Prognostic significance of trisomy 4 as the sole cytogenetic abnormality in acute myeloid leukemia
Introduction
Cytogenetics analysis performed at diagnosis is generally considered as the single most valuable prognostic factor in acute myeloid leukemia (AML) [1], [2], [3], [4], [5], [6], [7], [8], [9], [10]. Pretreatment cytogenetic abnormalities not only are predictive of success of induction therapy, but also provide an important basis for selection of postremission therapy [11], [12]. Isolated trisomies, such as 4, 8, 11, 13, 21 and 22 have been well described in patients with AML [6], [13], [14]. Apart from trisomy 8, the number of reported cases of other single trisomies in AML is small [6], [10]. Unlike structural rearrangements that have often led to the identification of causal genes that were subsequently used as specific diagnostic markers, the pathogenetic significance of trisomies is elusive in most cases.
The first case of trisomy 4 was reported in 1985. Since then, it has been reported in association with AML especially with FAB subtypes M2 and M4. Occasionally, it has been reported in association with acute lymphoblastic leukemia (ALL). The prognostic significance of this cytogenetic abnormality in patients with AML is not clear. According to SWOG/ECOG risk stratification criteria [8] for patients with AML, a patient with trisomy 4 is classified under the unknown risk status; UK-MRC classification [6] categorize it as an intermediate risk status, whereas, the German cooperative group [15] will assign this as a high risk abnormality. The rare occurrence and paucity of an adequate numbers of patients with this abnormality in any one individual clinical trial prevents meaningful evaluation of treatment outcome. In order to make recommendations regarding postremission therapy for patients with this abnormality, it is important to know the prognostic significance of this abnormality. Many centres now recommend unrelated alloBMT for AML patients with poor risk abnormalities in CR1 if a related donor is not available [16]. A CALGB study reported worse outcome of patients with isolated trisomies in the absence of stem cell transplant (SCT) [14]. It is not known at present whether patients with AML with trisomy 4 in CR1 should be considered for these high-risk treatment approaches.
To answer this question, we report four cases of AML with trisomy 4 as the sole cytogenetic abnormality diagnosed at our institute over the last 15 years and review the literature for all the reported cases of trisomy 4 as the sole karyotypic abnormality in AML. The main objective of this analysis was to evaluate the relationship of this abnormality with CR rates and survival outcomes in order to assess the prognostic significance of this rare cytogenetic abnormality in AML.
Section snippets
Case 1
A 59-year-old man presented in August 1993 with weakness, lethargy and easy bruising. He had been found to have a moderately enlarged spleen 3 months before presentation; however at that time no cause for the splenomegaly was identified. On examination he was pale and had bruises of different ages on both lower limbs. His spleen was palpable 10 cm, below the left costal margin. Investigations showed Hb 92 g/l, WBC count 46×109/l with 30% blast cells (BCs) and platelets 46×109/l. Bone marrow (BM)
Patients from reported literature
Using Mitelman’s cytogenetic database (http://cgap.nci.nih.gov/Chromosomes/Mitelman) and medline, 62 reported cases of tiresome 4 as the sole cytogenetic abnormality associated with various malignancies were identified. The following 15 patients were excluded from this analysis:1. Patients other than AML Breast cancer 2 Superficial fibromatosis 1 Biphenotypic acute leukemia (BAL) 2 ALL 3 Waldenstrom’s macroglobulinemia 1
2. Cytogenetics not available at presentation
23. Absence of trisomy 4 at presentation 2
Isolated trisomy 4 and AML
Fifty-one patients with AML (including four from the present report) were analysed to study disease demographics. Median age of this group (n=49, age information missing on two patients) was 58 years (range 9–86 years). There were 21 male and 30 female patients (male:female ratio 1:1.4). FAB subtype was available on 46 patients (M0=7, M1=10, M2=13, M4=14, M5=2). In five cases FAB subtype was not specified. These cases were reported from all over the world though predominantly from western
Discussion
Trisomy 4 as a sole chromosomal abnormality is very rare in acute leukemias. We could identify only five cases (four with AML and one with T-ALL) with this abnormality from our cytogenetic database of hematological malignancies consisting of over 1000 patients from 1987 to 2002. Most other groups have reported the same experience. Therefore, it is fair to say that the incidence of this abnormality in acute leukemias is probably around 0.5% or even less. It is worth mentioning that we did not
Acknowledgements
Contributions. V. Gupta provided the concept and design, collected and interpreted the data, drafted the article, provided critical revisions, statistical expertise, and collected and assembled the data. M.D. Minden contributed to the concept and design, provided critical revisions, gave final approval of the article, provided study materials/patients, obtained funding, and provided administrative support. Q-L. Yi contributed to the concept and design, provided data analysis and interpretation,
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