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Downs syndrome and acute lymphoblasticleukaemia: clinical features and response totreatment

J M Chessells, G Harrison, S M Richards, C C Bailey, F G H Hill, B E Gibson, I M HannA report from the MRC childhood leukaemia working party

Abstract

AimsTo examine the clinical and bio-

logical features of acute lymphoblastic

leukaemia in children with Downs syn-

drome (DS), to compare their survival

with other children, and to determine if

entry to trials and survival has improved.

MethodsExamination of presenting fea-

tures and response to treatment in pa-

tients treated in two consecutive national

trials, MRC UKALL X and XI.

ResultsThe proportion of children with

DS was significantly higher in UKALL XI

(1.9%) than UKALL X (0.9%). Childrenwith DS tended to be under 10 years and to

have the common ALL subtype. Cyto-

genetic analysis showed that favourable

features, such as high hyperdiploidy and

t(12;21) were less frequent but also that

there was a lack of translocations associ-

ated with a poor prognosis. Children with

DS showed no increase in risk of relapse at

any site but their survival and event free

survival were inferior to other children.

These results were caused by an increased

number of infective deaths during remis-

sion (11% compared to 2%). At five years

overall survival was 73% in DS children

compared with 82% in other children;event free survival was 53% compared to

63% in non-DS children.

ConclusionsEntry of children with DS

to national trials has increased and sur-

vival has improved. However they remain

at risk of relapse and also of treatment

related mortality. These findings empha-

sise the need for both intensive chemo-

therapy and optimal supportive care.(Arch Dis Child2001;85:321325)

Keywords: Down syndrome; leukemia; acutelymphoblastic leukemia; chemotherapy

Children with Downs syndrome (DS) are atincreased risk of both acute lymphoblastic leu-kaemia (ALL) and acute myeloid leukaemia(AML).1 In 1990 a review of the outcome forall children with DS and ALL who were diag-nosed in the UK between 1971 and 1986found that they often received non-standardtreatment and had a significantly worse prog-nosis than other children.2 We have now exam-ined the clinical features and outcome for thosechildren with DS and ALL diagnosed between1985 and 1997 and treated on MedicalResearch Council ALL trials to determine

whether their outlook, like those for childrenwith DS and AML,3 4 has improved.

Patients and methods

We have analysed the outcome for childrenwith DS and ALL who were treated on twoconsecutive UK protocols (MRC UKALL Xand XI) between 1985 and 1997 and comparedtheir clinical features and outcome withchildren without DS (non-DS).

Details of the two protocols have alreadybeen published; table 1 outlines the main

features of both. Patients in UKALL X (198590)5 all received daunorubicin as well as pred-nisolone, vincristine, and asparaginase duringinduction therapy and were randomised toreceive no, one, or two blocks of intensificationtherapy. All children received CNS directedtreatment with cranial irradiation and a courseof intrathecal methotrexate.

UKALL XI (199097)6 originally includedrandomisation in respect of one versus twointensification blocks, but was modified in1991 so that all patients received two blocks.Further modification was introduced in 1992(XI 92), with the omission of daunorubicin ininduction and the introduction of randomisa-tion in respect of a third prolonged intensifica-

tion block.7 Children in UKALL XI and XI92with an initial leucocyte count of less than 50 109/l were randomly assigned to receive acourse of intrathecal methotrexate injectionsand then regular intrathecal methotrexatetherapy throughout treatment or additionalhigh dose intravenous methotrexate, whilethose with a higher count were randomised tocranial irradiation and a course of intrathecalmethotrexate or high dose intravenous meth-otrexate and continuing intrathecal methotrex-ate.

Immunophenotyping of the leukaemia wasperformed locally, with a recommended panelof monoclonal antibodies and central review of

the results.

8

The leukaemias were classified asearly pre-B (CD 10 negative), common/pre-B,and T-ALL. Cytogenetics were also performedlocally and in UKALL X the results werereviewed by a reference panel,9 whereas inUKALL XI all results were reviewed at theLeukaemia Research Fund Database.10

DiVerences in clinical features, cytogenetics,and remission rate between DS and non-DSpatients were analysed using Fishers exact test(in 22 tables). The MantelHaenszel test wasused to determine trend in age and leucocytecount at presentation. KaplanMeier life tableswere constructed for survival data and were

Arch Dis Child2001;85:321325 321

MolecularHaematology Unit,Camelia BotnarLaboratories, Institute

of Child Health, 30Guilford Street,London WCIN 1EH,UK

J M Chessells

Clinical Trial ServiceUnit, Harkness

Building, RadcliVeInfirmary, OxfordOX2 6HE, UKG HarrisonS M Richards

Northern andYorkshire Region,Research School of

Medicine, 24 HydeTerrace, LeedsLS2 9LN, UK

C C Bailey

BirminghamChildrens Hospital,Steelhouse Lane,

Birmingham B4 6NH,UKF G H Hill

Royal Hospital for Sick

Children, GlasgowG3 8SJ, UK

B E Gibson

Hospital for SickChildren, GreatOrmond Street,

London WC1N 3JH,UKI M Hann

Correspondence to:Dr [email protected]

Accepted 6 July 2001

www.archdischild.com

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compared by means of the log rank test11 with

surviving patients being censored on 31 Octo-ber 2000 (UKALL XI) or 31 October 1998(UKALL X), when follow up was complete forthe vast majority of patients. The small numberof patients lost to follow up are censored at thedate they were last known to be alive.

ResultsCLINICAL FEATURES

Information about the presence of DS wasavailable for 3651 (98.6%) of the 3702 patientsentered into the trials and all comparativeanalysis has been confined to these patients.There were 55 children with DS in the twotrials, significantly more in UKALL XI with 40(1.9%) of the 2057 entrants than in UKALL Xwith 15 (0.9%) of 1594 children (p = 0.01).

Further confirmation of this improved entrywas obtained by analysis of children withleukaemia notified to the Childhood CancerResearch Group during the time of these twotrials. Between 1985 and 1990, 39% (14/36) of

children with DS and ALL were entered on theUKALL trials while in 199196, 74% (39/56)were entereda substantial and statisticallysignificant diVerence (p < 0.01) (unpublisheddata from the National Registry of childhoodtumours).

Table 2 shows the clinical features andimmunophenotype at presentation of childrenwith and without DS. There is no significantdiVerence in the proportion of males andfemales, or the distribution of leucocyte countsat presentation. The majority of children withDS were in the 29 year age group; there wereno infants under 1 year with DS and only twoaged 10 years or more.

Examination of immunophenotype showedthat all children with DS had the common orpre-B (CD10/CD 19 positive) phenotypethere were no cases of T or early pre-B (CD 10negative/CD19 positive) ALL.

Table 3 shows the results of cytogenetics.Significantly fewer children with DS had highhyperdiploid ALL (>50 chromosomes). Anumber of the most common specific cyto-genetic abnormalities such as t(9;22), t(4;11),and t(1;19) were not found in the DS group.The results of analysis for TEL/AML1, themost common genetic abnormality in acutelymphoblastic leukaemia, were only available in

Table 1 Outline of treatment in MRC UKALL X and XI

Time Treatment phase UKALL X UKALL XI XI-92 amendment

We eks 1 4 I nd uct io n D au no rub ic in d ay s 1 a nd 2, p re dn is ol on e,vincristine, intrathecal methotrexate,L-asparaginase

Same as UKALL X No daunorubicin

Weeks 58 First intensification Daunorubicin, vincristine, cytarabine,etoposide, and thioguanine for a 5 daycourse (regimens B and D)

Half randomised as in UKALL Xregimen D. All had firstintensification after May 1991

All patients had first intensification

Weeks 912 CNS directed therapy Cranial irradiation 18 Gy and course ofintrathecal methotrexate

High risk patients randomised between cranial irradiation plus intrathecalMTX versus regular intrathecal MTX plus high dose IV MTX.Randomisation between regular intrathecal MTX alone versus additional

high dose IV MTX for other patientsWeeks 13104 Continuing treatment Daily mercaptopurine, weekly

methotrexate, monthly prednisolone andvincristine

Same as in UKALL X with intrathecal MTX every 12 weeks for childrennot receiving cranial irradiation

Weeks 2024 Second intensification Same as first intensification (regimens Cand D)

All patients received second intensification

Weeks 3542 Third intensification Not applicable Not applicable Dexamethasone, vincristine,L-asparaginase, cyclophosphamide,cytarabine, and thioguanine,intrathecal methotrexate

Table 2 Comparison of clinical features in children with DS and non-DS patients

Clinical feature Total DS (%) Non-DS (%) p value

Total 3651 55 3596Sex

Male 2081 33 (60) 2048 (57)Female 1570 22 (40) 1548 (43) NS

Age (y)

01 314 2 (4) 312 (9)29 2805 51 (93) 2754 (77)10+ 532 2 (4) 530 (15) 0.05

WBC (109 /l)100 453 3 (5) 450 (13) NS

CNS involvementYes 59 1 (2) 58 (2)No 3592 54 (98) 3538 (98) NS

ImmunophenotypeT-ALL 343 0 (0) 343 (10)C/pre-B 2941 48 (87) 2893 (80)Null 124 0 (0) 124 (3) 0.01*

*T-ALLv Null/C/pre-B.

Table 3 Comparison of cytogenetic features in DS and non-DS patients

Feature Total with data DS (%)* Non-DS (%)* p value

Total 2465 39 2426Ploidy

Near-haploid 7 0 (0) 7 (


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652 patients with known DS status, and theabnormality was found in only one of the 16DS children tested and in 20% of the non-DSchildren.

RESPONSE TO TREATMENT

Table 4 compares the absolute number ofevents (relapses and deaths) in children withand without DS and the incidence of theseevents at five years. At the time of follow up,

49% of children with DS had suVered adverseevents and 38% had died. One child with DSdied from E coli septicaemia during inductiontherapy (a UKALL X patient). Six childrendied in remission, one shortly after inductionwith typhlitis. Four deaths were associated withintensification therapy and two of these werecaused by candida infection. One patient hadcombined pneumocystis and candida infec-tion. The proportion of remission deaths was

significantly higher in children with DS thanthe others (p < 0.001) but there were nosignificant diVerences in overall relapses, iso-lated or combined CNS relapses, or isolatedand combined marrow relapses between chil-dren with and without DS.

Fifteen children with DS were randomisedon UKALL XI to receive three intravenousmethotrexate infusions. Thirteen received allthree courses of methotrexate, nine without

any complications. Two children developedminor infections between the second and thirdcourses: one developed perianal blistering afterthe third course, and one developed neutrope-nia andE colisepsis after the third course. Twochildren only received two methotrexate infu-sions, one having a transient encephalopathyand one a transitory right hemiparesis and dys-phasia seven days after the second infusion.

The event free survival (EFS) for DSchildren is non-significantly inferior to that ofnon-DS children (2p = 0.1, fig 1). The EFS(95% confidence interval) for children with DSis 53% (3966%) at five years compared with63% (6165%) for all the others. Only a small

number of children with DS have beenfollowed up beyond that time, but one latemarrow relapse has been observed at over eightyears from diagnosis. There have been sevenrelapses after eight years in the non-DS group(three isolated marrow, one combined marrowand testis, one combined marrow and CNS,one CNS, and one isolated testicular relapse);two patients died in remission, one from a sec-ond malignancy (primitive neuroectodermaltumour) and one from late complications ofhigh dose therapy and bone marrow transplan-tation.

Figure 2 shows overall survival for the twogroups, with DS children having a poorerprognosis (2p = 0.007). At five years survival is73% (6184%) in children with DS and 82%(8183%) for the other children.

Formal tests of whether the gap in outcomebetween DS and non-DS children is diVerentin UKALL X compared with UKALL XI weremarginally significant (p = 0.02 for EFS;p = 0.03 for overall survival). In UKALL X DSchildren have a significantly worse prognosisthan non-DS children for both event free(p = 0.01) and overall survival (p < 0.001).However, in UKALL XI outcome for DS chil-dren is improved and the event free and overallsurvival diVerences between DS and non-DS

Table 4 Causes of treatment failure and comparative survival at 5 years in DS and non-DS patients

Events

DS (n = 55) Non-DS (n = 3596)

p valueNumber ofevents (%)

Outcome at5 years, %(95% CI)

Number ofevents (%)

Outcome at5 years, %(95% CI)

Event free survival 27 (49%) 53% (3966%) 1401 (39%) 63% (6165%) 0.1Survival 21 (38%) 73% (6184%) 799 (22%) 82% (8183%) 0.007No remission 1 (2%) Not applicable 50 (1%) Not applicable NSDeath in remission 6 (11%) 11% (320%) 88 (2%) 3% (23%) 0.1.

Figure 1 Event free survival comparing children with DS and others.

100

75

50

0

25

Years from entry

2p = 0.1

63%

53%

DS

%e

ventfree

2 3 410 5

Not DS

Figure 2 Overall sur vival in the s ame two groups of patients.

100

75

50

0

25

Years from entry

2p = 0.007

82%73%

DS

%s

tillalive

2 3 410 5

Not DS

Downs syndrome and acute lymphoblastic leukaemia 323




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children are much smaller and non-significant(p = 0.8 and p = 0.1 respectively). The relativeimprovement in outcome for DS childrenappears to be caused by a reduction in the riskof both death in remission and bone marrowrelapse (especially isolated marrow relapse). InUKALL X, three (21%) DS children died inremission and five (36%) had an isolated bonemarrow relapse; in the later UKALL XI trialthese figures were three (8%) and five (13%)

respectively.

DiscussionThese results confirm the typical clinical andbiological features of ALL in association withDS and show that the results of treatment haveimproved, although problems with manage-ment remain.

Our previous study2 of DS and ALL examined the survival of children registeredwith the Childhood Cancer Research Groupfrom 1971 to 1986. Twenty four of the 61patients either received no therapy or minimaltreatment. The remainder were treated withstandard protocols, but with many modifica-

tions. The five year survival was 28% (95% CI14.242.6%) overall; no child in the minimallytreated group survived in remission while 24%of the others remained in first remission at afollow up of two to nine years.

The present study is based on children whohave been entered into national trials andshows that relatively more children with DShave been entered into the more recentUKALL XI trial. The proportion of childrenwith DS in this trial (1.9%) is now comparablewith that reported in other series.1214 Thisfinding suggests that there has been increasedacceptance in the UK of the need for standard-ised treatment in children with DS and ALL,asfor those with AML. Nevertheless data from

the Childhood Cancer Research Group showthat one quarter of children are still not enteredinto trialsthe comparable figure for otherchildren is 1015%.

We observed a significant diVerence in theage distribution of patients with and withoutDS. Few DS children presented over 10 yearsof age, a finding confirmed by populationbased studies.1 No child with DS was under 1year at diagnosis; none had early pre-B ALL orleukaemia in association with the t(4;11). Thisis not a reflection of bias in ascertainment asinfants under 1 year were eligible for treatmenton UKALL X and no children with DS andALL have been entered into the MRC infant

protocol, which was open to entry during thetime of UKALL XI. The infrequency of ALLunder 1 year of age, and the lack of early pre-BALL has been noted in other series ofpatients.14 No children with DS in the presentseries had T-ALL, thus confirming our previ-ous observation,2 and that of others15 that ALLin children with DS is almost exclusively a dis-ease of pre-B cells.

Information about cytogenetics was avail-able in 39 of the DS patients. The main signifi-cant finding, as reported by others14 15 was thatfewer children with DS had high hyperdiploidALL. In this small series of patients there were

no cases of the more common non-randomtranslocations, t(9;22), t(1;19), and t(4;11),although other common abnormalities such asabnormal 9p and 12p were observed. Absenceof the more common translocations was notedin a combined series of children with DS fromSt Jude Childrens Hospital and the PaediatricOncology Group.15

Abnormalities of chromosome 21 are com-monly found in the leukaemic cells of children

with ALL. Indeed the most common cyto-genetic finding in paediatric ALL is the cryptict(12;21) involving the TEL gene on chromo-some 12p13 and the AML1 gene on chromo-some 21q22. This translocation has beenfound in 1636% of cases of paediatric ALL16

and in some reports it is associated with afavourable response to treatment. The t(12;21)was found in 20% of 637 non-DS samplestested but in only one of the 16 with DS. Thislow incidence concords with the results of asmall retrospective study by Lanza and col-leagues17 where none of a series of 11 patientswith DS and ALL had the rearrangement.These findings suggest that, despite the fact

that the AML1 gene is involved in the criticalDS region of chromosome 21,18 alternativemechanisms may be involved in the develop-ment of leukaemia.

Children with DS and ALL tend to lack bothfavourable and adverse prognostic factors andit appears that their risk of relapse is similar tothat of others. A large early study from theAmerican Childrens Cancer Group12 foundthat children with DS had a lower inductionrate but similar disease free survival to otherchildren. A report from the Paediatric Oncol-ogy Group evaluated outcome according totreatment intensity and found no diVerence inoutcome between DS and non-DS childrenamong more intensively treated patients.13 A

more recent publication combined data fromthis group with that from St Jude Childrensresearch hospital and failure in DS was largelycaused by treatment related toxicity.15 Modifi-cations of treatment were made in 43% of chil-dren with DS and ALL treated by theBerlinFrankfurtMunster group; these chil-dren had a worse event free survival than thosewithout treatment modifications.14

Our results show that both event free survivaland overall survival for children with DS haveimproved in comparison with the previous sur-vey from the UK. The five year survival of 28%(95% CI 1443%) observed in the previousstudy has improved to 73% (6184%), but

remains inferior to that of other children. Eventfree survival was also inferior although not sig-nificantly so, and the pattern of relapses wassimilar in DS and non-DS patients. The diVer-ence in outcome in our population was mainlycaused by remission deaths rather than relapseat any site and although there has been anoverall reduction in the numbers of deaths inremission in the most recent UKALL XI trial,the rate in DS children is still higher than innon-DS children.

Children with DS are known to be vulner-able to infection and when treated for ALLshow unusual sensitivity to methotrexate.19 We

324 Chessells, Harrison, Richards,Bailey,Hill, Gibson,Hann




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have not formally compared the toxicity expe-rienced by the DS children in UKALL XI withthe non-DS group but the majority of patientsexperienced no undue toxicity during highdose methotrexate, perhaps because of theschedule and rigid instructions for folinic acidrescue.

A more detailed analysis of mortality inUKALL X20 and UKALL XI21 has confirmedthat DS is significantly associated with risk of

infective deaths, particularly during intensifica-tion after remission induction. It is notable thatthree of the deaths in the DS children wereassociated with candida infection. The balancebetween giving suYciently intensive treatmentand avoiding excess morbidity and mortality isa diYcult one. Our results and those of othersemphasise the need for careful supervision ofthese children during treatment, prompt man-agement of suspected infection, and early insti-gation of antifungal therapy. EVorts should bemade to minimise modifications of therapy, asthe major risk of treatment failure now, as inprevious protocols, remains leukaemic relapse.

Members of the MRC Childhood Leukaemia Working Partyduring UKALL X and XI: CC Bailey, C Barton, V Broadbent,M Caswell, JM Chessells, PJ Darbyshire, SI Dempsey, JDurrant, OP Eden (Chairman), B Gibson, A Goodman, RGray, I Hann, CJ Harrison CJ, C Haworth, K Forman, F Hill,M Jenney, J Kernahan, DJ King, SE Kinsey, M Madden, JRMann, J Martin, ST Meller, C Mitchell, A Oakhill, M Radford,MM Reid, SM Richards, O Smyth, RF Stevens, A Thomas, FVargha-Khadem, AJ Vora, D Walker, D Webb, K Wheatley, AWill, K Windebank. JMC is supported by the LeukaemiaResearch Fund. We would like to thank Dr Christine Harrison,director of the LRF and UK Cancer Cytogenetics Group Data-base in Acute Lymphoblatic Leukaemia for the cytogeneticinformation and Mr Charles Stiller of the Childhood CancerResearch Group for information about national registration.

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4 Lange B. The management of neoplastic disorders ofhaematopoiesis in children with Downs syndrome. Br JHaematol2000;110:51224.

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1998;12:124955.9 Chessells JM, Swansbury GJ, Reeves B, et al. Cytogenetics

and prognosis in childhood lymphoblastic leukaemia:results of MRC UKALL X. Br J Haematol 1997;99:93100.

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12 Robison LL, Nesbit ME, Sather HN, et al. Down syndromeand acute leukemia in children: a 10-year retrospective sur-vey from Childrens Cancer Study Group. J Pediatr1984;105:23542.

13 Ragab AH, Abdel-Mageed A, Shuster JJ, et al. Clinical char-acteristics and treatment outcome of children with acutelymphocytic leukemia and Downs syndrome. A PediatricOncology Group study.Cancer1991;67:105763.

14 Dordelmann M, Schrappe M, Reiter A, et al . Downssyndrome in childhood acute lymphoblastic leukemia:clinical characteristics and treatment outcome in four con-secutive BFM trials. Berlin-Frankfurt-Munster Group.Leukemia1998;12:64551.

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17 Lanza C, Volpe G, Basso A, et al. The common TEL/AML1rearrangement does not represent a frequent event in acutelymphoblastic leukaemia occuring in children with Downsyndrome.Leukemia1997;11:8201.

18 Legare RD, Lu D, Gallagher M, et al. CBFA2, frequentlyrearranged in leukemia, is not responsible for a familialleukemia syndrome.Leukemia1997;11:211119.

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20 Wheeler K, Chessells JM, Bailey CC, Richards SM.Treatment related deaths during induction and in firstremission in acute lymphoblastic leukaemia: MRCUKALL X.Arch Dis Child1996;74:1017.

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