Hematopoietic Stem Cell Transplantation for Adult Philadelphia-Negative Acute Lymphoblastic Leukemia in the First Complete Remission in the Era of Minimal Residual Disease

  • Christianne Bourlon
  • Dennis Lacayo-Leñero
  • Sergio I. Inclán-Alarcón
  • Roberta Demichelis-Gómez
Leukemia (A Aguayo, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Leukemia


Purpose of Review

The purpose of this review is to discuss the potential role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for Philadelphia-negative (Ph) adult acute lymphoblastic leukemia (ALL) in first complete remission (CR1) in the era of minimal residual disease (MRD).

Recent Findings

Allo-HSCT continues to have a role in the therapy of a selected group of high-risk adult patients with ALL in CR1. Although the clinical significance of MRD has been studied less extensively in adults with ALL than in children, recent studies support its role as the strongest prognostic factor that can identify patients that are unlikely to be cured by standard chemotherapy and benefit from undergoing allo-HSCT. In addition, MRD status both pre- and post-HSCT has been found to correlate directly with the risk of relapse.


Currently, the clinical challenge consists on applying MRD and molecular failure to integrate novel agents and immunotherapy to lower MRD before allo-HSCT and to modulate the graft versus leukemia (GVL) effect after transplant.


Minimal residual disease Hematopoietic stem cell transplantation Acute lymphoblastic leukemia Adult patients Philadelphia negative ALL Early consolidation MRD status Intensified therapy MRD techniques Graft versus leukemia Graft versus host disease 



The authors would like to thank the Aramont Foundation for their support in the research activities of the Leukemia Clinic and Bone Marrow Transplant program at Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán.

Compliance with Ethical Standards

Conflict of Interest

Christianne Bourlon, Dennis Lacayo-Leñero, Sergio Inclán-Alarcón, and Roberta Demichelis-Gómez declare they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Paul S, Kantarjian H, Jabbour EJ. Adult acute lymphoblastic leukemia. Mayo Clinic Procedures. 2016;91(11):1645–66. Scholar
  2. 2.
    Pulte D, Jansen L, Gondos A, Katalinic A, Barnes B, Ressing M, et al. Survival of adults with acute lymphoblastic leukemia in Germany and the United States. PLoS One. 2014;9(1):e85554.
  3. 3.
    • Bassan R, Intermesoli T, Scattolin A, et al. Minimal residual disease assessment and risk-based therapy in acute lymphoblastic leukemia. Clin lymphoma Myeloma Leuk. 2017;17(S1):S2–9. This paper provides an overview of MRD analysis as an integral part of modern management of ALL. CrossRefGoogle Scholar
  4. 4.
    Rowe JM. Prognostic factors in adult acute lymphoblastic leukemia. Br J Haematol. 2010;150(4):380–405. Scholar
  5. 5.
    Gökbuget N, Kneba M, Raff T, 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(9):1868–76. Scholar
  6. 6.
    •• Dhédin N, Huynh A, Maury S, et al. Role of allogeneic stem cell transplantation in adult patients with Ph-negative acute lymphoblastic leukemia. Blood. 2015;125(16):2486–96. The authors reassess the role of allo-HSCT in previously GRAALL-2003 and GRAALL-2005 trials demonstrating that poor early MRD response, in contrast to conventional ALL risk factors, is an excellent tool to identify patients who may benefit from allo-HSCT in the setting of intensified adult ALL regimens. CrossRefPubMedGoogle Scholar
  7. 7.
    Bassan R, Spinelli O. Minimal residual disease monitoring in adult ALL to determine therapy. Curr Hematol Malig Rep. 2015;10(2):86–95. Scholar
  8. 8.
    Terwey TH, Hemmati PG, Nagy M, Pfeifer H, Gökbuget N, Brüggemann M, et al. Comparison of chimerism and minimal residual disease monitoring for relapse prediction after allogeneic stem cell transplantation for adult acute lymphoblastic leukemia. Biol Blood Marrow Transplant. 2014;20(10):1522–9.
  9. 9.
    Kotrova M, Trka J, Kneba M, Brüggemann M. Is next-generation sequencing the way to go for residual disease monitoring in acute lymphoblastic leukemia? Mol Diagn Ther. 2017;21(5):481–92. Scholar
  10. 10.
    Van Dongen JJM, Van der Velden VHJ, Brüggemann M, Orfao A. Minimal residual disease diagnostics in acute lymphoblastic leukemia: need for sensitive, fast, and standardized technologies. Blood. 2015;125(26):3996–4009. Scholar
  11. 11.
    Denys B, Van der Sluijs-Gelling AJ, Homburg C, et al. Improved flow cytometric detection of minimal residual disease in childhood acute lymphoblastic leukemia. Leukemia. 2012;27(3):635–41. Scholar
  12. 12.
    Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, et al. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009;11(1):54–9.
  13. 13.
    Brüggemann 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(3):1116.1123–3.
  14. 14.
    Campana D. Minimal residual disease monitoring in childhood acute lymphoblastic leukemia. Curr Opin Hematol. 2012;19(4):313–8. Scholar
  15. 15.
    • Salari F, Shahjahani M, Shahrabi S, Saki N. Minimal residual disease in acute lymphoblastic leukemia: optimal methods and clinical relevance, pitfalls and recent approaches. Medical Oncology. 2014;31(11):266. This paper provides information regarding the different methodologies and definitions of MRD. CrossRefPubMedGoogle Scholar
  16. 16.
    Rijneveld AW, Van der Holt B, Daenen SMGJ, et al. 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(11):1697–703. Scholar
  17. 17.
    Rytting ME, Thomas DA, O’Brien S, et al. Augmented Berlin-Frankfurt-Münster therapy in adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL). Cancer. 2014;120(23):3660–8. Scholar
  18. 18.
    Faderi S, Thomas DA, O’Brien S, et al. Augmented hyper-CVAD based on dose-intensified vincristine, dexamethasone, and asparginase in adult acute lymphoblastic leukemia salvage therapy. Clin Lymphoma Myeloma Leukemia. 2011;11(1):54–9. Scholar
  19. 19.
    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(4):1827–33. Scholar
  20. 20.
    Cornelissen JJ, Van der Holt B, Verhoef GE, et al. Myeloablative allogeneic versus autologous stem cell transplantation in adult patients with acute lymphoblastic leukemia in first complete remission: a prospective sibling donor versus no-donor comparison. Blood. 2009;113(6):1375–82. Scholar
  21. 21.
    Ram R, Gafter-Gvili A, Vidal L, Paul M, Ben-Bassat I, Shpilberg O, et al. Management of adult patients with acute lymphoblastic leukemia in first complete remission: systematic review and meta-analysis. Cancer. 2010;116(14):3447–57.
  22. 22.
    Hahn T, McCarthy PL, Hassebroek A, et al. Significant improvement in survival after allogeneic hematopoietic cell transplantation during a period of significantly increased use, older recipient age, and use of unrelated donors. J Clin Oncol. 2013;31(19):2437–49. Scholar
  23. 23.
    Lee S, Cho BS, Kim SY, Choi SM, Lee DG, Eom KS, et al. Allogeneic stem cell transplantation in first complete remission enhances graft-verus-leukemia effect in adults with acute lymphoblastic leukemia: antileukemic activity of chronic graft-versus-host-disease. Biol Blood Marrow Transplant. 2007;13(9):1083–94.
  24. 24.
    Nordlander A, Mattsson J, Ringden O, et al. Graft-versus-host disease is associated with a lower relapse incidence after hematopoietic stem cell transplantation in patients with acute lymphoblastic leukemia. Biol Blood Marrow Transplant. 2004;10(3):195–203. Scholar
  25. 25.
    Gustafsson-Jernberg A, Remberger M, Ringden O, et al. Graft-versus-leukemia effect in children: chronic GVHD has a significant impact on relapse and survival. Bone Marrow Transplant. 2003;31(3):175–81. Scholar
  26. 26.
    Berry DA, Zhou S, Higley H, Mukundan L, Fu S, Reaman GH, et al. Association of minimal residual disease with clinical outcome in pediatric and adult acute lymphoblastic leukemia: a meta-analysis. JAMA Oncol. 2017;3(7):e170580.
  27. 27.
    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(15):1595–604.
  28. 28.
    Bassan R, Spinelli O, Oldani E, Intermesoli T, Tosi M, Peruta B, et al. Different molecular levels of post-induction minimal residual disease may predict hematopoietic stem cell transplantation outcome in adult Philadelphia-negative acute lymphoblastic leukemia. Blood Cancer J. 2014;4(7):e225.
  29. 29.
    Pulsipher M, Langholz B, Wall D, et al. The addition of sirolimus to tacrolimus/methotrexate GVHD prophylaxis in children with ALL: a phase III COG/PBMTC trial. Blood. 2014;123(13):2017–25. Scholar
  30. 30.
    Sánchez J, Serrano J, Gómez P, et al. Clinical value of immunological monitoring of minimal residual disease in acute lymphoblastic leukemia after allogeneic transplantation. Br J Hematol. 2002;116(3):686–94. Scholar
  31. 31.
    Uzunel M, Jaksch M, Mattson J, Ringden O. Minimal residual disease detection after allogeneic stem cell transplantation is correlated to relapse in patients with acute lymphoblastic leukemia. Br J Haematol. 2003;122(5):788–94. Scholar
  32. 32.
    Patel B, Rai L, Buck G, Richards SM, Mortuza Y, Mitchell W, et al. Minimal residual disease is a significant predictor of treatment failure in non T-lineage adult acute lymphoblastic leukaemia: final results of the international trial UKALL XII/ECOG2993. Br J Haematol. 2010;148(1):80–9.
  33. 33.
    Bachanova V, Burke MJ, Yohe S, Cao Q, Sandhu K, Singleton TP, et al. Unrelated cord blood transplantation in adult and pediatric acute lymphoblastic leukemia: effect of minimal residual disease on relapse and survival. Biol Blood Marrow Transplant. 2012;18(6):963–8.
  34. 34.
    Sánchez-García J, Serrano J, Serrano-López J, et al. Quantification of minimal residual disease levels by flow cytometry at time of transplant predicts outcome after myeloablative allogeneic transplantation in ALL. Bone Marrow Transplant. 2013;48(3):396–401. Scholar
  35. 35.
    Spinelli O, Peruta B, Tosi M, Guerini V, Salvi A, Zanotti MC, et al. Clearance of minimal residual disease after allogeneic stem cell transplantation and the prediction of the clinical outcome of adult patient with high-risk acute lymphoblastic leukemia. Haematologica. 2007;92(5):612–8.
  36. 36.
    Zhao XS, Liu YR, Zhu HH, Xu LP, Liu DH, Liu KY, et al. Monitoring MRD with flow cytometry: an effective method to predict relapse for ALL patients after allogeneic hematopoietic stem cell transplantation. Ann Hematol. 2012;91(2):183–92.
  37. 37.
    Bader P, Niethammer D, Willasch A, Kreyenberg H, Klingebiel T. How and when should we monitor chimerism after allogeneic stem cell transplantation? Bone Marrow Transplant. 2005;35(2):107–19. Scholar
  38. 38.
    Brüggemann M, Raff T, Kneba M. Has MRD monitoring superseded other prognostic factors in adult ALL? Blood. 2012;120(23):4470–81. Scholar
  39. 39.
    Locatelli F, Zecca M, Rondelli R, Bonetti F, Dini G, Prete A, et al. Graft versus host disease prophylaxis with low-dose cyclosporine-A reduces the risk of relapse in children with acute leukemia given HLA-identical sibling bone marrow transplantation: results of a randomized trial. Blood. 2000;95(5):1572–9.Google Scholar
  40. 40.
    Bader P, Kreyenberg H, Hoelle W, Dueckers G, Handgretinger R, Lang P, et al. Increasing mixed chimerism is an important prognostic factor for unfavorable outcome in children with acute lymphoblastic leukemia after allogeneic stem-cell transplantation: possible role for pre-emptive immunotherapy? J Clin Oncol. 2000;22(9):1696–705.

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Christianne Bourlon
    • 1
  • Dennis Lacayo-Leñero
    • 1
  • Sergio I. Inclán-Alarcón
    • 1
  • Roberta Demichelis-Gómez
    • 1
  1. 1.Leukemia Clinic, Department of Hematology and OncologyInstituto Nacional de Ciencias Médicas y Nutrición Salvador ZubiránMexico CityMexico

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