The
n e w e ng l a n d j o u r na l
Tam wrongly argues that tuberculin skin testing has limited usefulness in Asia, where most persons have received BCG vaccination. Although it is true that among BCG-vaccinated populations there is a higher prevalence of positivity on tuberculin skin testing than on IGRA,3 it is important to note that the effect of BCG vaccination on the specificity of tuberculin skin testing depends on the strain of vaccine used, the age at which the vaccine was administered, and the number of doses that were administered.4 When the BCG vaccine is administered at birth, as it is in most of the world (including Asia),5 it has varied but limited effect on the specificity of tuberculin skin testing. Therefore, a history of vaccination can be ignored in the interpretation of the results of tuberculin skin testing later in life if preventive therapy is being considered. Furthermore, the speculative hypothesis that bacteriologically confirmed tuberculoma, which is a result of a homeostatic relationship between bacteria and the immune system, is a common manifestation of latent tuberculosis infection in Asia remains to be proved. Flood et al. echo what we propose in our review regarding the use of simplified guidelines and algorithms. We also agree with them on the missed opportunities to scale up the manage-
of
m e dic i n e
ment of latent tuberculosis infection in settings such as that in the United States. Haileyesus Getahun, M.D., Ph.D., M.P.H. World Health Organization Geneva, Switzerland
[email protected]
Richard E. Chaisson, M.D. Johns Hopkins University School of Medicine Baltimore, MD
Mario Raviglione, M.D. World Health Organization Geneva, Switzerland Since publication of their article, the authors report no further potential conflict of interest. 1. King TC, Upfal M, Gottlieb A, et al. T-SPOT.TB interferon-
gamma release assay performance in healthcare worker screening at nineteen U.S. hospitals. Am J Respir Crit Care Med 2015; 192:367-73. 2. Dorman SE, Belknap R, Graviss EA, et al. Interferon-γ release assays and tuberculin skin testing for diagnosis of latent tuberculosis infection in healthcare workers in the United States. Am J Respir Crit Care Med 2014;189:77-87. 3. Gao L, Lu W, Bai L, et al. Latent tuberculosis infection in rural China: baseline results of a population-based, multicentre, prospective cohort study. Lancet Infect Dis 2015;15:310-9. 4. Farhat M, Greenaway C, Pai M, Menzies D. False-positive tuberculin skin tests: what is the absolute effect of BCG and nontuberculous mycobacteria? Int J Tuberc Lung Dis 2006;10:1192204. 5. Zwerling A, Behr MA, Verma A, Brewer TF, Menzies D, Pai M. The BCG world atlas: a database of global BCG vaccination policies and practices. PLoS Med 2011;8(3):e1001012. DOI: 10.1056/NEJMc1508223
Dactinomycin in NPM1-Mutated Acute Myeloid Leukemia To the Editor: NPM1-mutated acute myeloid leukemia (AML) is a distinct leukemia entity that accounts for one third of cases of AML in adults.1 NPM1 is a crucial protein for normal nucleolar integrity and function. We hypothesized that the nucleolus of NPM1-mutated AML cells might be vulnerable to drugs that trigger a nucleolar stress response because it contains a low level of nonmutant NPM12 (owing to haploinsufficiency and cytoplasmic retention of nonmutant NPM1 by the NPM1 mutant1). Moreover, the p53-mediated nucleolar stress response is retained in NPM1mutated AML because NPM1-mutated AML cells lack p53 mutations or deletions.3 Among potentially active drugs, we focused on dactinomycin because it induces nucleolar stress by interfering with ribosome biogenesis through inhibition of RNA polymerase I.4 Dactinomycin is active in Wilms’ tumor and some 1180
other tumors, but we could find no study on dactinomycin use in AML. Therefore, we used it to treat a 60-year-old patient with NPM1-mutated AML without FLT3 internal tandem duplication mutations. Because dactinomycin lacks cardiotoxicity, we selected a patient for whom intensive chemotherapy was not appropriate owing to a low left ventricular ejection fraction (35%). Leukemia had progressed after an initial single cycle of azacitidine. Therefore, with the patient’s consent, we administered dactinomycin as an off-label single agent (approved by the institutional review board at Perugia Hospital), at a dose of 12.5 μg per kilogram of body weight per day for 5 consecutive days, as recommended for low-risk gestational trophoblastic tumors.5 Morphologic and immunohistochemical complete remission was achieved after two cycles of therapy (Fig. 1A through 1F), and we
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correspondence
A MGG Staining before Treatment
B MGG Staining after Two Treatment Cycles
C Hematoxylin and Eosin Staining before Treatment
D Hematoxylin and Eosin Staining after Two Treatment
E Immunostaining for NPM1 before Treatment
F Immunostaining for NPM1 after Two Treatment Cycles
Cycles
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G Quantitative RT-PCR Assay 2
3
H Hematologic Toxic Effects 4
5
6
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Platelet Neutrophil Treatment Hemoglobin Count Count Cycle
