Case-Based Review

Acute Myeloid Leukemia

2018 July/August;13(4):37-46

References

1. Dohner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N Engl J Med 2015;373:1136–52.

2. National Cancer Institute. Surveillance, Epidemiology, and End Results (SEER) Program. Cancer Stat Facts. Leukemia: Acute Myeloid Leukemia (AML). 2018;2018.

3. Dohner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 2017;129:424–47.

4. Liesveld JL, Lichtman MA. Acute myelogenous leukemia. In: Kaushansky K, Lichtman MA, Prchal JT, et al, eds. New York: Williams Hematology. 9th ed. New York: McGraw-Hill Education; 2015.

5. Randhawa JK, Khoury J, Ravandi-Kashani F. Adult acute myeloid leukemia. In: Kantarjian HM, Wolff RA, eds. The MD Anderson Manual of Medical Oncology. 3rd ed. New York: McGraw-Hill Medical; 2016.

6. Armstrong SA, Staunton JE, Silverman LB, et al. MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia. Nat Genet 2002;30:41–7.

7. Graubert TA, Mardis ER. Genomics of acute myeloid leukemia. Cancer J 2011;17:487–91.

8. Cancer Genome Atlas Research Network, Ley TJ, Miller C, Ding L, et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med 2013;368:2059–74.

9. Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med 2016;374:2209–21.

10. Lindsley RC, Mar BG, Mazzola E, et al. Acute myeloid leukemia ontogeny is defined by distinct somatic mutations. Blood 2015;125:1367–76.

11. Jaiswal S, Fontanillas P, Flannick J, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med 2014;371:2488–98.

12. Steensma DP, Bejar R, Jaiswal S, et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood 2015;126:9–16.

13. Jaiswal S, Natarajan P, Silver AJ, et al. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N Engl J Med 2017;377:111–21.

14. Genovese G, Kahler AK, Handsaker RE, et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med 2014;371:2477–87.

15. Pileri S, Ascani S, Cox M, et al. Myeloid sarcoma: clinico-pathologic, phenotypic and cytogenetic analysis of 92 adult patients. Leukemia 2007;21:340–50.

16. Vachhani P, Bose P. Isolated gastric myeloid sarcoma: a case report and review of the literature. Case Rep Hematol 2014;2014:541807.

17. Rowe JM. Clinical and laboratory features of the myeloid and lymphocytic leukemias. Am J Med Technol 1983;49:103–9.

18. Wolach O, Stone RM. Mixed-phenotype acute leukemia: current challenges in diagnosis and therapy. Curr Opin Hematol 2017;24:139–45.

19. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016;127:2391–405.

20. Assi R, Ravandi F. FLT3 inhibitors in acute myeloid leukemia: Choosing the best when the optimal does not exist. Am J Hematol 2018;93:553–63.

21. Patel JP, Gonen M, Figueroa ME, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med 2012;366:1079–89.

22. Ley TJ, Ding L, Walter MJ, et al. DNMT3A mutations in acute myeloid leukemia. N Engl J Med 2010;363:2424–33.

23. Dores GM, Devesa SS, Curtis RE, et al. Acute leukemia incidence and patient survival among children and adults in the United States, 2001-2007. Blood 2012;119:34–43.

24. 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.

25. Sorror ML, Storer BE, Elsawy M, et al. Intensive versus non-intensive induction therapy for patients (Pts) with newly diagnosed acute myeloid leukemia (AML) using two different novel prognostic models [abstract]. Blood 2016;128(22):216.

26. Quintás-Cardama A, Ravandi F, Liu-Dumlao T, et al. Epigenetic therapy is associated with similar survival compared with intensive chemotherapy in older patients with newly diagnosed acute myeloid leukemia. Blood 2012;120;4840-5.

27. Gupta N, Miller A, Gandhi Set al. Comparison of epigenetic versus standard induction chemotherapy for newly diagnosed acute myeloid leukemia patients ≥60 years old.Am J Hematol 2015;90:639-46.

28. Sorror ML, Storer BE, Fathi AT, et al. Development and validation of a novel acute myeloid leukemia-composite model to estimate risks of mortality. JAMA Oncol 2017;3:1675–82.

29. Rowe JM, Neuberg D, Friedenberg W, et al. A phase 3 study of three induction regimens and of priming with GM-CSF in older adults with acute myeloid leukemia: a trial by the Eastern Cooperative Oncology Group. Blood 2004;103:479–85.

30. Mandelli F, Vignetti M, Suciu S, et al. Daunorubicin versus mitoxantrone versus idarubicin as induction and consolidation chemotherapy for adults with acute myeloid leukemia: the EORTC and GIMEMA Groups Study AML-10. J Clin Oncol 2009;27:5397–403.

31. Gardin C, Chevret S, Pautas C, et al. Superior long-term outcome with idarubicin compared with high-dose daunorubicin in patients with acute myeloid leukemia age 50 years and older. J Clin Oncol 2013;31:321–7.

32. Fernandez HF, Sun Z, Yao X, et al. Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med 2009;361:1249–59.

33. Lee JH, Joo YD, Kim H, et al. A randomized trial comparing standard versus high-dose daunorubicin induction in patients with acute myeloid leukemia. Blood 2011;118:3832–41.

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

35. 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;125:3878–85.

36. Devillier R, Bertoli S, Prebet T, et al. Comparison of 60 or 90 mg/m(2) of daunorubicin in induction therapy for acute myeloid leukemia with intermediate or unfavorable cytogenetics. Am J Hematol 2015;90:E29–30.

37. Pautas C, Merabet F, Thomas X, et al. Randomized study of intensified anthracycline doses for induction and recombinant interleukin-2 for maintenance in patients with acute myeloid leukemia age 50 to 70 years: results of the ALFA-9801 study. J Clin Oncol 2010;28:808–14.

38. Lowenberg B. Sense and nonsense of high-dose cytarabine for acute myeloid leukemia. Blood 2013;121:26–8.

39. Lancet JE, Uy GL, Cortes JE, et al. Final results of a phase III randomized trial of CPX-351 versus 7 + 3 in older patients with newly diagnosed high risk (secondary) AML [abstract]. J Clin Oncol 2016;34(15_suppl):7000-7000.

40. Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med 2017;377:454–64.

41. Jen EY, Ko CW, Lee JE, et al. FDA approval: Gemtuzumab ozogamicin for the treatment of adults with newly-diagnosed CD33-positive acute myeloid leukemia. Clin Cancer Res 2018; doi: 10.1158/1078-0432. CCR-17-3179.

42. 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;19:3244–54.

43. 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;121:4854–60.

44. Burnett AK, Russell NH, Hills RK, et al. Addition of gemtuzumab ozogamicin to induction chemotherapy improves survival in older patients with acute myeloid leukemia. J Clin Oncol 2012;30:3924–31.

45. Castaigne S, Pautas C, Terre C, et al. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet 2012;379:1508–16.

46. 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;30:2670–7.

47. 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;126:291–9.

48. Welch JS, Petti AA, Miller CA, et al. TP53 and decitabine in acute myeloid leukemia and myelodysplastic syndromes. N Engl J Med 2016;375:2023–36.

49. Amadori S, Suciu S, Selleslag D, et al. Gemtuzumab ozogamicin versus best supportive care in older patients with newly diagnosed acute myeloid leukemia unsuitable for intensive chemotherapy: results of the randomized phase III EORTC-GIMEMA AML-19 trial. J Clin Oncol 2016;34:972–9.

50. Miyawaki S, Ohtake S, Fujisawa S, et al. A randomized comparison of 4 courses of standard-dose multiagent chemotherapy versus 3 courses of high-dose cytarabine alone in postremission therapy for acute myeloid leukemia in adults: the JALSG AML201 Study. Blood 2011;117:2366–72.

51. Schuurhuis GJ, Heuser M, Freeman S, et al. Minimal/measurable residual disease in AML: a consensus document from the European LeukemiaNet MRD Working Party. Blood 2018;131:1275–91.

52. 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.

53. Schlenk RF, Dohner K, Krauter J, et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med 2008;358:1909–18.

54. Pasquini MC, Logan B, Wu J, et al. Results of a phase III randomized, multi-center study of allogeneic stem cell transplantation after high versus reduced intensity conditioning in patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML): Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0901. Blood 2015;126:LBA–8.

55. Bose P, Vachhani P, Cortes JE. Treatment of relapsed/refractory acute myeloid leukemia. Curr Treat Options Oncol 2017;18:17,017-0456-2.

56. Burnett AK, Goldstone A, Hills RK, et al. Curability of patients with acute myeloid leukemia who did not undergo transplantation in first remission. J Clin Oncol 2013;31:1293–301.

57. 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;16:1025–36.

58. Taksin AL, Legrand O, Raffoux E, et al. High efficacy and safety profile of fractionated doses of Mylotarg as induction therapy in patients with relapsed acute myeloblastic leukemia: a prospective study of the alfa group. Leukemia 2007;21:66–71.

59. Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood 2017;130:722–31.

60. Fathi AT, DiNardo CD, Kline I, et al. Differentiation syndrome associated with enasidenib, a selective inhibitor of mutant isocitrate dehydrogenase 2: analysis of a phase 1/2 study. JAMA Oncol 2018;doi: 10.1001/jamaoncol.2017.4695.

61. Bejanyan N, Weisdorf DJ, Logan BR, et al. Survival of patients with acute myeloid leukemia relapsing after allogeneic hematopoietic cell transplantation: a center for international blood and marrow transplant research study. Biol Blood Marrow Transplant 2015;21:454–9.

62. Schroeder T, Rachlis E, Bug G, et al. Treatment of acute myeloid leukemia or myelodysplastic syndrome relapse after allogeneic stem cell transplantation with azacitidine and donor lymphocyte infusions--a retrospective multicenter analysis from the German Cooperative Transplant Study Group. Biol Blood Marrow Transplant 2015;21:653–60.

63. Davids MS, Kim HT, Bachireddy P, et al. Ipilimumab for patients with relapse after allogeneic transplantation. N Engl J Med 2016;375:143–53.

64. Marcucci G, Geyer S, Zhao W, et al. Adding KIT inhibitor dasatinib (DAS) to chemotherapy overcomes the negative impact of KIT mutation/over-expression in core binding factor (CBF) acute myeloid leukemia (AML): results from CALGB 10801 (Alliance) [abstract]. Blood 2014;124:8.

Relapsed/Refractory Disease

The treatment of relapsed and refractory AML constitutes a major challenge, with OS estimated around 10% at 3 years.⁵⁵ Currently, there is no standard salvage therapy in this setting, thus underscoring the need for clinical trials. For younger, fitter patients, the typical approach is to use intensive chemotherapy to achieve a second complete remission followed by a stem cell transplant. In younger patients, a second complete remission is achievable in about 55% of patients, although this rate is lower (~20%–30%) in more unselected patients.^56,57 About two thirds of those who achieve complete remission may be able to proceed to transplant.⁵⁷ For older patients where transplant is not possible, the goal is to use less intensive therapies that help with palliation. HMAs (azacitidine, decitabine) are used and have complete remission rates of 16% to 21% and median survival of 6 to 9 months in older patients.³ LDAC is another option in this setting. The recent approval of GO in this setting has further expanded the options. This approval was based on the outcomes of the phase 2 single-arm MyloFrance-1 study in which single-agent GO administered at 3 mg/m² on days 1, 4, and 7 led to complete remission in 15 of 57 patients.⁵⁸

With greater elucidation of the molecular characteristics of AML, the emergence of more effective targeted therapies is possible. Enasidenib, an inhibitor of mutant isocitrate dehydrogenase 2 (IDH2) protein that promotes differentiation of leukemic myeloblasts, recently received regulatory approval based on a single-arm trial. The overall response rate in this study was 38.5%, including a composite complete remission rate of 26.6% at a dose of 100 mg daily.⁵⁹ IDH differentiation syndrome, akin to the differentiation syndrome seen in acute promyelocytic leukemia, occurred in approximately 12% of the patients, with the most frequent manifestations being dyspnea, fever, pulmonary infiltrates, and hypoxia.⁶⁰

Survival of patients who relapse following transplant is particularly poor. A recent Center for International Blood and Marrow Transplant Research study found a 3-year OS ranging from a dismal 4% for those who present with early relapses (within 1 to 6 months) post-transplant to a more modest 38% for those who relapsed ≥ 3 years after their first transplant.⁶¹ The German Cooperative Transplant Study Group have suggested that azacitidine or chemotherapy followed by donor-lymphocyte infusions might improve responses over chemotherapy alone.⁶² Ipilimumab-based CTLA-4 blockade was reported to produce responses in a small cohort of patients, which was particularly notable in patients presenting with extramedullary manifestations of relapse.⁶³ In patients who are otherwise fit but have a florid relapse, a second transplant can sometimes be sought, but the value of a different donor for second transplant is unclear.³

Case 1 Conclusion

Given his relatively young age, suitability for intensive therapy, and the presence of a core- binding factor abnormality, the patient is treated with an induction regimen containing daunorubicin, cytarabine, and GO (7+3 + GO). He achieves complete remission. This is followed by consolidation chemotherapy with high-dose cytarabine and GO. Allo-SCT is reserved for later should the AML relapse. Note that dasatinib, a c-KIT inhibitor, can be added to the treatment regimens as per the results of the CALGB 10801 protocol.⁶⁴ Also, autologous SCT, instead of allo-SCT, can be considered in rare situations with relapsed core-binding factor AML (especially with inv(16) AML, younger patients, longer time in complete remission prior to relapse, and use of GO).