Modern therapy of acute myeloid leukaemia
Authors:
M. Čerňan; T. Szotkowski
Authors‘ workplace:
Hemato-onkologická klinika LF UP a FN Olomouc
Published in:
Transfuze Hematol. dnes,23, 2017, No. 1, p. 16-28.
Category:
Comprehensive Reports, Original Papers, Case Reports
Overview
Acute myeloid leukaemia is a clonal malignant disease affecting mainly elderly patients. This previously nearly always fatal disease is now curable in 35–40 % of younger patients. The basis of curative therapy has for several decades been induction chemotherapy using the protocol “7 + 3”, followed by consolidation therapy. A large proportion of patients treated with chemotherapy alone undergo relapse soon after treatment and die from disease progression. Allogeneic stem cell transplantation remains the most effective consolidation strategy for patients with intermediate and unfavourable prognosis based on cytogenetics. Cytogenetic and molecular-biology analyses show high heterogeneity of the disease. Acute myeloid leukaemia often arises from recurrent genetic changes that represent potential therapeutic targets for new drugs. Modern treatment modalities should involve molecularly targeted therapy, capable of stopping proliferation, in combination with chemotherapy and eradication of malignantly modified hematopoietic cells in the bone marrow without the need for allogeneic stem cell transplantation, analogously to the treatment of acute promyelocytic leukaemia. As the population ages, the number of patients with acute myeloid leukaemia is constantly growing and the need for new drugs is becoming urgent. A better understanding of disease biology and the development of new classes of drugs are essential prerequisites for improving patient prognosis. The article presents a review of current therapeutic strategies and new treatment modalities in the field of acute myeloid leukaemia therapy.
KEY WORDS:
acute myeloid leukaemia – induction chemotherapy – consolidation – transplantation – hypomethylating agents – FLT3 inhibitors
Sources
1. Kouchkovsky ID, Abdul-Hay M. Acute myeloid leukemia: a comprehensive review and 2016 update. Blood Cancer J 2016; 6(7): e441.
2. 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: 354–365.
3. Döhner 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): 453–474.
4. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia. Blood 2016; 127: 2391–2405.
5. NCCN Clinical practice guidelines in oncology: Acute myeloid leukemia. Version 2.2016. https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf
6. Rücker FG, Schlenk RF, Bullinger L, et al. TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome. Blood 2012; 119(9): 2114–2121.
7. Burnett A, Wetzler M, Löwenberg B. Therapeutic advances in acute myeloid leukemia. J Clin Oncol 2011; 29(5): 487–494.
8. Tawfik B, Pardee TS, Isom S, et al. Comorbidity, age, and mortality among adults treated intensively for acute myeloid leukemia (AML). J Geriatr Oncol 2016; 7(1): 24–31.
9. Sanz MA, Iacoboni G, Montesinos P, Venditti A. Emerging strategies for the treatment of older patients with acute myeloid leukemia. Ann Hematol 2016; 95(10): 1583–1593.
10. Deschler B, de Witte T, Mertelsmann R, et al. Treatment decision-making for older patients with high-risk myelodysplastic syndrome or acute myeloid leukemia: problems and approaches. Haematologica 2006; 91: 1513–1522.
11. Thol F, Schlenk RF, Heuser M, Ganser A. How I treat refractory and early relapsed acute myeloid leukemia. Blood 2015; 126: 319–327.
12. Döhner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N Engl J Med 2015; 373: 1136–1152.
13. Ossenkoppele G, Löwenberg B. How I treat the older patient with acute myeloid leukemia. Blood 2015; 125: 767–774.
14. Sekeres MA, Elson P, Kalaycio ME, et al. Time from diagnosis to treat-ment initiation predicts survival in younger, but not older, acute myeloid leukemia patients. Blood 2009; 113: 28–36.
15. Bertoli S, Bérard E, Huguet F, et al. Time from diagnosis to intensive chemotherapy initiation does not adversely impact the outcome of patients with acute myeloid leukemia. Blood 2013; 121: 2618–2626.
16. Röllig C, Ehninger G. How I treat hyperleukocytosis in acute myeloid leukemia. Blood 2015; 125: 3246–3252.
17. Manez AC, Raffoux E, Chevret S, et al. Pre-treatment with oral hydroxyurea prior to intensive chemotherapy improves early survival of patients with high hyperleukocytosis in acute myeloid leukemia. Leuk Lymphoma 2016; 57(10): 2281–2288.
18. Fernandez HF, Sun Z, Yao X, et al. Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med 2009; 361: 1249–1259.
19. Löwenberg 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): 1235–1248.
20. Burnett AK, Russell NH, Hills RK, et al. A randomized comparison of daunorubicin 90 mg/m2 vs 60 mg/m2 in AML induction: results from the UK NCRI AML17 trial in 1206 patients. Blood 2015; 125(25): 3878–3885.
21. Bloomfield CD, Lawrence D, Byrd JC, et al. Frequency of prolonged remission duration after high-dose cytarabine intensification in acute myeloid leukemia varies by cytogenetic subtype. Cancer Res 1998; 58: 4173–4179.
22. Weick JK, Kopecky KJ, Appelbaum FR, et al. A randomized investigation of high-dose versus standard-dose cytosine arabinoside with daunorubicin in patients with previously untreated acute myeloid leukemia: a Southwest Oncology Group study. Blood 1996; 88(8): 2841–2851.
23. Cornelissen JJ, Blaise D. Hematopoietic stem cell transplantation for patients with AML in first complete remission. Blood 2016; 127(1): 62–70.
24. Karas M. Akutní myeloidní leukemie u nemocných nad 60 let, možnosti její léčby a potenciální role alogenní transplantace krvetvorných buněk. Onkologie 2011; 5(2): 91–95.
25. Devine SM, Owzar K, Blum W, et al. Phase II study of allogeneic transplantation for older patients with acute myeloid leukemia in first complete remission using a reduced-intensity conditioning regimen: results from Cancer and Leukemia Group B 100103 (Alliance for Clinical Trials in Oncology). Blood and Marrow Transplant Clinical Trial Network 0502. J Clin Oncol 2015; 33(35): 4167–4175.
26. Juliusson G, Antunovic P, Derolf Å, et al. Age and acute myeloid leukemia: real world data on decision to treat and outcomes from the Swedish Acute Leukemia Registry. Blood 2009; 113: 4179–4187.
27. Ossenkoppele GJ, Janssen JJ, Loosdrecht AA. Risk factors for relapse after allogeneic transplantation in acute myeloid leukemia. Haematologica 2016; 101(1): 20–25.
28. Armistead PM, de Lima M, Pierce S, et al. Quantifying the survival benefit for allogeneic stem cell transplantation in relapsed acute myeloid leukemia. Biol Blood Marrow Transplant 2009; 15(11): 1431–1438.
29. Ferrara F, Morabito F, Latagliata R, et al. Aggressive salvage treat-ment is not appropriate for the majority of elderly patients with acute myeloid leukemia relapsed from first complete remission. Haematologica 2001; 86(8): 814–820.
30. Burnett AK, Milligan D, Prentice AG, et al. A comparison of low-dose cytarabine and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment. Cancer 2007; 109(6): 1114–1124.
31. Heiblig M, Elhamri M, Tigaud I, et al. Treatment with low-dose cytarabine in elderly patients (age 70 years or older) with acute myeloid leukemia: A single institution experience. Mediterr J Hematol Infect Dis 2016; 8(1): e2016009.
32. 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): 291–299.
33. Fenaux P, Mufti GJ, Hellström-Lindberg E. Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol 2010; 28(4): 562–569.
34. SÚKL: Vidaza 25mg/ml. Souhrn údajů o přípravku; www.sukl.cz.
35. Petti MC, Tafuri A, Latagliata R, et al. High-dose hydroxyurea in the treatment of poor-risk myeloid leukemias. Ann Hematol 2003; 82(8): 476–480.
36. The Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med 2013; 368: 2059–2074.
37. Saultz JN, Garzon R. Acute myeloid leukemia: A concise review. J Clin Med 2016; 5: 33.
38. Shafer D, Grant S. Update on rational targeted therapy in AML. Blood Rev 2016; 30(4): 275–283.
39. Wander SA, Levis MJ, Fathi AT. The evolving role of FLT3 inhibitors in acute myeloid leukemia: quizartinib and beyond.Ther Adv Hematol 2014; 5(3): 65–77.
40. Žák P, Ráčil Z, Zavřelová A. Význam clofarabinu v léčbě akutních myeloidních leukemií. Farmakoterapie 2009; 3: 264–268.
41. Racil Z, Toskova M, Dvorakova D, et al. Treatment of molecular relapse in patients with acute myeloid leukemia using clofarabine monotherapy. Am J Hematol 2012; 87(2): 211–213.
42. Holowiecki J, Grosicki S, Robak T, et al. Addition of cladribine to daunorubicin and cytarabine increases complete remission rate after a single course of induction treatment in acute myeloid leukemia. Multicenter, phase III study. Leukemia 2004; 18: 989-997.
43. Cortes JE, Goldberg SL, Feldman EJ, et al. Phase II, multicenter, randomized trial of CPX-351 (cytarabine:daunorubicin) liposome injection versus intensive salvage therapy in adults with first relapse AML. Cancer 2015; 121(2): 234–242.
44. 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): 1025–1036.
45. Nieto M, Demolis P, Béhanzin E, et al. The European Medicines Agency review of decitabine (Dacogen) for the treatment of adult patients with acute myeloid leukemia: Summary of the scientific assessment of the committee for medicinal products for human use. Oncologist 2016; (6): 692–700.
46. SÚKL: Dacogen 50mg. Souhrn údajů o přípravku; www.sukl.cz.
47. Sievers EL, Larson RA, Stadtmauer EA, et al. Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse. J Clin Oncol 2001; 19(13): 3244–3254.
48. Petersdorf SH, Kopecky KJ, Slovak M, et al. A phase 3 study of gemtuzumab ozogamicin during induction and postconsolidation therapy in younger patients with acute myeloid leukemia. Blood 2013; 121(24): 4854–4860.
49. Rowe JM, Löwenberg B. Gemtuzumab ozogamicin in acute myeloid leukemia: a remarkable saga about an active drug. Blood 2013; 121: 4838–4841.
50. Erba HP, Levy MY, Vasu S, et al. A phase 1b study of vadastuximab talirine in combination with 7+3 induction therapy for patients with newly diagnosed acute myeloid leukemia (AML). Blood 2016; 128(22): 211.
51. Bixby DL, Stein AS, Fathi AT, et al. Vadastuximab talirine monotherapy in older patients with treatment naive CD33-positive acute myeloid leukemia (AML). Blood 2016; 128(22): 590.
52. Fathi AT, Erba HP, Lancet JE, et al. Vadastuximab talirine plus hypomethylating agents: A well-tolerated regimen with high remission rate in frontline older patients with acute myeloid leukemia (AML). Blood 2016; 128(22): 591.
53. Gazdová J, Dvořáková D, Ježíšková I, Rázga F, Jurček T, Mayer J. Úloha FLT3 mutací v patogenezi akutní myeloidní leukemie. Transfuze Hematol Dnes 2009; 4: 229–236.
54. Stone RM, Mandrekar S, Sanford BL, et al. The multi-kinase inhibitor midostaurin (M) prolongs survival compared with placebo (P) in combination with daunorubicin (D)/cytarabine (C) induction (ind), high-dose C consolidation (consol), and as maintenance (maint) therapy in newly diagnosed acute myeloid leukemia (AML) patients (pts) age 18-60 with FLT3 mutations (muts): An international prospective randomized (rand) P-controlled double-blind trial (CALGB 10603/RATIFY [Alliance]). Blood 2015; 126: 6.
55. Man ChH, Fung TK, Ho Ch, et al. Sorafenib treatment of FLT3-ITD+ acute myeloid leukemia: favorable initial outcome and mechanisms of subsequent nonresponsiveness associated with the emergence of a D835 mutation. Blood 2012; 119: 5133–5143.
56. Röllig C, Serve H, Hüttmann A, et al. Addition of sorafenib versus placebo to standard therapy in patients aged 60 years or younger with newly diagnosed acute myeloid leukaemia (SORAML): a multicentre, phase 2, randomised controlled trial. Lancet Oncol 2015; 16(16): 1691–1699.
57. Sandmaier BM, Khaled SK, Oran B, et al. Results of a phase 1 study of quizartinib (AC220) as maintenance therapy in subjects with acute myeloid leukemia in remission following allogeneic hematopoietic cell transplantation. Blood 2014; 124: 428.
58. Cortes JE, Tallman MS, Schiller G, et al. Results of a phase 2 randomized, open-label, study of lower doses of quizartinib (AC220; ASP2689) in subjects with FLT3-ITD positive relapsed or refractory acute myeloid leukemia (AML). Blood 2013; 122: 494.
59. Stein EM, Tallman MS. Emerging therapeutic drugs for AML. Blood 2016; 127: 71–78.
60. Stein EM, Di Nardo C, Altman JK, et al. Safety and efficacy of AG-221, a potent inhibitor of mutant IDH2 that promotes differentiation of myeloid cells in patients with advanced hematologic malignancies: results of a phase 1/2 trial. Blood 2015; 126: 323.
61. Alvarez RH, Kantarjian H, Garcia-Manero G, et al. Farnesyl transferase inhibitor (tipifarnib, Zarnestra; Z) in combination with standard chemotherapy with idarubicin (Ida) and cytarabine (ara-C) for patients (pts) with newly diagnosed acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS). Blood 2006; 108: 565a–566a.
62. Harousseau JL, Martinelli G, Jedrzejczak WW, et al. A randomized phase 3 study of tipifarnib compared with best supportive care, including hydroxyurea, in the treatment of newly diagnosed acute myeloid leukemia in patients 70 years or older. Blood 2009; 114: 1166–1173.
63. Döhner H, Lübbert M, Fiedler W, et al. Randomized, phase 2 trial of low-dose cytarabine with or without volasertib in AML patients not suitable for induction therapy. Blood 2014; 124: 1426–1433.
64. Kantarjian HM, Martinelli G, Jabbour EJ, et al. Stage I of a phase 2 study assessing the efficacy, safety, and tolerability of barasertib (AZD1152) versus low-dose cytosine arabinoside in elderly patients with acute myeloid leukemia. Cancer 2013; 119: 2611–2619.
65. Garcia-Manero G, Atallah E, Khaled SK, et al. Phase 2 study of pracinostat and azacitidine in elderly patients with acute myeloid leukemia (AML) not eligible for induction chemotherapy: response and long-term survival benefit. Blood 2016; 128(22): 100A.
66. Garcia-Manero G, Atallah E, Khaled SK, et al. Final results from a phase 2 study of pracinostat in combination with azacitidine in elderly patients with acute myeloid leukemia (AML). Blood 2015; 126: 453.
Labels
Haematology Internal medicine Clinical oncologyArticle was published in
Transfusion and Haematology Today
2017 Issue 1
Most read in this issue
- Autoimmune haemolytic anaemia – diagnosis and treatment, including erythrocyte transfusions
- Modern therapy of acute myeloid leukaemia
- Experience with ruxolitinib in the treatment of myelofibrosis and polycythaemia vera at Czech haematological institutions
- Prevention and therapy of venous thromboembolism in cancer patients