Revaccination of Children after Completion of Standard Chemotherapy for Acute Leukemia

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1 MAJOR ARTICLE Revccintion of Children fter Completion of Stndrd Chemotherpy for Acute Leukemi Soonie R. Ptel, 1 Miguel Ortín, 1 Bernrd J. Cohen, 2 Ry Borrow, 5 Dine Irving, 3 Jonne Sheldon, 3 nd Pul T. Heth 4 1 Peditric Oncology Deprtment, Royl Mrsden Hospitl, Sutton, 2 Virus Reference Deprtment, Center for Infections, Helth Protection Agency, 3 Protein Reference Unit, St. Georges Hospitl, nd 4 Vccine Institute nd Child Helth, St. George s University of London, London, nd 5 Meningococcl Reference Unit, Mnchester Medicl Microbiology Prtnership, Mnchester Royl Infirmry, Mnchester, United Kingdom (See the rticle by Ptel et l. on pges nd the editoril commentry by Chisholm on pges 643 5) Bckground. After the tretment of ptients with cute leukemi, there is decrese in vccine-specific ntibody nd n incresed susceptibility to certin vccine-preventble diseses. A simple revccintion schedule is wrrnted. Method. Fifty-nine children (ge, 1 18 yers) who hd completed stndrd chemotherpy in ccordnce with Medicl Reserch Council of United Kingdom protocols were recruited. All children received single dose of Hemophilus influenze type b (Hib), tetnus, diphtheri, cellulr pertussis, meningococcus C, polio, mesles, mumps, nd rubell vccines 6 months fter completion of tretment. Antibody concentrtions were mesured before vccintion nd 2 4 weeks nd 12 months fter vccintion. Results. Prevccintion ntibody levels were protective for ll ptients for tetnus (geometric men concentrtion [GMC], 0.13 IU/mL; 95% CI, IU/mL), for 87% for Hib (GMC, 0.5 mg/ml; 95% CI, mg/ml), for 71% for mesles (GMC, 301 miu/ml; 95% CI, miu/ml), for 12% for meningococcus C (geometric men titer [GMT], 1:2.9; 95% CI, 1:2.2 to 1:3.9), nd for 11% for ll 3 poliovirus serotypes. Revccintion resulted in significnt increse in levels of ntibody to ech vccine ntigen, with 100% of ptients chieving optiml ntitetnus ntibody concentrtions (defined s 10.1 IU/mL; 1.5 IU/mL; 95% CI, IU/ ml), 93% chieving optiml ntibody concentrtions to Hib (defined s 11.0 mg/ml; 6.5mg/mL; 95% CI, mg/ml), 94% chieving optiml ntibody concentrtions to mesles (defined s 120 miu/ml; 2720 miu/ml; 95% CI, miu/ml), 96% chieving optiml ntibody concentrtions to meningococcus C (defined s 1:8; 1:1000; 95% CI, 1:483 1:2064), nd 85% chieving optiml ntibody concentrtions to ll the 3 poliovirus serotypes (defined s 1:8). For the mjority of subjects, protection persisted for t lest 12 months fter vccintion. Conclusion. Revccintion of children fter stndrd chemotherpy is importnt, nd protection cn be chieved in the mjority of these children using simple schedule of 1 vccine dose t 6 months fter completion of leukemi therpy. Leukemi is the most common form of childhood mlignncy; cute lymphoblstic leukemi (ALL) represents 80% of cses, nd cute myeloid leukemi (AML) represents 15% of cses [1]. The tretment of British children hs followed consecutive Medicl Reserch Council of United Kingdom protocols for ALL (MRC-UKALL), nd the tretment of chil- Received 27 July 2006; ccepted 18 October 2006; electroniclly published 24 Jnury Reprints or correspondence: Dr. Soonie R. Ptel, Peditric Dept., Mydy University Hospitl, Croydon, CR7 7YE, UK (soonier@doctors.org.uk). Clinicl Infectious Diseses 2007; 44: by the Infectious Diseses Society of Americ. All rights reserved /2007/ $15.00 DOI: / dren hs followed Medicl Reserch Council of United Kingdom protocols for AML (MRC- UKAML) protocols. Both protocols provide risk-strtified therpy [2, 3]. Over the yers, tretment hs gretly improved the durtion of disese-free survivl [2, 3]. It hs been suggested tht leukemi itself hs n effect on the dptive immune system [4, 5] nd, therefore, my impir ntibody responses to vccine ntigens. ALL nd AML trget lymphoid nd myeloid progenitor cells, respectively; their tretments lso trget these cells. Thus, both the disese nd its tretment will inevitbly cuse immunosuppression. Chemotherpy to tret cute leukemi is immunosuppressive. B lymphocyte [6] nd T lymphocyte levels decrese [7], nd there is reduction of totl Ig levels Revccintion of Children CID 2007:44 (1 Mrch) 635

2 t the completion of chemotherpy. IgM, IgG [5, 8 10], nd IgG2 re specificlly ffected [11]. B lymphocyte function nd T lymphocyte function usully recover 6 months fter completion of chemotherpy, lthough recovery my tke up to 1 yer [6, 7]. Normliztion of Ig levels usully occurs fter 1 yer [9]. An incresing number of children now survive s result of improvements in leukemi tretment nd supportive cre. Therefore, it is importnt to study the long-term effects of stndrd chemotherpy, such s its effects on immunity to vccine-preventble diseses. Reltively few studies hve exmined this specificlly in ptients treted for leukemi. Such studies hve generlly demonstrted decrese in protective ntibody levels fter completion of tretment [12 19]. Some hve suggested tht this decrese my be similr to tht experienced by helthy individuls [20]. Studies evluting revccintion ginst mesles, mumps, rubell, poliovirus, tetnus, diphtheri, nd Hemophilus influenze type b (Hib) fter completion of chemotherpy hve reveled vrible immune responses [12, 14 17, 19, 21]. To our knowledge, there re no published studies evluting the immunogenicity of meningococcus C conjugte (MCC) vccines in ptients treted for cute leukemi. There re few guidelines for the revccintion of children treted with stndrd ntileukemi chemotherpy. US guidelines recommend commencement of revccintion 3 months fter completion of chemotherpy [22]. The current UK guidelines recommend single dose of diphtheri-tetnus cellulr pertussis (DTP), inctivted poliovirus (IPV), MCC, Hib conjugte, nd mesles-mumps-rubell (MMR) vccines t 6 months fter completion of stndrd chemotherpy [23]. These recommendtions were primrily bsed on expert opinion nd dt from limited number of published studies [23]. The objectives of this study were to evlute these guidelines nd to specificlly evlute (1) the persistence of vccine-specific ntibody nd (2) the immunogenicity of 1 dose of MMR, tetnus toxoid, IPV, Hib conjugte, nd MCC vccines given to children t lest 6 months fter completion of stndrd chemotherpy for leukemi. PATIENTS AND METHODS Ptient popultion. The study ws conducted over 2-yer period (1 October 2002 through 30 September 2004). were recruited from the peditric deprtment t the Royl Mrsden Hospitl (Sutton, United Kingdom). Eligible ptients were previously vccinted children (ge, 1 18 yers) who hd completed stndrd chemotherpy 6 months before recruitment in ccordnce with the MRC- UKALL protocols (UKALL-97, UKALL-99, nd, for ptients with disese relpse, UKALL-R2) for those nd the MRC-UKAML protocols (UKAML10 or UKAML12) for those [2, 3]. The tretment regimen supported by the MRC-UKALL protocols is risk-strtified into regimens A, B, nd C, in which regimen A is the lest intensive nd regimen C is the most intensive. Informed consent ws obtined from the ptient or his/her prent. who refused to receive 1 specific vccine were still included in the study. Children were only excluded if there ws recognized contrindiction to receipt of vccine. Clinicl dt on ech ptient were obtined from the ptient, prents, nd ptient records. Dt on pst vccintions were obtined from prents or the ptient s generl prctitioner. Vccines nd schedule. When possible, the vccintions were given in the 2 sets. DTP (Infnrix, GlxoSmithKline), IPV (Imovx, AventisPsteur), nd Hib conjugte (Hiberix, GlxoSmithKline) vccines were dministered initilly, nd MCC (Meningitec, Wyeth) nd MMR (MMR II, Aventis- Psteur) vccines were dministered 1 month lter. When possible, blood smples were obtined for serologic testing t the sme time s they were obtined for routine blood tests. Blood smples were collected on the dy tht the revccintions were commenced, 2 4 weeks fter receipt of ech set of vccintions, nd 1 yer fter the commencement of revccintions. Five to 10 ml of blood ws collected. Blood ws centrifuged, nd serum ws seprted nd frozen in liquots t 20 C on the sme dy t The Royl Mrsden Hospitl, until the smples were tested in btches. Serum smples were trnsported frozen to the vrious lbortories. Antibody ssys. Serum ntibody concentrtions or titers were mesured for the following ntigens: Hib; tetnus; poliovirus serotypes 1, 2, nd 3; mesles; nd Neisseri meningitidis group C. Tetnus nd Hib ssys were performed t the Protein Reference Unit of St. George s Hospitl (London, United Kingdom). ELISA methods were used to mesure IgG ntibodies to tetnus toxoid (with n in-house method vlidted by the Protein Reference Unit) nd polyribosylribitol phosphte (PRP; Bindzyme; the Binding Site). A neutrliztion ssy ws used to detect neutrlizing ntibodies ginst poliovirus serotypes 1, 2, nd 3 nd ws performed t the Helth Protection Agency (Colindle, London) [24]. The plque reduction neutrliztion ssy ws used to mesure the level of neutrlizing mesles ntibodies. Titers were reported s the reciprocl of the highest serum dilution required to reduce the plques of the chllenge virus by 50%. End point titers were converted into concentrtions by direct comprison with the World Helth Orgniztion stndrd for ntimesles serum [25]; this ssy ws performed t the Helth Protection Agency. The level of serum bctericidl ntibody (SBA) ginst meningococcus C ws determined by serum bctericidl ssy using bby rbbit serum s n exogenous complement source [26]. SBA titers re expressed s the reciprocl of the finl serum dilution yielding 50% killing of 636 CID 2007:44 (1 Mrch) Ptel et l.

3 Tble 1. Chrcteristics of children with cute lymphoblstic leukemi (ALL) or cute myeloid leukemi (AML). For ll ptients All children (n p 59) Children (n p 46) Children (n p 13) Sex, no. of ptients Mle 34 Femle 25 Age t dignosis, medin yers (rnge) 5.4 ( ) 5.25 ( ) 6.7 ( ) Age t vccintion, medin yers (rnge) 8.0 ( ) 8.1 (4.1 18) 7.5 ( ) Time from end of tretment to vccintion, medin yers (IQR) 0.58 ( ) 0.58 ( ) 0.8 ( ) Time from vccintion nd serologic testing, medin dys (IQR) 31 ( ) Tretment regimen received, no. of ptients MRC-UKALL-A MRC-UKALL-B MRC-UKALL-C MRC-UKALLR MRC-UKAML NOTE. IQR, interqurtile rnge; MRC-UKALL, Medicl Reserch Council of United Kingdom protocols for tretment of ALL; MRC-UKAML, Medicl Reserch Council of United Kingdom protocols for tretment of AML. bcteri. This ssy ws performed t the Meningococcl Reference Unit (Mnchester, United Kingdom). Sttisticl nlysis. For sttisticl nlysis, ntibody concentrtions or titers tht were less thn the limit of the ssy s sensitivity were ssigned vlues equl to one-hlf of the lower detection limit. All ntibody concentrtions or titers were logtrnsformed to clculte geometric men concentrtion (GMC) or geometric men (GMT), with 95% CIs. Dt did not conform to norml distribution, so comprisons of GMC or GMT before nd fter vccintion (pired smples) were performed using the Wilcoxon signed rnk test, comprisons between 2 groups (unpired smples) were performed using the Mnn-Whitney U test, nd 3-wy comprisons were performed using the Kruskl-Wllis test. Comprisons of proportions were nlyzed by Fisher s exct test. Correltion between 2 continuous vribles ws nlyzed by Spermn s correltion coefficient. Dt re lso reported in terms of proportions of ptients who experienced seroconversion (defined s 4-fold increse in ntibody concentrtion or titer) nd who ttined protective concentrtions or titers. For Hib, nti-prp ntibody concentrtions 0.15 nd 1.0 mg/ml re thought to correlte with short-term nd long-term protection, respectively [27]. For tetnus, ntitetnus ntibody concentrtions of 0.01 nd 0.1 IU/ ml re correlted with short-term nd long-term protection, respectively [28]. Any detectble titer of neutrlizing ntibody ginst poliovirus is considered to be protective; for this study, neutrlizing ntibody titers 1:8 re considered to correlte with protection [28]. For mesles, concentrtion 120 miu/ ml is believed to correlte with protection (Cohen B, Audet S, Andrews N, Beeler J, on behlf of The World Helth Orgniztion Working Group on Mesles Plque Reduction Neutrliztion Test; personl communiction). For meningococcus C, n SBA titer 1:8 before vccintion nd n SBA titer 1: 128 fter vccintion re believed to correlte with protection [29, 30]. SBA titers in the rnge 1:8 1:64 fter vccintion re considered to be protective if vccintion results in 4-fold increse in the SBA titer [29]. Anlysis findings were considered to be sttisticlly significnt t 2-tiled P vlue of.05. Dt were nlyzed using SPSS sttisticl softwre, version 12.0 for Windows (SPSS). The ethics committee of the Royl Mrsden Hospitl pproved the study. RESULTS A totl of 59 ptients were recruited in the study. Demogrphic informtion regrding the ptients is presented in tble 1. The number of blood smples obtined vried by vccine ntigen nd time point, nd findings re shown in tbles 2 6. Fewer smples were vilble t the lter time points becuse ptients declined to provide dditionl smples, ptients did not ttend visit for blood smple collection, disese relpsed (2 ptients), or the time point ws not reched during the study period. Differing numbers of vccine ntigens were the result of insufficient serum smple sizes to llow ll ssys to be performed For ech vccine, there ws significnt increse in the ntibody concentrtion or titer fter dministrtion of 1 dose of Revccintion of Children CID 2007:44 (1 Mrch) 637

4 Tble 2. Geometric men concentrtion (GMC) of serum polyribosylribitol phosphte ntibody, before nd fter receipt of 1 dose of Hemophilus influenze type b conjugte vccine. Period No. of ptients with dt GMC of serum polyribosylribitol phosphte ntibody, mg/ml (95% CI) Before vccintion (n p 52) ( ) 0.5 ( ) 0.45 ( ) b After vccintion (n p 43) ( ) c 7.5 ( ) d 2.6 ( ) d One yer fter vccintion (n p 15) ( ) NOTE. Pired pre- nd postvccintion serologic test results were vilble for 40 ptients. ALL, cute lymphoblstic leukemi; AML, cute myeloid leukemi. P!.001 for before versus fter vccintion. b P p.02 for before versus fter vccintion. c P p.02 for fter versus 1 yer fter vccintion. d P!.05 for ptients versus ptients. Tble 3. Period Geometric men concentrtion of serum ntitetnus ntibody, before nd fter receipt of 1 dose of tetnus toxoid vccine. No. of ptients with dt the vccine. No correltion between prevccintion or postvccintion responses to ny vccine ws found for the following fctors: time between completion of tretment nd vccintion, time between vccintion nd serologic testing, ptient ge t dignosis nd t vccintion, pst vccintion history, nd MRC-UKALL tretment regimen. There were no significnt differences between ptients nd those with regrd to prevccintion ntibody levels. hd significntly greter increse in ntibody concentrtion in response to vccintion with Hib conjugte, tetnus toxoid, nd IPV vccines thn did ptients. The type of leukemi, however, did not significntly influence the proportion of ptients with protective responses ginst ny vccine ntigen. Hib. Ninety-five percent of ptients hd received t lest 1 dose of Hib conjugte vccine before the dignosis of leukemi. Before vccintion with Hib conjugte vccine, 86.5% of ptients hd nti-prp concentrtions 0.15 mg/ml, nd 25% hd concentrtions 1.0 mg/ml. There ws significnt increse in ntibody concentrtion fter vccintion (tble 2). Overll, 75% of ptients hd 4-fold increse in concentrtion, with 100% chieving concentrtion 0.15 mg/ml nd 93% chieving concentrtion 1.0 mg/ml. Twelve months fter vccintion, ntibody concentrtions hd significntly decresed (tble 2), lthough the concentrtion remined 1.0 mg/ml for ll ptients. Tetnus. hd received 3 doses of tetnus toxoid vccine before the dignosis of leukemi. Before vccintion, ll ptients hd n ntitetnus ntibody concentrtion 0.01 IU/mL, nd 57% hd concentrtion 0.1 IU/mL. There ws significnt increse in ntibody concentrtion fter vccintion (tble 3). Overll, 90% of ptients hd 4-fold increse in ntibody concentrtion, nd ll chieved concentrtion 0.1 IU/mL. Twelve months fter vccintion, ntibody concentrtions hd significntly decresed (tble 3), lthough the concentrtion remined 0.1 IU/mL for ll ptients. Poliovirus. hd received t lest 3 doses of polio vccine prior to the dignosis of leukemi. Before vccintion, only 11% of ptients hd protective levels of ntibody titer to ll 3 poliovirus serotypes. Protective titers to serotypes 1, 2, nd 3 were present in 67%, 60%, nd 14.5% of ptients, respectively. There ws significnt difference in the prevccintion ntibody GMT between serotypes; the GMT of serotype 3 ws significntly lower thn tht of serotypes 1 nd 2 (tble 4). After vccintion, there ws significnt increse in ntibody titers (tble 4). Overll, 85% of ptients chieved pro- GMC of serum ntitetnus ntibody, IU/mL (95% CI) Before vccintion (n p 54) ( ) 0.1 ( ) 0.26 ( ) After vccintion (n p 41) ( ) b 1.9 ( ) c 0.33 ( ) c One yer fter vccintion (n p 16) ( ) NOTE. Pired pre- nd postvccintion serologic test results were vilble for 39 ptients. ALL, cute lymphoblstic leukemi; AML, cute myeloid leukemi. P!.001 b P!.01 c P!.01 for before versus fter vccintion. for fter versus 1 yer fter vccintion. for ptients versus ptients. 638 CID 2007:44 (1 Mrch) Ptel et l.

5 Tble 4. vccine. Geometric men titer (GMT) of polio-neutrlizing ntibody, before nd fter receipt of 1 dose of inctivted poliovirus Period, poliovirus serotype No. of ptients with dt GMT of polio-neutrlizing ntibody (95% CI) Before vccintion (n p 55) Serotype ( ),b 9.8 ( ) 13.7 ( ) Serotype ( ),b 7.7 (6 9.9) 11.9 ( ) Serotype ( ),b 4.6 (4 5.2) 5.9 ( ) c After vccintion (n p 39) 31 8 Serotype 1 39 ( ) d 46.8 (30 79) e 16 ( ) e Serotype (24 59) 50 (30 83) e 12.3 (7.3 21) e Serotype 3 31 ( ) 41 (24 69) e 10.4 ( ) e One yer fter vccintion (n p 19) 15 4 Serotype ( ) Serotype 2 19 ( ) Serotype 3 12 (7 20.7) NOTE. Pired pre- nd postvccintion serologic test results were vilble for 36 ptients. ALL, cute lymphoblstic leukemi; AML, cute myeloid leukemi. P!.001 for before versus fter vccintion. b P!.001 for serotype 3 versus serotypes 1 nd 2. c P!.05 for before versus fter vccintion. d P!.05 for fter versus 1 yer fter vccintion. e P!.05 for ptients versus ptients. tective levels of ntibody titer to ll 3 serotypes; 95% chieved protective levels for serotype 1, 87% chieved protective levels for serotype 2, nd 87% chieved protective levels for serotype 3. More ptients chieved 4-fold increse in ntibody titers to serotype 3 (64%) thn to the other serotypes (50% for serotype 1 nd 58% for serotype 2). After vccintion, there were no significnt differences in ntibody GMTs between the serotypes. Twelve months fter vccintion, there ws decrese in the GMT for ll serotypes, nd the decrese ws sttisticlly significnt for serotype 1 (tble 4); only 47% of ptients still hd protective levels of ntibody titer to ll 3 serotypes t this time point. Mesles. Ninety-two percent of ptients hd received 1 dose of MMR vccine before the dignosis of leukemi. Before vccintion, 73.5% of ptients (75% of ptients with prior Tble 5. Geometric men concentrtion (GMC) of mesles-neutrlizing ntibody, before nd fter receipt of 1 dose of mesles-mumpsrubell vccine. Period No. of ptients with dt MMR vccintion nd 25% of ptients without prior MMR vccintion) hd ntibody concentrtions 120 miu/ml. There ws significnt increse in ntibody concentrtion fter dministrtion of single dose of MMR vccine (tble 5); 94% of ptients chieved protective concentrtions, nd 43% hd 4-fold increse in the concentrtion. Twelve months fter vccintion, there ws decrese in ntibody concentrtions, lthough the levels remined protective for ll ptients. Meningococcus C. Only 40% of ptients hd received dose of MCC vccine before the dignosis of leukemi. Before vccintion, 12% of children hd SBA titers 1:8. Of the children who hd received MCC before the commencement of chemotherpy, 17% hd protective titers. There ws significnt increse in the SBA titer fter vccintion (tble 6) tht ws independent of prior MCC vccintion sttus. Ninety-six GMC of mesles-neutrlizing ntibody, miu/ml (95% CI) Before vccintion (n p 49) ( ) 221 ( ) 700 ( ) After vccintion (n p 36) ( ) 3053 ( ) 1527 ( ) One yer fter vccintion (n p 17) ( ) NOTE. Pired pre- nd postvccintion serologic test results were vilble for 28 ptients. ALL, cute lymphoblstic leukemi; AML, cute myeloid leukemi. P!.001 for before versus fter vccintion. Revccintion of Children CID 2007:44 (1 Mrch) 639

6 Tble 6. Geometric men titer (GMT) of meningococcus C serum bctericidl ntibody, before nd fter receipt of 1 dose of meningococcus C conjugte vccine. Period No. of ptients with dt GMT of meningococcus C serum bctericidl ntibody (95% CI) Before vccintion (n p 49) ( ) 2.3 ( ) 2.5 ( ) b After vccintion (n p 28) ( ) 1120 ( ) 588 ( ) NOTE. Pired pre- nd postvccintion serologic test results were vilble for 26 ptients. ALL, cute lymphoblstic leukemi; AML, cute myeloid leukemi. P.001 for before versus fter vccintion. b P.05 for before versus fter vccintion. percent of children chieved titers 1:128 nd hd 4-fold increse in titer. There ws insufficient serum vilble to evlute the persistence of titers t 12 months fter vccintion. DISCUSSION At medin time of 7 months fter completion of stndrd chemotherpy for ALL nd AML, the mjority of children in our study hd levels of ntibody greter thn the minimum protective thresholds for tetnus (100%), Hib (87%), nd mesles (71%) ntigens. However, only 11% hd protective titers to ll poliovirus serotypes, despite receipt of previous vccintion with polio vccines, nd only 12% hd protective titers ginst N. meningitidis group C. These quoted protective levels my be relevnt only to previously helthy individuls nd my not be long lsting. Therefore, it is desirble to chieve higher levels in children recently completing tretment for leukemi, nd revccintion progrm is logicl. In keeping with other published studies [16, 17, 19], our ptients chieved good immune response to the vccine ntigens studied, with the mjority of children chieving protective ntibody responses. Some studies hve demonstrted tht younger ptient ge t vccintion is ssocited with more rpid decrese in protective ntibody levels [8, 9, 15, 17]. This ws not evident in our cohort. The intensity of ALL tretment cn influence immune responses [13, 16, 18]; most of our ptients received ALL tretment in ccordnce with the lest intensive MRC-UKALL regimen, nd 17% received tretment in ccordnce with the most intensive regimen; tretment intensity did not pper to influence immunity to the vccine ntigens studied. There were reltively few children who received the most intensive regimen ( n p 8), so this conclusion must be viewed with cution. Becuse ALL is disorder of lymphoid cells, it would seem logicl tht ALL nd its tretment my hve greter influence on dptive immune functions thn AML. Surprisingly, in our cohort, the ntibody response to ll vccines ws lower in ptients thn in those significntly so for Hib, tetnus, nd poliovirus vccines. Despite this, good levels of protection were chieved fter dministrtion of 1 dose of vccine. It should be noted tht there were only 13 ptients, nd this low number my limit our conclusions. It is not cler why ptients my hve poorer response, nd this group merits dditionl study, becuse they my benefit from second dose of vccine. There re few studies compring the influence of ALL nd AML on vccintion responses; one showed tht ptients hve lower levels of tetnus ntibody thn do ptients t the time of completion of chemotherpy [31]. The incidence of Hib disese is higher in children with leukemi thn in helthy children [32]. The nti-prp ntibody GMC of our ptients is similr to recently published previling nti-prp GMC in helthy, 2 4-yer-old British children [33]. Vccintion of our ptients resulted in significnt increse in the ntibody GMC to 6.5 mg/ml. One yer fter vccintion, the nti-prp GMC of our ptients hd decresed to 3.2 mg/ ml, but the level remined protective in ll children. Decresing ntibody concentrtions over time hve been demonstrted in children with mlignncies but re clerly feture in helthy children lso [32, 34]. All of the children in our study hd mintined protection to tetnus, nd ll chieved good responses to dose of tetnus toxoid vccine. Other studies hve reported lower rtes of mintennce of protective tetnus immunity (rnge, 38% 85% of ptients) [16 19]. As with our results, revccintion with single dose of tetnus toxoid vccine in other studies lso resulted in protective concentrtions in 77% 100% of ptients [16 18]. There re no dt vilble regrding immunity to meningococcl C disese nd immune response to MCC vccine fter leukemi chemotherpy. MCC vccine ws licensed in the United Kingdom in 1999, nd until recently, there hs been reltively little use in other countries. Therefore, this is, to our knowledge, the first study to evlute immune responses to MCC vccintion in this popultion. The previling SBA GMT in helthy infnts before vccintion is similr to tht in our cohort before vccintion [35]. 640 CID 2007:44 (1 Mrch) Ptel et l.

7 One dose of MCC vccine ppered to be sufficient for study children. However, we hve no dt on the persistence of titers 11 yer fter vccintion. Wning immunity in the United Kingdom hs resulted in the recent introduction of booster dose for young children. Additionl study of children with leukemi is wrrnted to ssess the durtion of protection ginst meningococcus C infection nd the need for lter booster doses. Mesles cn cuse life-thretening infection in immunocompromised children [36]. Limited dt re vilble regrding the incidence nd severity of mesles in children treted for leukemi. Our ptients, like those in previous studies [15, 17, 20], demonstrted lower rtes of seroconversion fter mesles vccintion thn did helthy individuls [37]. Some of our ptients did not hve ny response to mesles vccintion; however, the mjority chieved protective concentrtions fter receipt of 1 dose. One yer fter vccintion, levels remined protective in ll ptients. The seroconversion rtes of our ptients to IPV vccine re similr to those reported in helthy individuls [38]. As with other groups [39, 40], we observed tht levels of ntibody titer ginst serotype 3 were lower thn the levels of titer ginst serotypes 1 nd 2, both before nd fter vccintion. Becuse vccintion resulted in more ptients chieving 4-fold increse in ntibody to serotype 3, this difference ws no longer significnt fter vccintion. In this study, we did not formlly evlute the cost of universl revccintion fter leukemi tretment, compred with the cost of testing nd then selective revccintion. However, protective concentrtions or titers in this popultion my not be s vlid s in helthy children, leving open the question regrding wht levels to use s the bsis for revccintion. Furthermore, there re some vccines for which no serologicl correlte of protection exists (e.g., pertussis) or for which, in routine prctice, it is too difficult to hve levels mesured (e.g., polio). Clerly, for mny subjects, selective policy will lso men undergoing blood test nd then receiving n injection (s opposed to just receiving n injection). Universl revccintion is likely to be the esiest pproch from logisticl viewpoint. We hve demonstrted tht children who re treted in ccordnce with MRC-UKALL nd MRC-UKAML protocols mintin reltively good level of immunity ginst some vccine ntigens nd chieve protective ntibody responses to Hib, tetnus, meningococcus C, mesles, nd poliovirus with revccintion with 1 dose of vccine given 6 months fter completion of leukemi tretment. Therefore, we recommend this simple revccintion schedule. Additionl studies to evlute the response to vccintions given erlier fter completion of leukemi tretment should now be considered. Acknowledgments We thnk ll the children nd prents who prticipted in this study, s well s Yvonne Wright, who helped vccinte the children. Finncil support. The Children s Fund, Royl Mrsden Hospitl. Potentil conflicts of interest. St. George s Hospitl University of London nd P.T.H. hve received recent reserch grnts from Wyeth nd Snofi Psteur. R.B. hs received recent reserch grnts from Wyeth nd Bxter Bioscience nd hs been n d hoc consultnt to GlxoSmithKline, Snofi Psteur, Bxter Bioscience, nd Fujisw. All honorri re pid to Mnchester Children s University Hospitl Trust. All other uthors: no conflicts. References 1. Crist WM, Pui C-H. The leukemis. In: Behrmn RE, Kliegmn RM, Arvin AM, eds. Nelson textbook of peditrics, 15th ed. Pennsylvni: Prism Sunders, 1996: Chessels JM, Richrds SM, Biley CC, Lilleymn JS, Eden T. Gender nd tretment outcome in childhood lymphoblstic leukemi: report from the MRC UKALL trils. Br J Hemtol 1995; 89: Whetley K, Burnett AK, Goldstone AH, et l. A simple, robust, vlidted nd highly predictive index for the determintion of risk-directed therpy in cute myeloid leukemi derived from the MRC AML 10 tril. United Kingdom Reserch Council s Adult nd Childhood Leukemi Working Prties. Br J Hemtol 1999; 107: Spickermnn D, Guse A, Pfreundschuh M, Von Klle AK, Bohlen Diehl V. Impired ntibody levels to tetnus toxoid nd pneumococcl polyscchrides in cute leukemis. Leuk Lymphom 1994; 16: Abrhmsson J, Mrky I, Mellnder L. Immunoglobulin levels nd lymphocyte response to mitogenic stimultion in children with mlignnt disese during tretment nd follow-up. Act Peditr 1995; 84: Alnko S, Pelliniemi TT, Slmi TT. Recovery of blood B-lymphocytes nd serum immunoglobulins fter chemotherpy for childhood cute lymphoblstic leukemi. Cncer 1992; 69: Alnko S, Slmi TT, Pelliniemi TT. Recovery of blood T-cell subsets fter chemotherpy for childhood cute lymphoblstic leukemi. Peditr Hemtol Oncol 1994; 11: Cver TE, Slobod KS, Flynn PM, et l. Profound bnormlity of the B/T lymphocyte rtio during chemotherpy for peditric cute lymphoblstic leukemi. Leukemi 1998; 12: Mustf MM, Buchnn GR, Winick NJ, et l. Immune recovery in children with mlignncy fter cesstion of chemotherpy. J Peditr Hemtol Oncol 1998; 20: Mrtin Ibnez I, Arce Css A, Cruz Mrtinez O, Estell Agudo J, Mrtin Mteos MA. Humorl immunity in peditric ptients with cute lymphoblstic leukemi. Allergol Immunolpthol 2003; 31: Kristinsson VH, Kristinsson JR, Jonmundsson GK, Jonsson OG, Thorsson AV, Hrldsson A. Immunoglobulin clss nd subclss concentrtions fter tretment of childhood leukemi. Peditr Hemtol Oncol 2001; 18: Vn der Does-vn den Berg A, Hermns J, Ngel J, vn Steenis G. Immunity to diptheri, pertussis, tetnus nd poliomyelitis in children with cute lymphoblstic leukemi fter cesstion of chemotherpy. Peditrics 1981; 67: Ridgwy D, Wolff LJ, Deforest A. Immuniztion response vries with intensity of cute lymphoblstic leukemi therpy. Am J Dis Child 1991; 145: Smith S, Schiffmn G, Krylcin G, Bongur V. Immunodeficiency in long-term survivors of cute lymphoblstic leukemi treted with Berlin-Frnkfurt-Munster therpy. J Peditr 1995; 127: Nilsson A, De Milito A, Engström P, et l. Current chemotherpy protocols for childhood cute lymphoblstic leukemi induce loss of humorl immunity to virl vccintion ntigens. Peditrics 2002; 109: Ek T, Mellnder L, Hhn-Zoric M, Abrhmsson J. Intensive tretment Revccintion of Children CID 2007:44 (1 Mrch) 641

8 for childhood cute lymphoblstic leukemi reduces immune responses to diphtheri, tetnus nd Hemophilus influenze type b. J Peditr Hemtol Oncol 2004; 26: Zignol M, Percchi M, Tridello G, et l. Assessment of humorl immunity to poliomyelitis, tetnus, heptitis B, mesles, rubell, nd mumps in children fter chemotherpy. Cncer 2004; 101: Fioredd F, Plebni A, Hnu G, et l. Re-immunistion schedule in leukemic children fter intensive chemotherpy: possible strtegy. Eur J Hemtol 2005; 74: Vn Tilburg CM, Snders EAM, Rovers MM, Wolfs TFW, Bierings MB. Loss of ntibodies nd response to (re-)vccintion in children fter tretment for cute lymphoblstic leukemi: systemtic review. Leukemi 2006; 20: Ercn TE, Soycn LY, Apk H, et l. Antibody titers nd immune response to diphtheri-tetnus-pertussis nd mesles-mumps-rubell vccintion in children treted for cute lymphoblstic leukemi. J Peditr Hemtol Oncol 2005; 27: Kung FH, Orgel HA, Wllce WW, Hmburger RN. Antibody production following immunistion with diphtheri nd tetnus toxoids in children receiving chemotherpy during remission of mlignnt disese. Peditrics 1984; 74: Centers for Disese Control nd Prevention. Recommendtions of the Advisory Committee on Immuniztion Prctices (ACIP): use of vccines nd immune globulins in persons with ltered immunocompetence. MMWR Recomm Rep 1993; 42(RR-4): Royl College of Peditrics nd Child Helth (RCPCH). Immuniztion of the immunocompromised child: best prctice sttement. RCPCH, Albrecht P, vn Steenis G, vn Wezel AL, Slk JE. Stndrdiztion of poliovirus neutrlizing ntibody tests. Rev Infect Dis 1984; 6(Suppl 2): S Mrkowitz LE, Sepulved J, Diz-Orteg JL, et l. Immunistion of six-month-old infnts with different doses of Edmonston-Zgreb nd Schwrz mesles vccines. N Engl J Med 1990; 322: Mslnk SE, Gheesling LL, LiButti DE, et l. Stndrdiztion nd multi-lbortory comprison of Neisseri Meningitidis serogroup A nd C serum bctericidl ssys. Clin Dign Lb Immunol 1997; 4: Käythy H, Peltol H, Krnko V, Mäkelä P. The protective level of serum ntibodies to the cpsulr polyscchride of Hemophilus influenze type b. J Infect Dis 1983; 147: Plotkin SA. Immunologic correltes of protection induced by vccintion. Peditr Infect Dis J 2001; 20: Borrow R, Andrews N, Goldbltt D, Miller E. Serologicl bsis for the use of meningococcl sergroup C conjugte vccines in the United Kingdom: re-evlution of correltes of protection. Infect Immun 2001; 69: Andrews N, Borrow R, Miller E. Vlidtion of serologicl correlte of protection for meningococcl C conjugte vccine using efficcy estimtes from post-licensure surveillnce in Englnd. Clin Dign Lb Immunol 2003; 10: Hmmrström V, Puksen K, Svensson H, Oberg G, Pul C, Ljungmn P. Tetnus immunity in ptients with hemtologicl mlignncy. Support Cre Cncer 1998; 6: Feldmn S, Gigliotti F, Shenep JL, Roberson PK, Lott L. Risk of Hemophilus influenze type b disese in children with cncer nd response of immunocompromised leukemic children to conjugte vccine. J Infect Dis 1990; 161: Johnson N, Ruggeberg JU, Blfour GF, et l. Hemophilus influenze type b reemergence fter combintion immuniztion. Emerg Infect Dis 2004; 12: Heth PT, Booy R, Azzoprdi HJ, et l. Antibody concentrtion nd clinicl protection fter Hib conjugte vccintion in the United Kingdom. JAMA 2000; 284: Richmond P, Borrow R, Miller E, et l. Meningococcl serogroup C conjugte vccine is immunogenic in infncy nd primes for memory. J Infect Dis 1999; 179: Kpln LJ, Dum RS, Smron M, McCrthy CA. Severe mesles in immunocompromised ptients. JAMA 1992; 267: Robertson CM, Bennett VJ, Jefferson N, Myon-White RT. Serologicl evlution of mesles, mumps, nd rubell vccine. Arch Dis Child 1988; 63: Sutter RW, Ptrirc PA, Suleimn AJ, et l. Prlytic poliomyelitis in Omn: ssocition between regionl differences in ttck rte nd vritions in ntibody responses to orl poliovirus vccine. Int J Epidemiol 1993; 22: Ljungmn P, Durj V, Mgnius L. Response to immunistion ginst polio fter llogeneic mrrow trnsplnttion. Bone Mrrow Trnsplnt 1991; 7: Moriniere BJ, vn Loon FP, Rhodes PH, et l. Immunogenecity of supplementl dose of orl versus inctivted poliovirus vccine. Lncet 1993; 341: CID 2007:44 (1 Mrch) Ptel et l.