Personalized Approach to Diagnosis and Treatment of Acute Myeloid Leukemia
Received Date: Jul 15, 2013 / Accepted Date: Jul 26, 2013 / Published Date: Jul 28, 2013
Recent advances in disease pathogenesis and modern technologies are gradually transforming conventional medicine into personalized medicine. The personalized approach to diagnosis of leukemic patients consists of comprehensive and individualized evaluation based on characteristics of the tumor cell morphology, immunophenotype,cytogenetic and molecular aberrations as well as the patient’s overall genetic make-up. Such a diagnostic approach, in addition to guiding individualized treatment, will help to identify new molecular targets for therapy.
Recent advances in disease pathogenesis and modern technologies are gradually transforming conventional medicine into personalized medicine. The personalized approach to diagnosis of leukemic patients consists of comprehensive and individualized evaluation based on characteristics of the tumor cell morphology, immunophenotype, cytogenetic and molecular aberrations as well as the patient’s overall genetic make-up. Such a diagnostic approach, in addition to guiding individualized treatment, will help to identify new molecular targets for therapy.
Acute myeloid leukemia (AML) is a type of aggressive neoplasm characterized by clonal expansion of myeloid blasts in the bone marrow, blood, or other tissue. AML is the most common acute leukemia in the USA with an estimated 14,590 new cases and 10,370 deaths in the USA in 2012 . AML is a heterogeneous group of diseases, and can be further devided into multiple subclasses.
Diagnosis and Classification of Acute Myeloid Leukemia
The earlier French-American-British (FAB) classification of AML is mainly based on morphology and cytochemistry , and it classifies AML into eight groups, namely AML-M0 to -M7 (Table 1). The most recent WHO classification proposed in 2008 is based on morphology, immunophenotype, genetic abnormalities and clinical history . It divides AML into four major categories with multiple subgroups (Table 2). The inclusion of genetic subgroups has great prognostic and therapeutic significance.
|M0||Minimally differentiated acute myeloblastic leukemia|
|M1||Acute myeloblastic leukemia, without maturation|
|M2||Acute myeloblastic leukemia, with granulocytic maturation|
|M3||Acute Promyelocytic Leukemia(APL)|
|M4||Acute Myelomonocytic Leukemia, And Acute Myelomonocytic With Eosinophilia (M4eo)|
|M5||Acute Monoblastic Leukemia(M5a) and Acute Monocytic Leukemia(M5b)|
|M6||Acute erythroid leukemias|
|M7||Acute megakaryoblastic leukemia|
Table 1: Eight FAB subtypes were proposed in 1976.
|Acute myeloid leukemia with recurrent genetic abnormalities|
|AML with t(8;21)(q22;q22); (RUNX1;RUNX1T1)|
|AML with inv(16)(p13.1q22) or t((16;16)(p13.1;q22); (CBFB-MYH11)|
|APL with t(15;17)(q22;q12); (PML-RARA)|
|AML with t(9;11)(p22;q23); (MLLT3-MLL)|
|AML with t(6;9)(p23;q34); (DEK-NUP214)|
|AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2); (RPN1-EVI1)|
|AML (megakaryoblastic) with t(1;22)(p13;q13); (RBM15-MKL1)|
|Provisional entity: AML with mutated NPM1|
|Provisional entity: AML with mutated CEBPA|
|Acute myeloid leukemia with myelodysplasia-related changes|
|Therapy-related myeloid neoplasms|
|Acute myeloid leukemia, not otherwise specified|
|Similar to FAB subgroups|
Table 2: 2008 WHO Classification of Acute Myeloid Leukemia.
Morphology and immunophenotype
AML is currently defined as a leukemia with 20% or more myeloid blasts in the bone marrow or blood. A myeloblast is an early precursor of myeloid lineage. It typically has immature nuclear features and expresses common myeloid markers such as CD13 or CD33, along with stem cell marker CD34 or early myeloid marker CD117. Further immunophenotyping can identify the cell of origin and the level of differentiation of the blasts, and aid in subclassication of AML into granulocytic, monocytic, erythroid, megakaryocytic, or minimally differentiated AML .
Certain cytogenetic abnormalities have been frequently observed in AML, and some are distinctively associated with specific subtypes of AML (Table 2). Most importantly, cytogenetic abnormalities are currently recognized as one of the most significant factors in predicting clinical outcomes of AML patients [4-6]. Several cytogenetic risk groups have been proposed . The favorable risk group includes Core- Binding Factor (CBF) abnormalities, t(8; 21) and inv(16)/t(16;16), which are associated with high rate of Complete Remission (CR) and longer survival . The t(15;17) underlies acute promyelocytic leukemia, which is one of the most curable types of leukemia . The unfavorable risk group includes complex cytogenetic abnormalities (≥ 3 cytogenetic aberrations), abnormalities of the long arm of chromosome 3, deletions of the long arm of chromosome 5 and monosomies of chromosomes 5 or 7 . Recent studies have shown that patients with Monosomy Karyotype (MK) have significantly shorter overall survival than patients with non-MK yet unfavorable aberrations. Therefore, it is proposed that MK identifies a distinct subgroup of patients with the most unfavorable clinical outcome . The intermediate risk group includes normal karyotype and abnormalities other than those described in the favorable and unfavorable groups .
In addition to chromosomal aberrations, gene mutations and duplications are frequently observed in AML patients. Approximately 40-50% of AML patients have a normal karyotype, but have shown a wide range of clinical outcomes [4,5]. Therefore, it is particularly important to identify molecular prognostic factors that can improve risk stratification in this group of patients. It has been shown that 85% of AML patients with a normal karyotype have gene mutations, in particular, NPM1, FLT3 and CEBPA . These mutations have prognostic significance and are being used in diagnosis . Patients with NPM1 mutation without FLT3-ITD have a better CR rate, and improved overall survival and disease-free survival, comparable to those of CBF AML [11,12]. Similarly, patients with biallelic mutations of CEBPA gene have longer overall survival than patients with no or single allelic mutation . On the other hand, FLT3-ITD has negative prognostic influence, resulting in shorter remission duration and poorer survival outcome compared with patients with wild-type FLT3 [14,15]. Prognostic significance of many of the newly identified molecular markers is still unclear. However, continued study may provide new insight into their importance in clinical outcome and response to certain therapeutic drugs.
Personalized Treatment of Acute Myeloid Leukemia
Therapy of AML includes traditional cytotoxic chemotherapy, targeted therapy, epigenetic therapy, and stem cell transplantation. Risk stratification based on cytogenetics and molecular markers plays a crucial role in guiding personalized treatment.
Traditional treatment adjustment based on specific leukemia characteristics
In AML patients with unfavorable cytogenetic and/or molecular risk, traditional chemotherapy protocol has not produced ideal outcomes. More accurate risk stratification will help better ‘targeting’ of patients who may benefit from chemotherapy dose adjustment and hematopoietic cell transplantation. In prospectively randomized studies, high-dose daunorubicin compared with standard dose resulted in a higher rate of complete remission and improved overall survival [16,17]. However, intensifying cytarabine has failed to improve clinical outcome [18-20]. Currently, myeloablative allogeneic stem cell transplantation (alloSCT) is recommended for poor-risk but not good-risk AML. AlloSCT, autologous transplant and consolidation chemotherapy are considered of equivalent benefit for intermediaterisk AML .
Advances in molecular diagnostics have resulted in significant advances in identification of new targets for therapy. Many new therapies are being tested in clinical trials.
Monoclonal antibodies target specific antigens expressed on malignant cells and can direct chemotherapy drugs to the targeted cells without affecting normal cells. Gemtuzumab ozogamicin is an immunoconjugate between anti-CD33 antibody and calicheamicin, and has been used as an addition to standard chemotherapy for AML patients. The outcome is controversial. While the Southwest Oncology Group (SWOG) study in 2010 failed to show improvement in CR rate and survival , other studies using lower dose gemtuzumab ozogamicin during standard front-line chemotherapy showed survival benefit [23,24].
Patients with FLT3 mutations, in particular FLT3-ITD, have inferior prognosis. Several FLT3 inhibitors, e.g. lestaurtinib (CEP-701), sunitinib (SU-11248), tandutinib (MLN-518), midostaurin (PKC-412), sorafenib (BAY-93006) and anti-FLT3 monoclonal antibody (IMCEB10), are being evaluated in clinical trials as single agent therapy and in combination with conventional chemotherapy . In a clinical trial of midostaurin combined with standard induction chemotherapy, addition of midostaurin demonstrated higher CR rate and improved overall survival .
CXCR4 is a chemokine receptor and serves as the principle regulator of stem cell homing and retention in the bone marrow. Increased CXCR4 expression has been associated with increased risk of relapse and decreased survival in AML. Plerixafor is a small molecule of CXCR4 inhibitor. A phase 1/2 study using Plerixafor in combination with chemotherapy to treat relapsed or refractory AML patients showed improved CR rate .
DNA hypermethylation represses transcription of the promoter regions of tumor suppressor genes. As opposed to conventional cytotoxic chemotherapy, the use of hypomethylating agents, such as azacytidine and decitabine, offer the possibility of disease control, without necessarily achieving CR in AML patients considered unfit for standard chemotherapy .
Other new agents, such as an inhibitor of NEDD8 activating enzyme (MLN4924) , an antisense oligonucleotide to X-linked inhibitor of apoptosis proteins (AEG 35156) , and WT1 tumor antigen-loaded dendritic cells , all have shown anti-AML activity and are attractive future options.
New technologies have allowed us to further categorize newly diagnosed AML patients into previously unrecognized biologic and/ or prognostic subgroups. Array-based technologies using comparative genome hybridization and single nucleotide polymorphism (SNPs) have been conducted successfully in AML patients and have provided valuable information [32-34]. The development of Next-Generation Sequencing (NGS) methods has revolutionized our ability to diagnose diseases and is now able to analyze disease-associated genetic abnormalities based on the entire genome of an individual patient. Specifically, NGS is now being applied to studies of cancer genomes such as targeted oncogene or tumor-suppressing gene sequencing, exome, transcriptome, methylome, histone-associated genome and whole-genome sequencing [35,36]. Equipped with these new technologies, we are advancing towards an era of disease diagnosis derived not only from population-based genetic information but also tailored from genetic information of an individual patient hence leading to personalized approaches to diagnose and treat a patient. Such an individualized approach will undoubtedly offer more efficient and less toxic therapy to AML in the future.
- Surveillance, Epidemiology, and End Results (SEER) stat fact sheets: acute myeloid leukemia (2012). Cancer Statistics Review (1975-2010). National Cancer Institute.
- Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, et al. (1976) Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group. Br J Haematol 33: 451-458.
- Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, et al. (2009) The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood 114: 937-951.
- Byrd JC, Mrózek K, Dodge RK, Carroll AJ, Edwards CG, et al. (2002) 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: 4325-4336.
- Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, et al. (1998) 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: 2322-2333.
- Marcucci G, Haferlach T, Döhner H (2011) Molecular genetics of adult acute myeloid leukemia: prognostic and therapeutic implications. J Clin Oncol 29: 475-486.
- Appelbaum FR, Kopecky KJ, Tallman MS, Slovak ML, Gundacker HM, et al. (2006) The clinical spectrum of adult acute myeloid leukaemia associated with core binding factor translocations. Br J Haematol 135: 165-173.
- Wang ZY, Chen Z (2008) Acute promyelocytic leukemia: from highly fatal to highly curable. Blood 111: 2505-2515.
- Döhner H, Estey EH, Amadori S, Appelbaum FR, Büchner T, et al. (2010) Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 115: 453-474.
- Voutiadou G, Papaioannou G, Gaitatzi M, Lalayanni C, Syrigou A, et al. (2013) Monosomal karyotype in acute myeloid leukemia defines a distinct subgroup within the adverse cytogenetic risk category. Cancer Genet 206: 32-36.
- Verhaak RG, Goudswaard CS, van Putten W, Bijl MA, Sanders MA, et al. (2005) Mutations in nucleophosmin (NPM1) in acute myeloid leukemia (AML): association with other gene abnormalities and previously established gene expression signatures and their favorable prognostic significance. Blood 106: 3747-3754.
- Fernandez-Mercado M, Yip BH, Pellagatti A, Davies C, Larrayoz MJ, et al. (2012) Mutation patterns of 16 genes in primary and secondary acute myeloid leukemia (AML) with normal cytogenetics. PLoS One 7: e42334.
- Green CL, Koo KK, Hills RK, Burnett AK, Linch DC, et al. (2010) Prognostic significance of CEBPA mutations in a large cohort of younger adult patients with acute myeloid leukemia: impact of double CEBPA mutations and the interaction with FLT3 and NPM1 mutations. J Clin Oncol 28: 2739-2747.
- Dunna NR, Rajappa S, Digumarti R, Vure S, Kagita S, et al. (2010) Fms like tyrosine kinase (FLT3) and nucleophosmin 1 (NPM1) mutations in de novo normal karyotype acute myeloid leukemia (AML). Asian Pac J Cancer Prev 11: 1811-1816.
- Whitman SP, Archer KJ, Feng L, Baldus C, Becknell B, et al. (2001) Absence of the wild-type allele predicts poor prognosis in adult de novo acute myeloid leukemia with normal cytogenetics and the internal tandem duplication of FLT3: a cancer and leukemia group B study. Cancer Res 61: 7233-7239.
- Fernandez HF, Sun Z, Yao X, Litzow MR, Luger SM, et al. (2009) Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med 361: 1249-1259.
- Löwenberg B, Ossenkoppele GJ, van Putten W, Schouten HC, Graux C, et al. (2009) High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med 361: 1235-1248.
- Schiller G, Gajewski J, Nimer S, Territo M, Ho W, et al. (1992) A randomized study of intermediate versus conventional-dose cytarabine as intensive induction for acute myelogenous leukaemia. Br J Haematol 81: 170-177.
- Weick JK, Kopecky KJ, Appelbaum FR, Head DR, Kingsbury LL, et al. (1996) 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 88: 2841–2851.
- Rowe JM, Tallman MS (1997) Intensifying induction therapy in acute myeloid leukemia: has a new standard of care emerged? Blood 90: 2121-2126.
- Koreth J, Schlenk R, Kopecky KJ, Honda S, Sierra J, et al. (2009) Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission: systematic review and meta-analysis of prospective clinical trials. JAMA 301: 2349-2361.
- Petersdorf S, Kopecky K, Stuart RK, Larson RA, Nevill TJ, et al. (2009) Preliminary results of Southwest Oncology Group Study S0106: an international intergroup phase 3 randomized trial comparing the addition of gemtuzumab ozogamicin to standard induction therapy versus standard induction therapy followed by a second randomization to post-consolidation gemtuzumab ozogamicin versus no additional therapy for previously untreated acute myeloid leukemia. Blood (ASH Annual Meeting Abstracts) 114: Abstract 790.
- Castaigne S, Pautas C, Terré C, Raffoux E, Bordessoule D, et al. (2012) 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 379: 1508-1516.
- Burnett AK, Hills RK, Milligan D, Kjeldsen L, Kell J, et al. (2011) Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol 29: 369-377.
- Kayser S, Levis MJ (2013) FLT3 tyrosine kinase inhibitors in acute myeloid leukemia: clinical implications and limitations. Leuk Lymphoma .
- Stone RM, Fischer T, Paquette R, Schiller G, Schiffer CA, et al. (2012) Phase IB study of the FLT3 kinase inhibitor midostaurin with chemotherapy in younger newly diagnosed adult patients with acute myeloid leukemia. Leukemia 26: 2061-2068.
- Uy GL, Rettig MP, Motabi IH, McFarland K, Trinkaus KM, et al. (2012) A phase 1/2 study of chemosensitization with the CXCR4 antagonist plerixafor in relapsed or refractory acute myeloid leukemia. Blood 119: 3917-3924.
- Ferrara F (2013) Conventional chemotherapy or hypomethylating agents for older patients with acute myeloid leukaemia? Hematol Oncol .
- Swords RT, Kelly KR, Smith PG, Garnsey JJ, Mahalingam D, et al. (2010) Inhibition of NEDD8-activating enzyme: a novel approach for the treatment of acute myeloid leukemia. Blood 115: 3796-3800.
- Katragadda L, Carter BZ, Borthakur G (2013) XIAP antisense therapy with AEG 35156 in acute myeloid leukemia. Expert Opin Investig Drugs 22: 663-670.
- Van Tendeloo VF, Van de Velde A, Van Driessche A, Cools N, Anguille S, et al. (2010) Induction of complete and molecular remissions in acute myeloid leukemia by Wilms' tumor 1 antigen-targeted dendritic cell vaccination. Proc Natl Acad Sci U S A 107: 13824-13829.
- Godley LA, Cunningham J, Dolan ME, Huang RS, Gurbuxani S, et al. (2011) An integrated genomic approach to the assessment and treatment of acute myeloid leukemia. Semin Oncol 38: 215-224.
- Suela J, Alvarez S, Cigudosa JC (2007) DNA profiling by arrayCGH in acute myeloid leukemia and myelodysplastic syndromes. Cytogenet Genome Res 118: 304-309.
- Watt CD, Bagg A (2010) Molecular diagnosis of acute myeloid leukemia. Expert Rev Mol Diagn 10: 993-1012.
- Welch JS, Link DC (2011) Genomics of AML: clinical applications of next-generation sequencing. Hematology Am Soc Hematol Educ Program 2011: 30-35.
- Rao AV, Smith BD (2013) Are results of targeted gene sequencing ready to be used for clinical decision making for patients with acute myelogenous leukemia? Curr Hematol Malig Rep 8: 149-155.
Citation: Lyu X, Zhao RY, Chen Q (2013) Personalized Approach to Diagnosis and Treatment of Acute Myeloid Leukemia. J Clin Exp Pathol 3:143. Doi: 10.4172/2161-0681.1000143
Copyright: © 2013 Lyu X, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Select your language of interest to view the total content in your interested language
Share This Article
Open Access Journals
- Total views: 13993
- [From(publication date): 6-2013 - Mar 06, 2021]
- Breakdown by view type
- HTML page views: 10004
- PDF downloads: 3989