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Editorials
Figure 1. Mechanism of action of gemtuzumab ozogamicin.
statistical significance. However, comparison of hazard rates using P-values focuses on the relative value of an intervention rather than the absolute value. A good way to examine the latter is as the “number needed to treat” (NNT) to prevent a single event (or a single death); this information is often omitted from reports of clinical trials. Here, however, Lambert et al. note that at one year, 6 peo- ple would need to be treated with GO to prevent one event, while at year 3, NNT was 4. Such NNT values imply that most people do not benefit from GO when it is added to 7+3.
Can we identify who will benefit? Since GO binds to CD33 it seems plausible that higher levels of CD33 expression might be associated with a better outcome fol- lowing use of GO. Likewise, since it is known that GO, like agents such anthracyclines, is extruded from AML blasts by ATP-binding cassette transporter proteins medi- ating multidrug resistance (MDR), there may also be a relationship between extrusion and response to GO. Pollard et al. noted that children in the COG study who were in the highest 75% of CD33 expression had superior EFS regardless of cytogenetic group when given GO but not in the control group (no GO),11 and similar findings
have been reported in adults for patients with favorable and intermediate cytogenetics.12,13 A higher dose (e.g. 6 mg/m2 rather than 3 mg/m2) may benefit patients with low, but not high, CD33 expression.13 It should be kept in mind that quantification of neither CD33 expression nor MDR is currently a routine task. Attempts to enhance GO activity by use of cyclosporine A to block MDR do not appear to have been successful.14
More recently, attention has focused on the role of CD33 single nucleotide polymorphisms (SNPs) in affect- ing response to GO. Such SNPs regulate the expression of CD33 isoforms. SNPs denoted as TT result in a lack of exon 2, resulting in absence of the antibody-binding site for GO on CD33, as well as in diagnostic immunopheno- typic panels. Using data from the aforementioned COG study,7 Lamba et al. found only children with the CC SNP (51% of 816 children), which encodes a full exon 2 result- ing in the presence of a GO binding site on CD33, bene- fitted from addition of GO to chemotherapy regardless of cytogenetics or CD33 expression.15 However, this finding has not been confirmed by the UK NCRI/MRC group,16 although a similar proportion of patients (47% of 563 patients) had the CC SNP as in Lamba et al.,15 and the
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haematologica | 2019; 104(1)