Clinical Utility Of Fish Detection Of Recurring Numerical And Structural Chromosomal Abnormalities In Acute Myeloid Leukemia

The convention established by the Fourth International Workshop on Chromosomes in Leukemia[32] serves as the basis for the definition of a clonal abnormality. In clinical cytogenetics, the presence of two or more trisomic or structurally rearranged cells, or three or more monosomic cells, is considered clonal.[4] Following this criterion, a number of recurring clonal cytogenetic abnormalities have been identified in AML based on G-banded studies alone. Selected chromosomal abnormalities found in AML are given in Table 1. The reader is referred to Refs. [6,18] for details and more in-depth discussions.

There are three areas in which FISH is particularly useful in the management of myeloid disease. Perhaps most importantly, FISH is an important part of the diagnostic workup of myeloid malignancy. As noted above, the presence or absence of specific recurrent cytogenetic abnormalities has a major impact on the treatment of AML. Cytogenetically occult lesions, detectable only by FISH, are known to occur,[33] and these could potentially dictate the difference between hematopoietic stem cell transplantation and simple consolidation chemotherapy as postinduction treatment. Moreover, the choice of postinduction chemotherapy is to some extent influenced by cytogenetics, because highdose cytarabine has been shown to be most effective in the setting of core-binding factor mutations, detected cytogenetically as t(8;21) and inv(16)/t(16;16) chromosome rearrangements.1-34-1 In these diseases, high-dose cytarabine is more strongly indicated than in other types of AML.[35]

Because FISH and traditional cytogenetic banding techniques can have discrepant results,[24,33,36,37] it is important to consider both techniques in the initial cytogenetic assessment of AML. Consideration of the strengths and weaknesses of both cytogenetic techniques (FISH and conventional G-banding) makes it clear how these two assays are complementary in the diagnosis of AML. While FISH has the advantage of being able to evaluate many more cells than conventional cytogenetics, it has the requirement of a prior determination of suspected cytogenetic abnormalities for which one will probe. Because the number of reported cytogenetic abnormalities in AML is large, one cannot search for all such abnormalities at once. In practice, specific FISH probes can be used when the clinical situation and/or morphological criteria suggest specific abnormalities. For example, an FAB diagnosis of acute monocytic leukemia with bone marrow eosinophilia should prompt one to FISH for chromosomes 8, 21, and 16. Acute myeloid leukemia arising after an antecedent hematological disorder should be evaluated with FISH for chromosomes 5, 7, and 8.[37]

FISH is equally important in follow-up of patients treated with either transplant or chemotherapy.[38] For patients relapsing from standard dose consolidation chemotherapy, high-dose antineoplastic therapy with

Fig. 4 A simplified illustration of the FISH protocol. (From Ref. [25].)

allogeneic hematopoietic stem cell transplantation is the only known curative modality. Because transplantation is most successful when the disease burden is low, and because FISH is, in general, a more sensitive test than standard cytogenetics, FISH should be a standard part of posttreatment monitoring in all patients with a history of AML with known cytogenetic abnormalities.

In the posttransplant setting, donor lymphocyte infusion (DLI) can be considered to treat relapsed disease. Although this therapy is most useful in CML, it has been

Fig. 5 A simplified schematic representation of the detection of a fusion gene resulting from a translocation using FISH. Variations of the same basic paradigm enable the detection of most structural chromosomal rearrangements commonly found in AML and other hematopoietic disorders.

used in AML as well, wherein, again, treatment with the smallest possible disease burden is felt to be the most likely to succeed. As for postchemotherapy follow-up, cytogenetics and FISH should be standard posttransplant follow-up for all patients with a history of AML with known cytogenetic abnormalities.

There is an additional use for FISH in the posttransplant setting. Because a goal of hematopoietic stem cell transplantation is to completely replace the host's diseased marrow with donor marrow, it is important to demonstrate that this has in fact happened. Donor-host chimerism can be followed by several methods, some of which are labor intensive. In the case in which the donor and host are of opposite sexes, FISH for the X and Y chromosomes can be used to efficiently monitor for persistence, recurrence, or disappearance of host hematopoiesis. This becomes particularly important with the recent development of nonmyeloablative preparative regimens and reduced intensity transplants. Using these strategies, conversion to complete donor chimerism can take up to several months, and DLI may be given simply for persistent host chimerism. In such a clinical setting, an accurate assessment of the levels of donor and host chimerism is crucial and is most simply performed, if the donor and host are sex-mismatched, by FISH.

Finally, one word of caution needs to be mentioned. FISH alone, while more sensitive than conventional cytogenetics, is not a replacement for the standard assay. A clinical error is to order FISH for known chromosomal abnormalities without conventional cytogenetics. This

Table 1 Selected recurrent chromosomal abnormalities found in AML

Selected chromosomal abnormalities

Selected genetic loci

Prognostic significance

inv(3)(q21q26), t(3;3)(q21;q26), ins(3;3)(q26;q21q26)

Getting Started With Dumbbells

Getting Started With Dumbbells

The use of dumbbells gives you a much more comprehensive strengthening effect because the workout engages your stabilizer muscles, in addition to the muscle you may be pin-pointing. Without all of the belts and artificial stabilizers of a machine, you also engage your core muscles, which are your body's natural stabilizers.

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