic syndromes. J Clin Oncol Off J Am Soc Clin Oncol. 2017;35(11):1154-1161.
Bornhäuser M, Kienast J, Trenschel R, et al. Reduced-intensity conditioning versus standard conditioning before allogeneic haemopoietic cell transplantation in patients with acute myeloid leukaemia in first complete remission: a prospective, open-label randomised phase 3 trial. Lancet Oncol. 2012;13(10):1035-1044.
Scott BL, Pasquini MC, Fei M, et al. Myeloablative versus reducedintensity conditioning for hematopoietic cell transplantation in acute myelogenous leukemia and myelodysplastic syndromeslong- term follow-up of the BMT CTN 0901 clinical trial. Transplant Cell Ther. 2021;27(6):483.e1-483.e6.
Rambaldi A, Grassi A, Masciulli A, et al. Busulfan plus cyclophosphamide versus busulfan plus fludarabine as a preparative regimen for allogeneic haemopoietic stem-cell transplantation in patients with acute myeloid leukaemia: an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2015;16(15): 1525-1536.
Popat U, Mehta R, Bassett R, et al. Myeloablative fractionated busulfan conditioning regimen in older patients: results of a phase II study. Blood (ASH Abstr.) 2019;134(Supplement 1):256.
Baron F, Labopin M, Peniket A, et al. Reduced-intensity conditioning with fludarabine and busulfan versus fludarabine and melphalan for patients with acute myeloid leukemia: a report from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Cancer. 2015;121(7): 1048-1055.
Eapen M, Brazauskas R, Hemmer M, et al. Hematopoietic cell transplant for acute myeloid leukemia and myelodysplastic syndrome: conditioning regimen intensity. Blood Adv. 2018;2(16): 2095-2103.
Damlaj M, Alkhateeb HB, Hefazi M, et al. Fludarabine-busulfan reduced-intensity conditioning in comparison with fludarabinemelphalan is associated with increased relapse risk in spite of pharmacokinetic dosing. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2016;22(8):1431-1439.
Kawamura K, Kako S, Mizuta S, et al. Comparison of conditioning with fludarabine/busulfan and fludarabine/melphalan in allogeneic transplantation recipients 50 years or older. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2017;23(12):2079-2087.
Ciurea SO, Kongtim P, Varma A, et al. Is there an optimal conditioning for older patients with AML receiving allogeneic hematopoietic cell transplantation?. Blood. 2020;135(6):449-452.
Gyurkocza B, Gutman J, Nemecek ER, et al. Treosulfan, fludarabine, and 2-Gy total body irradiation followed by allogeneic hematopoietic cell transplantation in patients with myelodysplastic syndrome and acute myeloid leukemia. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2014;20(4):549-555.
Danylesko I, Shimoni A, Nagler A. Treosulfan-based conditioning before hematopoietic SCT: more than a BU look-alike. Bone Marrow Transplant. 2012;47(1):5-14.
Garcia JS, Kim HT, Murdock HM, et al. Adding venetoclax to fludarabine/busulfan RIC transplant for high risk MDS and AML is feasible, safe, and active. Blood Adv. 2021;5(24):5536-5545.
Vandenhove B, Canti L, Schoemans H, et al. How to make an immune system and a foreign host quickly cohabit in peace? The challenge of acute graft-versus-host disease prevention after allogeneic hematopoietic cell transplantation. Front Immunol. 2020;11:583564.
Bonifazi F, Solano C, Wolschke C, Sessa M, Patriarca F, Zallio F, et al. Acute GVHD prophylaxis plus ATLG after myeloablative allogeneic haemopoietic peripheral blood stem-cell transplantation from HLA-identical siblings in patients with acute myeloid leukaemia in remission: final results of quality of life and longterm outcome analysis of a phase 3 randomised study. Lancet Haematol. 2019;6(2):e89-99. Available from: https://linkinghub. elsevier.com/retrieve/pii/S235230261830214X
Walker I, Panzarella T, Couban S, Couture F, Devins G, Elemary M, et al. Pretreatment with anti-thymocyte globulin versus no anti-thymocyte globulin in patients with haematological malignancies undergoing haemopoietic cell transplantation from unrelated donors: a randomised, controlled, open-label, phase 3, multicentre trial. Lancet Oncol. 2016;17(2):164-173. Available from: https://linkinghub.elsevier.com/retrieve/pii/ S1470204515004623
Socié G, Schmoor C, Bethge WA, et al. Chronic graft-versus-host disease: long-term results from a randomized trial on graft-versushost disease prophylaxis with or without anti-T-cell globulin ATG-Fresenius. Blood. 2011;117(23):6375-6382.
Kröger N, Solano C, Wolschke C, Bandini G, Patriarca F, Pini M, et al. Antilymphocyte globulin for prevention of chronic graftversus- host disease. N Engl J Med. 2016;374(1):43-53. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26735993
Baron F, Labopin M, Blaise D, Lopez-Corral L, Vigouroux S, Craddock C, et al. Impact of in vivo T-cell depletion on outcome of AML patients in first CR given peripheral blood stem cells and reduced-intensity conditioning allo-SCT from a HLA-identical sibling donor: a report from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant. 2014;49(3):389-396. Available from: http://www.nature.com/articles/bmt2013204
Soiffer RJ, Lerademacher J, Ho V, Kan F, Artz A, Champlin RE, et al. Impact of immune modulation with anti-T-cell antibodies on the outcome of reduced-intensity allogeneic hematopoietic stem cell transplantation for hematologic malignancies. Blood. 2011;117(25):6963-6970. Available from: http://www. bloodjournal.org/cgi/doi/10.1182/blood-2011-01-332007
Shichijo T, Fuji S, Nagler A, et al. Personalizing rabbit antithymocyte globulin therapy for prevention of graft-versus-host disease after allogeneic hematopoietic cell transplantation: is there an optimal dose?. Bone Marrow Transplant. 2020;55(3):505-522.
Devillier R, Labopin M, Chevallier P, et al. Impact of antithymocyte globulin doses in reduced intensity conditioning before allogeneic transplantation from matched sibling donor for patients with acute myeloid leukemia: a report from the acute leukemia working party of European group of Bone Marro. Bone Marrow Transplant. 2018;53(4):431-437.
Sandmaier BM, Kornblit B, Storer BE, Olesen G, Maris MB, Langston AA, et al. Addition of sirolimus to standard cyclosporine plus mycophenolate mofetil-based graft-versus-host disease prophylaxis for patients after unrelated non-myeloablative haemopoietic stem cell transplantation: a multicentre, randomised, phase 3 trial. Lancet Haematol. 2019;6(8):e409-418. Available from: http://www.ncbi.nlm.nih.gov/pubmed/31248843
Nunes NS, Kanakry CG. Mechanisms of graft-versus-host disease prevention by post-transplantation cyclophosphamide: an evolving understanding. Front Immunol. 2019;10:2668.
Sanz J, Galimard J-E, Labopin M, et al. Post-transplant cyclophosphamide after matched sibling, unrelated and haploidentical donor transplants in patients with acute myeloid leukemia: a comparative study of the ALWP EBMT. J Hematol Oncol. 2020;13(1):46.
El Fakih R, Hashmi SK, Ciurea SO, et al. Post-transplant cyclophosphamide use in matched HLA donors: a review of literature and future application. Bone Marrow Transplant. 2020;55(1): 40-47.
De Jong C, Meijer E, Bakunina K, et al. Post-transplantation cyclophosphamide after allogeneic hematopoietic stem cell transplantation: results of the prospective randomized HOVON-96 trial in recipients of matched related and unrelated donors. Blood (ASH Abstr.) 2019;134(Supplement 1):1.
Bolaños-Meade J, Reshef R, Fraser R, Fei M, Abhyankar S, Al-Kadhimi Z, et al. Three prophylaxis regimens (tacrolimus, mycophenolate mofetil, and cyclophosphamide; tacrolimus, methotrexate, and bortezomib; or tacrolimus, methotrexate, and maraviroc) versus tacrolimus and methotrexate for prevention of graft-versus-host disease with haemopoietic cell transplantation with reduced-intensity conditioning: a randomised phase 2 trial with a non-randomised contemporaneous control group (BMT CTN 1203). Lancet Haematol. 2019;6(3):e132-143. Available from: https://linkinghub.elsevier.com/retrieve/pii/S2352302618302217
Brissot E, Lapobin M, Labussière H, et al. Post-transplantation cyclophosphamide vs. antithymocyte globulin after ric regimen allo-hct: first analysis of a prospective randomized multicenter trial in recipients of 10/10 matched donors. Bone Marrow Transplant. 2021;56:12.
Lee CJ, Savani BN, Mohty M, et al. Post-remission strategies for the prevention of relapse following allogeneic hematopoietic cell transplantation for high-risk acute myeloid leukemia: expert review from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transpl. Bone Marrow Transplant. 2019;54(4):519-530.
Kantarjian HM, Roboz GJ, Kropf PL, et al. Guadecitabine (SGI- 110) in treatment-naive patients with acute myeloid leukaemia: phase 2 results from a multicentre, randomised, phase 1/2 trial. Lancet Oncol. 2017;18(10):1317-1326.
Perl AE, Martinelli G, Cortes JE, et al. Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. N Engl J Med. 2019;381(18):1728-1740.
Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017;130(6):722-731.
DiNardo CD, Stein EM, de Botton S, et al. Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N Engl J Med. 2018;378(25):2386-2398.
Pollyea DA, Tallman MS, de Botton S, et al. Enasidenib, an inhibitor of mutant IDH2 proteins, induces durable remissions in older patients with newly diagnosed acute myeloid leukemia. Leukemia. 2019;33(11):2575-2584.
Yan B, Claxton D, Huang S, Qiu Y. AML chemoresistance: the role of mutant TP53 subclonal expansion and therapy strategy. Exp Hematol. 2020;87:13-19.
Cluzeau T, Sebert M, Rahmé R, et al. Eprenetapopt plus azacitidine in TP53-mutated myelodysplastic syndromes and acute myeloid leukemia: a phase II study by the Groupe Francophone des Myélodysplasies (GFM). J Clin Oncol Off J Am Soc Clin Oncol. 2021;39(14):1575-1583.
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 (AML). Blood. 2012;119(14):3361-3369. Available from: http:// www.bloodjournal.org/cgi/doi/10.1182/blood-2011-09-377044
Ehx G, Fransolet G, de Leval L, D'Hondt S, Lucas S, Hannon M, et al. Azacytidine prevents experimental xenogeneic graft-versushost disease without abrogating graft-versus-leukemia effects. Oncoimmunology. 2017;6(5):e1314425. Available from: https:// www.tandfonline.com/doi/full/10.1080/2162402X.2017.1314425
Bewersdorf JP, Allen C, Mirza A-S, et al. Hypomethylating agents and FLT3 inhibitors as maintenance treatment for acute myeloid leukemia and myelodysplastic syndrome following allogeneic hematopoietic stem cell transplant - a systematic review and meta-analysis. Transplant Cell Ther. 2021;27(12):997. e1-997.e11.
El Chaer F, Borate U, Duléry R, et al. Azacitidine maintenance after allogeneic hematopoietic cell transplantation for MDS and AML. Blood Adv. 2021;5(6):1757-1759.
Platzbecker U, Middeke JM, Sockel K, et al. Measurable residual disease-guided treatment with azacitidine to prevent haematological relapse in patients with myelodysplastic syndrome and acute myeloid leukaemia (RELAZA2): an open-label, multicentre, phase 2 trial. Lancet Oncol. 2018;19(12):1668-1679.
Oran B, de Lima M, Garcia-Manero G, et al. A phase 3 randomized study of 5-azacitidine maintenance vs observation after transplant in high-risk AML and MDS patients. Blood Adv. 2020;10(21):5580-5588.
Bazarbachi A, Bug G, Baron F, et al. Clinical practice recommendation on hematopoietic stem cell transplantation for acute myeloid leukemia patients with FLT3-internal tandem duplication: a position statement from the Acute Leukemia Working Party of the European Society for Blood and Marrow. Haematologica. 2020;105(6):1507-1516.
Burchert A, Bug G, Fritz LV, et al. Sorafenib maintenance after allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia with FLT3-internal tandem duplication mutation (SORMAIN). J Clin Oncol Off J Am Soc Clin Oncol. 2020;38(26):2993-3002.
Xuan L, Wang Y, Huang F, et al. Sorafenib maintenance in patients with FLT3-ITD acute myeloid leukaemia undergoing allogeneic haematopoietic stem-cell transplantation: an openlabel, multicentre, randomised phase 3 trial. Lancet Oncol. 2020;21(9):1201-1212.
Schmid C, Schleuning M, Ledderose G, Tischer J, Kolb H-J. Sequential regimen of chemotherapy, reduced-intensity conditioning for allogeneic stem-cell transplantation, and prophylactic donor lymphocyte transfusion in high-risk acute myeloid leukemia and myelodysplastic syndrome. J Clin Oncol Off J Am Soc Clin Oncol. 2005;23(24):5675-5687.
Liu H. Emerging agents and regimens for AML. J Hematol Oncol. 2021;14(1):49.
Barrett AJ. Acute myeloid leukaemia and the immune system: implications for immunotherapy. Br J Haematol. 2020;188(1):147-158.
Hansrivijit P, Gale RP, Barrett J, Ciurea SO. Cellular therapy for acute myeloid leukemia - current status and future prospects. Blood Rev. 2019;37:100578.
Phelan R, Arora M, Chen M. Current use and outcome of hematopoietic stem cell transplantation: CIBMTR US summary slides. 2020. https://www.cibmtr.org/ReferenceCenter/SlidesReports/ SummarySlides/pages/index.aspx
