Allogeneic Stem Cell Transplantation in Patients >40 Years of Age With Acute Lymphoblastic Leukemia: Reduced Intensity Versus Myeloablative Conditioning.
Journal
Transplantation
ISSN: 1534-6080
Titre abrégé: Transplantation
Pays: United States
ID NLM: 0132144
Informations de publication
Date de publication:
01 Dec 2023
01 Dec 2023
Historique:
medline:
28
11
2023
pubmed:
30
6
2023
entrez:
30
6
2023
Statut:
ppublish
Résumé
The outcome in older patients with acute lymphoblastic leukemia (ALL) remains unsatisfactory due to high relapse and nonrelapse mortality (NRM) rates. Allogeneic stem cell transplantation (alloHSCT) as postremission therapy has an important role in reducing relapse rate, albeit its application is limited in older adult patients due to alloHSCT-related morbidity and mortality. Reduced-intensity conditioning (RIC) alloHSCT has been developed as a less toxic conditioning regimen, but comparative studies with myeloablative conditioning (MAC) are limited in patients with ALL. In this retrospective study, RIC-alloHSCT (n = 111) was compared with MAC-alloHSCT (n = 77) in patients aged 41 to 65 y with ALL in first complete remission. MAC was predominantly applied by combining high-dose total body irradiation and cyclophosphamide, whereas RIC mainly consisted of fludarabine and 2 Gy total body irradiation. Unadjusted overall survival was 54% (95% confidence interval [CI], 42%-65%) at 5 y in MAC recipients compared with 39% (95% CI, 29%-49%) in RIC recipients. Overall survival and relapse-free survival were not significantly associated with type of conditioning after adjusted for the covariates age, leukemia risk status at diagnosis, donor type, and donor and recipient gender combination. NRM was significantly lower after RIC (subdistribution hazard ratio: 0.41, 95% CI, 0.22-0.78; P = 0.006), whereas relapse was significantly higher (subdistribution hazard ratio: 3.04, 95% CI, 1.71-5.40; P < 0.001). Collectively, RIC-alloHSCT has resulted in less NRM, but it was also found to be associated with a significantly higher relapse rate. These results suggest that MAC-alloHSCT may provide a more effective type of consolidation therapy for the reduction of relapse and that RIC-alloHSCT may be restricted to patients at higher risk for NRM.
Sections du résumé
BACKGROUND
BACKGROUND
The outcome in older patients with acute lymphoblastic leukemia (ALL) remains unsatisfactory due to high relapse and nonrelapse mortality (NRM) rates. Allogeneic stem cell transplantation (alloHSCT) as postremission therapy has an important role in reducing relapse rate, albeit its application is limited in older adult patients due to alloHSCT-related morbidity and mortality. Reduced-intensity conditioning (RIC) alloHSCT has been developed as a less toxic conditioning regimen, but comparative studies with myeloablative conditioning (MAC) are limited in patients with ALL.
METHODS
METHODS
In this retrospective study, RIC-alloHSCT (n = 111) was compared with MAC-alloHSCT (n = 77) in patients aged 41 to 65 y with ALL in first complete remission. MAC was predominantly applied by combining high-dose total body irradiation and cyclophosphamide, whereas RIC mainly consisted of fludarabine and 2 Gy total body irradiation.
RESULTS
RESULTS
Unadjusted overall survival was 54% (95% confidence interval [CI], 42%-65%) at 5 y in MAC recipients compared with 39% (95% CI, 29%-49%) in RIC recipients. Overall survival and relapse-free survival were not significantly associated with type of conditioning after adjusted for the covariates age, leukemia risk status at diagnosis, donor type, and donor and recipient gender combination. NRM was significantly lower after RIC (subdistribution hazard ratio: 0.41, 95% CI, 0.22-0.78; P = 0.006), whereas relapse was significantly higher (subdistribution hazard ratio: 3.04, 95% CI, 1.71-5.40; P < 0.001).
CONCLUSIONS
CONCLUSIONS
Collectively, RIC-alloHSCT has resulted in less NRM, but it was also found to be associated with a significantly higher relapse rate. These results suggest that MAC-alloHSCT may provide a more effective type of consolidation therapy for the reduction of relapse and that RIC-alloHSCT may be restricted to patients at higher risk for NRM.
Identifiants
pubmed: 37389645
doi: 10.1097/TP.0000000000004706
pii: 00007890-990000000-00475
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2561-2567Informations de copyright
Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.
Déclaration de conflit d'intérêts
The authors declare no funding or conflicts of interest.
Références
Dinmohamed AG, Szabo A, van der Mark M, et al. Improved survival in adult patients with acute lymphoblastic leukemia in The Netherlands: a population-based study on treatment, trial participation and survival. Leukemia. 2016;30:310–317.
Lennmyr E, Karlsson K, Ahlberg L, et al.; Swedish Adult Acute Lymphoblastic Leukaemia Group (SVALL). Survival in adult acute lymphoblastic leukaemia (ALL): a report from the Swedish ALL Registry. Eur J Haematol. 2019;103:88–98.
Siegel SE, Stock W, Johnson RH, et al. Pediatric-inspired treatment regimens for adolescents and young adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: a review. JAMA Oncol. 2018;4:725–734.
Dombret H, Cluzeau T, Huguet F, et al. Pediatric-like therapy for adults with ALL. Curr Hematol Malig Rep. 2014;9:158–164.
Ram R, Wolach O, Vidal L, et al. Adolescents and young adults with acute lymphoblastic leukemia have a better outcome when treated with pediatric-inspired regimens: systematic review and meta-analysis. Am J Hematol. 2012;87:472–478.
de Bont JM, van der Holt B, Dekker AW, et al. Significant difference in outcome for adolescents with acute lymphoblastic leukemia treated on pediatric vs adult protocols in the Netherlands. Leukemia. 2004;18:2032–2035.
Boissel N, Auclerc MF, Lheritier V, et al. Should adolescents with acute lymphoblastic leukemia be treated as old children or young adults? Comparison of the French FRALLE-93 and LALA-94 trials. J Clin Oncol. 2003;21:774–780.
DeFilipp Z, Advani AS, Bachanova V, et al. Hematopoietic cell transplantation in the treatment of adult acute lymphoblastic leukemia: updated 2019 evidence-based review from the American Society for Transplantation and Cellular Therapy. Biol Blood Marrow Transplant. 2019;25:2113–2123.
Gupta V, Richards S, Rowe J; Acute Leukemia Stem Cell Transplantation Trialists’ Collaborative Group. Allogeneic, but not autologous, hematopoietic cell transplantation improves survival only among younger adults with acute lymphoblastic leukemia in first remission: an individual patient data meta-analysis. Blood. 2013;121:339–350.
Bassan R, Hoelzer D. Modern therapy of acute lymphoblastic leukemia. J Clin Oncol. 2011;29:532–543.
Cornelissen JJ, van der Holt B, Verhoef GE, et al.; Dutch-Belgian HOVON Cooperative Group. Myeloablative allogeneic versus autologous stem cell transplantation in adult patients with acute lymphoblastic leukemia in first remission: a prospective sibling donor versus no-donor comparison. Blood. 2009;113:1375–1382.
Goldstone AH, Richards SM, Lazarus HM, et al. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008;111:1827–1833.
Thomas X, Boiron JM, Huguet F, et al. Outcome of treatment in adults with acute lymphoblastic leukemia: analysis of the LALA-94 trial. J Clin Oncol. 2004;22:4075–4086.
Hunault M, Harousseau JL, Delain M, et al.; GOELAMS (Groupe Ouest-Est des Leucémies Airguës et Maladies du Sang) Group. Better outcome of adult acute lymphoblastic leukemia after early genoidentical allogeneic bone marrow transplantation (BMT) than after late high-dose therapy and autologous BMT: a GOELAMS trial. Blood. 2004;104:3028–3037.
Cornelissen JJ, Carston M, Kollman C, et al. Unrelated marrow transplantation for adult patients with poor-risk acute lymphoblastic leukemia: strong graft-versus-leukemia effect and risk factors determining outcome. Blood. 2001;97:1572–1577.
Gokbuget N. Treatment of older patients with acute lymphoblastic leukaemia. Drugs Aging. 2018;35:11–26.
Giebel S, Labopin M, Socie G, et al. Improving results of allogeneic hematopoietic cell transplantation for adults with acute lymphoblastic leukemia in first complete remission: an analysis from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Haematologica. 2017;102:139–149.
Roth-Guepin G, Canaani J, Ruggeri A, et al. Allogeneic stem cell transplantation in acute lymphoblastic leukemia patients older than 60 years: a survey from the acute leukemia working party of EBMT. Oncotarget. 2017;8:112972–112979.
Bacigalupo A. Hematopoietic stem cell transplants after reduced intensity conditioning regimen (RI-HSCT): report of a workshop of the European Group for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant. 2000;25:803–805.
Giebel S, Marks DI, Boissel N, et al. Hematopoietic stem cell transplantation for adults with Philadelphia chromosome-negative acute lymphoblastic leukemia in first remission: a position statement of the European Working Group for Adult Acute Lymphoblastic Leukemia (EWALL) and the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant. 2019;54:798–809.
Rijneveld AW, van der Holt B, Daenen SM, et al.; Dutch-Belgian HOVON Cooperative group. Intensified chemotherapy inspired by a pediatric regimen combined with allogeneic transplantation in adult patients with acute lymphoblastic leukemia up to the age of 40. Leukemia. 2011;25:1697–1703.
Daenen S, van der Holt B, Dekker AW, et al.; HOVON. Intensive chemotherapy to improve outcome in patients with acute lymphoblastic leukemia over the age of 40: a phase II study for efficacy and feasibility by HOVON. Leukemia. 2012;26:1726–1729.
Rijneveld AW, van der Holt B, de Weerdt O, et al.; Dutch-Belgian HOVON Cooperative group. Clofarabine added to intensive treatment in adult patients with newly diagnosed ALL: the HOVON-100 trial. Blood Adv. 2022;6:1115–1125.
Maris M, Sandmaier BM, Maloney DG, et al. Non-myeloablative hematopoietic stem cell transplantation. Transfus Clin Biol. 2001;8:231–234.
Fine JPGR. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc. 1999;1999:496–509.
Gratwohl A. The EBMT risk score. Bone Marrow Transplant. 2012;47:749–756.
Marks DI, Wang T, Perez WS, et al. The outcome of full-intensity and reduced-intensity conditioning matched sibling or unrelated donor transplantation in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia in first and second complete remission. Blood. 2010;116:366–374.
Mohty M, Labopin M, Volin L, et al.; Acute Leukemia Working Party of EBMT. Reduced-intensity versus conventional myeloablative conditioning allogeneic stem cell transplantation for patients with acute lymphoblastic leukemia: a retrospective study from the European Group for Blood and Marrow Transplantation. Blood. 2010;116:4439–4443.
Massenkeil G, Nagy M, Neuburger S, et al. Survival after reduced-intensity conditioning is not inferior to standard high-dose conditioning before allogeneic haematopoietic cell transplantation in acute leukaemias. Bone Marrow Transplant. 2005;36:683–689.
Tanaka J, Kanamori H, Nishiwaki S, et al. Reduced-intensity vs myeloablative conditioning allogeneic hematopoietic SCT for patients aged over 45 years with ALL in remission: a study from the Adult ALL Working Group of the Japan Society for Hematopoietic Cell Transplantation (JSHCT). Bone Marrow Transplant. 2013;48:1389–1394.
Bachanova V, Marks DI, Zhang MJ, et al. Ph+ ALL patients in first complete remission have similar survival after reduced intensity and myeloablative allogeneic transplantation: impact of tyrosine kinase inhibitor and minimal residual disease. Leukemia. 2014;28:658–665.
Giralt S, Ballen K, Rizzo D, et al. 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. 2009;15:367–369.
Peric Z, Labopin M, Peczynski C, et al. Comparison of reduced-intensity conditioning regimens in patients with acute lymphoblastic leukemia >45 years undergoing allogeneic stem cell transplantation-a retrospective study by the Acute Leukemia Working Party of EBMT. Bone Marrow Transplant. 2020;55:1560–1569.
Kebriaei P, Anasetti C, Zhang MJ, et al.; Acute Leukemia Committee of the CIBMTR. Intravenous busulfan compared with total body irradiation pretransplant conditioning for adults with acute lymphoblastic leukemia. Biol Blood Marrow Transplant. 2018;24:726–733.
Eder S, Canaani J, Beohou E, et al. Thiotepa-based conditioning versus total body irradiation as myeloablative conditioning prior to allogeneic stem cell transplantation for acute lymphoblastic leukemia: a matched-pair analysis from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Am J Hematol. 2017;92:997–1003.
Mitsuhashi K, Kako S, Shigematsu A, et al.; Adult Acute Lymphoblastic Leukemia Working Group of the Japan Society for Hematopoietic Cell Transplantation. Comparison of cyclophosphamide combined with total body irradiation, oral busulfan, or intravenous busulfan for allogeneic hematopoietic cell transplantation in adults with acute lymphoblastic leukemia. Biol Blood Marrow Transplant. 2016;22:2194–2200.
Cahu X, Labopin M, Giebel S, et al.; Acute Leukemia Working Party of EBMT. Impact of conditioning with TBI in adult patients with T-cell ALL who receive a myeloablative allogeneic stem cell transplantation: a report from the acute leukemia working party of EBMT. Bone Marrow Transplant. 2016;51:351–357.
Peters C, Dalle J-H, Locatelli F, et al. TBI or chemotherapy based conditioning for children and adolescents with ALL: a prospective randomized multicenter-study ‘FORUM’ on behalf of the AIEOP-BFM-ALL-SG, IBFM-SG, INTREALL-SG and EBMT-PD-WP. J Clin Oncol. 2021;39:295–307.
Khimani F, Dutta M, Faramand R, et al. Impact of total body irradiation-based myeloablative conditioning regimens in patients with acute lymphoblastic leukemia undergoing allogeneic hematopoietic stem cell transplantation: systematic review and meta-analysis. Transplant Cell Ther. 2021;27:620.e1–620.e9.
Pavlu J, Labopin M, Niittyvuopio R, et al. Measurable residual disease at myeloablative allogeneic transplantation in adults with acute lymphoblastic leukemia: a retrospective registry study on 2780 patients from the acute leukemia working party of the EBMT. J Hematol Oncol. 2019;12:108.
Abdul Wahid SF, Ismail NA, Mohd-Idris MR, et al. Comparison of reduced-intensity and myeloablative conditioning regimens for allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia and acute lymphoblastic leukemia: a meta-analysis. Stem Cells Dev. 2014;23:2535–2552.