Acute Myeloid Leukemias: 10-Year Therapy Experience

MYELOID TUMORS ,

О.Yu. Baranova1, A.S. Antipova1, O.D. Zakharov2, N.A. Falaleeva1, G.I. Kaletin1, A.D. Shirin1, G.R. Arakelyan1, N.N. Tupitsyn1, M.A. Frenkel’1, N.A. Kupryshina1, T.N. Obukhova3, E.V. Domracheva3, V.B. Larionova1, E.V. Ogorodnikova1, E.A. Osmanov1

1 N.N. Blokhin Russian Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

2 Municipal Outpatient’s Hospital No. 11 under the Department of Healthcare of Moscow, 14 Kravchenko str., Moscow, Russian Federation, 119331

3 Hematology Research Center under the Ministry of Health of the Russian Federation, 4а Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

For correspondence: Ol’ga Yur’evna Baranova, PhD, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: +7(499)324-28-64; e-mail: baranova-crc@mail.ru

For citation: Baranova OYu, Antipova AC, Zakharov OD, et al. Acute Myeloid Leukemias: 10-Year Therapy Experience. Clinical oncohematology. 2015;8(3):287–301 (In Russ).

ABSTRACT

Objective. To assess treatment outcomes of 132 patients with acute myeloid leukemia (AML) treated in hematology department of the N.N. Blokhin Russian Cancer Research Center over the period from January, 2003, till November, 2014.

Methods. 106 patients with primary AML and 26 patients with secondary AML and AML arising from MDS were enrolled in this study. Median age was 43.5 years (varied from 15 to 82). The study design provided 1 cycle of remission induction according to the 3+7+7 scheme (idarubicin 12 mg/m2 on days 1–3, cytarabine 100 mg/m2 every 12 h on days 1–7, etoposide 75 mg/m2 on days 1–7), 2 cycles of consolidation according to the HAI scheme (cytarabine 3 g/m2 on days 1, 3, 5; idarubicin 10 mg/m2 on days 2, 4), and 6 cycles of maintenance treatment according the 1+5+5 scheme for patients younger than 60 years (cytarabine 100 mg/m2 every 12 h on days 1–5, idarubicin 15 mg/m2 on day 1, etoposide 75 mg/m2 on days 1–5). The treatment protocol for patients aged 60–65 did not include etoposide, and the cytarabine dose was reduced to 1 g/m2 at the remission consolidation stage.

Results. The analysis of treatment efficacy in 71 patients younger than 60 years with primary AML demonstrated that the percentage of complete remissions (CR) was 77.5 %. In 41 (74.5 %) patients the CR was achieved after the 1st induction cycle. The 5-year overall survival (OS) and relapse-free survival (RFS) rates were 43 % and 52 %, respectively. In the favorable cytogenetic risk group, the CR rate was 90 %, 5-year ОS and RFS were 65 % and 100 %, respectively; in the intermediate cytogenetic risk group these parameters were 90.5 %, 45 %, and 48 %, respectively. In the high risk group, CR was achieved in 36.4 % patients achieved; the resistant disease was observed in 63.6 % of cases, 2-years ОS and DFS rates were 16 % and 0 %, respectively. Among patients aged 60–65 years receiving intensified consolidation therapy, the CR rate was 61.5 %, the resistant disease was observed in 23.1 % of cases. The early mortality rate was 15.4 %, and the 3-year ОS and DFS rates were 14 % and 50 %, respectively.

Conclusion. The treatment program with intensified consolidation demonstrated high long-term survival rates in patients with primary AML younger than 60 years. The best results were obtained in the favorable cytogenetic risk group. Management of patients over 60 years of age and patients with AML in high-risk cytogenetic group is still a challenge.

Keywords: acute myeloid leukemia, high doses cytarabine.

Received: April 2, 2015

Accepted: May 31, 2015

Read in PDF (RUS)pdficon

REFERENCES

  1. Henderson E. Acute myelogenous leukemia. In: Hematology. 3rd edition. McGraw-Hill Book Company; 1983. pp. 239–53.
  2. Кассирский И.А., Алексеев Г.А. Клиническая гематология. М.: Государственное издательство медицинской литературы, 1962.
    [Kassirskii IA, Alekseev GA. Klinicheskaya gematologiya. (Clinical hematology.) Moscow: Gosudarstvennoe izdatel’stvo meditsinskoi literatury Publ.; 1962. (In Russ)]
  3. Bennet J, Catovsky D, Daniel M, et al. Proposals for the classification of the Acute Leukaemias. French-American-British (FAB) Co-operative Group. Br J Haematol. 1976;33(4):451–8. doi: 10.1111/j.1365-2141.1976.tb03563.x.
  4. Паровичникова Е.Н., Троицкая В.В., Клясова Г.А. и др. Лечение больных острыми миелоидными лейкозами по протоколу российского многоцентрового рандомизированного исследования OMЛ-01.10: результаты координационного центра. Терапевтический архив. 2014;86(7):14–23.
    [Parovichnikova EN, Troitskaya VV, Klyasova GA, et al. Treatment of patients with acute myeloid leukemias according to the protocol of Russian multicenter randomized trial AML-01.10: coordination center results. Terapevticheskii arkhiv. 2014;86(7):14–23. (In Russ)]
  5. Burnett AK, Russell NH, Hills RK, et al. A randomised comparison of daunorubicin 90mg/m2 vs 60mg/m2 in AML induction: results from the UK NCRI AML17 trial in 1206 patients. 56th ASH Annual Meeting and Exposition; 2014. Oral and Poster Abstracts.
  6. Cornelissen JJ, Versluis J, Passweg JR, et al. Comparative therapeutic value of post-remission approaches in patients with acute myeloid leukemia aged 40–60 years. Leukemia. 2015;29(5):1041–50. doi: 10.1038/leu.2014.332.
  7. Breems DA, Lowenberg B. Acute myeloid leukemia and the position of autologous stem cell transplantation. Semin Hematol. 2007;44(4):259–66. doi: 10.1053/j.seminhematol.2007.08.002.
  8. Byrd JC, Dodge RK, Carroll A, et al. Patients with t(8;21)(q22;q22) and acute myeloid leukemia have superior failure-free and overall survival when repetitive cycles of high-dose cytarabine are administered. J Clin Oncol. 1999;17(12):3767–75.
  9. Schlenk RF, Benner A, Krauter J, et al. Individual patient data-based meta-analysis of patients aged 16 to 60 years with core binding factor acute myeloid leukemia: a survey of the German Acute Myeloid Leukemia Intergroup. J Clin Oncol. 2004;22(18):3741–50. doi: 10.1200/jco.2004.03.012.
  10. Marcucci G, Mrozek K, Ruppert AS, et al. Prognostic factors and outcome of core binding factor acute myeloid leukemia patients with t(8;21) differ from those of patients with inv(16): a Cancer and Leukemia Group B study. J Clin Oncol. 2005;23(24):5705–17. doi: 10.1200/jco.2005.15.610.
  11. Bennett J, Catovsky D, Daniel M, et al. Proposed revised criteria for the classification of acute myeloid leukemia. A report of the French-American-British Group. Ann Intern Med. 1985;103(4):620–5. doi: 10.7326/0003-4819-103-4-620.
  12. Bene MC, Castoldi G, Knapp W, et al. Proposals for the immunological classification of acute leukemias. European Group for the Immunological Characterization of Leukemias (EGIL). Leukemia. 1995;9:1783–6.
  13. Brunning RD, Matutes E, Borowitz V, et al. Acute leukemias of ambiguous lineage. In: Jaffe ES, Harris NL, Stein H, Vardiman JW. World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press; 2001. pp. 106–7.
  14. Borowitz MJ, Bene MC, Harris NL, et al. Acute leukemias of ambiguous lineage. In: Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th edition. Lyon: IARC Press; 2008. pp. 150–5.
  15. Маркина И.Г. Клиническое значение иммунофенотипирования острых нелимфобластных лейкозов: Дис. ¼ канд. мед. наук. М., 2000.
    [Markina IG. Klinicheskoe znachenie immunofenotipirovaniya ostrykh nelimfoblastnykh leikozov. (Clinical significance of immunophenotyping of acute non-lymphoblastic leukaemia.) [dissertation] Moscow; 2000. (In Russ)]
  16. Баранова О.Ю., Волкова М.А., Френкель М.А. и др. Анализ результатов различных программ терапии острых нелимфобластных лейкозов М0-М2, М4-М7 ФАБ-вариантами (по данным Российского онкологического научного центра имени Н.Н. Блохина, РАМН). Гематология и трансфузиология. 2003;2:3–10.
    [Baranova OYu, Volkova MA, Frenkel’ MA, et al. Analysis of results of different therapy programs for acute non-lymphoblastic leukemias of M0-M2, M4-M7 FAB types (based on data of NN. Blokhin Russian Cancer Research Center under the Russian Academy of Medical Sciences). Gematologiya i transfuziologiya. 2003;2:3–10. (In Russ)]
  17. Herzig RH, Lazarus HM, Wolf SN, et al. High-dose cytosine arabinoside therapy with and without anthracycline antibiotics for remission reinduction of acute nonlymphoblastic leukemia. J Clin Oncol. 1985;3(7):992–7.
  18. Mayer RJ, Davis RB, Schiffer CA, et al. Intensive postremission chemotherapy in adults with acute myeloid leukemia. Cancer and Leukemia Group B. N Engl J Med. 1994;331(14):896–903. doi: 10.1056/nejm199410063311402.
  19. Bishop JF, Matthews JP, Young GA, et al. A randomized study of high-dose cytarabine in induction in acute myeloid leukemia. Blood. 1996;87:1710–7.
  20. 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):2841–51.
  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(18):4173–9.
  22. Bishop JF, Lowenthal RM, Joshua D, et al. Australian Leukemia Study Group: Etoposide in acute nonlymphocytic leukemia. Blood. 1990:75:27–32.
  23. Vogler WR, Velez-Garcia E, et al. A phase III trial comparing idarubicin and daunorubicin in combination with cytarabine in acute myelogenous leukemia: a Southeastern Cancer Study Group study. J Clin Oncol. 1992;10(7):1103–11.
  24. Arlin Z, Case DC Jr, Moore J, et al. Randomized multicenter trial of cytosine arabinoside with mitoxantrone or daunorubicin in previously untreated adult patients with acute nonlymphocytic leukemia (ANLL). Leukemia. 1990;4(3):177–83.
  25. Wheatley K, Burnett A, Goldstone A, et al. A simple, robust, validated and highly predictive index for the determination of risk-directed therapy in acute myeloid leukemia derived from the MRC AML 10 trial. Br J Haematol. 1999;107(1):69–79. doi: 10.1046/j.1365-2141.1999.01684.x.
  26. Lowenberg B, Downing JR, Burnett A. Acute myeloid leukemia. N Engl J Med. 1999;341(14):1051–62. doi: 10.1056/nejm199909303411407.
  27. Wolff SN, Marion J, Stein RS, et al. High-dose cytosine arabinoside and daunorubicin as consolidation therapy for acute nonlymphocytic leukemia in first remission: a pilot study. Blood. 1985;65(6):1407–11.
  28. Phillips GL, Reece DE, Shpherd MJ, et al. High-dose cytarabine and daunorubicin induction and postremission chemotherapy for the treatment of acute myelogenous leukemia in adults. Blood. 1991;77(7):1429–35.
  29. Савченко В.Г., Паровичникова Е.Н., Афанасьев Б.В. и др. Клинические рекомендации российских экспертов по лечению больных острыми миелоидными лейкозами в возрасте моложе 60 лет. Терапевтический архив. 2014;7:4–13.
    [Savchenko VG, Parovichnikova EN, Afanas’ev BV, et al. Clinical recommendations by Russian experts for treatment of patients younger the 60 years with acute myeloid leukemias. Terapevticheskii arkhiv. 2014;7:4–13. (In Russ)]
  30. National Comprehensive Cancer Network (NCCN) Guidelines for AML Treatment Version 2; 2014. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#aml.
  31. 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. doi: 10.1182/blood-2009-07-235358.
  32. Калетин Г.И. Оценка некоторых новых схем терапии острых лейкозов взрослых: Дис. ¼ канд. мед. наук. М., 1994.
    [Kaletin GI. Otsenka nekotorykh novykh skhem terapii ostrykh leikozov vzroslykh. (Evaluation of some new treatment regimens for acute leukemias in adults.) [dissertation] Moscow; 1994. (In Russ)]
  33. Ustun C, Marcucci G. Emerging diagnostic and therapeutic approaches in core binding factor acute myeloid leukaemia. Curr Opin Hematol. 2015;22(2):85–91. doi: 10.1097/moh.0000000000000124.
  34. 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). 56th ASH Annual Meeting and Exposition; 2014. Oral and Poster Abstracts.
  35. Flurcken A, Schneider T, Singh A, et al. Flow Cytometry-Based Maturity Score As a Novel Prognostic Parameter in AML. 56th ASH Annual Meeting and Exposition; 2014: Abstract 1006.
  36. Lowenberg B. Sense and nonsense of High-dose cytarabine for acute myeloid leukemia. Blood. 2013;121(1):26–8. doi: 10.1182/blood-2012-07-444851.
  37. Lowenberg B, Pabst T, Vellenga E, et al. Cytarabine dose for acute myeloid leukemia. N Engl J Med. 2011;364(11):1027–36. doi: 10.1056/nejmoa1010222.
  38. Schaich M, Rollig C, Soucek S, et al. Cytarabine dose of 36 g/m2 compared with 12 g/m2 within first consolidation in acute myeloid leukemia: results of patients enrolled onto the prospective randomized AML96 study. J Clin Oncol. 2011;29(19):2696–702. doi: 10.1200/jco.2010.33.7303.
  39. 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(8):2366–72. doi: 10.1182/blood-2010-07-295279.
  40. Juliusson G, Antunovic P, Derolf A, 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(18):4179–87. doi: 10.1182/blood-2008-07-172007.
  41. Lopez A, de la Rubia J, Martin G, et al. Recent improvements in outcome for elderly patients with de novo acute myeloblastic leukemia. Leuk Res. 2001;25(8):685–92. doi: 10.1016/s0145-2126(01)00006-6.
  42. Appelbaum FR, Gundacker H, Head DR. Age and acute myeloid leukemia. Blood. 2006;107(9):3481–5. doi: 10.1182/blood-2005-09-3724.
  43. Kantarjian H, O’Brien S, Cortes J, et al. Results of intensive chemotherapy in 998 patients age 65 years or older with acute myeloid leukemia or high-risk myelodysplastic syndrome: predictive prognostic models for outcome. Cancer. 2006:106(5):1090. doi: 10.1002/cncr.21723.
  44. Lowenberg B, Zittoun R, Kerkhofs H, et al. On the value of intensive remission-induction chemotherapy in elderly patients of 65+ years with acute myeloid leukemia: a randomized phase III study of the European Organization for Research and Treatment of Cancer Leukemia Group. J Clin Oncol. 1989;7(9):1268–74.
  45. 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):1114–24. doi: 10.1002/cncr.22496.