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Acute Myeloid Leukemia: How Do We Measure Success?

  • Acute Myeloid Leukemias (H Erba, Section Editor)
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Abstract

The development and approval of novel, effective therapies for acute myeloid leukemia (AML) has lagged behind other malignancies. Judging success of therapy with meaningful endpoints is critical to development of new treatments. Overall survival (OS) has typically been the parameter necessary for regulatory approval of experimental therapy in AML. Herein, we discuss different strategies to define outcomes for patients with AML and their relative challenges.

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References

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

  1. Sasine JP, Schiller GJ. Emerging strategies for high-risk and relapsed/refractory acute myeloid leukemia: novel agents and approaches currently in clinical trials. Blood Rev. 2015;29(1):1–9.

    Article  CAS  PubMed  Google Scholar 

  2. Appelbaum FR, Rosenblum D, Arceci RJ, et al. End points to establish the efficacy of new agents in the treatment of acute leukemia. Blood. 2007;109(5):1810–6.

    Article  CAS  PubMed  Google Scholar 

  3. Willemze R, Suciu S, Meloni G, et al. High-dose cytarabine in induction treatment improves the outcome of adult patients younger than age 46 years with acute myeloid leukemia: results of the EORTC-GIMEMA AML-12 trial. J Clin Oncol. 2014;32(3):219–28.

    Article  CAS  PubMed  Google Scholar 

  4. Lowenberg B, Ossenkoppele GJ, van Putten W, et al. High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med. 2009;361(13):1235–48.

    Article  PubMed  Google Scholar 

  5. Hernan MA, Hernandez-Diaz S, Robins JM. Randomized trials analyzed as observational studies. Ann Intern Med. 2013;159(8):560–2.

    PubMed  Google Scholar 

  6. Ravandi F, Ritchie EK, Sayar H, et al. Vosaroxin plus cytarabine versus placebo plus cytarabine in patients with first relapsed or refractory acute myeloid leukaemia (VALOR): a randomised, controlled, double-blind, multinational, phase 3 study. Lancet Oncol. 2015;16(9):1025–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kandoth C, Mclellan MD, Vandin F, et al. Mutational landscape and significance across 12 major cancer types. Nature. 2013;502(7471):333–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. The Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med 2013;368:2059–74.

  9. Grimwade D, Ivey A, Huntly BJ. Molecular landscape of acute myeloid leukemia in younger adults and its clinical relevance. Blood. 2016;127(1):29–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Schiller GJ. High-risk acute myelogenous leukemia: treatment today … tomorrow. Hematol Am Soc Hematol Educ Program. 2013;2013:201–8.

    Google Scholar 

  11. Andre T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004;350(23):2343–51.

    Article  CAS  PubMed  Google Scholar 

  12. Herndon TM, Demko SG, Jiang X, et al. U.S. Food and Drug Administration approval: peginterferon-alfa-2b for the adjuvant treatment of patients with melanoma. Oncologist. 2012;17(10):1323–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Estey E, Othus M, Lee SJ, Appelbaum FR, Gale RP. New drug approvals in acute myeloid leukemia: what’s the best end point? Leukemia. 2016;30(3):521–5.

    Article  CAS  PubMed  Google Scholar 

  14. Luskin MR, Lee J-W, Fernandez HF, Lazarus H, Rowe J, Tallman M et al. Results of the ECOG E1900 trial in younger adults with AML using an event free survival endpoint are concordant with results based on overall survival: potential for a surrogate endpoint to facilitate rapid approval of therapies in AML. Blood 2014;124:2599.

  15. Burnett AK, Hills RK, Hunter AE, et al. The addition of gemtuzumab ozogamicin to low-dose Ara-C improves remission rate but does not significantly prolong survival in older patients with acute myeloid leukaemia: results from the LRF AML14 and NCRI AML16 pick-a-winner comparison. Leukemia. 2013;27(1):75–81.

    Article  CAS  PubMed  Google Scholar 

  16. Kantarjian HM, Thomas XG, Dmoszynska A, et al. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol. 2012;30(21):2670–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Dombret H, Seymour JF, Butrym A, et al. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 2015;126(3):291–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Walter RB, Kantarjian HM, Huang X, et al. Effect of complete remission and responses less than complete remission on survival in acute myeloid leukemia: a combined eastern cooperative oncology group, southwest oncology group, and M. D. Anderson cancer center study. J Clin Oncol. 2010;28(10):1766–71.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Cheson BD, Bennett JM, Kopecky KJ, et al. Revised recommendations of the International working group for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. J Clin Oncol. 2003;21(24):4642–9.

    Article  PubMed  Google Scholar 

  20. Dohner H, Estey EH, Amadori S, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 2010;115(3):453–74.

    Article  PubMed  Google Scholar 

  21. Przepiorka D, Ko CW, Deisseroth A, et al. FDA approval: blinatumomab. Clin Cancer Res. 2015;21(18):4035–9.

    Article  CAS  PubMed  Google Scholar 

  22. Freireich EJ, Gehan EA, Sulman D, Boggs DR, Frei 3rd E. The effect of chemotherapy on acute leukemia in the human. J Chronic Dis. 1961;14:593–608.

    Article  CAS  PubMed  Google Scholar 

  23. Todisco E, Ciceri F, Oldani E, et al. The CIBMTR score predicts survival of AML patients undergoing allogeneic transplantation with active disease after a myeloablative or reduced intensity conditioning: a retrospective analysis of the gruppo Italiano trapianto Di midollo Osseo. Leukemia. 2013;27(10):2086–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 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(23):3730–8.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Vidriales MB, Perez-Lopez E, Pegenaute C, et al. Minimal residual disease evaluation by flow cytometry is a complementary tool to cytogenetics for treatment decisions in acute myeloid leukaemia. Leuk Res. 2016;40:1–9.

    Article  PubMed  Google Scholar 

  26. Walter RB, Buckley SA, Pagel JM, et al. Significance of minimal residual disease before myeloablative allogeneic hematopoietic cell transplantation for AML in first and second complete remission. Blood. 2013;122(10):1813–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Walter RB, Gyurkocza B, Storer BE, et al. Comparison of minimal residual disease as outcome predictor for AML patients in first complete remission undergoing myeloablative or nonmyeloablative allogeneic hematopoietic cell transplantation. Leukemia. 2015;29(1):137–44.

    Article  CAS  PubMed  Google Scholar 

  28. Grimwade D, Freeman SD. Defining minimal residual disease in acute myeloid leukemia: which platforms are ready for “prime time”? Blood. 2014;124(23):3345–55.

    Article  CAS  PubMed  Google Scholar 

  29. Al-Mawali A, Gillis D, Lewis I. The role of multiparameter flow cytometry for detection of minimal residual disease in acute myeloid leukemia. Am J Clin Pathol. 2009;131(1):16–26.

    Article  PubMed  Google Scholar 

  30. Araki D, Wood BL, Othus M, et al. Allogeneic hematopoietic cell transplantation for acute myeloid leukemia: time to move toward a minimal residual disease-based definition of complete remission? J Clin Oncol. 2016;34(4):329–36.

    Article  PubMed  Google Scholar 

  31. Zhou Y, Othus M, Araki D, et al. Pre- and post-transplant quantification of measurable (‘minimal’) residual disease via multiparameter flow cytometry in adult acute myeloid leukemia. Leukemia. 2016.

  32. Freeman SD, Virgo P, Couzens S, et al. Prognostic relevance of treatment response measured by flow cytometric residual disease detection in older patients with acute myeloid leukemia. J Clin Oncol. 2013;31(32):4123–31.

    Article  PubMed  Google Scholar 

  33. Terwijn M, van Putten WL, Kelder A, et al. High prognostic impact of flow cytometric minimal residual disease detection in acute myeloid leukemia: data from the HOVON/SAKK AML 42A study. J Clin Oncol. 2013;31(31):3889–97.

    Article  PubMed  Google Scholar 

  34. Kern W, Voskova D, Schoch C, Hiddemann W, Schnittger S, Haferlach T. Determination of relapse risk based on assessment of minimal residual disease during complete remission by multiparameter flow cytometry in unselected patients with acute myeloid leukemia. Blood. 2004;104(10):3078–85.

    Article  CAS  PubMed  Google Scholar 

  35. Venditti A, Buccisano F, Del Poeta G, et al. Level of minimal residual disease after consolidation therapy predicts outcome in acute myeloid leukemia. Blood. 2000;96(12):3948–52.

    CAS  PubMed  Google Scholar 

  36. Kohnke T, Sauter D, Ringel K, et al. Early assessment of minimal residual disease in AML by flow cytometry during aplasia identifies patients at increased risk of relapse. Leukemia. 2015;29(2):377–86.

    Article  CAS  PubMed  Google Scholar 

  37. Farrar JE, Schuback HL, Ries RE, et al. Genomic profiling of pediatric acute myeloid leukemia reveals a changing mutational landscape from disease diagnosis to relapse. Cancer Res. 2016.

  38. Bodini M, Ronchini C, Giaco L, et al. The hidden genomic landscape of acute myeloid leukemia: subclonal structure revealed by undetected mutations. Blood. 2015;125(4):600–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kim T, Yoshida K, Kim YK, et al. Clonal dynamics in a single AML case tracked for 9 years reveals the complexity of leukemia progression. Leukemia. 2016;30(2):295–302.

    CAS  PubMed  Google Scholar 

  40. Shlush LI, Zandi S, Mitchell A, et al. Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature. 2014;506(7488):328–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ploen GG, Nederby L, Guldberg P, et al. Persistence of DNMT3A mutations at long-term remission in adult patients with AML. Br J Haematol. 2014;167(4):478–86.

    Article  CAS  PubMed  Google Scholar 

  42. Wong TN, Miller CA, Klco JM, et al. Rapid expansion of preexisting nonleukemic hematopoietic clones frequently follows induction therapy for de novo AML. Blood. 2016;127(7):893–7.

    Article  CAS  PubMed  Google Scholar 

  43. Luthra R, Patel KP, Reddy NG, et al. Next-generation sequencing-based multigene mutational screening for acute myeloid leukemia using MiSeq: applicability for diagnostics and disease monitoring. Haematologica. 2014;99(3):465–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Ivey A, Hills RK, Simpson MA, et al. Assessment of minimal residual disease in standard-risk AML. N Engl J Med. 2016;374(5):422–33.

    Article  CAS  PubMed  Google Scholar 

  45. Kronke J, Schlenk RF, Jensen KO, 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;29(19):2709–16.

    Article  PubMed  Google Scholar 

  46. Klco JM, Miller CA, Griffith M, et al. Association between mutation clearance after induction therapy and outcomes in acute myeloid leukemia. Jama. 2015;314(8):811–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Mahon FX, Rea D, Guilhot J, et al. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre stop Imatinib (STIM) trial. Lancet Oncol. 2010;11(11):1029–35.

    Article  CAS  PubMed  Google Scholar 

  48. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799–807.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787–98.

    Article  CAS  PubMed  Google Scholar 

  50. Vannucchi AM, Kiladjian JJ, Griesshammer M, et al. Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med. 2015;372(5):426–35.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Lehrnbecher T, Zimmermann M, Reinhardt D, Dworzak M, Stary J, Creutzig U. Prophylactic human granulocyte colony-stimulating factor after induction therapy in pediatric acute myeloid leukemia. Blood. 2007;109(3):936–43.

    Article  CAS  PubMed  Google Scholar 

  52. Sung L, Aplenc R, Alonzo TA, Gerbing RB, Lehrnbecher T, Gamis AS. Effectiveness of supportive care measures to reduce infections in pediatric AML: a report from the children’s oncology group. Blood. 2013;121(18):3573–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Wheatley K, Goldstone AH, Littlewood T, Hunter A, Burnett AK. Randomized placebo-controlled trial of granulocyte colony stimulating factor (G-CSF) as supportive care after induction chemotherapy in adult patients with acute myeloid leukaemia: a study of the United Kingdom medical research council adult leukaemia working party. Br J Haematol. 2009;146(1):54–63.

    Article  CAS  PubMed  Google Scholar 

  54. Strauss RG, Connett JE, Gale RP, et al. A controlled trial of prophylactic granulocyte transfusions during initial induction chemotherapy for acute myelogenous leukemia. N Engl J Med. 1981;305(11):597–603.

    Article  CAS  PubMed  Google Scholar 

  55. Pagano L, Caira M, Candoni A, et al. Evaluation of the practice of antifungal prophylaxis use in patients with newly diagnosed acute myeloid leukemia: results from the SEIFEM 2010-B registry. Clin Infect Dis. 2012;55(11):1515–21.

    Article  CAS  PubMed  Google Scholar 

  56. Vehreschild JJ, Bohme A, Buchheidt D, et al. A double-blind trial on prophylactic voriconazole (VRC) or placebo during induction chemotherapy for acute myelogenous leukaemia (AML). J Infect. 2007;55(5):445–9.

    Article  PubMed  Google Scholar 

  57. Annino L, Chierichini A, Anaclerico B, et al. Prospective phase II single-center study of the safety of a single very high dose of liposomal amphotericin B for antifungal prophylaxis in patients with acute myeloid leukemia. Antimicrob Agents Chemother. 2013;57(6):2596–602.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Kern W, Behre G, Rudolf T, et al. Failure of fluconazole prophylaxis to reduce mortality or the requirement of systemic amphotericin B therapy during treatment for refractory acute myeloid leukemia: results of a prospective randomized phase III study, German AML cooperative group. Cancer. 1998;83(2):291–301.

    Article  CAS  PubMed  Google Scholar 

  59. Bergmann OJ, Mogensen SC, Ellermann-Eriksen S, Ellegaard J. Acyclovir prophylaxis and fever during remission-induction therapy of patients with acute myeloid leukemia: a randomized, double-blind, placebo-controlled trial. J Clin Oncol. 1997;15(6):2269–74.

    CAS  PubMed  Google Scholar 

  60. Glait-Santar C, Desmond R, Feng X, et al. Functional niche competition between normal hematopoietic stem and progenitor cells and myeloid leukemia cells. Stem Cells. 2015;33(12):3635–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Geyh S, Rodriguez-Paredes M, Jager P, et al. Functional inhibition of mesenchymal stromal cells in acute myeloid leukemia. Leukemia. 2016;30(3):683–91.

    Article  CAS  PubMed  Google Scholar 

  62. Cogle CR, Goldman DC, Madlambayan GJ, et al. Functional integration of acute myeloid leukemia into the vascular niche. Leukemia. 2014;28(10):1978–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Boyd AL, Campbell CJ, Hopkins CI, et al. Niche displacement of human leukemic stem cells uniquely allows their competitive replacement with healthy HSPCs. J Exp Med. 2014;211(10):1925–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Krevvata M, Silva BC, Manavalan JS, et al. Inhibition of leukemia cell engraftment and disease progression in mice by osteoblasts. Blood. 2014;124(18):2834–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Hanoun M, Zhang D, Mizoguchi T, et al. Acute myelogenous leukemia-induced sympathetic neuropathy promotes malignancy in an altered hematopoietic stem cell niche. Cell Stem Cell. 2014;15(3):365–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Bosse RC, Wasserstrom B, Meacham A, et al. Chemosensitizing AML cells by targeting bone marrow endothelial cells. Exp Hematol. 2016;44(5):363–377.e365.

    Article  CAS  PubMed  Google Scholar 

  67. Le Y, Fraineau S, Chandran P, et al. Adipogenic mesenchymal stromal cells from bone marrow and their hematopoietic supportive role: towards understanding the permissive marrow microenvironment in acute myeloid leukemia. Stem Cell Rev. 2016;12(2):235–44.

    Article  PubMed  Google Scholar 

  68. Natanson C, Kern SJ, Lurie P, Banks SM, Wolfe SM. Cell-free hemoglobin-based blood substitutes and risk of myocardial infarction and death: a meta-analysis. Jama. 2008;299(19):2304–12.

    Article  CAS  PubMed  Google Scholar 

  69. Anselmo AC, Modery-Pawlowski CL, Menegatti S, et al. Platelet-like nanoparticles: mimicking shape, flexibility, and surface biology of platelets to target vascular injuries. ACS Nano. 2014;8(11):11243–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Bertram JP, Williams CA, Robinson R, Segal SS, Flynn NT, Lavik EB. Intravenous hemostat: nanotechnology to halt bleeding. Science translational medicine. 2009;1(11):11ra22.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Gardner A, Mattiuzzi G, Faderl S, et al. Randomized comparison of cooked and noncooked diets in patients undergoing remission induction therapy for acute myeloid leukemia. J Clin Oncol. 2008;26(35):5684–8.

    Article  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. UCLA Department of Medicine, Division of Hematology and Oncology, Orthopedic Hospital Research Center/BSRB, 615 Charles E. Young Drive South, Room 545, Los Angeles, CA, 90095, USA

    Joshua P. Sasine

  2. UCLA Department of Medicine, Division of Hematology and Oncology, Aramont Foundation for Clinical/Translational Research in Human Malignancies, Room 42–121 Center for Health Sciences, David Geffen School of Medicine at UCLA, Los Angeles, 90095, CA, USA

    Gary J. Schiller

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Correspondence to Joshua P. Sasine.

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Joshua P. Sasine declares no potential conflicts of interest. Gary J. Schiller declares research support and scientific advisory board activy from Sunesis Pharmaceuticals.

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

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This article is part of the Topical Collection on Acute Myeloid Leukemias

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Sasine, J.P., Schiller, G.J. Acute Myeloid Leukemia: How Do We Measure Success?. Curr Hematol Malig Rep 11, 528–536 (2016). https://doi.org/10.1007/s11899-016-0346-x

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