Skip to content
My WebMD Sign In, Sign Up

Cancer Health Center

Font Size

Adult Acute Myeloid Leukemia Treatment (PDQ®): Treatment - Health Professional Information [NCI] - Classification of Adult Acute Myeloid Leukemia


No unique chromosomal abnormalities are associated with myeloid sarcoma.[57,79] AML with maturation and t(8; 21)(q22; q22) and AMML Eo with in (16)(p13; q22) or t(16;16)(p13; q22) may be observed and monoblastic sarcoma may be associated with translocations involving 11q23.[57] The presence of myeloid sarcoma in patients with the otherwise good-risk t(8; 21) AML may be associated with a lower complete remission rate and decreased remission duration.[80] Myeloid sarcoma occurring in the setting of MDS or MPD is equivalent to blast transformation. In the case of AML, the prognosis is that of the underlying leukemia.[57] Although the initial presentation of myeloid sarcoma may appear to be isolated, several reports indicate that isolated myeloid sarcoma is a partial manifestation of a systemic disease and should be treated with intensive chemotherapy.[79,81,82]

Acute Leukemias of Ambiguous Lineage

Acute leukemias of ambiguous lineage (also known as acute leukemias of undetermined lineage, mixed phenotype acute leukemias, mixed lineage acute leukemias, and hybrid acute leukemias) are types of acute leukemia in which the morphologic, cytochemical, and immunophenotypic features of the blast population do not allow classification in myeloid or lymphoid categories; or the types have morphologic and/or immunophenotypic features of both myeloid and lymphoid cells or both B and T lineages (i.e., acute bilineal leukemia and acute biphenotypic leukemia).[83,84,85,86,87] These rare leukemias account for less than 4% of all cases of acute leukemia and occur in all age groups but are more frequent in adults.[83] Clinical features include symptoms and complications caused by cytopenias, i.e., fatigue, infections, and bleeding disorders. (Refer to the PDQ summary on Fatigue for more information.)

Morphologic and immunophenotypic features of these acute leukemias include the following:[83,84,86,87]

  • Undifferentiated acute leukemia in which the leukemic cells lack any differentiating characteristics and lack markers for a given lineage.
  • Bilineal acute leukemia in which a dual population of blasts exhibits morphologic features and markers of two distinct lineages, i.e., myeloid and lymphoid or B and T.
  • Biphenotypic acute leukemia in which the blasts exhibit the morphological features of only one lineage but express markers of more than one lineage.

The differential diagnosis includes myeloid antigen-positive ALL or lymphoid-positive AML (from which biphenotypic acute leukemia should be distinguished) and minimally differentiated AML (from which undifferentiated acute leukemia must be distinguished).

Cytogenetic abnormalities are observed in a high percentage of bilineal and biphenotypic leukemias.[84,85,88,89] Approximately 33% of cases have the Philadelphia chromosome, and some cases are associated with t(4; 11)(q21; q23) or other 11q23 abnormalities. In general, the prognosis appears to be unfavorable, particularly in adults; the occurrence of the translocation t(4; 11) or the Philadelphia chromosome are especially unfavorable prognostic indicators.[83,85,90]


  1. Brunning RD, Matutes E, Harris NL, et al.: Acute myeloid leukaemia: introduction. In: Jaffe ES, Harris NL, Stein H, et al., eds.: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press, 2001. World Health Organization Classification of Tumours, 3, pp 77-80.
  2. Bennett JM, Catovsky D, Daniel MT, et al.: Proposed revised criteria for the classification of acute myeloid leukemia. A report of the French-American-British Cooperative Group. Ann Intern Med 103 (4): 620-5, 1985.
  3. Cheson BD, Cassileth PA, Head DR, et al.: Report of the National Cancer Institute-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia. J Clin Oncol 8 (5): 813-9, 1990.
  4. Brunning RD, Matute E, Harris NL, et al.: Acute myeloid leukemia with multilineage dysplasia. In: Jaffe ES, Harris NL, Stein H, et al., eds.: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press, 2001. World Health Organization Classification of Tumours, 3, pp 88-9.
  5. Steensma DP, Tefferi A: The myelodysplastic syndrome(s): a perspective and review highlighting current controversies. Leuk Res 27 (2): 95-120, 2003.
  6. Huh YO, Jilani I, Estey E, et al.: More cell death in refractory anemia with excess blasts in transformation than in acute myeloid leukemia. Leukemia 16 (11): 2249-52, 2002.
  7. Greenberg P, Anderson J, de Witte T, et al.: Problematic WHO reclassification of myelodysplastic syndromes. Members of the International MDS Study Group. J Clin Oncol 18 (19): 3447-52, 2000.
  8. Estey E, Thall P, Beran M, et al.: Effect of diagnosis (refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, or acute myeloid leukemia [AML]) on outcome of AML-type chemotherapy. Blood 90 (8): 2969-77, 1997.
  9. Strupp C, Gattermann N, Giagounidis A, et al.: Refractory anemia with excess of blasts in transformation: analysis of reclassification according to the WHO proposals. Leuk Res 27 (5): 397-404, 2003.
  10. Valk PJ, Verhaak RG, Beijen MA, et al.: Prognostically useful gene-expression profiles in acute myeloid leukemia. N Engl J Med 350 (16): 1617-28, 2004.
  11. Haferlach T, Kohlmann A, Schnittger S, et al.: Global approach to the diagnosis of leukemia using gene expression profiling. Blood 106 (4): 1189-98, 2005.
  12. Verhaak RG, Wouters BJ, Erpelinck CA, et al.: Prediction of molecular subtypes in acute myeloid leukemia based on gene expression profiling. Haematologica 94 (1): 131-4, 2009.
  13. Brunning RD, Matutes E, Flandrin G, et al.: Acute myeloid leukaemia with recurrent genetic abnormalities. In: Jaffe ES, Harris NL, Stein H, et al., eds.: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press, 2001. World Health Organization Classification of Tumours, 3, pp 81-7.
  14. Caligiuri MA, Strout MP, Gilliland DG: Molecular biology of acute myeloid leukemia. Semin Oncol 24 (1): 32-44, 1997.
  15. Downing JR: The AML1-ETO chimaeric transcription factor in acute myeloid leukaemia: biology and clinical significance. Br J Haematol 106 (2): 296-308, 1999.
  16. 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 58 (18): 4173-9, 1998.
  17. Byrd JC, Mrózek K, Dodge RK, et al.: Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood 100 (13): 4325-36, 2002.
  18. Palmieri S, Sebastio L, Mele G, et al.: High-dose cytarabine as consolidation treatment for patients with acute myeloid leukemia with t(8;21). Leuk Res 26 (6): 539-43, 2002.
  19. Grimwade D, Walker H, Oliver F, et al.: The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children's Leukaemia Working Parties. Blood 92 (7): 2322-33, 1998.
  20. Baer MR, Stewart CC, Lawrence D, et al.: Expression of the neural cell adhesion molecule CD56 is associated with short remission duration and survival in acute myeloid leukemia with t(8;21)(q22;q22). Blood 90 (4): 1643-8, 1997.
  21. Raspadori D, Damiani D, Lenoci M, et al.: CD56 antigenic expression in acute myeloid leukemia identifies patients with poor clinical prognosis. Leukemia 15 (8): 1161-4, 2001.
  22. Marlton P, Keating M, Kantarjian H, et al.: Cytogenetic and clinical correlates in AML patients with abnormalities of chromosome 16. Leukemia 9 (6): 965-71, 1995.
  23. Poirel H, Radford-Weiss I, Rack K, et al.: Detection of the chromosome 16 CBF beta-MYH11 fusion transcript in myelomonocytic leukemias. Blood 85 (5): 1313-22, 1995.
  24. Kwaan HC, Wang J, Boggio LN: Abnormalities in hemostasis in acute promyelocytic leukemia. Hematol Oncol 20 (1): 33-41, 2002.
  25. Barbui T, Falanga A: Disseminated intravascular coagulation in acute leukemia. Semin Thromb Hemost 27 (6): 593-604, 2001.
  26. de Thé H, Chomienne C, Lanotte M, et al.: The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor alpha gene to a novel transcribed locus. Nature 347 (6293): 558-61, 1990.
  27. Melnick A, Licht JD: Deconstructing a disease: RARalpha, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia. Blood 93 (10): 3167-215, 1999.
  28. Lo Coco F, Diverio D, Falini B, et al.: Genetic diagnosis and molecular monitoring in the management of acute promyelocytic leukemia. Blood 94 (1): 12-22, 1999.
  29. Zaccaria A, Valenti A, Toschi M, et al.: Cryptic translocation of PML/RARA on 17q. A rare event in acute promyelocytic leukemia. Cancer Genet Cytogenet 138 (2): 169-73, 2002.
  30. Castaigne S, Chomienne C, Daniel MT, et al.: All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia. I. Clinical results. Blood 76 (9): 1704-9, 1990.
  31. Tallman MS, Andersen JW, Schiffer CA, et al.: All-trans-retinoic acid in acute promyelocytic leukemia. N Engl J Med 337 (15): 1021-8, 1997.
  32. Tallman MS, Andersen JW, Schiffer CA, et al.: All-trans retinoic acid in acute promyelocytic leukemia: long-term outcome and prognostic factor analysis from the North American Intergroup protocol. Blood 100 (13): 4298-302, 2002.
  33. Fenaux P, Chastang C, Chevret S, et al.: A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia. The European APL Group. Blood 94 (4): 1192-200, 1999.
  34. Jansen JH, Löwenberg B: Acute promyelocytic leukemia with a PLZF-RARalpha fusion protein. Semin Hematol 38 (1): 37-41, 2001.
  35. Giugliano E, Rege-Cambrin G, Scaravaglio P, et al.: Two new translocations involving the 11q23 region map outside the MLL locus in myeloid leukemias. Haematologica 87 (10): 1014-20, 2002.
  36. König M, Reichel M, Marschalek R, et al.: A highly specific and sensitive fluorescence in situ hybridization assay for the detection of t(4;11)(q21;q23) and concurrent submicroscopic deletions in acute leukaemias. Br J Haematol 116 (4): 758-64, 2002.
  37. Kim HJ, Cho HI, Kim EC, et al.: A study on 289 consecutive Korean patients with acute leukaemias revealed fluorescence in situ hybridization detects the MLL translocation without cytogenetic evidence both initially and during follow-up. Br J Haematol 119 (4): 930-9, 2002.
  38. Gilliland DG, Griffin JD: The roles of FLT3 in hematopoiesis and leukemia. Blood 100 (5): 1532-42, 2002.
  39. Levis M, Small D: FLT3: ITDoes matter in leukemia. Leukemia 17 (9): 1738-52, 2003.
  40. Kottaridis PD, Gale RE, Frew ME, et al.: The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood 98 (6): 1752-9, 2001.
  41. Yanada M, Matsuo K, Suzuki T, et al.: Prognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations for acute myeloid leukemia: a meta-analysis. Leukemia 19 (8): 1345-9, 2005.
  42. Wang L, Lin D, Zhang X, et al.: Analysis of FLT3 internal tandem duplication and D835 mutations in Chinese acute leukemia patients. Leuk Res 29 (12): 1393-8, 2005.
  43. Schlenk RF, Döhner K, Krauter J, et al.: Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med 358 (18): 1909-18, 2008.
  44. Gahn B, Haase D, Unterhalt M, et al.: De novo AML with dysplastic hematopoiesis: cytogenetic and prognostic significance. Leukemia 10 (6): 946-51, 1996.
  45. Head DR: Revised classification of acute myeloid leukemia. Leukemia 10 (11): 1826-31, 1996.
  46. Leith CP, Kopecky KJ, Chen IM, et al.: Frequency and clinical significance of the expression of the multidrug resistance proteins MDR1/P-glycoprotein, MRP1, and LRP in acute myeloid leukemia: a Southwest Oncology Group Study. Blood 94 (3): 1086-99, 1999.
  47. Leith CP, Kopecky KJ, Godwin J, et al.: Acute myeloid leukemia in the elderly: assessment of multidrug resistance (MDR1) and cytogenetics distinguishes biologic subgroups with remarkably distinct responses to standard chemotherapy. A Southwest Oncology Group study. Blood 89 (9): 3323-9, 1997.
  48. Mrózek K, Heinonen K, de la Chapelle A, et al.: Clinical significance of cytogenetics in acute myeloid leukemia. Semin Oncol 24 (1): 17-31, 1997.
  49. Brunning RD, Matutes E, Flandrin G, et al.: Acute myeloid leukaemias and myelodysplastic syndromes, therapy related. In: Jaffe ES, Harris NL, Stein H, et al., eds.: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press, 2001. World Health Organization Classification of Tumours, 3, pp 89-91.
  50. Smith SM, Le Beau MM, Huo D, et al.: Clinical-cytogenetic associations in 306 patients with therapy-related myelodysplasia and myeloid leukemia: the University of Chicago series. Blood 102 (1): 43-52, 2003.
  51. Ellis M, Ravid M, Lishner M: A comparative analysis of alkylating agent and epipodophyllotoxin-related leukemias. Leuk Lymphoma 11 (1-2): 9-13, 1993.
  52. Olney HJ, Mitelman F, Johansson B, et al.: Unique balanced chromosome abnormalities in treatment-related myelodysplastic syndromes and acute myeloid leukemia: report from an international workshop. Genes Chromosomes Cancer 33 (4): 413-23, 2002.
  53. Mauritzson N, Albin M, Rylander L, et al.: Pooled analysis of clinical and cytogenetic features in treatment-related and de novo adult acute myeloid leukemia and myelodysplastic syndromes based on a consecutive series of 761 patients analyzed 1976-1993 and on 5098 unselected cases reported in the literature 1974-2001. Leukemia 16 (12): 2366-78, 2002.
  54. Pedersen-Bjergaard J, Andersen MK, Christiansen DH, et al.: Genetic pathways in therapy-related myelodysplasia and acute myeloid leukemia. Blood 99 (6): 1909-12, 2002.
  55. Leone G, Voso MT, Sica S, et al.: Therapy related leukemias: susceptibility, prevention and treatment. Leuk Lymphoma 41 (3-4): 255-76, 2001.
  56. Bloomfield CD, Archer KJ, Mrózek K, et al.: 11q23 balanced chromosome aberrations in treatment-related myelodysplastic syndromes and acute leukemia: report from an international workshop. Genes Chromosomes Cancer 33 (4): 362-78, 2002.
  57. Brunning RD, Matutes E, Flandrin G, et al.: Acute myeloid leukaemia not otherwise categorised. In: Jaffe ES, Harris NL, Stein H, et al., eds.: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press, 2001. World Health Organization Classification of Tumours, 3, pp 91-105.
  58. Venditti A, Del Poeta G, Stasi R, et al.: Minimally differentiated acute myeloid leukaemia (AML-M0): cytochemical, immunophenotypic and cytogenetic analysis of 19 cases. Br J Haematol 88 (4): 784-93, 1994.
  59. Roumier C, Eclache V, Imbert M, et al.: M0 AML, clinical and biologic features of the disease, including AML1 gene mutations: a report of 59 cases by the Groupe Français d'Hématologie Cellulaire (GFHC) and the Groupe Français de Cytogénétique Hématologique (GFCH). Blood 101 (4): 1277-83, 2003.
  60. Béné MC, Bernier M, Casasnovas RO, et al.: Acute myeloid leukaemia M0: haematological, immunophenotypic and cytogenetic characteristics and their prognostic significance: an analysis in 241 patients. Br J Haematol 113 (3): 737-45, 2001.
  61. Abu-Duhier FM, Goodeve AC, Wilson GA, et al.: FLT3 internal tandem duplication mutations in adult acute myeloid leukaemia define a high-risk group. Br J Haematol 111 (1): 190-5, 2000.
  62. Alsabeh R, Brynes RK, Slovak ML, et al.: Acute myeloid leukemia with t(6;9) (p23;q34): association with myelodysplasia, basophilia, and initial CD34 negative immunophenotype. Am J Clin Pathol 107 (4): 430-7, 1997.
  63. Stanley M, McKenna RW, Ellinger G, et al.: Classification of 358 cases of acute myeloid leukemia by FAB criteria: analysis of clinical and morphologic features. In: Bloomfield CD, ed.: Chronic and Acute Leukemias in Adults. Boston, Ma: Martinus Nijhoff Publishers, 1985, pp 147-74.
  64. Haferlach T, Schoch C, Schnittger S, et al.: Distinct genetic patterns can be identified in acute monoblastic and acute monocytic leukaemia (FAB AML M5a and M5b): a study of 124 patients. Br J Haematol 118 (2): 426-31, 2002.
  65. Panagopoulos I, Isaksson M, Lindvall C, et al.: Genomic characterization of MOZ/CBP and CBP/MOZ chimeras in acute myeloid leukemia suggests the involvement of a damage-repair mechanism in the origin of the t(8;16)(p11;p13). Genes Chromosomes Cancer 36 (1): 90-8, 2003.
  66. Fenaux P, Vanhaesbroucke C, Estienne MH, et al.: Acute monocytic leukaemia in adults: treatment and prognosis in 99 cases. Br J Haematol 75 (1): 41-8, 1990.
  67. Cigudosa JC, Odero MD, Calasanz MJ, et al.: De novo erythroleukemia chromosome features include multiple rearrangements, with special involvement of chromosomes 11 and 19. Genes Chromosomes Cancer 36 (4): 406-12, 2003.
  68. Domingo-Claros A, Larriba I, Rozman M, et al.: Acute erythroid neoplastic proliferations. A biological study based on 62 patients. Haematologica 87 (2): 148-53, 2002.
  69. Olopade OI, Thangavelu M, Larson RA, et al.: Clinical, morphologic, and cytogenetic characteristics of 26 patients with acute erythroblastic leukemia. Blood 80 (11): 2873-82, 1992.
  70. Bernstein J, Dastugue N, Haas OA, et al.: Nineteen cases of the t(1;22)(p13;q13) acute megakaryblastic leukaemia of infants/children and a review of 39 cases: report from a t(1;22) study group. Leukemia 14 (1): 216-8, 2000.
  71. Nichols CR, Roth BJ, Heerema N, et al.: Hematologic neoplasia associated with primary mediastinal germ-cell tumors. N Engl J Med 322 (20): 1425-9, 1990.
  72. Carroll A, Civin C, Schneider N, et al.: The t(1;22) (p13;q13) is nonrandom and restricted to infants with acute megakaryoblastic leukemia: a Pediatric Oncology Group Study. Blood 78 (3): 748-52, 1991.
  73. Dastugue N, Lafage-Pochitaloff M, Pagès MP, et al.: Cytogenetic profile of childhood and adult megakaryoblastic leukemia (M7): a study of the Groupe Français de Cytogénétique Hématologique (GFCH). Blood 100 (2): 618-26, 2002.
  74. Pagano L, Pulsoni A, Vignetti M, et al.: Acute megakaryoblastic leukemia: experience of GIMEMA trials. Leukemia 16 (9): 1622-6, 2002.
  75. Athale UH, Razzouk BI, Raimondi SC, et al.: Biology and outcome of childhood acute megakaryoblastic leukemia: a single institution's experience. Blood 97 (12): 3727-32, 2001.
  76. Zipursky A, Brown EJ, Christensen H, et al.: Transient myeloproliferative disorder (transient leukemia) and hematologic manifestations of Down syndrome. Clin Lab Med 19 (1): 157-67, vii, 1999.
  77. Zipursky A, Thorner P, De Harven E, et al.: Myelodysplasia and acute megakaryoblastic leukemia in Down's syndrome. Leuk Res 18 (3): 163-71, 1994.
  78. Kounami S, Aoyagi N, Tsuno H, et al.: Additional chromosome abnormalities in transient abnormal myelopoiesis in Down's syndrome patients. Acta Haematol 98 (2): 109-12, 1997.
  79. Yamauchi K, Yasuda M: Comparison in treatments of nonleukemic granulocytic sarcoma: report of two cases and a review of 72 cases in the literature. Cancer 94 (6): 1739-46, 2002.
  80. Byrd JC, Weiss RB, Arthur DC, et al.: Extramedullary leukemia adversely affects hematologic complete remission rate and overall survival in patients with t(8;21)(q22;q22): results from Cancer and Leukemia Group B 8461. J Clin Oncol 15 (2): 466-75, 1997.
  81. Hayashi T, Kimura M, Satoh S, et al.: Early detection of AML1/MTG8 fusion mRNA by RT-PCR in the bone marrow cells from a patient with isolated granulocytic sarcoma. Leukemia 12 (9): 1501-3, 1998.
  82. Imrie KR, Kovacs MJ, Selby D, et al.: Isolated chloroma: the effect of early antileukemic therapy. Ann Intern Med 123 (5): 351-3, 1995.
  83. Brunning RD, Matutes E, Borowitz M: Acute leukaemias of ambiguous lineage. In: Jaffe ES, Harris NL, Stein H, et al., eds.: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press, 2001. World Health Organization Classification of Tumours, 3, pp 106-7.
  84. Hanson CA, Abaza M, Sheldon S, et al.: Acute biphenotypic leukaemia: immunophenotypic and cytogenetic analysis. Br J Haematol 84 (1): 49-60, 1993.
  85. Legrand O, Perrot JY, Simonin G, et al.: Adult biphenotypic acute leukaemia: an entity with poor prognosis which is related to unfavourable cytogenetics and P-glycoprotein over-expression. Br J Haematol 100 (1): 147-55, 1998.
  86. Matutes E, Morilla R, Farahat N, et al.: Definition of acute biphenotypic leukemia. Haematologica 82 (1): 64-6, 1997 Jan-Feb.
  87. Sulak LE, Clare CN, Morale BA, et al.: Biphenotypic acute leukemia in adults. Am J Clin Pathol 94 (1): 54-8, 1990.
  88. Carbonell F, Swansbury J, Min T, et al.: Cytogenetic findings in acute biphenotypic leukaemia. Leukemia 10 (8): 1283-7, 1996.
  89. Pane F, Frigeri F, Camera A, et al.: Complete phenotypic and genotypic lineage switch in a Philadelphia chromosome-positive acute lymphoblastic leukemia. Leukemia 10 (4): 741-5, 1996.
  90. Killick S, Matutes E, Powles RL, et al.: Outcome of biphenotypic acute leukemia. Haematologica 84 (8): 699-706, 1999.

WebMD Public Information from the National Cancer Institute

Last Updated: February 25, 2014
This information is not intended to replace the advice of a doctor. Healthwise disclaims any liability for the decisions you make based on this information.
Next Article:

Today on WebMD

Building a Support System
cancer fighting foods
precancerous lesions slideshow
quit smoking tips
Jennifer Goodman Linn self-portrait
what is your cancer risk
colorectal cancer treatment advances
breast cancer overview slideshow
prostate cancer overview
lung cancer overview slideshow
ovarian cancer overview slideshow
Actor Michael Douglas