Nej Me 1302063

8/22/2019 Nej Me 1302063

1/3

editorials

n engl j med 368;19 nejm.org may 9, 2013 1839

first step was the process of screening a varietyof leukemia samples for mutations in the codingregion of approximately 2000 genes associatedwith cancer signaling, including all kinases.This screening showed CSF3Rmutations in 16 of27 patients with CNL and atypical CML (59%);by contrast, the mutation was rare in patients

with AML (1 of 92) and other leukemias.Next, samples with the CSF3Rmutation were

tested in vitro with chemical kinase inhibitorsand small interfering RNA directed against ki-nases known to be activated by normal CSF3R.8These studies suggested that different types ofCSF3R mutations had differential sensitivity todifferent therapeutic agents. Frameshift or non-sense mutations that truncated the cytoplasmictail of CSF3R appeared to deregulate and activateits downstream signaling partners SRC kinaseand TNK2 kinase (and thus were sensitive to themultikinase inhibitor dasatinib). Membrane prox-imal mutations appeared to cause ligand-inde-pendent activation of the downstream effectorJAK2 and thus were susceptible to the JAK in-hibitor ruxolitinib. The authors confirmed thetransforming potential and differential drug sen-sitivity using in vitro colony-forming assays.Finally, the authors treated a patient whose leu-kemia harbored a CSF3R proximal membranemutation. As predicted from these studies, thepatient had a response to the JAK inhibitor ruxoli-tinib, with dramatic decreases in white-cell,neutrophil, and platelet counts.

In addition to the obvious therapeutic benefitin these rare disorders, this study is important ina broader sense. It shows the power of geneticscreening to uncover new potential drug targetsand provide a rationale for using drugs that arealready available for other indications. Notably,the association between the CSF3Rmutation andCNL and atypical CML was found in a large se-quencing of the usual suspects of cancer sig-naling. Skeptics often deride large-scale screen-

ing studies as f ishing expeditions, although these

are actually an excellent idea if the object is tocatch fish. Furthermore, the work went fromidentif ication of the CSF3Rmutation, through invitro studies, to a successful clinical applicationwithout a murine model. Thus, this study bucksthe common notion that one cannot learn any-thing of significance without engineering a

mouse that nature itself could not create.E. Donnall Thomas, winner (with Joseph E.

Murray) of the Nobel Prize in Physiology orMedicine in 1990 for his pioneering work on allo-geneic transplantation, often said that medicalscience did work not by giant breakthroughs butby small, calculated steps. This study shows thepotential power of studying a small problem verycraftily and is an example of what geneticallyinformed treatment may look like in the nearfuture. This is how we will beat cancer, onegene, one disease at a time.

Disclosure forms provided by the author are available with thefull text of this article at NEJM.org.

From the Clinical Research Division, Fred Hutchinson CancerResearch Center, Seattle.

1. Druker BJ, Guilhot F, OBrien SG, et al. Five-year follow-upof patients receiving imatinib for chronic myeloid leukemia.N Engl J Med 2006;355:2408-17.2. Levine RL, Wadleigh M, Cools J, et al. Activating mutation inthe tyrosine kinase JAK2 in polycythemia vera, essential throm-bocythemia, and myeloid metaplasia with myelofibrosis. CancerCell 2005;7:387-97.3. Maxson JE, Gotlib J, Pollyea DA, et al. Oncogenic CSF3Rmuta-tions in chronic neutrophilic leukemia and atypical CML. N EnglJ Med 2013;368:1781-90.

4. Beekman R, Touw IP. G-CSF and its receptor in myeloid ma-lignancy. Blood 2010;115:5131-6.5. Beekman R, Valkhof MG, Sanders MA, et al. Sequential gainof mutations in severe congenital neutropenia progressing toacute myeloid leukemia. Blood 2012;119:5071-7.6. Hernndez JM, del Caizo MC, Cuneo A, et al. Clinical, hema-tological and cytogenetic characteristics of atypical chronic my-eloid leukemia. Ann Oncol 2000;11:441-4.7. Bhm J, Schaefer HE. Chronic neutrophilic leukaemia: 14 newcases of an uncommon myeloproliferative disease. J Clin Pathol2002;55:862-4.8. Tyner JW, Yang WF, Bankhead A III, et al. Kinase pathwaydependence in primary human leukemias determined by rapidinhibitor screening. Cancer Res 2013;73:285-96.

DOI: 10.1056/NEJMe1302363

Copyright 2013 Massachusetts Medical Societ y.

Early-Life Wheezing and Respiratory Syncytial Virus PreventionRobert F. Lemanske, Jr., M.D.

Wheezing illnesses in preschool children have

perplexed clinicians for decades in terms of their

differential diagnosis, short-term and long-term

treatment, and prognosis with regard to the

subsequent development of asthma. Although

wheezing illnesses have been described in more

The New England Journal of Medicine

Downloaded from nejm.org on September 26, 2013. For personal use only. No other uses without permission.

Copyright 2013 Massachusetts Medical Society. All rights reserved.

8/22/2019 Nej Me 1302063

2/3

Th e n e w e n g l a n d j o u r n a l o f me dicine

n engl j med 368;19 nejm.org may 9, 20131840

than 50% of preschool children, many eventu-

ally outgrow this problem.1 A major concern

with using wheezing to define an illness is the

subjectivity involved in assessing this symptom

in terms of caregiver recognition, agreement be-

tween parental and physician assessment, and

recognition of the degree of severity that por-

tends subsequent administration of systemic glu-cocorticoids or hospitalization.2 Nonetheless,

because more objective pulmonary-function stud-

ies are difficult to perform in the majority of

preschool children, wheezing has been used as

a surrogate marker to identify clinically relevant

lower-airway obstruction.

Viral respiratory tract illnesses, particularlythose due to infection with respiratory syncytialvirus (RSV)3 or human rhinovirus (HRV),4 havefrequently been associated with the developmentof persistent wheezing, childhood asthma, or

both. These findings suggest that the preventionof infection with either virus has the potentialto reduce the risk of either or both of theseoutcomes.

On the basis of these relationships, it seemsplausible that currently available anti-RSV ther-apy could reduce the risk of recurrent wheezingsecondary to RSV infection. Using a retrospectiveand nonrandomized study design, Simes et al.treated premature infants with palivizumab andcompared them with an untreated cohortmatched for chronologic and gestational age.During a 24-month follow-up period, physician-diagnosed recurrent wheezing was significantlyless frequent in the treated group.5 This reductionin wheezing frequency was seen only in childrenwho did not have a family history of atopy.6

In this issue of the Journal, Blanken and col-leagues extend these observations in a random-ized, double-blind, placebo-controlled trial usingthe total number of wheezing days in the firstyear of life as the primary outcome.7 Remark-ably, premature infants treated with palivizumab

had a significant 61% relative decrease in thetotal number of wheezing days during the firstyear of life. Moreover, the effect of RSV preven-tion on the number of wheezing days persistedin the post-prophylaxis period (i.e., starting at2 months after the last injection). As anticipated,palivizumab treatment reduced hospitalizationsrelated to RSV infection; in addition, treatmenthad a significant effect on reducing rates of med-ically attended nonhospitalized RSV infection.

Given the limitations inherent in using wheez-ing as a primary outcome measure discussedpreviously, these data show rather convincinglythat palivizumab treatment can reduce both RSVinfection rates and subsequent recurrent wheez-ing in preterm infants. These relationships werenoted despite rather low rates of parental pro-

curement of nasopharyngeal-swab samples (29%)and respiratory pathogen detection (60%) dur-ing wheezing episodes. However, study coordi-nator and investigator oversight of the trial wasexcellent, with more than 90% of scheduled in-jections completed in both the placebo andpalivizumab groups.

With the potentially strong association be-tween early-life wheezing and the developmentof childhood asthma, what do these data meanin terms of predicting future asthma risk in thispopulation of high-risk infants? Two of the most

important risk factors for asthma in childrenare the presence of allergic sensitization8 andwheezing during viral4 or perhaps bacterial9 re-spiratory tract illnesses in the first few years oflife. Recent data from the Childhood Originsof Asthma birth cohort study suggest that aller-gic sensitization may be causative in the subse-quent development of virus-induced wheezing.10One proposed mechanistic pathway to explainthese sequential relationships involves the im-pairment of innate responses to viral pathogensowing to the cross-linking of IgE receptors,which results in increased airway inf lammationand the subsequent loss of lung function in sen-sitized persons.11

It is important to recognize, however, thatother asthma-risk pathways, which are inde-pendent of allergic sensitization, may also con-tribute to increased asthma risk. One such path-way may involve genetic variation at the 17q21locus and virus-induced wheezing illnesses. In arecent study, variants at this locus were associ-ated with HRV wheezing illnesses in early life

but not with RSV wheezing illnesses. The asso-ciations of 17q21 variants with asthma were re-stricted to children who previously had HRVwheezing illnesses, resulting in a significant in-teraction effect with respect to asthma risk.These associations were independent of the pres-ence or absence of allergic sensitization.12

In the current study, the effect of RSV pre-vention with palivizumab on the total numberof wheezing days was similar regardless of pa-




8/22/2019 Nej Me 1302063

3/3

editorials

n engl j med 368;19 nejm.org may 9, 2013 1841

rental history of atopy. As stated previously,Simes et al.6 found that palivizumab reducedwheezing only in children without a family his-tory of atopy. The fact that a genetic backgroundof atopy did not influence wheezing frequencyin either study suggests that palivizumab treat-ment, while decreasing morbidity in infancy, may

have limited effects on at least some asthma-risk pathways. Whether more definitive evalua-tions of allergic sensitization (i.e., allergen-spe-cific IgE testing) and 17q21 locus variation ortreatment of term infants would alter these find-ings, improve risk predictions, or influence thenatural history of asthma warrants further study.

Disclosure forms provided by the author are available with thefull text of this article at NEJM.org.

From the Departments of Pediatrics and Medicine, Universityof Wisconsin School of Medicine and Public Health, Madison.

1. Martinez FD, Wright AL, Taussig LM, et al. Asthma andwheezing in the first six years of life. N Engl J Med 1995;332:133-8.2. Skytt N, Bnnelykke K, Bisgaard H. To wheeze or not towheeze: that is not the question. J Allergy Clin Immunol 2012;130(2):403.e5-407.e5.3. Wu P, Hartert TV. Evidence for a causal relat ionship betweenrespiratory syncytial virus infection and asthma. Expert RevAnti Infect Ther 2011;9:731-45.

4. Jackson DJ, Gangnon RE, Evans MD, et al. Wheezing rhino-virus illnesses in early life predict asthma development in high-risk children. Am J Respir Crit Care Med 2008;178:667-72.5. Simes EA, Groothuis JR, Carbonell-Estrany X, et al. Paliviz-umab prophylaxis, respiratory syncytial virus, and subsequentrecurrent wheezing. J Pediatr 2007;151:34-42.6. Simes EA, Carbonell-Estrany X, Rieger CH, et al. The effectof respiratory syncytial virus on subsequent recurrent wheezingin atopic and nonatopic children. J Allergy Clin Immunol

2010;126:256-62.7. Blanken MO, Rovers MM, Molenaar JM, et al. Respiratorysyncytial virus and recurrent wheeze in healthy preterm infants.N Engl J Med 2013;368:1791-9.8. Sly PD, Boner AL, Bjrksten B, et al. Early identification ofatopy in the prediction of persistent asthma in children. Lancet2008;372:1100-6.9. Bisgaard H, Hermansen MN, Bnnelykke K, et al. Associa-tion of bacteria and viruses with wheezy episodes in young chil-dren: prospective birth cohort study. BMJ 2010;341:c4978.10. Jackson DJ, Evans MD, Gangnon RE, et al. Evidence for acausal relationship between allergic sensitization and rhinovi-rus wheezing in early life. Am J Respir Crit Care Med 2012;185:281-5.11. Durrani SR, Montville DJ, Pratt AS, et al. Innate immuneresponses to rhinovirus are reduced by the high-affinity IgE re-

ceptor in allergic asthmatic children. J Allergy Clin Immunol2012;130:489-95.12. aliskan M, Bochkov YA, Kreiner-Mller E, et al. Rhinoviruswheezing illness and genetic risk of childhood-onset asthma.N Engl J Med 2013;368:1398-407.

DOI: 10.1056/NEJMe1302063

Copyright 2013 Massachusetts Medical Societ y.

applyforjobsatthenejmcareercenter

Physicians registered at the NEJM CareerCenter can apply for jobs electronically.A personal account created when you register allows you to apply for positions,

using your own cover letter and CV, and keep track of your job-application history.Visit NEJMjobs.org for more information.




Documents

Nej Me 1302063