Opinion statement
Assigning the correct treatment to those with acute leukemia is challenging and requires careful assessment of both the disease and the patient. Our ability to assign relapse risk to disease is evolving and incorporates cytogenetics, molecular lesions, and assessment of minimal residual disease after initial treatment. Allogeneic hematopoietic progenitor cell transplantation (alloHCPT) is one of the most efficacious treatments available to the physician. In adult acute lymphoblastic leukemia (ALL) despite the treatment risk, patients with a matched sibling who achieve CR should be referred for transplant. Prospective trials investigating the role of unrelated donors are in progress. There is little prospective evidence, but nonetheless encouraging data, to support referring older patients for alloHPCT using reduced intensity conditioning (RIC) regimens. In acute myeloid leukemia (AML), all high-risk patients and the majority of intermediate-risk patients with a matched sibling should be offered alloHPCT in CR1. In addition there is evidence that some patients previously assigned as good-risk would benefit from sibling transplant. Use of unrelated donors will expand the numbers eligible for transplant and should be considered when a matched-sibling is not available particularly in high-risk patients. Similarly to ALL, the use of RIC is allowing transplantation to be offered to those deemed too old or unfit for myeloablative conditioning. The importance of enrolling patients into suitable prospective clinical trials cannot be overstated.
Similar content being viewed by others
References and Recommended Reading
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Pui CH, Evans WE. Treatment of acute lymphoblastic leukemia. N Eng J Med. 2006;354:166–78.
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: 1827–33.
Moorman AV, Harrison CJ, Buck GA, et al. Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALL-XII/Eastern Cooperatice Oncology Group (ECOG) 2993 trial. Blood. 2007;109:3189–97.
Jones LK, Saha V. Philadelphia positive acute lymphoblastic leukemia of childhood. Br J Haematol. 2005;130:489–500.
Bassan R, Spinelli O, Oldani E, 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).
Bruggeman M, Raff T, Flohr T, et al. Clinical significance of minimal residual disease quantification in adult patients with standard risk acute lymphoblastic leukemia. Blood. 2006;107:1116–23.
Stow P, Key L, Chen X. Clinical significance of low levels of minimal residual disease at the end of remission induction therapy in childhood acute lymphoblastic leukemia. Blood. 2010;115:4657–6.
Thiebaut A, Vernant JP, Degos L, et al. Adult acute lymphocytic leukemia study testing chemotherapy and autologous and allogeneic transplantation. A follow-up report of the French protocol LALa 87. Hematol Oncol Clin North Am. 2000;14:1353–66.
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;22:4075–86.
Labar B, Suciu S, Zittoun R, et al. Allogeneic stem cell transplantation in acute lymphoblastic leukemia and non-Hodgkin’s lymphoma for patients < or = 50 years old in first complete remission: results of the EORTC ALL-3 trial. Haematologica. 2004;89:809–17.
Ram R, Gafter-Gvili A, Vidal L, et al. Management of adult patients with acute lymphoblastic leukemia in first complete remission. Cancer. 2010;116:3447–5.
Hunault M, Harousseau JL, Delain M, et al. Better outcome of adult acute lymphoblastic leukaemia afterearly genoidetical allogeneic bone marrow transplantation (BMT) than after late high-dose therapy and autologous BMT: a GOELAMS trial. Blood. 2004;104:3028–37.
Marks DI, Perez WS, He W, et al. Unrelated donor transplants in adults with Philadelphia-negative acute lymphoblastic leukemia in first complete remission. Blood 2008; 112:426–34.
Dahlke J, Kroger N, Zabelina T, et al. Comparable results in patients with acute lymphoblastic leukemia after related and unrelated stem cell transplantation. Bone Marrow Transplant. 2006;37:155–63.
Patel B, Kirkland KE, Szydlo R, et al. Favorable outcomes with alemtuzamab-conditioned unrelated donor stem cell transplantation in adults with high-risk Philadelphia chromosome-negative acute lymphoblastic leukemia in first complete remission. Haematologica. 2009;94:1399–406.
Stein A, O’Donnell M, Synder D, et al. Reduced-intensity stem cell transplantation for high-risk acute lymphoblastic leukemia. Biol Blood Marrow Transplant. 2007;13:134a.
Marks DI, Wang T, Perez WS. 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 remission. Blood 2010; 116: 366–74.
Mohty M, Labopin M, Volin L. Reduced-intensity versus conventional myeloablative conditioning allogeneic stem cell transplantation for patients with acute lymphoblastic leukemia: a retospective study from the European Group for Blood and Marrow Transplantation. Blood. 2010;116:4439–43.
Fielding AK, Richards SM, Chopra R, et al. Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood. 2007;109:944–50.
Lee S, Kim YJ, Min CK, et al. The effect of first-line imatinib interim therapy on the outcome of allogeneic stem cell transplantation in adults with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukaemia. Blood. 2005;105:3449–57.
Qureshi A, Richards S, Ajay J, et al. Outcome of thrombosis in UKALL 2003-Anticoagulation and Re-exposure to Asparaginase is feasible and safe. Blood (ASH Annual Meeting Abstracts). 2008;112:900.
Delannoy A, Delabesse E, Lheritier V, et al. Imatinib and methylprednisolone alternated with chemotherapy improve the outcome of elderly patients with Philadelphia positive acute lymphoblastic leukemia: results of the GRALL AFR09 study. Leukemia. 2006;20:1526–32.
Yanada M, Takeuchi J, Sugiura I, et al. High complete remission rate and promising outcome by combination chemotherapy for newly diagnosed BCR-ABL-positive acute lymphoblastic leukaemia: a phase II study by the Japan Adult Leukemia Study Group. J Clin Oncol. 2006;24:460–6.
de Labarthe A, Rousselot P, Hugue-Rigal F, et al. Group for Research on Adult Acute Lymphoblastic Leukemia (GRALL). Imatinib combined with induction or consolidation chemotherapy in patients with de novo Philadelphia chromosome-positive acute lymphoblastic leukaemia: results of the GRAAPH-2003 study. Blood. 2007;109:1408–13.
Pfiefer H, Wassman B, Pavlova A, et al. Kinase domain mutations of BCR-ABL frequently precede imatinib-based therapy and give rise to relapse in patients with de novo Philadelphia-positive acute lymphoblastic leukemia (Ph + ALL). Blood. 2007;110:727–34.
Jones D, Thomas D, Yin CC, et al. Kinase domain point mutations in Philadelphia chromosome-positive acute lymphoblastic leukemia emerge after therapy with BCR-ABL kinase inhibitors. Cancer. 2008;113:985–94.
Hu Y, Liu Y, Pelletier S, et al. Requirement of Src kinases Lyn, Hck and Fgr for BCR-ABL1-induced B-lymphoblastic leukemia but not chronic myeloid leukemia. Nat Genet. 2004;36:453–61.
Graham ML. Pegasparaginase: a review of clinical studies. Adv Drug Delivery Rev. 2003;55:1293–302.
Doer D, Yampolsky H, Cohen LJ, et al. Pharmacodynamics and safety of intravenous pegaspargase during remission inductionin adults aged 55 years or younger with newly diagnosed lymphoblastic leukemia. Blood. 2007;109:2744–50.
Wetzler M, Sanford BL, Kurtzberg J, et al. Effective asparagines depletion with pegylated asparaginase results in improved outcomes in adult acute lymphoblastic leukemia: Cancer and Leukemia Group B Study 9511. Blood. 2007;109:4164–7.
Hunault-Berger M, Chevallier P, Delain M, et al. Changes in antithrombin and fibrinogen levels during induction chemotherapy with L-asparaginase in adults patients with acute lymphoblastic leukemia or lymphoblastic lymphoma. Use of supportive coagulation therapy and clinical outcome: the CAPELAL study. Haematologica. 2008;93:1488–94.
Schultz KR, Bowman WP, Aledo A, et al. Improved early event-free survival in children with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukaemia: a children’s oncology group study. J Clin Oncol. 2009;27:5175–81.
Fielding AK, Richards SM, Lazarus HM, et al. Does imatinib change the outcome in Philadelphia chromosome positive acute lymphoblastic leukemia in adults? Data from the UKALLXII/ECOG2993 study. Blood. 2007;110:10a.
Thomas DA, O’Brien S, Joregensen JL, et al. Prognostic significance of CD20 expression in adults with de novo precursor B-lineage acute lymphoblastic leukemia. Blood. 2009;113:6330–7.
Bachanova V, Sandhu K, Yohe S, et al. Allogeneic hematopoietic stem cell transplantation overcomes the adverse prognostic impact of CD20 expression in acute lymphoblastic leukaemia. Blood. 2011;117:5261–3.
Dworzak MN, Schumich A, Printz D, et al. CD20 up-regulation in pediatric B-cell precursor acute lymphoblastic leukemia during induction treatment: setting the stage for anti-CD20 directed immunotherapy. Blood. 2008;112:3982–8.
Topp MS, Kufer P, Gökbuget N, 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: 2493–98.
Usvasalo A, Raty R, Knuutila S, et al. Acute lymphoblastic leukaemia in adolescents and young adults in Finland. Haematologica. 2008;93:1161–8.
Ramanujachar R, Richards S, Hann I, et al. Adolescents with acute lymphoblastic leukaemia: outcome on UK national paediatric (ALL97) and adult (UKALLXII/E2993) trials. Pediatr Blood Cancer. 2007;48:254–61.
Ribera JM, Oriol A, Sanz MA, et al. Comparison of the results of the treatment of adolescents and young adults with standard-risk acute lymphoblastic leukemia with the Programa Espanol de Tratamiento en Hematologia pediatric-based protocol ALL-96. J Clin Oncol. 2008;26:1843–9.
Huguet F, Leguay T, Raffoux E, et al. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukaemia: the GRAALL-2003 study. J Clin Oncol. 2009;27:911–8.
Grimwade D, Walker H, Oliver F, et al. The importance of diagnostic cytogenetics on outcome in AML; analysis of 1,1612 patients entered into the MRC AML 10 trial. The medical research council adult and children’s leukaemia working parties. Blood. 1998;92:2322–33.
Grimwade D, Hills RK, Moorman AV, et al. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood 2010;116:354–65.
Beghini A, Peterlongo P, Ripamonti CB, et al. C-kit mutations in core binding factor leukemias. Blood. 2000;95:726–7.
Cairoli R, Beghini A, Grillo G, et al. Prognostic impact of c-KIT mutations in core binding factor leukemias: an Italian retrospective study. Blood. 2006;107:3463–8.
Mardis ER, Ding L, Dooling DJ, et al. Recurring mutations found by sequencing an acute myeloid leukemia geneome. N Engl J Med. 2009;361(11):1058–66.
Pashka P, Schlenk RF, Gaidzik VI, et al. IDH1 and IDH2 mutations are frequent genetic alterations in acute myeloid leukemia and confer adverse prognosis in cytogenetically normal acute myeloid leukemia with NPM1 mutation without FLT3 internal tandem duplication. J Clin Oncol. 2010;28:3636–43.
Green CL, Koo KK, Hills RK, et al. Prognostic significance of CEBPA mutations in a large cohort of younger adult patients with acute myeloid leukemia: impact of double CEBPA mutations and the interaction with FLT3 and NPM1 mutations. J Clin Oncol. 2010;28:2739–47.
Grimwade D, Jovanovic JV, Hills RK, et al. Prosepective minimal residual disease monitoring to predict relapse of acute promyelocytic leukaemia and to direct pre-emptive arsenic trioxide therapy. J Clin Oncol. 2009;27:3650–8.
Corbacioglu A, Scholl C, Schlenk RF, et al. Prognostic impact of minimal residual disease in CBFB-MYH11I-postive acute myeloid leukemia. J Clin Oncol. 2010;28:3724–9.
Krönke J, Schlenk RF, Jensen K-O, et al. Monitoring of Minimal Residual Disease in NPM1-Mutated Acute Myeloid Leukemia: A Study From the German-Austrian Acute Myeloid Leukemia Study Group. J Clin Oncol 2011; May 9 Epub ahead of print. A recent study demonstrating the utility of MRD monitoring in AML with one of the most frequent genetic lesions. It is likely that MRD monitoring for risk-stratification will enter clinical practice, particularly for the large number of patients in the intermediate risk category.
Buccisano F, Maurillo L, Spagnoli A, et al. Cytogenetic and molecular diagnostic characterization combined to postconsolidation minimal residual disease assessment by flow cytometry improves risk stratification in adult acute myeloid leukemia. Blood. 2010;116:2295–302.
Koreth J, Schlenk R, Kopecky KJ, et al. Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission: systematic review and meta-analysis of prospective clinical trials. JAMA 2009; 301:2349–61.
Schlenk RF, Dohner K, Krauter J, et al. German Austrian Acute Myeloid Leukemia Study Group. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med 2008; 358:1909–18.
Cornelissen JJ, van Putten WL, Verdonck LF, et al. Results of a HOVON/SAKK donor versus no-donor analysis of myeloablative HLA-identical sibling stem cell transplantation in first remission acute myeloid leukemia in young and middle-aged adults: benefits for whom? Blood. 2007;109:3658–66.
Fernandez HF, Sun Z, Yao X, et al. Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med. 2009;361:1249–59.
Schlenk RF, Dohner K, Mack S, et al. Prospective evaluation of allogeneic hematopoietic stem-cell transplantation from matched related and matched unrelated donors in younger adults with high-risk acute myeloid leukemia: German-Austrian trial AMLHD98A. J Clin Oncol. 2010;28:4642–8.
Walter RB, Pagel JM, Gooley TA, et al. Comparison of matched unrelated and matched related donor myeloablative hematopoietic cell transplantation for adults with acute myeloid leukemia in first remission. Leukemia. 2010;24:1276–82.
Laughlin MJ, Eapen M, Rubinstein P, et al. Outcomes after transplantation of cord blood or bone marrow from unrelated donors in adults with leukemia. N Eng J Med. 2004;351:2265–75.
Rocha V, Labopin M, Sanz G, et al. Transplants of umbilical-cord blood or bone marrow from unrelated donors in adults with acute leukemia. N Eng J Med. 2004;351:2276–85.
Eapen M, Rocha V, Sanz G, et al. Effect of graft source on unrelated donor haemopoietic stem-cell transplantation in adults with acute leukaemia: a retrospective analysis. Lancet Oncol. 2010;11:653–60.
Brunstein CG, Gutman JA, Weisdorf DJ, et al. Allogeneic hematopoietic cell transplantation for hematological malignancy: relative risks and benefits of double umbilical cord. Blood. 2010;116:4693–9.
Gyurkocza, B., Storb, R., Storer, B. et al. Nonmyeloablative Allogeneic Hematopoietic Cell Transplanation in Patients With Acute Myeloid Leukemia. J Clin Oncol 2010; 28: 2859–67.
Patil S, Spencer A, Schwarer A, et al. Reduced-intensity conditioned allogeneic haeatopoietic stem cell transplantation results in durable disease-free and overall survival in patients with poor prognosis myeloid and lymphoid malignancies: eighty-month follow-up. Bone Marrow Transplant. 2010;45:1154–60.
Craddock C, Nagra S, Peniket A, et al. Factors predicting long-term survival after T-cell depleted reduced intensity allogeneic stem cell transplantation for acute myeloid leukemia. Haematologica. 2010;95:989–95.
Mohty M, de Lavallade H, Ladaique P, et al. The role of reduced intensity conditioning allogeneic stem cell transplantation in acute myeloid leukemia: a donor vs no donor comparison. Leukemia. 2005;19:916–20.
Kurosawa S, Yamaguchi T, Uchida N, et al. Comparison of allogeneic hematopoietic cell transplantation and chemotherapy in elderly patients with non-M3 acute myeloid leukemia in first complete remission. Biol Blood Marrow Transplant. 2011;17:401–11.
Ho VT, Kim HT, Aldridge J, et al. Use of Matched Unrelated Donors Comapared with Matched Related Donors is Associated with Lower Relapse and Superior Progression-Free Survival after Reduced-Intensity Conditioning Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant. 2010; {Epub ahead of print December 27th}
Brunstein CG, Fuchs EJ, Carter SL, et al. Alternative donor transplantation: results of parallel phase II trials using HLA-mismatched related bone marrow or unrelated umbilical cord grafts. Blood 2011; [Epub ahead of print April 28th}
Ringden O, Labopin M, Ehninger G, et al. Reduced intensity conditioning compared with myeloablative conditioning using unrelated donor transplants in patients withy acute myeloid leukemia. J Clin Oncol. 2009;27:4570–7.
Luger S, Ringden O, Perez WS, et al. Similar outcomes using myeloablative versus reduced intensity and non-myeloablative allogeneic transplant preparative regimens for AML or MDS: from the center for international blood and marrow transplant research. Blood. 2008;112:348.
Shimoni A, Hardan I, Shem-Tov N, et al. Allogeneic hematopoietic stem-cell transplanation in AML and MDS using myeloablative versus reduced-intensity conditioning: the role of dose intensity. Leukemia. 2006;20:322–8.
Fung HC, Stein A, Slovak M, et al. A long-term follow-up report on allogeneic stem cell transplantation for patients with primary refractory acute myelogenous leukemia: impact of cytogenetic characteristics on transplantion outcome. Biol Blood Marrow Transplant. 2003;9:766–71.
Duval M, Klein JP, He W, et al. Hematopoietic stem-cell transplantation for acute leukemia in relapse or primary induction failure. J Clin Oncol 2010; 28: 3730–8.
Breems DA, Van Putten WL, Huijens PC, et al. Prognostic index for adults patients with acute myeloid leukemia in first relapse. J Clin Oncol. 2005;23:1969–78.
Kurosawa S, Yamaguchi T, Miyawaki S, et al. Prognostic factors and outcomes of adult patients with acute myeloid leukemia after first relapse. Haematologica. 2010;95:1857–64.
Disclosure
No potential conflicts of interest relevant to this article were reported.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Sellar, R., Goldstone, A.H. & Lazarus, H.M. Redefining Transplant in Acute Leukemia. Curr. Treat. Options in Oncol. 12, 312–328 (2011). https://doi.org/10.1007/s11864-011-0166-0
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11864-011-0166-0