64 F I S I O T E R A P I E SEPTEMBER 1981 LEU K A EM IA IN CHILDREN C .D . K A R A B U S , M .B . C h.B., M .M ed .(P aed ), D .C .H ., M .R .C .P ., F R .C .P .E .* S U M M A R Y T h e tw o m a jo r v a rie tie s o f le u k a e m ia in c h ild h o o d are a c u te ly m p h o c y tic a n d a c u te m y e lo b la s tic le u k a e m ia . S u b c la s s ific a tio n o f a c u te ly m p h o c y tic le u k a e m ia has d e fin e d g r o u p s w ith a g o o d o r p o o r p ro g n o s is a n d dif~ fe r e n t tr e a tm e n t stra te g ie s are e m p lo y e d . O verall, a b o u t one th ird o f cases m a y be c ured a n d re su lts in g o o d p ro g n o sis disease are e ve n better. T h e d iffe r e n t varieties o f a cute m y e lo id le u k a e m ia a ll r e s p o n d less w e ll to tre a t­ m e n t, w ith th e m a jo r p r o b le m b e ing o n e o f m a in ten a n c e o f disease re m issio n . C u rr e n t tre a tm e n t o f b o th fo r m s o f le u k a e m ia are o u tlin e d . A lth o u g h a d v a n c e s in the m a n a g e m e n t o f c h ild h o o d le u k a e m ia , in p a rtic u la r the ly m p h o c y tic v a rie ty , h a v e b e en tr u ly r e m a r k a b le o v er th e p a st th ir ty years, fu r th e r p ro g ress is necessary. G rea te r r e fin e m e n t o f c h e m o th e ra p y o r th e use o f b one m a r ro w tra n sp la n ta tio n are th e lik e ly a v e n u e s f o r f u tu r e im p r o v e m e n t in p rognosis. T h e h is to ry o f le u k a e m ia is a fa irly s h o r t o n e . T h e e a rly n in e te e n th c e n tu ry F r e n c h m e d ic a l lite r a tu r e c o n ­ ta in s re p o rts o f p a tie n ts w ith fe a tu re s su g g e stiv e of le u k a e m ia . H o w e v e r, th e sig n ific a n c e o f th e fin d in g s w as re a liz e d in 1874 by B e n n e tt in E d in b u r g h a n d th e g re a t R u d o lf V irc h o w in B e rlin w h o a lm o st s im u l­ ta n e o u s ly p u b lis h e d a c c o u n ts o f p a tie n ts w ith la rg e sp le en s a n d a p e c u lia r a p p e a ra n c e o f th e b lo o d . In e ac h c ase th e re w e re m a n y m o re w h ite th a n re d co rp u scle s. V irc h o w u se d th e d e sc rip tiv e te rm o f W eisses B lut w h ic h , tra n s la te d in to G re e k a few y e a rs la te r, b e c a m e le u k a e m ia . I n 1870 N e u m a n n re c o g n iz e d t h a t le u k a e m ia w as a d ise ase o f th e b o n e m a rro w . N o t r e a tm e n t w as a v a ila b le u n til F a r b e r a n d c o lle a g u e s (1948) a t th e B o sto n C h ild r e n ’s H o s p ita l, a c h ie v e d th e firs t c o m p le te re m issio n o f a c u te le u k a e m ia w ith th e d ru g a m in o p - te rin . T h is w as th e s ta r t o f a c h e m o th e ra p e u tic a tta c k o n c a n c e r o f a II ty p es w hich h a s b e e n n o ta b ly su c c ess­ ful in c h ild re n . T o d a y it is p o ssib le t h a t o n e t h ir d of c h ild h o o d c ases o f a c u te ly m p h o c y tic le u k a e m ia m a y be c u re d o f th e ir dise ase (G e o rg e e t al., 1979). L e u k a e m ia is a m a lig n a n c y o f t h e b lo o d -fo rm in g o rg a n s a n d a ffe c ts p rim a rily th e b o n e m a rro w , liver, sp le e n a n d ly m p h n o d e s. A n u n c o n tro lle d in c re a s e of w h ite b lo o d cells a n d th e ir p re c u rso rs o c c u rs in th e s e a n d o th e r b o d y tissues. In th e b lo o d th e re a re u su a lly o b ­ v io u s c h a n g e s a lth o u g h th e n u m b e r o f le u c o c y te s is o f te n n o t in c re a s e d . H o w e v e r, th e fin d in g o f p rim itiv e o r b la s t cells in th e b lo o d is su g g e stiv e o f a c u te le u ­ k a e m ia . A b o u t 2 0 % o f all le u k a e m ia s o c c u r in c h ild re n , w ith th e g re a te s t m o r ta lity b e tw e e n 2 a n d 5 y e ars o f age. L e u k a e m ia is th e c o m m o n e s t c a n c e r o f c h ild h o o d , in c o n tra s t to a d u lts , w h e re solid tu m o u rs su c h as b re a s t a n d lu n g c a n c e r o c c u r m o re fre q u e n tly . N e v e rth e le ss , it is n o t as c o m m o n in c h ild re n as th e p u b lic ity g iv en to it m a y su g g e st. L e u k a e m ia a ffects a b o u t 4 p e r 100 000 o f th e c h ild h o o d p o p u la tio n p e r y e a r in th e U S A . If th e in c id e n c e h e r e is th e sa m e, w hich is n o t k n o w n , th e re m a y b e 4 0 0 n e w cases p e r y e a r in th e R e p u b lic . T h e c au ses o f h u m a n le u k a e m ia a re u n k n o w n . A g e n etic p re d is p o sitio n , ra d ia tio n o r c h e m ic a ls a n d v ira l in fe c ­ tio n s a re fa c to rs to w h ic h m o s t a tte n tio n h a s b e e n given. T h e p o ss ib ility o f a g e n e tic basis fo r h u m a n le u k a e m ia * H a e m a to lo g y /O n c o lo g y S e rv ice , R e d C ro ss W a r M e m o ria l C h ild r e n ’s H o s p ita l a n d D e p a r tm e n t of P a e d ia tric s , U n iv e rs ity o f C a p e T o w n . R e ce iv e d 1 M a y 1981. O P S O M M IN G D ie tw ee h o o fg r o e p e le u k e m ie in k in d e rs is a k u te lim fo s itie s e en a k u te m ie lo b la stie s e le u k e m ie . S u b k la s si- fis e r in g van a k u te lim fo s itie s e le u k e m ie h e t g ro e p e m e t ’n g o e ie o f 'n s w a k p ro g n o s e o n d e r s k e i e n v e rskillen d e b e h a n d e lin g e w o r d g e b r u ik . I n d ie a lg e m e e n k a n een- d e rd e van g evalle g e n ee s w o rd en in g o e ie p ro g n o se g ro e p e is re su lta te s e lfs beter. D ie v e r s k ille n d e groepe van a k u te m ie lo ie d e le u k e m ie reageer m in d e r g o e d o p b e h a n d elin g , w aar die h o o fp r o b le e m die in s ta n d h o u d in g van sie k te r e m is sie is. D ie h u id ig e b e h a n d e lin g v a n beide v o r m s v an le u k e m ie w o r d o m s k r y f. H o e w e l v o o ru itg a n g in die h a n terin g v a n le u k e m ie in k in d e rs, veral in die lim fo s itie s e g ro e n , w a a rlik m e r k w a a r d ig w a s g e d u r e n d /^ d ie a fg e lo p e d e rtig jaar, is v e r d e re v o o ru itg a n g n o d ii V e r fy n in g van c h e m o te r a p ie o f die g e b r u ik van b een- m u r g o o r p la n tin g is d ie m e e s w a a r s k y n lik e rig tin g s van to e k o m s tig e v e r b e te r in g v a n p ro g n o se . is o f g re a t c o n c e rn to p a re n ts o f a c h ild w ith th e dise ase. F a m ilie s c a n be re a ss u re d th a t le u k a e m ia is d e fin ite ly n o t in h e rite d th ro u g h a m u ta n t g e n e as in h a e m o p h ilia . T h e re seem s, h o w e v e r, to b e a slig h tly in c re a s e d p re d is p o s itio n to d e v e lo p a c u te le u k a e m ia in close re la tiv e s o f a n a ffe c te d c h ild . F a m ilia l cases o f th e d ise ase a re in fa c t so ra re t h a t th is p o s s ib ility n e ed n o t b e ta k e n in to a c c o u n t w h e n f u tu r e p re g n a n c ie s a re c o n sid e re d . A g e n e tic fa c to r in c a u s a tio n o f le u k a e m ia se e m s to b e o p e ra tiv e in c h ild re n w ith D o w n ’s s y n d ro m e a n d in th e id e n tic a l tw in of a c h ild w ith le u k a e m ia w h o h a s a v e ry h ig h risk o f d e v e lo p in g th e d ise ase s h o rtly a f te r his sib lin g (M ille r 1967). T h e b e st e sta b lish e d c a u s e in h u m a n le u k a e m ia is io n is in g r a d ia ­ tio n , such as X -ra y s o r a to m ic r a d ia tio n . A b o u t 250 cases o f le u k a e m ia o c c u rre d in th e p o p u la tio n of H iro s h im a a n d N a g a s a k i w ho w ere e x p o se d to ra d ia tio n . P a tie n ts g iv e n ra d ia tio n th e r a p y also h a v e a h ig h e r i n ­ c id e n c e o f le u k a e m ia . H o w e v e r, su c h e x p o su re s o c c u r o n ly in v e ry u n u s u a l c irc u m s ta n c e s a n d th e re is no ev id e n c e t h a t the tin y d o se o f r a d ia tio n to w h ic h o r ­ d in a ry p e o p le a re ex p o se d , in c lu d in g d ia g n o s tic X -ra y s, c a n c au se le u k a e m ia . V iru se s h a v e b e e n id e n tifie d le u k a e m ia o f fow ls, m ic e , ra ts , c ats a n d o th e r a n im f , b u t so fa r n o h u m a n le u k a e m ia v iru se s h a v e b e e n d e ^ m o n s tra te d . H o w viruses c au se le u k a e m ia in a n im a ls is n o t c e rta in . K a p la n (1974) h a s su g g e ste d t h a t th e y d o so in c o n c e rt w ith the a n im a l’s g e n e tic s u s c e p tib ility a n d p o ssib ly o th e r e x te rn a l trig g e r fa c to rs. T h e v iru se s c au sin g le u k a e m ia , e x c e p t fo r th o s e o f th e c a t a n d so m e fow l le u k a e m ia s , a re n o t in fe c tio u s in th e o r d in a r y sen se of b e in g a b le to s p re a d to o th e r a n im a ls . I t d oes n o t seem th a t a le u k a e m ia v iru s c a n b e p a sse d to o th e r species:' it is v irtu a lly c e rta in t h a t h u m a n s d o n o t get le u k a e m ia fro m in fec te d c ats (H a n e s et al., 1970). L e u k a e m ia s a re c la ss ifie d a c c o rd in g to th e p r e d o m i­ n a n t c ell ty p e a n d th e u n tr e a te d c lin ic a l c o u rse , a c u te o r c h ro n ic . C h ro n ic le u k a e m ia is ra re in c h ild h o o d a n d th e tw o m a jo r p a e d ia tric ty p es a re th u s a c u te ly m p h o ­ c y tic a n d a c u te m y e lo id (or g ra n u lo c y tic ) le u k a e m ia s . P r io r to 1948 th e su rv iv a l o f a n e w ly d ia g n o s e d p a tie n t w ith a c u te le u k a e m ia w as se ld o m lo n g e r th a n 4 m o n th s . C L IN IC A L P R E S E N T A T IO N O F A C U T E L E U K A E M IA T h e r e a re th re e m a jo r g ro u p s o f p re s e n tin g signs a n d sy m p to m s in le u k a e m ia : n o n s p e c ific sy ste m ic effe c ts, R ep ro du ce d by S ab in et G at ew ay u nd er li ce nc e gr an te d by th e P ub lis he r (d at ed 2 01 3. ) SEPTEMBER 1981 P H Y S I O T H E R A P Y 65 fe a tu re s re la te d to in v a s io n o f th e b o n e m a rro w a n d those d u e to in filtra tio n o f o rg a n s o th e r th a n th e b o n e m arro w . F e v e r is th e c o m m o n e s t sy s te m ic c o m p la in t a n d m a y in itia lly b e m is d ia g n o se d as a n in fe c tio n , w h ich in fa c t n o t in f r e q u e n tly c oexists. T h e b o n e m a rro w u su a lly is v irtu a lly c o m p le te ly re p la c e d b y le u k a e m ia b la s t cells a n d th is in te rfe re s w ith n o rm a l b lo o d fo r ­ m a tio n . D e c re a se d re d cell p ro d u c tio n re su lts in a n a e m ia w ith its s y m p to m s o f p a llo r, le th a rg y a n d b re a th le s s ­ ness. Im p a ire d p la te le t p r o d u c tio n m a y le a d to p u rp u ra , easy b ru isin g a n d b le e d in g f r o m th e n o s e a n d gum s. In fe c tio n s a re f r e q u e n t o w ing to lac k o f p r o d u c tio n o f n o rm a l w h ite cells. In v a s io n o f o th e r o rg a n s m a y c au se e n la rg e m e n t o f liv e r, sp le e n o r ly m p h n o d e s w h ile less o fte n in v o lv e m e n t o f th e b r a in ,or testis m a y b e th e p re se n tin g f e a tu re . B o n e p a in o r re fu s a l to w alk in y o ung c h ild re n is a c o m m o n sy m p to m a n d o c c u rs in a b o u t 2 5 % o f cases. I t m a y be m is ta k e n fo r rh e u m a tic fe v er (S c h a ller, 1972) o r e v en a n o ste itis. D IA G N O S IS 7 T h e h a llm a rk o f a c u te le u k a e m ia is th e b la s t cell, a n im m a tu re o r p rim itiv e ly m p h o c y te o r g ra n u lo c y te . T h e d ia g n o s is m a y b e su s p e c te d fro m th e b lo o d fin d ­ ings. A n a e m ia a n d th ro m b o c y to p e n ia a re u su a l. T h e w h ite cell c o u n t m a y b e v e ry m u c h ra is e d a b o v e th e n o rm a l 4 0 0 0 - 12 OOU/rnm3 a n d in th ese c ases b last cells a re u su a lly o b v io u s. H o w e v e r, in m a n y c ases th e n u m ­ b e r o f w h ite b lo o d c ells is n o rm a l o r low a n d th e b la s t cells m a y n o t b e p ro m in e n t. A s p ira tio n o f cells fro m th e b o n e m a rro w is m a n d a to ry fo r c o n firm in g th e d ia g ­ nosis. In m o s t c ases th e m a rro w is p a c k e d w ith leu- k a e m ic b la s ts w h ile n o rm a l m a rro w cells a re d e c re a s e d o r a b se n t. T h e se c o n d ste p a f te r e sta b lish in g th e d ia g n o s is is to d istin g u ish b e tw e e n a c u te ly m p n o c v tic le u k a e m ia (A L L ) a n d a c u te m y e lo id le u k a e m ia (A M L ). T h is m a y be p o ss ib le fro m th e a p p e a ra n c e o f th e b la s t cells b u t in so m e cases sp e c ia l c y to c h e m ic a l sta in s a re n e c e ssa ry to d if f e r e n tia te th e tw o v a rie tie s. T h e d is tin c tio n is im ­ p o rta n t. D ru g s e ffe c tiv e in A L L a re g e n e ra lly o f little use in A M L a n d , o f m o re re le v a n c e to th e p a tie n t, th e p ro g n o sis fo r A L L is m u c h b e tte r th a n t h a t o f A M L . T h e fin al d ia g n o s tic ste p is th a t o f su b c la s sify in g th e a c u te le u k a e m ia s . Acute L ym p h ocytic L eukaem ias ̂ A L L h a s b e e n su b d iv id e d in to th r e e ty p e s (L I , L2 a n d L3) b a s e d o n th e a p p e a ra n c e o f th e b la s t cells (B e n n ett er al., 1976). T h is c la ss ific a tio n is re p ro d u c ib le an d a p p e a rs to in d ic a te a p ro g re s siv e ly p o o r e r p ro g n o sis. F o rtu n a te ly , th e L I v a rie ty w h ic h c a rrie s th e b e st p ro g n o sis is th e ty p ic a l fo rm o f c h ild h o o d A L L . Im ­ m u n e stu d ie s h a v e a lso d e sig n a te d th re e classes o f A L L : th o se w ith T -c e ll m a rk e rs , B-cell le u k a e m ia a n d le u ­ k a e m ia w ith o u t e ith e r m a rk e r, th e s o -c a lle d n u ll-c ell disease. N u ll-c e ll A L L h a s a m u c h b e tt e r p ro g n o sis th a n e ith e r th e T - o r B -cell v a rie tie s. I t to o is th e c o m ­ m o n e s t c h ild h o o d v a rie ty , o c c u rrin g in a b o u t 8 0 % of cases. T h e fin d in g t h a t A L L is a h e te ro g e n o u s dise ase, h as led to th e d e v e lo p m e n t o f d if f e r e n t tr e a tm e n t s tr a te ­ gies. M o re in te n siv e th e ra p y is g iv en to th e v a rie tie s w ith a w o rs e p ro g n o sis. So f a r, u n f o r tu n a te ly , th is h a s n o t im p ro v e d th e o u tlo o k fo r th e c h ild w ith p o o r p ro g ­ no sis A L L . T h e p re s e n tin g f e a tu re s w h ic h a ffe c t th e p ro g n o sis in A L L a re given in T a b le 1. In a d d itio n g in s h a v e a b e tte r c h a n c e of c u re th a n b o y s a n d , in th e U S A as w ell as in o u r e x p erien c e , b la c k c h ild re n re s p o n d less well to t r e a tm e n t t h a n d o w h ites. T h e re d o e s n o t se e m to b e a n y d iffe re n c e in th e re s p o n s e of c o lo u re d o r w h ite c h ild re n (K a ra b u s a n d H a rtle y , 1981). A cu te M y elo id L eukaem ia T h e r e a re se v e ra l d iffe re n t m o rp h o lo g ic a l v a rie tie s o f A M L , d e p e n d in g o n th e p r e d o m in a n t cell p re s e n t. A c u te m y e lo b la s tic , p ro m y e lo c y tic , m y e lo m o n o c y tic , m o n o c y tic a n d e ry th ro le u k a e m ia a re th e m a in ty p es. In g e n e ra l a ll ty p es re s p o n d less w ell to c h e m o th e ra p y th a n th e ly m p h o c y tic leuK aem ias. In m o st p u b lis h e d stu d ie s o n ly a b o u t 1 5 % . o f c h ild re n w ith a c u te le u k a e m ia h a v e A M L w h ile 8 0 % h a v e A L L . H o w e v e r th e in c id e n c e o f A M L m a y b e h ig h e r in b la c k c h ild re n . In a series o f 258 c h ild re n se e n a t th e R e d C ro ss C h ild r e n ’s H o s p ita l, w h ic h in c lu d e d 48 b la c k p a tie n ts , 3 0 % A M L a n d 64'% A L L . ( K a ra b u s a n d H a rtle y , 1981). M A N A G E M E N T O ne o f th e m o s t im p o r ta n t fa c to rs d e te rm in in g w h e th e r a ch ild w ith c a n c e r su rv iv e s his illness is w here he is n e a le d . As c h ild h o o d c a n c e r is re la tiv e ly u n c o m ­ m o n , p a tie n ts sh o u ld be re fe r r e d im m e d ia te ly to a c h ild r e n ’s c a n c e r c e n tre . S tu d ie s in b o th th e U S A (F a rb e r, 1966) a n d B rita in (W itts, 1971) in d ic a te th a t th e o u tlo o k fo r a ch ild tr e a te d a t a n e x p e rie n c e d p a e d ia tr ic c e n tre is m u c h b e tte r t h a n th a t o f th e p a tie n t tre a te d b y p a e d ia tric ia n s w ith o u t s p e c ia l e x p e rtis e in c a n c e r m a n a g e m e n t. T h e m a n a g e m e n t o f a c h ild w ith le u k a e m ia in v o lv e s g e n e ra i su p p o rtiv e c are , t r e a tm e n t of le u k a e m ic effects su c h as a n a e m ia , b le e d in g a n d in fe c tio n a n d a sp e c ific a tta c k o n th e p rim a ry d ise ase itself. G en eral Supportive Care In o rd e r to re m o v e u n c e r ta in ty a n d a tte m p t to a lla y a n x ie ty , t h e d ia g n o s is sh o u ld b e e sta b lish e d p ro m p tly a n d c o m p le te ly . I t s h o u ld th e n be d isc u sse d fu lly , o p e n ly a n d h o n e s tly w ith b o th p a re n ts . D e p e n d in g on his age, th e p a tie n t s h o u ld a lso b e g iv e n so m e e x p la ­ n a tio n o f h is c o n d itio n . T h e fa m ily s h o u ld b e to ld a b o u t th e n a tu r e o f le u k a e m ia , its su s p e c te d c au ses a n d w h a t th e t r e a tm e n t a n d th e c o u rse o f th e illness is lik e ly to be. P o te n tia l sid e -e ffe c ts o f th e th e ra p y s h o u ld b e T A B L E I. P ro g n o s tic fe a tu re s in a c u te ly m p h o c y tic leu k a em ia. F ea tu re G o o d B a d A g e in y e ars 3 - 6 U n d e r 1, o v e r 10 C e ll ty p e L I L 2 o r L3 I m m u n o lo g ic m a rk e rs N u ll T o r B W h ite c ell c o u n t Less th a n 10 000 M o re t h a n 50 000 M a rro w a fte r 14 d a y s tre a tm e n t R e m iss io n N o re m iss io n Im m u n o g lo b u lin s N o rm a l D e c re a se d R ep ro du ce d by S ab in et G at ew ay u nd er li ce nc e gr an te d by th e P ub lis he r (d at ed 2 01 3. ) 66 F I S I O T E R A P I E SEPTEMBER 1981 m a d e k n o w n p r i o r to th e i r o c c u rre n c e . T h e p a e d ia t r i­ c ia n sh o u ld a tte m p t to re d u c e g u ilt fe e lin g s in th e p a r e n ts a n d re a s s u re th e m t h a t th e d ise a s e is n o t h e re d ita ry , c o n ta g io u s o r th e re s u lt o f a n y la c k of p a re n ta l c a re . H o s p ita lis a tio n s h o u ld b e as b r ie f a s p o s ­ sib le — m a in ly to e s ta b lish th e d ia g n o s is a n d d u rin g p e rio d s o f h a z a rd o u s in fe c tio n o r b le e d in g . O n c e in r e ­ m issio n th e c h ild s h o u ld b e tre a te d as a n o rm a l p e rso n , a tte n d sc h o o l a n d p a r tic ip a te in a ll h is f o r m e r a c tiv itie s. T h e tre a tin g p a e d ia tr ic ia n s h o u ld m a k e h im s e lf e asily a cc essib le to th e p a r e n ts if th e y w ish to d isc u ss a p ro b le m o r r e q u e s t f u r th e r in fo rm a tio n . L eukaem ic Supportive Care C h ild re n p re s e n tin g w ith le u k a e m ia a re o fte n a n a e m ic a n d b le e d in g . T r a n s fu s io n s o f p a c k e d re d cells o r p la te ­ le ts m a y b e n e c e ssa ry . F e v e r is c o m m o n ly p r e s e n t a n d , a lth o u g h it m a y b e d u e to th e d ise ase a n d n o t a n in ­ fe c tio n , it is w ise to tr e a t a ll su c h p a tie n ts w ith b ro a d s p e c tru m in tra v e n o u s a n tib io tic s . F a ilu r e to d o so m a y re s u lt in d e a th fro m se p tic a e m ia as th e c h ild in re la p se c a n n o t c o m b a t in fe c tio n s e ffe c tiv e ly . T ra n s fu s io n s o f w h ite b lo o d c ells m a y b e u se fu l. I n itia lly , m e ta b o lic c o m p lic a tio n s m a y le a d to k id n e y fa ilu r e a n d e le c tro ­ ly te d is tu rb a n c e s w h ic h s h o u ld b e p re v e n te d . Sp ecific T reatm ent o f L e u k a e m ia In th e 30 y e a rs sin c e F a r b e r ’s re p o rt, c h e m o th e ra p y h a s re v o lu tio n is e d th e t r e a tm e n t o f le u k a e m ia . T h e first a n d m o s t im p o r ta n t g o a l o f tr e a tm e n t is to a c h ie v e a c o m p le te re m is s io n o f dise ase. T h is o c c u rs w h e n th e p a tie n t, h is b lo o d p ic tu r e a n d b o n e m a rro w a re a ll n o rm a l. I t d o e s n o t, h o w e v e r, m e a n a c u re , th e u lti­ m a te a im o f th e ra p y . T h e re m iss io n m u s t b e m a in ta in e d fo r a p ro lo n g e d p e rio d in o r d e r to c u re le u k a e m ia . O n c e re m iss io n is e n d e d b y re la p se o f dise ase, th e p o s ­ sib ility o f c u re b y c h e m o th e ra p y b e c o m e s re m o te a n d o t h e r t r e a tm e n t m o d a litie s su c h as b o n e m a rro w tr a n s ­ p la n ta tio n s h o u ld b e c o n sid e re d . A c u te L ym p h ocytic L eukaem ia I n a ll ty p e s o f c h ild h o o d A L L , re m iss io n s c a n u s u a l­ ly b e in d u c e d easily . T h e s ta n d a rd re g im e n o f p r e d n i­ so n e , v in c ris tin e a n d a s p a ra g in a s e is e ffe c tiv e in 9 5 % o f p a tie n ts a n d re m is s io n is u su a lly a c h ie v e d w ith in f o u r w eeks. T h e s e d ru g s a re th e n d is c o n tin u e d a n d th e se c o n d p h a s e o f tr e a tm e n t, th a t o f c e n tra l n e rv o u s sy ste m (C N S ) p ro p h y la x is th e n b e g in s. C N S p r o p h y ­ laxis, in tro d u c e d a b o u t te n y e ars a g o , h a s b e e n a n im p o r ta n t ste p in in c re a s in g th e c u re r a te o f c h ild h o o d A L L . C ra n ia l r a d io th e r a p y is g iv en w ith in tra th e c a l in je c tio n s o f m e th o tr e x a te fo r a p e rio d o f tw o to th re e w eeks. B e c a u se o f o c c a sio n a l u n d e s ira b le sid e -effe cts, in c lu d in g im m u n e s u p p re ss io n , le a rn in g d is a b ility a n d e v en b ra in d a m a g e , stu d ie s h a v e b e e n u n d e r ta k e n in a n a tte m p t to re d u c e to a m in im u m th e a m o u n t o f C N S tr e a tm e n t n e e d e d to p re v e n t lo c a l le u k a e m ia . T h e d o se o f r a d io th e r a p y h a s b e e n su c c e ss fu lly re d u c e d by 2 5 % (N e s b it e t al., 1981) a n d in c h ild re n w h o s e in itial p re s e n tin g sig n s in d ic a te a g o o d p ro g n o sis, r a d io th e ra p y m a y b e o m itte d a lto g e th e r. T h e fin a l p h a s e o f tre a tm e n t is c o n tin u a tio n th e ra p y . I n m o s t re g im e n s th is in clu d e s 6 -m e rc a p to p u rin e a n d m e th o tre x a te , b o t h g iv e n b y m o u th . P a tie n ts s h o u ld b e m o n ito r e d f r e q u e n tly w h ile o n tr e a tm e n t a n d th e d o se s a d ju s te d as in d ic a te d b y th e b lo o d c o u n t. T h e r a p y is u s u a lly c o n tin u e d f o r 2$ to 3 y e ars. A b o u t 5 0 % o f c h ild re n w ith A L L c a n b e e x p e c te d to c o m p le te th e c o u rse o f tr e a tm e n t w ith o u t re la p se . In a series o f 46 c h ild re n o f a ll ra c e s t r e a te d a t th e R e d C ro ss C h ild r e n ’s H o s p ita l b e tw ee n 1970 a n d 1975, 20 c o m p le te d th e ra p y (K a ra b u s a n d H a rtle y , 1981). A n o th e r 2 0 % can b e e x p e c te d to re la p se su b ­ s e q u e n tly , u s u a lly w ith in th e firs t y e a r o r tw o a fte r s to p p in g tre a tm e n t. T h is fig u re is n o t re d u c e d b y c o n ­ t in u in g th e r a p y b e y o n d th r e e y e ars. I n boys, re la p se n o t in fre q u e n tly in v o lv e s th e te ste s, w h ic h s h o u ld b e b io p s ie d b e fo re sto p p in g th e ra p y . I f le u k a e m ic in v o lv e ­ m e n t is fo u n d , th e teste s s h o u ld b e irr a d ia te d and c h e m o th e ra p y c o n tin u e d t o r a l u r i h e r tw o years. A f te r f o u r y e a rs o ff tre a tm e n t, a c h ild w ith A L L is p r o b a b ly c u re d (G e o rg e e t al., 1979), B a d -p ro g n o sis A L L C h ild re n w ith p re s e n tin g signs in d ic a tin g a p o o r p ro g n o s is (T a b le 1) a re g e n e ra lly g iv en a m o re in te n siv e c o u rs e o f c h e m o th e ra p y . A lth o u g h re m iss io n s a re u su a lly a c h ie v e d , e a rly re ­ la p s e a n d d e a th is still th e u s u a l o u tc o m e . A c u te M y e l o id L e u k a e m ia T h e p h a se s o f tre a tm e n t a re th e sa m e as fo r A L L b u t th e re s u lts less su c c essfu l. R e m is s io n in d u c tio n d ru g s m o s t o fte n in c lu d e c y to s in e a ra b in o s id e , d a u n o ru b ic in a n d so m e tim e s o th e rs su c h as th io g u a n in e a n d a z a c y ti- d in e. O n ly 6 0 - 70% a c h ie v e a re m iss io n . C N S p r o p h y l­ a x is is s im ila r to t h a t u se d in A L L b u t th e m a jo r p ro b le m is th e in a b ility o f c h e m o th e ra p y to m a in ta in th e re m is­ sion. A lth o u g h th e b e s t re su lts (W ein stein e t al., 1980) in ­ d ic a te th a t a b o u t 2 5 % o f p a tie n ts a re a b le to s to p tr e a tm e n t, u p to n o w few h a v e su rv iv e d fo r lo n g e r th a n fiv e y e a rs fro m d iag n o sis. O ther M od es o f T reatm ent in L eukaem ia I m m u n o th e r a p y . A n im m u n e a tta c k on le u k a e m ia w ith e ith e r tu b e rc u lo s is v a c c in e as a n o n s p e c ific im m u n e s tim u la n t o r tre a te d le u k a e m ia cells h a s n o t b e e n p ro v e d su c c essfu l. B o n e M a r r o w T r a n sp la n ta tio n . P ro m isin g re su lts h a v e b e e n re p o rte d b y T h o m a s e t al., (1979) a n d th is p ro c e ­ d u r e sh o u ld c e rta in ly b e c o n s id e re d in c h ild re n w h o h a v e re la p s e d o n c h e m o th e ra p y . T r a n s p la n ta tio n is m u c h m o re su c c e ssfu l if d o n e d u rin g le u k a e m ic re m is ­ sio n . I m m u n e in c o m p a ta b ility b e tw e e n d o n o r a n d re?, c ip ie n t is a m a jo r b a r ri e r to su c c ess a n d th e c o m p l i c / tio n a n d m o r ta lity r a te o f th e p r o c e d u r e is h ig h . ^ P ro g re s s in th e t r e a tm e n t o f c h ild h o o d le u k a e m ia , e sp e c ia lly th e ly m p h o c y tic v a rie ty , h a s b een r e m a rk a b le in th e p a s t 30 y e ars. Im p ro v e m e n ts in th e c h e m o th e ra p y o f p o o r p ro g n o sis A L L as w e ll as t h a t o f re m iss io n m a in te n a n c e o f A M L a re g re a tly n e ed e d . M o re effe c tiv e u se o f e x is tin g d ru g s as w ell as th e d e v e lo p m e n t of n e w a g e n ts m a y b o th c o n tr ib u te t o g re a te r success. F u r t h e r d e v e lo p m e n t a n d u n d e rs ta n d in g o f m a rro w tr a n s p la n t a tio n s h o u ld in c re a s e th e c u re r a te e ven f u r ­ th e r. R eferen ces B e n n e tt, J. M ., C a to v s k y , D ., D a n ie l, M -T ., F la n d r in , G ., G a lto n , D . A . G ., G ra ln ic k , H . R . a n d S u lta n , C. (1976). P ro p o s a ls f o r th e c la ss ific a tio n o f th e a c u te le u k a e m ia s : F re n c h -A m e ric a n -B ritis h (F A B ) c o -o p e r­ a tiv e g ro u p , B r. J. H a e m a to l, 33, 451 - 458. F a r b e r, S., D ia m o n d , L. K ., M e rc e r, R . D ., S ylvester, R . F . a n d W o lff, J. A . (1948). T e m p o r a r y re m issio n s in a c u te le u k a e m ia in c h ild re n p ro d u c e d b y fo lic a c id a n ta g o n is t 4 - a m in o p te ro y lg lu ta m ic a cid . N e w E n g l. J. M e d , 283, 787 - 793. R ep ro du ce d by S ab in et G at ew ay u nd er li ce nc e gr an te d by th e P ub lis he r (d at ed 2 01 3. ) SEPTEMBER 1981 P H Y S I O T H E R A P Y 67 F a r b e r, S. (1966). C h e m o th e ra p y in th e tre a tm e n t of le u k a e m ia a n d W ilm s tu m o u r. J .A .M . A . , 198, 826 - 828. G e o rg e, S. L., A u r, R. J. A ., M a u e r. A . M . a n d S im one, J. V. (1979). A r e a p p ra is a l o f th e r e s u lts o f sto p p in g th e ra p y in c h ild h o o d le u k a e m ia . N e w E n g l. J. M e d ., 300, 2 6 9 - 2 7 3 . H a n e s, B., G a r d n e r , M . B., L o o sli, C . G ., H e id b re d e r, G ., K o g a n , B ., M a ry la n d e r, M . a n d H e u b n e r. R . J. (1970). P e t a sso c ia tio n s w ith se lected h u m a n cancers: A h o u se h o ld q u e s tio n n a ire survey. J. N a ll. C a n c er In st., 45, 1 1 5 5 - 1162 K a p lan , H . S. (1974). L e u k a e m ia a n d ly m p h o m a in ex­ p e rim e n ta l a n d d o m e s tic a n im a ls . Ser. H a e m a t o l , 7, 94 - 103. K a ra b u s , C. D . a n d H a rtle y , P . S. (1981). P ro g n o s is in a c u te ly m p h o c y tic le u k a e m ia . S u b m itte d to S A M e d i­ cal C ongress, P re to ria . M iller, R . W . (1967). P e rso n s w ith e x c e p tio n a lly h ig h risk o f le u k a e m ia . C a n c e r R e s ., 27, 242 0 - 2423. N e sb it. M . E ., S a th e r, H . N ., R o b iso n , L. L ., O rte g a, J., L u tm a n , P. S., D ’A n g io , G . J. a n d H a m m o n d , G . D . (1981). P re s y m p to m a tic c e n tra l n e rv o u s system th e ra p y in p re v io u s ly u n tre a te d c h ild h o o d a c u te ly m ­ p h o b la s tic leu k a e m ia : C o m p a ris o n o f 1 800 r a d a n d a n d 2 400 r a d . L a n c e t 1, 461 - 466. S c h a lle r, J. (1972). A rth ritis as a p re s e n tin g m a n if e s ta ­ tio n o f m a lig n a n c y in c h ild re n . J. P ediatr., 81, 793 - 795. T h o m a s, E . E)., S a n d e rs, J. E ., F lo u r n a y , N ., J o h n s o n , F . L ., B u c k n er, C. D ., C lift, R . A ., F e fe r, A ., G o o d e ll, B. W ., S to rb , R . a n d W e id e rn , P. L . (1979). M a r r o w tra n s p la n ta tio n f o r p a tie n ts w ith a c u te ly m ­ p h o b la s tic le u k a e m ia in re m issio n . B lo o d , 54, 468- 476. W ein stein , H . J., M a y e r, R . J., R o s e n th a l, D . S., C a m itta , B. M ., C o ra l, F . S., N a th a n , D . G . a n d F re i, E . (1980). T re a tm e n t o f a c u te m y e lo g e n o u s le u ­ k a e m ia in c h ild re n a n d a d u lts. N e w E ngl. J. M e d ., 303, 473 - 478. W itts, L . J. a n d o th e rs (1971). D u r a tio n o f su rv iv a l of c h ild re n w ith a c u te le u k a e m ia . B rit. M e d . / . , 4, 7 - 9 . T H E CHILD WITH HAEM O PH ILIA C. D . K A R A B U S , M .B . C h.B ., M .M e d . (P aed ), D .C .H .,M .R .C .P ., F .R .C .P .E .* S U M M A R Y H a e m o p h ilia s are b lee d in g d iso rd e rs d u e to an in ­ h e rite d d e fe c t in p r o d u c tio n o f c lo ttin g fa cto rs. I n S o u th A fr ic a 867 h a e m o p h ilia c s h a v e been re g istered a n d 309 o f these are b o y s u n d e r 15 y e a r s o f age. H a e m o p h ilia A a n d B m a k e up a b o u t 85 - 9 0 % o f a ll cases. T h e y are in h e r ite d in a s e x -lin k e d m a n n e r a n d th u s a ffe c t m a le s o n ly . T h e m a n ife s ta tio n s o f h a e m o p h ilia are due to b leeding chara c te ristica lly in v o lv in g the jo in ts. T he d iso rd er v aries in se v e rity a n d in th e m o s t se v ere ly a ffe c te d ch ild re n , re p e a te d h a e m a rtliro se s m a y lea d to crippling. E arly a d m in istra tio n o f c lo ttin g fa c to r, p r e ­ fera b ly g iv e n a t th e c h ild ’s h o m e , p h y s io th e r a p y to p re v e n t m u sc le w a stin g a n d reg u la r a ss e s sm e n t by a c o -o rd in a te d te a m o f paediatrician, p h y sio th e ra p ist, o r­ th opaedic su rg eo n a n d d e n tis t a t the h o s p ita l are n eces­ sary fo r su c c e ssfu l m a n a g e m e n t. T h e se fa c ilitie s can he Tbrganised o n ly at a c o m p re h e n s iv e h a e m o p h ilia tre a tm e n t “centre treating a large n u m b e r o f bleeders. H a e m o p h ilia is a te rm used f o r a g ro u p o f life -lo n g b lee d in g d iso rd e rs re s u ltin g fro m a n in h e rite d d e fe c t in th e p ro d u c tio n o f o n e o r o th e r o f th e p la s m a c lo t­ tin g fa c to rs. T h e s e p ro te in s , re s p o n s ib le f o r n o rm a l b lo o d c o a g u la tio n , a re d e sig n a te d b y th e R o m a n n u m e ra ls I to X I I I . T h e c o m m o n e s t d is o rd e r is h a e m o ­ p h ilia A o r cla ssic h a e m o p h ilia w h ic h w a s p ro b a b ly re co g n ise d as e a rly as th e se c o n d c e n tu ry . T h e B a b y lo n ia n T a lm u d d e sc rib e s a d e c is io n o f R a b b i S im o n b e n G a m a lie l to ex cu se fro m th e r ite o f c ir­ cu m c isio n th e n e w b o rn so n o f a w o m a n w h o se siste rs’ sons b led to d e a th on th e b a s is th a t ‘th e r e a re fa m ilie s w h o se b lo o d is lo o se , w h ile in o th e rs it c o a g u la te s ’. In 1803 th e firs t m o d e rn d e s c rip tio n w as g iven b y J. C. O tto . H a e m o p h ilia w a s c alled th e ‘b le e d e rs d ise a s e ’ a nd la te r ‘th e d ise a s e o f K in g s ’ b e c a u se o f its o c cu r- H a e m a to lo g y /O n c o lo g y S ervice, R e d C ro ss W a r M e m o ria l C h ild r e n ’s H o s p ita l a n d D e p a r tm e n t of P a e d ia tric s, U n iv e rs ity o f C a p e T o w n . R e ce iv e d 1 M a y 1981. O P S O M M IN G H e m o filie is ’n b lo e d in g sie k te te w y te aan 'n oorge- e rjd e d e fe k in die v e rva a rd ig in g v an sto lH n g sfa k to r e . In S u id - A fr ik a is 867 lie m o filie ly e r s g eregistreer en 309 g e va lle is s e u n s o n d e r 15 jaar. H e m o filie A en B be- slaan o m tr e n t 85 - 9 0 % van a lle g evalle. H u lle w o rd o o rg e e rf in ’n s e k s g e s k a k e k le m a n ie r en ta s d u s slegs m a n lik e lye rs aan. D ie k e n m e r k e v an h e m o filie is te w y te aan b lo e d in g s, w at s p e s ifie k g e w rig te a antas. D ie sie k te v arieer in d ie gra a d v a n a a n ta stin g en in d ie k in ­ d e rs w at ergste a a n g e ta s is, k a n h e rh a a ld e h e m a r tr o s e tot erge k r e u p e lh e id lei. V ro e e to e d ie n in g v a n s to llin g sfa k - tor, v e r k ie s fik tuis, fis io te r a p ie oin sp ie r v e rv a l te voor- k o m en g e re e ld e e v a lu e r in g d e u r ’n g e k o d r d in e e r d e span besta a n d e uit ’n kin d e rsp esia lis, fis io te ra p e u t, o rto p e d ie se c h iru rg en ta n d a rts by die h o s p ita a l h n o d ig v ir sitk- s :s v o lle h a n te rin e . H ie rd ie fa siliteite k an sleg s bv ’n om - v a tte n d e h e m o filie b e h a n d e lin g se n tr u m , w a t ’n g ro o t a a n ta l b lo eie rs b e h a n d el, g e o rg a n ise er w ord. re n c e a m o n g d e s c e n d a n ts o f Q u e e n V ic to ria in th e ro y a l fa m ilie s o f B rita in , S p a in a n d R u ssia . H a e m o p h ilia A is d u e to a d e fic ie n c y in f a c to r V I I I c lo ttin g a c tiv ity w h ile h a e m o p h ilia B (C h ristm a s D ise a se) re su lts fro m d e fe c tiv e f a c to r I X p ro d u c tio n . B o th a re in h e rite d in a re ce ssiv e X -lin k e d m a n n e r a n d th e re fo re , w ith ra re e x c e p tio n s, a re m a n ife s t o n ly in m ales. C lin ic a lly h a e m o p h ilia A a n d B a re in d is tin g u is h ­ a b le a n d to g e th e r th e y m a k e u p a b o u t 85 - 9 0 % o f all c ases o f h a e m o p h ilia . H a e m o p h ilia A is 5 to 6 tim e s m o re c o m m o n th a n h a e m o p h ilia B. O f th e o th e r h a e ­ m o p h ilia s , V o n W ille b ra n d d ise a s e is th e th ird m o st c o m m o n , c o m p risin g a b o u t 1 0 % of p a tie n ts . A ll th e o th e r clotting: fa c to r d e fic ie n c ie s to g e th e r m a k e u p less th a n 5 % o f cases. T h e s e d is o rd e rs a re a u to s o m a lly tra n s m itte d a n d th e r e f o r e m a y a ffe c t fe m a le s as well as m ale s. H A E M O P H IL IA A A N D B H a e m o p h ilia is re la tiv e ly u n c o m m o n b u t n o t ra re . T h e in c id e n c e o f h a e m o p h ilia A a n d B h a s b e e n fo u n d R ep ro du ce d by S ab in et G at ew ay u nd er li ce nc e gr an te d by th e P ub lis he r (d at ed 2 01 3. )