THE RESULT OF TREATING CHILDRENS ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) IN DR. SARDJITO HOSPITAL WITH WK-ALL PROTOCOL, 1999- !!

M"#$%&'( S, Sumadiono, Sutaryo, Purwanto Division of Childhood Hematology-Oncology, Faculty of Medicine, Gad ah Mada !niversity, "ogya#arta, $ndonesia A)&%*$+%. B$+,-*."/0% &fter'(() the $ndonesian Pediatric Oncology *or#ing Grou+ started using high and intermediate-dose methotre,ate for +ediatric &--% However, the num.ers of dro+outs were high .ecause of financial constraints% $n '(((, the *i aya /usuma 0*/-&--1 +rotocol was develo+ed as an intended costeffective treatment% O)12+%'32&. 2o evaluate and to investigate the Overall Survival 0OS1, Disease Free Survival 0DFS1 of our &-- +atients% M$%2*'$# $/0 M2%(.0. 3etween 4anuary 'st '((( to Decem.er 5'st 6776, ''5 children younger than '8 y, with newly diagnosed &-- in Dr% Sard ito Hos+ital, "ogya#arta were retros+ectively analy9ed% !ntil Decem.er 5'st 677), +atients were treated with */-&-- +rotocol% R2&"#%&. Of the ''5 +atients who started on the */-&-- +rotocol, '8 0'5:1 dro++ed out and ') 0'6:1 died during induction, and ; 08:1 did not achieve com+lete remission% Of the <= 0;(:1 who achieved com+lete remission, 6( 05<:1 rela+sed, whereas '< 08(:1 in the .one marrow% Overall, 6;>''5 +atients 065:1 dro++ed out from thera+y, more than a half 08=:1 in induction% Of the remaining =< +atients, 68 06(:1 died from com+lication? ') 0';:1 in induction, '' 0'5:1 after induction% Se+ticemia was considered the causes of death in '' 0)):1% Si, years overall OS, DFS, are ;6>=< 0<':1, 6<>=< 05':1 res+ectively% C./+#"&'./. Dro+ out 065:1 still a ma or reason of failure, and +ro.a.ly non-com+liance is also a .ig +ro.lem% &lmost one third of +atients were lost through com+lications% Se+ticemia is a ma or cause of death% @ela+se at 5<: is reasona.le for a .asic +rotocol, and non-com+liance may .e +art of the .ac#ground% Currently, 6< +atients 05':1 survive Disease-free, after median follow-u+ of almost 5 years% A)&%*$,. L$%$* )2#$,$/-. Se a# tahun '((), !nit /elom+o# /er a Hematologi On#ologi &na# $D&$ telah menera+#an +em.erian methotre,at dosis tinggi dan menengah untu# ana#-ana# +enderita &--% Aamun dida+at#an ang#a dro+-out yang tinggi ter#ait masalah .iaya% Se a# tahun '(((, dengan +ertim.angan efe#tivitas dan .iaya di#em.ang#an +rotocol */@-% T"1"$/. Meneliti dan mengevaluasi +enderita yang hidu+ (overall survival) dan +enderita yang .e.as dari +enya#it (disease free survival) dari seluruh +enderita &-- yang #ami rawat% B$($/ 0$/ +$*$ ,2*1$. Penelitian retros+e#tif% Data +enderita &-- ana# .aru di @S Dr% Sard ito "ogya#arta mulai ' 4anuari '((( hingga 5' Desem.er 6776 dianalisis% 2erda+at ''5 ana# .erumur B '8 tahun yang menda+at#an tera+i dengan +rotocol */@-% H$&'#. ''5 +enderita .aru &-- men alani tera+i dengan +roto#ol */@-% '8 0'5:1 dro+ out dan ') 0'6:1 meninggal saat fase indu#si, ; 08:1 tida# menca+ai remisi #om+lit% Dari <= 0;(:1 yang menca+ai remisi #om+lit, 6( 05<:1 mengalami rela+s, di mana '< 08(:1 di.u#ti#an dengan as+irasi sumsum tulang% Secara #eseluruhan, 6; dari ''5 +enderita 065:1 yang dro+ out dari tera+i, le.ih dari se+aroh 08=:1 saat fase indu#si% Sisanya =< +enderita, 68 06(:1 meninggal oleh #arena #om+li#asi? ') 0';:1 saat indu#si, '' 0'5:1 setelah indu#si% Se+ticemia men adi +enye.a. #ematian +ada '' 0)):1 +enderita% Selama ; tahun +enelitian, +enderita yang hidu+ secara #eseluruhan adalah ;6>=< 0<':1, dan 6<>=< 05':1 dinyata#an .e.as +enya#it% K2&'45"#$/. Dro+ out masih meru+a#an alasan #egagalan tera+i yang utama 065:1, yang #emung#inan a#i.at fa#tor #etida#-+atuhan% Ham+ir '>5 +enderita meninggal a#i.at #om+li#asi% Se+ticemia meru+a#n +enye.a. #ematian yang utama% &ng#a rela+s se.esar 5<: masih .isa diterima untu# tera+i dasar, hal ini #emung#inan .esar oleh #arena fa#tor #etida#-+atuhan% Dalam #urun ham+ir 5 tahun follow-u+ dida+at#an 6< 05':1 +enderita yang ter.e.as dari +enya#it%

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Keywords: Acute lymphoblastic Leukemia-WK-ALL protocol-Survival

INTRODUCTION 2he outloo# for children with &-- has im+roved dramatically% However, u+ to now, $ndonesia has not yet had a national +rotocol for acute lym+ho.lastic leu#emia 0&--1% Starting in '((=, when we have national wor#sho+ meeting for $ndonesian +ediatric oncologist in "ogya#arta, $ndonesia, 2he *i aya /usuma 0*/1 &-- +rotocol was .orne% 2his descri+tion was ta#en for the economical constraints% Since '(((, we have */ &---+rotocol study% 2his +rotocol was develo+ed in order to im+rove the cure and survival rates of childhood &-- with still consider the cost effectiveness of the regimen% $n our study, all children with newly diagnosed acute lym+ho.lastic leu#emia 0&--1 were classified into two su.grou+s according to age, white .lood cell 0*3C1, organomegaly, and ris# grou+%

PATIENTS AND METHODS P$%'2/%&. 3etween 4anuary '((( and Decem.er 6776, ''5 children with &-- -' and -6 who .elow '8 years of age, and have no treatment +reviously with corticosteroid or chemothera+y started on */-&-- +rotocol% Diagnosis and thera+y was centrali9ed to the De+artment of +ediatric, D@% Sard ito Hos+ital, "ogya#arta% $nformed consent was o.tained according the inform consent form Hos+ital Medical @ecord% 2he diagnosis was esta.lished .y analy9ing .one marrow as+irates, including standard mor+hology according to the French-&merican-3ritish 0F&31 classification 03ennett et al, '(=81% Percentage of .lasts cell at least 68:% 2he criteria of high ris# grou+ were less than ' year or more than '7 years oldC white .lood cell count 0*3C1 more than 87,777>ulC +resent of mediastinal mass according the chest , ray, +resent of CAS 0Central Aervous System1 leu#emia cells% 3eside that, if the .last in +eri+heral .lood still more than '777>ul after one wee# with de,ametha9one, must .e include to the high-ris# grou+% CAS involvement was diagnosis

if more than 8 leucocytes>ill were identified in the cere.ros+inal fluid 0CSF1 in com.ination with detecta.le leu#emia cells in the cytos+in and> or with occurrence of neurological sym+toms 0e%g% cranial nerve +alsy1% Com+lete remission 0C@1 was defined as a normocellular .one marrow 03M1 with less than 8:% 3M as+iration was done at )6 days induction or after com+lete treatment, no .lasts cells in +eri+heral .lood, no CAS leu#emia, and no infiltration of leu#emia cells in others organ% Partial remission 0P@1 was defined as a normocellular 3M with .lasts cell 8 to 67: in 677 nuclear cells% @ela+se was defined as +resenting .last cells more than 67: in 677 nuclear cells in 3M, and>or +resenting of .lats cells in +eri+heral .lood, and>or +resenting of .last cells in CSF slide at least twice with interval 6) hours or more, and>or +resent of leu#emia cell infiltration in others organ% T*2$%42/% P*.%.+.# 2he treatment outline of */-&-- +rotocol is shown in Figure '% One-induction courses were followed .y consolidation, re-induction, and maintenance courses% For the standard ris# grou+, without re-induction% 2he chemothera+y for induction consist de,ametha9one orally ; mg>m6, Dinvristine '%8 mg>m6 0ma,imum dose was 6 mg1 iv, at day <, '), 6', 6= and 58 0diluted with normal saline or aEuadest until '7 ml, .olus slowly duration 8-'7 minutes1C Daunoru.icine 0 ust for high ris# grou+1 57 mg>m6 )-h infusionC --&s+aragines 0--&s+1 ;,777 u>m6 )-h infusionC $ntrathecal methotre,ate was given on the first day, '), and )6 at age-ad usted doses? .elow ' year, ; mgC ' year old, = mgC 6 year old '7 mgC 5 years and older, '6 mg% -euco+enia and> or throm.ocyto+enia was not indication to reduce the dose of chemothera+y in this course% $f allergic reaction was found with --&s+ 0+roduce fro F-coli1, the treatment can continue with Frwina Caratova with the same doses, or antihistamine can .e use for allergic reaction% Several courses of intensive +ost-remission chemothera+y com.ining non-cross resistant agents, administered every wee#, ) to ; wee#s% @andomi9ed studies have .een conducted to com+are the efficacy of different consolidation --&s+aragines and +lace.o for &-- +atients% Com.ination of --&s+aragines and Daunoru.icine has .een given as a re-induction treatment for high-ris# grou+% Consolidation consisted of com.ination ;-MP

87 mg>m6 orallyC intrathecal M2G it at wee# '7, '', and '6C --&s+ ;,777 u>m6 $D at wee# <, =, and (, )-h infusion% @e-induction consisted intrathecal M2G at wee# '5 and '<C de,ametha9one orally ; mg>m6 5 doses since wee# '5 to '=C daunoru.icine 57 mg>m6 )-h infusion at wee# '5, '8, and '<C --&s+ ;,777 u>m6 at wee# '5, '8, and '<% S%$%'&%'+$# $/$#6&'&. 2he S2&2$S2$C&- P&C/&GF FO@ 2HF SOC$&- SC$FACFS 0SPSS1 software was used in the statistical analysis% 2he +ro.a.ility of Overall Survival 0OS1, Fvents Free Survival 0FFS1, and Disease-free Survival 0DFS1 were calculated using the /a+lan-Meier method% $n the analysis of OS, events included all +atients who were surviving since at diagnosis% FFS, events included induction failure 0early death, death in a+lasia and resistant disease1, death in remission, rela+se disease% Children who did not achieve remission were e,cluded from analysis of DFS 0Mantel, '(;;1% Figure '% 2he Outline of */-&---S@ +rotocol

Figure 6% 2he Outline of */-&---H@ +rotocol

RESULTS P$%'2/%& C($*$+%2*'&%'+ */-&-- +rotocol study included a total ''5 +atients? the clinical characteristics are +resented in 2a.le $% One +atient 07%(:1 was less than ' year of age, ') 0'6%):1 were '7 to '8-years old at diagnosis% 2wenty-seven +atients 065%(:1 of the children had *3C H 87,777>ul%

TABLE I. P$%'2/% C($*$+%2*'&%'+&

F2$%"*2 Se, Male Female &ge at diagnosis B ' years '-( years '7-'8 years *3C B '7,777>ul H '7,777-87,777>ul H 87,777-'77,777>ul H '77,777>ul CAS disease &.sent Present S+lenomegaly &.sent Present Mediastinal mass &.sent Present 2esticular enlargement &.sent Present T.%$# (/7 118) ;6 8' ' (= ') 8= 6= '5 ') P2*+2/%$-2 (9) 88 )8 7%( =;%< '6%) 8'%5 6)%= ''%8 '6%)

''' 6 65 (7 '77 '5 ''5 7

(=%6 '%= 67%) <(%; ==%8 ''%8 '77 7

T.#2*$/+2 %. T*2$%42/% During induction and intensification, most +atients develo+ed fever and Aeutrogena% Most of them were treated with intravenous amino glycoside and third and fourth generation ce+halos+orin% $f fever still +ersisted, oral antifungal would .e added% R2&5./&2, R2#$5&2, $/0 D2$%( I/0"+%'./ %*2$%42/% C@ was o.tained in <= 0;(:1 of the''5 children treated according to */-&-+rotocol, ') 0'6:1 diedC ; 08:1 had resistant disease, and '8 0'5:1 were dro++ed from treatment% 0Figure 61% Patients treated on */-&-- +rotocol had a high ris# of to,ic death in remission% Have remaining =< children, 68 06(:1 died from com+lication% ') 0';:1 in inductionC '' 0'5:1 after induction% Se+ticemia was considered the causes of death in '' 0)):1 0Fig%)1% P.&%-*24'&&'./ %(2*$56 2he outcome according to +ost-remission treatment is shown in Fig% )% Of the <= +atients who achieved com+lete remission, 6( 05<:1 were rela+seC ''0'):1 diedC and '' 0'):1 dro++ed out from treatment 0Figure 51% Of the <= +atients who achieved com+lete remission, 6( +atients 06<:1 rela+sed% 2he rela+ses were +redominantly located in the .one marrow 08(:1% Fight +atients 06=:1 suffered from CAS rela+se, and ) 0'5:1 with others rela+sed 0Fig%;1% Most rela+se occurred within the maintenance course% D*.5520 ."% ./ WK-ALL 5*.%.+.# Overall, 6;>''5 children 065:1 dro++ed out from thera+y, whereas '8 08=:1 in induction, and '' 0)6:1 after remission 0Fig%81 T$)#2 II. M$'/ ."%+.42& .: WK-ALL
S%$/0$*0 R'&, N 9 ;= ;7 ; )5 6 55 H'-( R'&, N 9 )8 )7 = 8< ) ;< T.%$# N ''5 ') ; 9 '77

&ll +atients Farly death @esistant disease

@emission @ela+se Death in C@ CC@ '6>677) OS at ; years FFS at ; years DFS at ; years

8' 67 < 6<

;8 <) ;) << << )' 5=

6< < ) =

58 6; 5; 65 ;' 5( 6;

<= 6< '' 58 Overall <' 85 ))

Response of Induction Treatment

80

70

60

50

Total 40

30

20

10

0 Dropped out Died Response Persistant disease Remission

Figure 5% @es+onse of $nduction 2reatment

Post-remission therapy

30

25

20

Total

15

10

Relapse

Died

Dropped out

outcome

Figure )% Post-remission 2hera+y

<

Death case

14

12

10

Total
6

Induction 14

Post Remission 11

Total

Phase

Figure 8% Death Case .ased on Phase

Relapse cases

18 16 14 12 10

Total
8 6 4 2 0

BM 17

CNS 8

Others 4

Total

Type of Relapse

Figure ;% 2he ty+e of @ela+se

O32*$## ."%+.42 2a.le $$ and Figs <, =, and (+resent the main result of the */-&-- +rotocol% 2he remission rate was ;(:% 2he OS, FFS, and DFS at ; years were <':, 85: and )) : res+ectively% 2he standard ris# has higher of +ercentage of OS, FFS, and DFS than highris# grou+%

Figure <% Pro.a.ility of Survival in */-&-- +rotocol

Figure =% Pro.a.ility of FFS in */-&-- Protocol

Figure (% Pro.a.ility of DFS in */-&-- Protocol

DISCUSSION 2he treatment results of childhood &-- have steadily im+roved over the +ast 67 years% 2he estimated 8-< years event-free survival were re+orted to .e 88-<=: 0Fden O3, et al '(('C Chessels 4M et al, '((8, Schorin M& et al, '(()1% 2o im+rove the curate of childhood &--, several ris# factors should .e considered regarding the treatment strategy% Generally, .etween ' and ( year of age, *3C B 87777 +er micro litre, a.sent of mediastinal mass and CAS -eu#emia are used as criteria for low-ris# &--% 3ased on the conce+t in the current study all the &-- children +atients were classified in to two su.grou+ according those criteria as a high ris# and standard ris# +atients% Our analysis suggests that the dro+out still is ma or reason of failure, and +ro.a.le non-com+liance in the remaining +assions is also .ig +ro.lem% Overall, 6; from ''5 +atients 065: were dro++ed out from thera+y due to many +ro.lem for instant the financial reason, critical conditions of +assions, +ersistence of the .lood cells 0more than

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'777 !- after one wee# receive .ethametason% Some of the +atients develo+s se+ticemia, so, the chemothera+y had not .een given +ro+erly, eleven +atients 0)6: were dro++ed out after remission do to the rela+se1% Our result similar with +reviously study% $n .oth 2aiwan CCG studies, +rotocol 2C--=6' and 2C--=)6 re+orted that there were also high dro++ed out rates 056: and ';%=:1% 2he authors +ostulated that the inferior results were due lac# of financial su++ort to the families, +essimistic attitudes of the families and some medical +ersonnel, high remission death rates, and +ossi.ly the Euestiona.le com+liance with maintenance thera+y% 0/ong Shing MM, et al% '(((1% 2he second +ro.lem is to,ic death, were as almost, one third of remaining +atients the lost though com+lication and se+ticemia is mayor cause of death% $n our de+artment most of +assions come from +oor family while for the several +eriod they did not get funding from the government% $n order to cover hos+itali9ation cost, that was most im+ortant reason for non-com+liance% 2reatment related mortality in -ondon with national multicentre study has .een analy9ed for induction and first remission 0including after intensification treatment1% 2here was 6%5: induction death, whereas =): of these followed a .acterial and fungal infection% 2hirty-seven infective remission deaths occurred, which including caused .y Pneumocystis carinii +neumonia 0*heeler / et al, '((;1% @ela+se of leu#emia 05<:1 was the main cause of treatment failure% &s com+ared with the M@C !/&-- G study in Hong /ong we have a higher incidence of rela+ses 06)%;:1 0/ong Shing at al, '(((1% -arge +art of the im+rovement in survival is clearly attri.uta.le to advances in treatment methods, +articularly, the increasing efficacy of com.ination chemothera+y% How ever not a children .enefited eEually from this develo+ment 0Styler C%&%, '(((1% Our analysis, si,-years overall OS, FFS, and DFS, are ;6>=< 0<':1, 55>;6 085:1, and 6<>;6 0)):1 res+ectively% 2he +atterns survival for children &-- in !/, which treated with !/&-- +rotocol show, that 8-year survival rate was <7: during '(=7-=), while in '((7-() the rate was <7: 0Stiller C&, '(((1% 2he Hong /ong study has .etter result on overall survival and FFS 0<8: and ;;:1, res+ectively with more aggressive treatment 0/ong Shing, et al, '(((1% $n 4a+an, one of &-- study was done in 677' with &-(7 regimen, and the result of 8-years FFS was ;<%): 0$shii F, et al, 677'1% 2he standard ris#

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grou+ has a su+erior of ;-years Survival, FFS, and DFS to the high-ris# grou+ 0<<: vs% ;':C )': vs% 5(:C 57: vs%6;:1 res+ectively% 2he F!@OC&@F study mentioned a.out Dariation in survival of Furo+ean children with &--% During '(=8-'(=(, the 8-year survival rate from over =7 to 8;: 0with the e,ce+tion of FstoniaC 5):C various country, (7:C and Furo+ean weighted was <6:% Survival was +articularly favora.le in 0south1 Sweden, Finland, Germany and 2he Aetherlands and rather unfavora.le in Fstonia 0Coe.ergh 4*, 677'1% However, the incidence of rela+se was higher in standard ris# to that high-ris# grou+ 05;: vs% 65:1% 2he +ossi.ility reason for that +ro.lem was, in our study, the criteria for classified ust .ased on F&3 0France &merican 3ritish1 criteria, without any .etter su++orting e,amination such as immuno+henoty+ing, #aryoty+ingC criteria for remission still a conventional, no minimal residual disease e,amination% 3ased on this fact, we do not #now whether the +atients really include in standard ris# or should .e high ris#% $f we loo#ed the +rotocol it self, the high-ris# grou+ received more drug 0daunoru.icine1 and added the one +hase re-induction% 2hose +ossi.ilities reason might cause a higher rela+se cases in standard ris# grou+% For high-ris# &--, the */-&-- IH@ +rotocol regimen including induction, consolidation, re-induction and maintenance thera+ies did not im+rove +atient outcome% Failure to achieve remission in the high-ris# grou+ was (:% 2he added once daunoru.icine 57 mg>m6, did not give .etter C@ for H@ grou+% CONCLUSION 2he survival of children with &-- living in develo+ing countries is lower than that of children in develo+ed countries% 2he failure of treatment mostly due to the lac# of financial su++ort to the families, +essimistic attitudes of the families and some medical +ersonnel, high remission death rates, and +ossi.ly the Euestiona.le com+liance with maintenance thera+y% REFERENCES

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'% Chessels 4M, 3ailey C, @ichards SM%, '((8% $ntensification of treatment and survival in all children with lym+ho.lastic leu#emia? @esults of !/ Medical @esearch Council 2rial !/&-- G% -ancetC 5)8?')5-=% 6% Coe.ergh 4*%, Pastore G%, Gatta G%, Cora99iari $%, /am+s *%, 677'% Dariation in survival of Furo+ean children with acute lym+ho.lastic leu#emia, diagnosed in '(<=-'((6?the F!@OC&@F study% Furo+ean 4ournal of Cancer 5<? ;=<-()% 5% Fden O3, -illeyman 4S, @ichard S%,'(('% @esults of medical @esearch Council Childhood -eu#emia 2rial !/&-- D$$ 0re+ort to the Medical @esearch Council on .ehalf of the wor#ing +arty on leu#emia in childhood1% 3r 4 HaematolC <=?'=<(; )% $shii F, Fguchi H%, Matsu9a#i &%, /oga H%, "anai F%, et al% 677'% Outcome of &cute -ym+ho.lastic -eu#emia in Children with &-(7 @egimen? $m+act of @es+onse to 2reatment and Se, Difference on Prognostic Factors% Medical and Pediatric Oncology 5<?'7-'(% 8% Schorin M&, 3lattner S, and Gel.er @D%, '(()% 2reatment of childhood &--? @esults of Dana-Far.er Cancer $nstitute>ChildrenJs Hos+ital &cute -ym+ho.lastic -eu#emia Consortium Protocol =8-7'% 4 Clin Oncol?'6?<)7-<% ;% Shing MM/, -i C/%, Chi# /&%, -am 2/%, -ai HDH%, et al% '(((% Outcomes and Prognostic Factors of Chinese Children with &cute -ym+ho.lastic -eu#emia in Hong /ong? Preliminary @esults% Medical and Pediatric Oncology 56?''<-65% <% Stiller C&%, Fatoc# FM%, '(((% Patterns of care and survival for children with acute lym+ho.lastic leu#emia diagnosed .etween '(=7 and '(()% &rch Dis ChildC ='?676-=%

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=% *heeler /, Chessells 4M%, 3aiely CC%, @ichards SM%, '((;% 2reatment related deaths during induction and in first remission in acute lym+ho.lastic leu#emia? M@C !/&-- G% &rchives of Disease in ChildhoodC<)? '7'-<%

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