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).
Giebel, Sebastian; Marks, David I.; Boissel, Nicolaset al.
2019 • In Bone Marrow Transplantation, 54, p. 798-809
[en] Allogeneic hematopoietic stem cell transplantation (HSCT) in first complete remission is a standard of care for adult patients with Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) and high risk of relapse. However, the stratification systems vary among study groups. Inadequate response at the level of minimal residual disease is the most commonly accepted factor indicating the need for alloHSCT. In this consensus paper on behalf of the European Working Group for Adult Acute Lymphoblastic Leukemia and the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation, we summarize available evidence and reflect current clinical practice in major European study groups regarding both indications for HSCT and particular aspects of the procedure including the choice of donor, source of stem cells and conditioning. Finally, we propose recommendations for daily clinical practice as well as for planning of prospective trials.
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).
Giebel S, Labopin M, Socié G, Beelen D, Browne P, Volin L, 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;102:139–49.
Terwey TH, Hemmati PG, Martus P, Dietz E, Vuong LG, Massenkeil G, et al. A modified EBMT risk score and the hematopoietic cell transplantation-specific comorbidity index for pre-transplant risk assessment in adult acute lymphoblastic leukemia. Haematologica. 2010;95:810–8.
Shouval R, Labopin M, Bondi O, Mishan-Shamay H, Shimoni A, Ciceri F, et al. Prediction of allogeneic hematopoietic stem-cell transplantation mortality 100 days after transplantation using a machine learning algorithm: a European Group for Blood and Marrow Transplantation Acute Leukemia Working Party Retrospective Data Mining Study. J Clin Oncol. 2015;33:3144–51.
Passweg JR, Baldomero H, Bader P, Bonini C, Cesaro S, Dreger P, et al. Hematopoietic stem cell transplantation in Europe 2014: more than 40,000 transplants annually. Bone Marrow Transplant. 2016;51:786–92.
Passweg JR, Baldomero H, Bader P, Bonini C, Duarte RF, Dufour C, et al. Use of haploidentical stem cell transplantation continues to increase: the 2015 European Society for Blood and Marrow Transplant activity survey report. Bone Marrow Transplant. 2017;52:811–7.
Giebel S, Stella-Holowiecka B, Krawczyk-Kulis M, Gökbuget N, Hoelzer D, Doubek M, et al. Status of minimal residual disease determines outcome of autologous hematopoietic SCT in adult ALL. Bone Marrow Transplant. 2010;45:1095–101.
Attal M, Blaise D, Marit G, Payen C, Michallet M, Vernant JP, et al. Consolidation treatment of adult acute lymphoblastic leukemia: a prospective, randomized trial comparing allogeneic versus autologous bone marrow transplantation and testing the impact of recombinant interleukin-2 after autologous bone marrow transplantation. BGMT Group. Blood. 1995;86:1619–28.
Hunault M, Harousseau JL, Delain M, Truchan-Graczyk M, Cahn JY, Witz F, et al. 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;104:3028–37.
Cornelissen JJ, van der Holt B, Verhoef GE, van’t Veer MB, van Oers MH, Schouten HC, et al. 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;113:1375–82.
Sebban C, Lepage E, Vernant JP, Gluckman E, Attal M, Reiffers J, et al. Allogeneic bone marrow transplantation in adult acute lymphoblastic leukemia in first complete remission: a comparative study. French Group of Therapy of Adult Acute Lymphoblastic Leukemia. J Clin Oncol. 1994;12:2580–7.
Thomas X, Boiron JM, Huguet F, Dombret H, Bradstock K, Vey N, et al. Outcome of treatment in adults with acute lymphoblastic leukemia: analysis of the LALA-94 trial. J Clin Oncol. 2004;22:4075–86.
Labar B, Suciu S, Zittoun R, Muus P, Marie JP, Fillet G, et al. Allogeneic stem cell transplantation in acute lymphoblastic leukemia and non-Hodgkin’s lymphoma for patients
Ribera JM, Oriol A, Bethencourt C, Parody R, Hernández-Rivas JM, Moreno MJ, et al. Comparison of intensive chemotherapy, allogeneic or autologous stem cell transplantation as post-remission treatment for adult patients with high-risk acute lymphoblastic leukemia. Results of the PETHEMA ALL-93 trial. Haematologica. 2005;90:1346–56.
Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, 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;111:1827–33.
Szczepański T. Why and how to quantify minimal residual disease in acute lymphoblastic leukemia? Leukemia. 2007;21:622–6.
Garand R, Beldjord K, Cavé H, Fossat C, Arnoux I, Asnafi V, et al. Flow cytometry and IG/TCR quantitative PCR for minimal residual disease quantitation in acute lymphoblastic leukemia: a French multicenter prospective study on behalf of the FRALLE, EORTC and GRAALL. Leukemia. 2013;27:370–6.
Holowiecki J, Krawczyk-Kulis M, Giebel S, Jagoda K, Stella-Holowiecka B, Piatkowska-Jakubas B, et al. Status of minimal residual disease after induction predicts outcome in both standard and high-risk Ph-negative adult acute lymphoblastic leukaemia. The Polish Adult Leukemia Group ALL 4-2002 MRD Study. Br J Haematol. 2008;142:227–37.
Gökbuget N, Kneba M, Raff T, Trautmann H, Bartram CR, Arnold R, et al. Adult patients with acute lymphoblastic leukemia and molecular failure display a poor prognosis and are candidates for stem cell transplantation and targeted therapies. Blood. 2012;120:1868–2876.
Bruggemann M, Raff T, Flohr T, Gökbuget N, Nakao M, Droese J, et al. Clinical significance of minimal residual disease quantification in adult patients with standard-risk acute lymphoblastic leukemia. Blood. 2006;107:1116–23.
Bassan R, Spinelli O, Oldani E, Intermesoli T, Tosi M, Peruta B, et al. Improved risk classification for risk-specific therapy based on the molecular study of minimal residual disease (MRD) in adult acute lymphoblastic leukemia (ALL). Blood. 2009;113:4153–62.
Ribera JM, Oriol A, Morgades M, Montesinos P, Sarrà J, González-Campos J, et al. Treatment of high-risk Philadelphia chromosome-negative acute lymphoblastic leukemia in adolescents and adults according to early cytologic response and minimal residual disease after consolidation assessed by flow cytometry: final results of the PETHEMA ALL-AR-03 trial. J Clin Oncol. 2014;32:1595–604.
Dhédin N, Huynh A, Maury S, Tabrizi R, Beldjord K, Asnafi V, et al. Role of allogeneic stem cell transplantation in adult patients with Ph-negative acute lymphoblastic leukemia. Blood. 2015;125:2486–96.
Seftel MD, Neuberg D, Zhang MJ, Wang HL, Ballen KK, Bergeron J, et al. Pediatric-inspired therapy compared to allografting for Philadelphia chromosome-negative adult ALL in first complete remission. Am J Hematol. 2016;91:322–9.
Aldoss I, Tsai NC, Slovak ML, Palmer J, Alvarnas J, Marcucci G, et al. Cytogenetics does not impact outcomes in adult patients with acute lymphoblastic leukemia undergoing allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2016;22:1212–7.
Den Boer ML, van Slegtenhorst M, De Menezes RX, Cheok MH, Buijs-Gladdines JG, Peters ST, et al. A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study. Lancet Oncol. 2009;10:125–34.
Jain N, Roberts KG, Jabbour E, Patel K, Eterovic AK, Chen K, et al. Ph-like acute lymphoblastic leukemia: a high-risk subtype in adults. Blood. 2017;129:572–81.
Fukano R, Sunami S, Sekimizu M, Takimoto T, Mori T, Mitsui T, et al. Clinical features and prognosis according to immunophenotypic subtypes including the early T-cell precursor subtype of T-lymphoblastic lymphoma in the Japanese Pediatric Leukemia/Lymphoma Study Group ALB-NHL03 Study. J Pediatr Hematol Oncol. 2018;40:e34–e37.
Bond J, Graux C, Lhermitte L, Lara D, Cluzeau T, Leguay T, et al. Early response-based therapy stratification improves survival in adult early thymic precursor acute lymphoblastic leukemia: a Group for Research on Adult Acute Lymphoblastic Leukemia Study. J Clin Oncol. 2017;35:2683–91.
Beldjord K, Chevret S, Asnafi V, Huguet F, Boulland ML, Leguay T, et al. Oncogenetics and minimal residual disease are independent outcome predictors in adult patients with acute lymphoblastic leukemia. Blood. 2014;123:3739–49.
Marks DI, Rowntree C. Management of adults with T-cell lymphoblastic leukemia. Blood. 2017;129:1134–42.
Giebel S, Beohou E, Labopin M, Seesaghur A, Baron F, Ciceri F, et al. Trends in the use of hematopoietic stem cell transplantation for adults with acute lymphoblstic leukemia: a report from the Acute Leukemia Working Party of the EBMT. Haematologica. 2016;101(Suppl. 1):196(S524).
Tomblyn MB, Arora M, Baker KS, Blazar BR, Brunstein CG, Burns LJ, et al. Myeloablative hematopoietic cell transplantation for acute lymphoblastic leukemia: analysis of graft sources and long-term outcome. J Clin Oncol. 2009;27:3634–41.
Nishiwaki S, Miyamura K, Ohashi K, Kurokawa M, Taniguchi S, Fukuda T, et al. Impact of a donor source on adult Philadelphia chromosome-negative acute lymphoblastic leukemia: a retrospective analysis from the Adult Acute Lymphoblastic Leukemia Working Group of the Japan Society for Hematopoietic Cell Transplantation. Ann Oncol. 2013;24:1594–602.
Luznik L, O'Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M, et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. 2008;14:641–50.
Santoro N, Ruggeri A, Labopin M, Bacigalupo A, Ciceri F, Gülbaş Z, et al. Unmanipulated haploidentical stem cell transplantation in adults with acute lymphoblastic leukemia: a study on behalf of the Acute Leukemia Working Party of the EBMT. J Hematol Oncol. 2017;10:113.
Srour SA, Milton DR, Bashey A, Karduss-Urueta A, Al Malki MM, Romee R, et al. Haploidentical transplantation with post-transplantation cyclophosphamide for high-risk acute lymphoblastic leukemia. Biol Blood Marrow Transplant. 2017;23:318–24.
Marks DI, Aversa F, Lazarus HM. Alternative donor transplants for adult acute lymphoblastic leukaemia: a comparison of the three major options. Bone Marrow Transplant. 2006;38:467–75.
Terakura S, Atsuta Y, Tsukada N, Kobayashi T, Tanaka M, Kanda J, et al. Comparison of outcomes of 8/8 and 7/8 allele-matched unrelated bone marrow transplantation and single-unit cord blood transplantation in adults with acute leukemia. Biol Blood Marrow Transplant. 2016;22:330–8.
Davies SM, Ramsay NK, Klein JP, Weisdorf DJ, Bolwell B, Cahn JY, et al. Comparison of preparative regimens in transplants for children with acute lymphoblastic leukemia. J Clin Oncol. 2000;18:340–7.
Eroglu C, Pala C, Kaynar L, Yaray K, Aksozen MT, Bankir M, et al. Comparison of total body irradiation plus cyclophosphamide with busulfan plus cyclophosphamide as conditioning regimens in patients with acute lymphoblastic leukemia undergoing allogeneic hematopoietic stem cell transplant. Leuk Lymphoma. 2013;54:2474–9.
Cahu X, Labopin M, Giebel S, Aljurf M, Kyrcz-Krzemien S, Socié G, et al. 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;51:351–7.
Giebel S, Miszczyk L, Slosarek K, Moukhtari L, Ciceri F, Esteve J, et al. Extreme heterogeneity of myeloablative total body irradiation techniques in clinical practice: a survey of the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Cancer. 2014;120:2760–5.
Marks DI, Forman SJ, Blume KG, Pérez WS, Weisdorf DJ, Keating A, et al. A comparison of cyclophosphamide and total body irradiation with etoposide and total body irradiation as conditioning regimens for patients undergoing sibling allografting for acute lymphoblastic leukemia in first or second complete remission. Biol Blood Marrow Transplant. 2006;12:438–53.
Czyz A, Labopin M, Giebel S, Socié G, Apperley J, Volin L, et al. Cyclophosphamide versus etoposide in combination with total body irradiation as conditioning regimen for adult patients with Ph-negative acute lymphoblastic leukemia undergoing allogeneic stem cell transplant: on behalf of the ALWP of the European Society for Blood and Marrow Transplantation. Am J Hematol. 2018;93:778–85.
Arai Y, Kondo T, Shigematsu A, Tanaka J, Ohashi K, Fukuda T, et al. Improved prognosis with additional medium-dose VP16 to CY/TBI in allogeneic transplantation for high risk ALL in adults. Am J Hematol. 2018;93:47–57.
Belkacemi Y, Labopin M, Giebel S, Loganadane G, Miszczyk L, Michallet M, et al. Single-dose daily fractionation is not inferior to twice-a-day fractionated total-body irradiation before allogeneic stem cell transplantation for acute leukemia: a useful practice simplification resulting from the SARASIN Study. Int J Radiat Oncol Biol Phys. 2018;102:515–26.
Friedman DL, Rovo A, Leisenring W, Locasciulli A, Flowers ME, Tichelli A, et al. Increased risk of breast cancer among survivors of allogeneic hematopoietic cell transplantation: a report from the FHCRC and the EBMT-Late Effect Working Party. Blood. 2008;111:939–44.
Mitsuhashi K, Kako S, Shigematsu A, Atsuta Y, Doki N, Fukuda T, et al. 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.
Kebriaei P, Anasetti C, Zhang MJ, Wang HL, Aldoss I, de Lima M, et al. Intravenous busulfan compared to total body irradiation pre-transplant conditioning for adults with acute lymphoblastic leukemia. Biol Blood Marrow Transplant. 2018;24:726–33.
Eder S, Canaani J, Beohou E, Labopin M, Sanz J, Arcese W, 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.
Rosko A, Wang HL, de Lima M, Sandmaier B, Khoury HJ, Artz A, et al. Reduced intensity conditioned allograft yields favorable survival for older adults with B-cell acute lymphoblastic leukemia. Am J Hematol. 2017;92:42–49.
Okasha D, Kirkwood AA, Wrench B, Lawrie E, Zuborne Alapi K, Clifton-Hadley L, et al. Post-induction MRD predicts high relapse risk following reduced intensity conditioned allogeneic stem cel transplantation: a prospective study of adult ALL (UKALL 14, ISRCTN 66541317). Haematologica. 2017;102 Suppl 2:326(S802).
Holtick U, Albrecht M, Chemnitz JM, Theurich S, Shimabukuro-Vornhagen A, Skoetz N, et al. Comparison of bone marrow versus peripheral blood allogeneic hematopoietic stem cell transplantation for hematological malignancies in adults - a systematic review and meta-analysis. Crit Rev Oncol Hematol. 2015;94:179–88.
Finke J, Bethge WA, Schmoor C, Ottinger HD, Stelljes M, Zander AR, et al. Standard graft-versus-host disease prophylaxis with or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: a randomised, open-label, multicentre phase 3 trial. Lancet Oncol. 2009;10:855–64.
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;17:164–73.
Kröger N, Solano C, Wolschke C, Bandini G, Patriarca F, Pini M. et al. Antilymphocyte globulin for prevention of chronic graft-versus-host disease. N Engl J Med. 2016;374:43–53.
Czerw T, Labopin M, Giebel S, Socié G, Volin L, Fegueux N, et al. Anti-thymocyte globulin improves survival free from relapse and graft-versus-host disease after allogeneic peripheral blood stem cell transplantation in patients with Philadelphia-negative acute lymphoblastic leukemia: An analysis by the Acute Leukemia Working Party of the EBMT. Cancer. 2018;124:2523–33.
Roth-Guepin G, Canaani J, Ruggeri A, Labopin M, Finke J, Cornelissen JJ, 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;8:112972–9.
Topp MS, Kufer P, Gökbuget N, Goebeler M, Klinger M, Neumann S, et al. Targeted therapy with the T-cell-engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival. J Clin Oncol. 2011;29:2493–8.
Gökbuget N, Dombret H, Bonifacio M, Reichle A, Graux M, Faul C, et al. Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia. Blood. 2018;131:1522–31.
Kantarjian H, Ravandi F, Short NJ, Huang X, Jain N, Sasaki K, et al. Inotuzumab ozogamicin in combination with low-intensity chemotherapy for older patients with Philadelphia chromosome-negative acute lymphoblastic leukaemia: a single-arm, phase 2 study. Lancet Oncol. 2018;19:240–8.
Kantarjian H, Jabbour E. Incorporating immunotherapy into the treatment strategies of B-cell adult acute lymphoblastic leukemia: the role of blinatumomab and inotuzumab ozogamicin. Am Soc Clin Oncol Educ Book. 2018;23:574–8.