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Editorials
3. Labbé RF, Dewanji A. Iron assessment tests: transferrin receptor vis-à- vis zinc protoporphyrin. Clin Biochem. 2004;37(3):165-174.
4. Teshome EM, Prentice AM, Demir AY, Andang'o PEA, Verhoef H. Diagnostic utility of zinc protoporphyrin to detect iron deficiency in Kenyan preschool children: a community-based survey. BMC Hematol. 2017;17:11.
5. Tillyer ML, Tillyer CR. Zinc protoporphyrin assays in patients with alpha and beta thalassaemia trait. J Clin Pathol. 1994;47(3):205-208.
6 Harthoorn-Lasthuizen EJ, Lindemans J, Langenhuijsen MM. Combined
use of erythrocyte zinc protoporphyrin and mean corpuscular volume in differentiation of thalassemia from iron deficiency anemia. Eur J Haematol. 1998;60(4):245-251.
7. Park CH, Valore EV, Waring AJ, Ganz T. Hepcidin, a urinary antimicro- bial peptide synthesized in the liver. J Biol Chem. 2001;276(11):7806- 7810.
8. Ganz T. Hepcidin and iron regulation, 10 years later. Blood. 2011;117(17):4425-4433.
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hepcidin and decrease iron absorption from daily or twice-daily doses
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1942
Is DNA a better assay for residual disease in chronic myeloid leukemia?
Jerald Radich
Fred Hutchinson Cancer Research Center, Seattle, Washington, USA E-mail: jradich@fhcrc.org
doi:10.3324/haematol.2018.205583
Chronic myeloid leukemia (CML) is not a public health menace. Despite its rarity, it has, and con- tinues to be, the guiding path for the concept of genetically informed medicine (here you can choose your own favorite alternative catch phrase: bench to bedside medicine, personalized medicine, precision medicine, etc.). CML was the first disease where a specific chromo- somal abnormality, the Philadelphia chromosome, was identified, and the first disease where the genetic under- pinnings of this chromosome abnormality were discov- ered (the juxtaposition of portions of the BCR gene from chromosome 22 to the tyrosine kinase domains from chromosome 9).1 This unique BCR-ABL fusion gene drives the pathophysiology of the disease, and thus has led to the remarkable discovery of the tyrosine kinase inhibitors (TKIs), which have fundamentally changed the natural history of the disease. Only decades ago, the lifes- pan of a chronic phase CML patient was less than seven years while now these patients enjoy a survival roughly that of the normal population.2,3
Chronic myeloid leukemia has also been the model of disease monitoring using specific molecular markers. In this case, the BCR-ABL chimeric RNA is used to assess disease burden, and the clinical significance of BCR-ABL levels are so compelling as to drive treatment milestones based on BCR-ABL levels that are codified in European
and US CML guidelines.4-6 Here, too, CML has laid the groundwork for other diseases to use so-called minimal (more recently, “measurable”) residual disease (MRD) to drive treatment decisions and measure clinical trial results.
In CML, BCR-ABL is typically measured by testing peripheral blood RNA. RNA is used since the potential breakpoints between BCR and ABL cover many kilobases of DNA sequence, making an easy PCR procedure impos- sible. Rather, the mRNA species is predictable with only two major splicing variations, making quantitative RT- PCR fairly straightforward. After considerable effort (mostly from the Adelaide group), RNA monitoring has been standardized in an International Scale, making the results comparable across more and more labs world- wide.6 The test is very sensitive, with levels of disease burden usually quantifiable to levels of four to five mag- nitudes from the standardized IS baseline (where a 4-log reduction of BCR-ABL on the IS would equal 0.01%IS, termed MR4)
However, the RNA assay for BCR-ABL is not perfect. RNA is less stable than DNA, and thus is more suscepti- ble to transit times, temperatures, etc.7,8 This problem is ameliorated by the use of two control housekeeping genes, but these are subject to the same influences that affect the target gene, and it is perhaps a bit of a leap to
haematologica | 2018; 103(12)