Martinelli et al.1 reported a relatively large incidence of therapy-related acute myeloid leukemia (TRAL) in a retrospective Italian MS cohort (0.93%). In contrast, we observed a much lower TRAL incidence in a large retrospective German cohort (range of 0.25% to 0.41%)2 similar to 2 prospective studies,3,4 despite observation intervals comparable to Martinelli et al. In addition to methodologic aspects, differences may also relate to other factors including pretreatment and treatment protocols.
A 3-month treatment regimen is common in Germany, as demonstrated in one pivotal phase III trial5; 68.9% of the Italian patients were treated bimonthly or monthly. In addition, dose adjustment—according to leukocyte nadir—is not described in the Italian study but is required per the Summary of Product Characteristics in Germany. It is conceivable that higher dosages over a shorter time may pose an increased risk for toxicity. Potentially additive or genotoxic cotreatment further complicates data analysis. Besides the introduction of uniform treatment algorithms, larger collaborative studies should focus on potential risk factors as well as individual predisposition, e.g., pharmacogenomic characteristics.
This is important since treatment alternatives are still sparse in rapidly progressing secondary progressive MS.
Author Response
We agree that there is variability in TRAL incidence in patients with MS. We observed this in our multicenter study1 where TRAL incidence among centers ranged from 0/167 to 4/115. It is also recognized that published single cohort studies may be more biased toward high incidence than unpublished data.
Our data contradict other studies2,–,4 with similar observational follow-up, but there were methodologic differences, including sample size (3,2201 vs 1,1562 or 8023); follow-up of at least 1 year; and the closely linked network of Italian centers. Furthermore, 2 new acute myeloid leukemia cases were confirmed in the last year in our original cohort.
As Chan et al. suggest, we suspect that risk might be related to a specific treatment regimen or cotreatment, but we did not find this association. Moreover, monthly3 and 3-monthly infusions2 appear to have similar incidences. We believe that without a means of identifying susceptibility,6 the risk of TRAL must always be considered, perhaps with some type of “regional” stratification. There are currently 106 cases reported worldwide, one-third of which may be fatal.
Footnotes
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Author disclosures are available upon request (journal{at}neurology.org).
- Copyright © 2012 by AAN Enterprises, Inc.
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