Tyrosine kinase inhibitors represent today's treatment of choice in chronic myeloid leukemia (CML). Allogeneic hematopoietic stem cell transplantation (HSCT) is regarded as salvage therapy. This prospective randomized CML-study IIIA recruited 669 patients with newly diagnosed CML between July 1997 and January 2004 from 143 centers. Of these, 427 patients were considered eligible for HSCT and were randomized by availability of a matched family donor between primary HSCT (group A; N=166 patients) and best available drug treatment (group B; N=261). Primary end point was long-term survival. Survival probabilities were not different between groups A and B (10-year survival: 0.76 (95% confidence interval (CI): 0.69-0.82) vs 0.69 (95% CI: 0.61-0.76)), but influenced by disease and transplant risk. Patients with a low transplant risk showed superior survival compared with patients with high- (P<0.001) and non-high-risk disease (P=0.047) in group B; after entering blast crisis, survival was not different with or without HSCT. Significantly more patients in group A were in molecular remission (56% vs 39%; P=0.005) and free of drug treatment (56% vs 6%; P<0.001). Differences in symptoms and Karnofsky score were not significant. In the era of tyrosine kinase inhibitors, HSCT remains a valid option when both disease and transplant risk are considered.

1 Medizinische Klinik Klinikum Bremen Mitte Bremen Germany

2 Medizinische Klinik Klinikum Augsburg Augsburg Germany

2 Medizinische Klinik St Vincentius Kliniken Karlsruhe Germany

2 Medizinische Klinik Städtisches Klinikum Karlsruhe Karlsruhe Germany

3 Medizinische Klinik Medizinische Fakultät Mannheim der Universität Heidelberg Germany

3 Medizinische Klinik Universitätsmedizin Mainz Mainz Germany

Abteilung für Hämatologie und Stammzelltransplantation Asklepios Klinik St Georg Hamburg Germany

Abteilung Hämatologie und Internistische Onkologie Universitätsklinikum Regensburg Regensburg Germany

Department of Hematology Medical University of Gdansk Gdańsk Poland

Department of Internal Medicine Hemato Oncology University Hospital and Masaryk University Brno Czech Republic

Division d'Hematologie CHUV Lausanne Switzerland

Institut für Medizinische Informationsverarbeitung Biometrie und Epidemiologie Ludwig Maximilians Universität München München Germany

Institut für Pathologie Medizinische Hochschule Hannover Germany

Interdisziplinäre Klinik und Poliklinik für Stammzelltransplantation Universitätsklinikum Hamburg Eppendorf Hamburg Germany

Klinik 1 für Innere Medizin Universitätsklinikum Köln Köln Germany

Klinik für Hämatologie Hämostaseologie Onkologie und Stammzelltransplantation Medizinische Hochschule Hannover Hannover Germany

Klinik für Hämatologie Onkologie Immunologie Palliativmedizin Infektiologie und Tropenmedizin Klinikum Schwabing München München Germany

Klinik für Hämatologie und Onkologie St Antonius Hospital Eschweiler Eschweiler Germany

Klinik für Hämatologie und Onkologie St Marien Hospital Hagen Hagen Germany

Klinik für Hämatologie und Onkologie Universitätsmedizin Göttingen Göttingen Germany

Klinik für Hämatologie Universitätsklinikum Düsseldorf Düsseldorf Germany

Klinik für Hämatologie Universitätsspital Basel Basel Switzerland

Klinik für Innere Medizin 1 Universität des Saarlandes Homburg Germany

Klinik für Innere Medizin 2 Universitätsklinikum Jena Jena Germany

Klinik für Innere Medizin 3 Klinikum Kempten Oberallgäu Kempten Germany

Klinik für Innere Medizin 3 Universitätsklinikum Ulm Ulm Germany

Klinik für internistische Onkologie und Hämatologie Krankenhaus Barmherzige Brüder Regensburg Germany

Klinik für Knochenmarktransplantation und Hämatologie Onkologie Idar Oberstein Germany

Klinik für Knochenmarktransplantation Universitätsklinikum Essen Essen Germany

Klinik für Onkologie und Hämatologie HELIOS St Johannes Klinik Duisburg Duisburg Germany

KMT Zentrum Deutsche Klinik für Diagnostik Wiesbaden Germany

Medizinische Klinik 1 Bürgerhospital Stuttgart Stuttgart Germany

Medizinische Klinik 3 und Poliklinik Universitätsklinikum München München Germany

Medizinische Klinik 5 Klinikum Nürnberg Nord Nürnberg Germany

Medizinische Klinik 5 Universitätsklinikum Heidelberg Heidelberg Germany

Medizinische Klinik mit Schwerpunkt Hämatologie Virchow Klinikum Charité Universitätsmedizin Berlin Germany

Medizinische Klinik und Poliklinik Universitätsklinikum Würzburg Würzburg Germany

MLL Münchner Leukämielabor GmbH München Germany

Onkologische Schwerpunktpraxis Bielefeld Germany

Universitätsklinik für Hämatologie Inselspital Bern Bern Switzerland

Zentrum für Integrierte Onkologie Universitätsklinikum Bonn Bonn Germany

Zobrazit více v PubMed

Apperley JF. Chronic myeloid leukaemia. Lancet 2015; 385: 1447–1459. PubMed

Hehlmann R. A chance of cure for every patient with chronic myeloid leukemia? N Engl J Med 1998; 338: 980–982. PubMed

O'Brien S, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003; 348: 994–1004. PubMed

Speck B, Bortin MM, Champlin R, Goldman JM, Herzig RH, McGlave PB et al. Allogeneic bone-marrow transplantation for chronic myelogenous leukaemia. Lancet 1984; 1: 665–668. PubMed

Copelan EA. Hematopoietic stem-cell transplantation. N Engl J Med 2006; 354: 1813–1826. PubMed

Fefer A, Einstein AB, Thomas ED, Buckner CD, Clift RA, Glucksberg H et al. Bone-marrow transplantation for hematologic neoplasia in 16 patients with identical twins. N Engl J Med 1974; 290: 1389–1393. PubMed

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: 476–482. PubMed PMC

Gratwohl A, Baldomero H, Gratwohl M, Aljurf M, Bouzas LF, Horowitz M et al. Quantitative and qualitative differences in use and trends of hematopoietic stem cell transplantation: a Global Observational Study. Haematologica 2013; 98: 1282–1290. PubMed PMC

Baccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, Apperley JF et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood 2013; 122: 872–884. PubMed PMC

National Cancer Institute at the National Institutes of Health. Treatment options for chronic-phase CML. High-dose therapy followed by allogeneic BMT or SCT. Available at: http://www.cancer.gov/cancertopics/pdq/treatment/CML/HealthProfessional/Page4#Section_271 (last assessed 21 February 2015).

Hughes TP, Hochhaus A, Branford S, Müller MC, Kaeda JS, Foroni L et al. Long-term prognostic significance of early molecular response to imatinib in newly diagnosed chronic myeloid leukemia: an analysis from the International Randomized Study of Interferon and STI571 (IRIS). Blood 2010; 116: 3758–3765. PubMed PMC

Hehlmann R, Berger U, Pfirrmann M, Heimpel H, Hochhaus A, Hasford J et al. Drug treatment is superior to allografting as first-line therapy in chronic myeloid leukemia. Blood 2007; 109: 4686–4692. PubMed

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: 2091–2101. PubMed PMC

Gratwohl A, Hermans J, Goldman JM, Arcese W, Carreras E, Devergie A et al. Risk assessment for patients with chronic myeloid leukaemia before allogeneic blood or marrow transplantation. Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Lancet 1998; 352: 1087–1092. PubMed

Gratwohl A, Brand R, Niederwieser D, Baldomero H, Chabannon C, Cornelissen J et al. Introduction of a quality management system and outcome after hematopoietic stem-cell transplantation. J Clin Oncol 2011; 29: 1980–1986. PubMed

Saussele S, Lauseker M, Gratwohl A, Beelen DW, Bunjes D, Schwerdtfeger R et al. Allogeneic hematopoietic stem cell transplantation (allo SCT) for chronic myeloid leukemia in the imatinib era: evaluation of its impact within a subgroup of the randomized German CML Study IV. Blood 2010; 115: 1880–1885. PubMed

Oyekunle A, Zander AR, Binder M, Ayuk F, Zabelina T, Christopeit M et al. Outcome of allogeneic SCT in patients with chronic myeloid leukemia in the era of tyrosine kinase inhibitor therapy. Ann Hematol 2013; 92: 487–496. PubMed

Hehlmann R, Hochhaus A, Kolb HJ, Hasford J, Gratwohl A, Heimpel H et al. Interferon-alpha before allogeneic bone marrow transplantation in chronic myelogenous leukemia does not affect outcome adversely, provided it is discontinued at least 90 days before the procedure. Blood 1999; 94: 3668–3677. PubMed

CML Autograft Trials Collaboration. Autologous stem cell transplantation in chronic myeloid leukaemia: a meta-analysis of six randomized trials. Cancer Treat Rev 2007; 33: 39–47. PubMed

Lauseker M, Hasford J, Pfirrmann M, Hehlmann R, , German CMLSG. The impact of health care settings on survival time of patients with chronic myeloid leukemia. Blood 2014; 123: 2494–2496. PubMed

Warlick E, Ahn KW, Pedersen TL, Artz A, de Lima M, Pulsipher M et al. Reduced intensity conditioning is superior to nonmyeloablative conditioning for older chronic myelogenous leukemia patients undergoing hematopoietic cell transplant during the tyrosine kinase inhibitor era. Blood 2012; 119: 4083–4090. PubMed PMC

Soverini S, Hochhaus A, Nicolini FE, Gruber F, Lange T, Saglio G et al. BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet. Blood 2011; 118: 1208–1215. PubMed

Pfirrmann M, Saussele S, Hochhaus A, Reiter A, Berger U, Hossfeld DK et al. Explaining survival differences between two consecutive studies with allogeneic stem cell transplantation in patients with chronic myeloid leukemia. J Cancer Res Clin Oncol 2014; 140: 1367–1381. PubMed PMC

Simon R, Makuch RW. A non-parametric graphical representation of the relationship between survival and the occurence of an event: application to responder versus non-responder bias. StatMed 1984; 3: 35–44. PubMed

Mantel N, Byar DP. Evaluation of response-time data involving transient states: an illustration using heart-transplant data. J Am Stat Assoc 1974; 69: 81–86.

Hasford J, Pfirrmann M, Hehlmann R, Allan NC, Baccarani M, Kluin-Nelemans JC et al. A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. Writing Committee for the Collaborative CML Prognostic Factors Project Group. J Natl Cancer Inst 1998; 90: 850–858. PubMed

Innes AJ, Apperley JF. Chronic myeloid leukemia-transplantation in the tyrosine kinase era. Hematol Oncol Clin N Am 2014; 28: 1037–1053. PubMed

Hehlmann R, Muller MC, Lauseker M, Hanfstein B, Fabarius A, Schreiber A et al. Deep molecular response is reached by the majority of patients treated with imatinib, predicts survival, and is achieved more quickly by optimized high-dose imatinib: results from the randomized CML-study IV. J Clin Oncol 2014; 32: 415–423. PubMed

Gragert L, Eapen M, Williams E, Freeman J, Spellman S, Baitty R et al. HLA match likelihoods for hematopoietic stem-cell grafts in the U.S. registry. N Engl J Med 2014; 371: 339–348. PubMed PMC

Pavey T, Hoyle M, Ciani O, Crathorne L, Jones-Hughes T, Cooper C et al. Dasatinib, nilotinib and standard-dose imatinib for the first-line treatment of chronic myeloid leukaemia: systematic reviews and economic analyses. Health Technol Assess (Winchester, England) 2012; 16, iii-iv, 1–277. PubMed

Mo XD, Jiang Q, Xu LP, Liu DH, Liu KY, Jiang B et al. Health-related quality of life of patients with newly diagnosed chronic myeloid leukemia treated with allogeneic hematopoietic SCT versus imatinib. Bone Marrow Transplant 2014; 49: 576–580. PubMed

European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia

Assessment of imatinib as first-line treatment of chronic myeloid leukemia: 10-year survival results of the randomized CML study IV and impact of non-CML determinants