|Year : 2015 | Volume
| Issue : 2 | Page : 82-84
Acute myeloid leukemia associated with rapid acquisition of FLT3-internal tandem duplications, ecotropic virus integration site-1 and Wilms' tumor 1 genes overexpression 4 months after an intermediate-risk myelodysplastic syndrome diagnosis
Branimir V Spassov1, Gueorgui N Balatzenko2, Margarita L Guenova3
1 Department of Clinical Haematology, Specialized Hospital for Active Treatment of Haematological Diseases, Sofia 1756, Bulgaria
2 Laboratory of Cytogenetics and Molecular Biology, Specialized Hospital for Active Treatment of Haematological Diseases, Sofia 1756, Bulgaria
3 Laboratory of Haematopathology and Immunology, Specialized Hospital for Active Treatment of Haematological Diseases, Sofia 1756, Bulgaria
|Date of Web Publication||7-Jul-2015|
Branimir V Spassov
Department of Clinical Haematology, 6 Plovdivsko Pole Street, Sofia 1756
Source of Support: None, Conflict of Interest: None
The myelodysplastic syndromes (MDS) are heterogeneous diseases with the different time period of progression to acute myeloid leukemia (AML). We report a case of a 38-year-old male with intermediate risk MDS, presence of normal karyotype and no expression of FLT3-internal tandem duplications (ITD), ecotropic virus integration site-1 (EVI-1) and Wilms' tumor 1 (WT1). Four months later, overt AML was diagnosed. The presence of normal karyotype was once again observed, but the molecular analysis revealed FLT3-ITD presence and over-expression of WT1 and EVI-1 genes. Complete remission was achieved after high-dose induction chemotherapy, and high-dose cytarabine consolidation was carried out. Three months later a relapse with a fatal outcome occurred. The case is the first report of a quick MDS progression to AML within 4 months due to rapid acquisition of several molecular abnormalities. This case suggests that frequent molecular screening for relevant genetic abnormalities might be useful for early detection of disease progression, particularly in normal karyotype cases.
Keywords: Acute myeloid leukemia, ecotropic virus integration site-1, FLT3-internal tandem duplications, Wilms′ tumor 1
|How to cite this article:|
Spassov BV, Balatzenko GN, Guenova ML. Acute myeloid leukemia associated with rapid acquisition of FLT3-internal tandem duplications, ecotropic virus integration site-1 and Wilms' tumor 1 genes overexpression 4 months after an intermediate-risk myelodysplastic syndrome diagnosis. J Appl Hematol 2015;6:82-4
|How to cite this URL:|
Spassov BV, Balatzenko GN, Guenova ML. Acute myeloid leukemia associated with rapid acquisition of FLT3-internal tandem duplications, ecotropic virus integration site-1 and Wilms' tumor 1 genes overexpression 4 months after an intermediate-risk myelodysplastic syndrome diagnosis. J Appl Hematol [serial online] 2015 [cited 2022 Sep 28];6:82-4. Available from: https://www.jahjournal.org/text.asp?2015/6/2/82/160208
| Introduction|| |
The myelodysplastic syndromes (MDS) are heterogeneous diseases from clinical, cytogenetic and molecular aspects. The survival of patients with MDS varies between a few months and 20 years. The World Health Organization classification subdivides MDS into eight subtypes. The revised international prognostic scoring system (IPSS-R) categorizes MDS patients into five risk groups based on blast percentage, karyotype, absolute neutrophil and platelet (PLT) count and hemoglobin level with different median survival and different time period of acute myeloid leukemia (AML) development.  Since cytogenetic abnormalities are observed in only 30-50% of de novo MDS cases, molecular mutations may serve as potential markers to extend the spectrum of diagnostic and prognostic parameters in MDS. ,
Mutations of the FLT3-gene, a member of the class-III-receptor tyrosine kinase family, play a central role in AML. , The FLT3-internal tandem duplications (FLT3-ITD) are one of the most frequent mutations in AML with unfavorable prognosis and could be found in 20-27% of these patients. The ecotropic virus integration site-1 (EVI-1) is an oncogenic transcription factor associated with human myeloid malignancy. The aberrant EVI-1 expression occurs in approximately 8-10% of human adult AML and confers poor prognosis. , The Wilms' tumor 1 (WT1) gene overexpression could be detected in 74% AML-patients at time of diagnosis and is associated with negative prognosis.
At present time, the precise relationship between MDS and AML is still unclear, and the role of molecular mutations in leukemic transformation in MDS is not well-defined.
Here, we report a patient with intermediate-risk category MDS and a very quick AML development due to the acquisition of FLT3-ITD and over-expression of both WT1 and EVI-1 genes.
| Case history|| |
A 38-year-old male patient was referred to our clinical department in March 2009 with a month history of fatigue. No previous exposure to potential carcinogens was reported. Physical examination revealed neither hepatosplenomegaly nor lymphadenomegaly. Laboratory analysis showed a tri-lineage cytopenia-white blood cell (WBC) count - 2.1 × 10 9 /l; absolute neutrophil count - 0.7 × 10 9 /l; hemoglobin - 93 g/l and PLT count - 40 × 10 9 /l. Differential leukocyte count revealed no circulating blast cells. A bone marrow aspiration resulted in dry tap while trephine biopsy revealed a hypercellular bone marrow due to increased numbers of the granulocytic and megakaryocytic series represented by all maturational stages without evident dysplasia. Blast cells were <5%, and the erythroid lineage was relatively preserved. Fine reticulin network was revealed by Gomori staining. A normal karyotype was observed by conventional cytogenetics. Molecular analysis on RNA, extracted from bone marrow cells, using reverse transcription polymerase chain reaction revealed no expression of AML1-ETO, CBFβ-MYH11, MLL-AF6, MLL-AF9, FLT3-ITD, MLL-PTD, EVI-1, MLF1, and WT1. Screening for BCR-ABL rearrangements and JAK2 gene V617F mutation were also negative. All molecular results were confirmed 1-month later. A diagnosis of MDS, unclassifiable with reticulin myelofibrosis was established. The patient was allocated in intermediate-risk category MDS since his calculated IPSS risk score was 3.5.
The patient's hemoglobin level remained low (65-90 g/l) despite several blood transfusions. Four months later, in July 2009, elevated WBC count up to 15.5 × 10 9 /l was detected, and an overt AML was diagnosed based on the presence of 48% circulating and 78% bone marrow blasts. The patient's sample was analyzed on a BD FACSCanto II Flow Cytometer with FACSDiva Software (Becton Dickinson, San Jose, CA) and myeloid phenotype of the leukemic blasts was observed: Myeloperoxidase (+), CD13 (+), CD33 (+), CD64 (+), CD15 (+), HLA-DR (+), CD117 (+), CD11b (+), CD34 (−), with an aberrant co-expression of CD7. Despite the presence of normal karyotype (46, XY), the molecular analysis revealed the presence of FLT3-ITD and over-expression of both WT1 and EVI-1 genes [Figure 1]. The patient was resistant to the standard induction chemotherapy (7 + 5 + 3) with cytarabine, etoposide, and farmorubicine. Complete remission was achieved in September 2009 after one course of IDA-FLAG (idarubicine, fludarabine, cytarabine and granulocyte colony stimulating factor) resulting in the disappearance of FLT3-ITD (−) and presence of only 0.012% minimal residual disease detected by flow cytometry. Three consolidation courses with high-dose cytarabine were carried out. The patient refused allogeneic stem cell transplantation and 3 months later a relapse with a fatal outcome occurred despite the initiation of intensive re-induction therapy.
|Figure 1: Molecular analyses of the main molecular abnormalities. NC egative control (H2O); PC ositive control. With arrows are indicated 3 consecutive analysis of the respective markers|
Click here to view
| Discussion|| |
This case is of particular clinical interest in two aspects. Firstly, it clearly demonstrates rapid acquisition of several molecular abnormalities - FLT3-ITD, and overexpression of EVI-1 and WT1 genes within 3 months. Secondly, despite that initial prognostic stratification into the intermediate risk group using IPSS-R, an extremely quick progression to AML was registered, probably associated with the acquisition of the above-mentioned abnormalities.
Risk assessment and prognostic stratification in MDS have become increasingly important since the introduction of new therapeutic options for MDS, such as allogeneic stem cell transplantation, intensive chemotherapy regimens for high-risk MDS and new compounds including azacitidine and lenalidomide. At present, IPSS-R is the standard tool for MDS risk assessment. Since cytogenetics included in the IPSS-R provide the basis for prognostic predictions only in some patients, additional molecular parameters are needed for a more detailed characterization of the biology and prognosis of this heterogeneous disorder.
In our case, the patient with MDS was assigned to the intermediate-risk subgroup. According to IPSS-R, the median leukemia-free survival and overall survival of these patients are 34.4 and 37 months respectively.  However, the development of AML in our patient took only 3 months.
Our clinical case shows that the progression from the initial stages of MDS to AML can be accompanied by the acquisition of molecular mutations that are known to play an important role in AML, such as the FLT3-ITD, WT1 and EVI-1. The progression of MDS to AML supports the two-hit theory, according to which at least two different types of mutations are needed for the development of AML; the class I mutations (which are frequently represented by mutations of receptor tyrosine kinases) mediate myeloproliferation, while the class II mutations lead to an arrest in differentiation in hematopoiesis. , It can, therefore, be hypothesized that a single molecular event leads to the early stages of MDS, but additional mutations are needed to cause leukemic transformation.
| Conclusion|| |
This case suggests that more frequent molecular screening for more relevant genetic abnormalities might be useful for early detection of disease progression, particularly in cases with normal karyotype.
Financial Support and Sponsorship
Conflicts of Interest
There are no conflicts of interest.
| References|| |
Voso MT, Fenu S, Latagliata R, Buccisano F, Piciocchi A, Aloe-Spiriti MA, et al.
Revised International Prognostic Scoring System (IPSS) predicts survival and leukemic evolution of myelodysplastic syndromes significantly better than IPSS and WHO Prognostic Scoring System: Validation by the Gruppo Romano Mielodisplasie Italian Regional Database. J Clin Oncol 2013;31:2671-7.
Fenaux P. Chromosome and molecular abnormalities in myelodysplastic syndromes. Int J Hematol 2001;73:429-37.
Bacher U, Haferlach T, Kern W, Haferlach C, Schnittger S. A comparative study of molecular mutations in 381 patients with myelodysplastic syndrome and in 4130 patients with acute myeloid leukemia. Haematologica 2007;92:744-52.
Fröhling S, Schlenk RF, Breitruck J, Benner A, Kreitmeier S, Tobis K, et al.
Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: A study of the AML Study Group Ulm. Blood 2002;100:4372-80.
Levis M, Small D. Novel FLT3 tyrosine kinase inhibitors. Expert Opin Investig Drugs 2003;12:1951-62.
Lugthart S, van Drunen E, van Norden Y, van Hoven A, Erpelinck CA, Valk PJ, et al.
High EVI1 levels predict adverse outcome in acute myeloid leukemia: Prevalence of EVI1 overexpression and chromosome 3q26 abnormalities underestimated. Blood 2008;111:4329-37.
Gröschel S, Lugthart S, Schlenk RF, Valk PJ, Eiwen K, Goudswaard C, et al.
High EVI1 expression predicts outcome in younger adult patients with acute myeloid leukemia and is associated with distinct cytogenetic abnormalities. J Clin Oncol 2010;28:2101-7.
Knudson AG. Two genetic hits (more or less) to cancer. Nat Rev Cancer 2001;1:157-62.
Gilliland DG, Griffin JD. The roles of FLT3 in hematopoiesis and leukemia. Blood 2002;100:1532-42.