THE RESULT OF TREATING CHILDREN’S ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) IN DR. SARDJITO HOSPITAL WITH WK-ALL

PROTOCOL, 1999-2002

Mulatsih S, Sumadiono, Sutaryo, Purwanto

Division of Childhood Hematology-Oncology, Faculty of Medicine, Gadjah Mada University, Yogyakarta, Indonesia

Abstract.Background. After1994 the Indonesian Pediatric Oncology Working Group started using high and intermediate-dose methotrexate for pediatric ALL. However, the numbers of dropouts were high because of financial constraints. In 1999, the Wijaya Kusuma (WK-ALL) protocol was developed as an intended cost-effective treatment.Objectives. To evaluate and to investigate the Overall Survival (OS), Disease Free Survival (DFS) of our ALL patients.Material and Method. Between January 1st 1999 to December 31st 2002, 113 children younger than 15 y, with newly diagnosed ALL in Dr. Sardjito Hospital, Yogyakarta were retrospectively analyzed. Until December 31st 2004, patients were treated with WK-ALL protocol.Results. Of the 113 patients who started on the WK-ALL protocol, 15 (13%) dropped out and 14 (12%) died during induction, and 6 (5%) did not achieve complete remission. Of the 78 (69%) who achieved complete remission, 29 (37%) relapsed, whereas 17 (59%) in the bone marrow. Overall, 26/113 patients (23%) dropped out from therapy, more than a half (58%) in induction. Of the remaining 87 patients, 25 (29%) died from complication: 14 (16%) in induction, 11 (13%) after induction. Septicemia was considered the causes of death in 11 (44%). Six years overall OS, DFS, are 62/87 (71%), 27/87 (31%) respectively. Conclusion. Drop out (23%) still a major reason of failure, and probably non-compliance is also a big problem. Almost one third of patients were lost through complications. Septicemia is a major cause of death. Relapse at 37% is reasonable for a basic protocol, and non-compliance may be part of the background. Currently, 27 patients (31%) survive Disease-free, after median follow-up of almost 3 years.

Abstrak.Latar belakang. Sejak tahun 1994, Unit Kelompok Kerja Hematologi Onkologi Anak IDAI telah menerapkan pemberian methotrexat dosis tinggi dan menengah untuk anak-anak penderita ALL. Namun didapatkan angka drop-out yang tinggi terkait masalah biaya. Sejak tahun 1999, dengan pertimbangan efektivitas dan biaya dikembangkan protocol WKRL.Tujuan. Meneliti dan mengevaluasi penderita yang hidup (overall survival) dan penderita yang bebas dari penyakit (disease free survival) dari seluruh penderita ALL yang kami rawat.Bahan dan cara kerja. Penelitian retrospektif. Data penderita ALL anak baru di RS Dr. Sardjito Yogyakarta mulai 1 Januari 1999 hingga 31 Desember 2002 dianalisis. Terdapat 113 anak berumur < 15 tahun yang mendapatkan terapi dengan protocol WKRL.Hasil. 113 penderita baru ALL menjalani terapi dengan protokol WKRL. 15 (13%) drop out dan 14 (12%) meninggal saat fase induksi, 6 (5%) tidak mencapai remisi komplit. Dari 78 (69%) yang mencapai remisi komplit, 29 (37%) mengalami relaps, di mana 17 (59%) dibuktikan dengan aspirasi sumsum tulang. Secara keseluruhan, 26 dari 113 penderita (23%) yang drop out dari terapi, lebih dari separoh (58%) saat fase induksi. Sisanya 87 penderita, 25 (29%) meninggal oleh karena komplikasi: 14 (16%) saat induksi, 11 (13%) setelah induksi. Septicemia menjadi penyebab kematian pada 11 (44%) penderita. Selama 6 tahun penelitian, penderita yang hidup secara keseluruhan adalah 62/87 (71%), dan 27/87 (31%) dinyatakan bebas penyakit.Kesimpulan. Drop out masih merupakan alasan kegagalan terapi yang utama (23%), yang kemungkinan akibat faktor ketidak-patuhan. Hampir 1/3 penderita meninggal akibat komplikasi. Septicemia merupakn penyebab kematian yang utama. Angka relaps sebesar 37% masih bisa diterima untuk terapi dasar, hal ini kemungkinan besar oleh karena faktor ketidak-patuhan. Dalam kurun hampir 3 tahun follow-up didapatkan 27 (31%) penderita yang terbebas dari penyakit.

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

INTRODUCTION

The outlook for children with ALL has improved dramatically. However, up to now, Indonesia has not yet had a national protocol for acute lymphoblastic leukemia (ALL). Starting in 1998, when we have national workshop meeting for Indonesian pediatric oncologist in Yogyakarta, Indonesia, The Wijaya Kusuma (WK) ALL protocol was borne. This description was taken for the economical constraints. Since 1999, we have WK ALL-protocol study. This protocol was developed in order to improve the cure and survival rates of childhood ALL with still consider the cost effectiveness of the regimen. In our study, all children with newly diagnosed acute lymphoblastic leukemia (ALL) were classified into two subgroups according to age, white blood cell (WBC), organomegaly, and risk group.

PATIENTS AND METHODS

Patients.

Between January 1999 and December 2002, 113 children with ALL L1 and L2

who below 15 years of age, and have no treatment previously with corticosteroid or

chemotherapy started on WK-ALL protocol. Diagnosis and therapy was centralized to the

Department of pediatric, DR. Sardjito Hospital, Yogyakarta. Informed consent was

obtained according the inform consent form Hospital Medical Record.

The diagnosis was established by analyzing bone marrow aspirates, including

standard morphology according to the French-American-British (FAB) classification

(Bennett et al, 1985). Percentage of blasts cell at least 25%.

The criteria of high risk group were less than 1 year or more than 10 years old;

white blood cell count (WBC) more than 50,000/ul; present of mediastinal mass

according the chest x ray, present of CNS (Central Nervous System) leukemia cells.

Beside that, if the blast in peripheral blood still more than 1000/ul after one week with

dexamethazone, must be include to the high-risk group. CNS involvement was diagnosis

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if more than 5 leucocytes/ill were identified in the cerebrospinal fluid (CSF) in

combination with detectable leukemia cells in the cytospin and/ or with occurrence of

neurological symptoms (e.g. cranial nerve palsy).

Complete remission (CR) was defined as a normocellular bone marrow (BM) with

less than 5%. BM aspiration was done at 42 days induction or after complete treatment,

no blasts cells in peripheral blood, no CNS leukemia, and no infiltration of leukemia cells

in others organ. Partial remission (PR) was defined as a normocellular BM with blasts

cell 5 to 20% in 200 nuclear cells.

Relapse was defined as presenting blast cells more than 20% in 200 nuclear cells

in BM, and/or presenting of blats cells in peripheral blood, and/or presenting of blast cells

in CSF slide at least twice with interval 24 hours or more, and/or present of leukemia cell

infiltration in others organ.

Treatment Protocol

The treatment outline of WK-ALL protocol is shown in Figure 1. One-induction

courses were followed by consolidation, re-induction, and maintenance courses. For the

standard risk group, without re-induction. The chemotherapy for induction consist

dexamethazone orally 6 mg/m2, Vinvristine 1.5 mg/m2 (maximum dose was 2 mg) iv, at

day 7, 14, 21, 28 and 35 (diluted with normal saline or aquadest until 10 ml, bolus slowly

duration 5-10 minutes); Daunorubicine (just for high risk group) 30 mg/m2 4-h infusion;

L-Asparagines (L-Asp) 6,000 u/m2 4-h infusion; Intrathecal methotrexate was given on

the first day, 14, and 42 at age-adjusted doses: below 1 year, 6 mg; 1 year old, 8 mg; 2

year old 10 mg; 3 years and older, 12 mg. Leucopenia and/ or thrombocytopenia was not

indication to reduce the dose of chemotherapy in this course. If allergic reaction was

found with L-Asp (produce fro E-coli), the treatment can continue with Erwina Caratova

with the same doses, or antihistamine can be use for allergic reaction.

Several courses of intensive post-remission chemotherapy combining non-cross

resistant agents, administered every week, 4 to 6 weeks. Randomized studies have been

conducted to compare the efficacy of different consolidation L-Asparagines and placebo

for ALL patients. Combination of L-Asparagines and Daunorubicine has been given as a

re-induction treatment for high-risk group. Consolidation consisted of combination 6-MP

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50 mg/m2 orally; intrathecal MTX it at week 10, 11, and 12; L-Asp 6,000 u/m2 IV at

week 7, 8, and 9, 4-h infusion. Re-induction consisted intrathecal MTX at week 13 and

17; dexamethazone orally 6 mg/m2 3 doses since week 13 to 18; daunorubicine 30

mg/m2 4-h infusion at week 13, 15, and 17; L-Asp 6,000 u/m2 at week 13, 15, and 17.

Statistical analysis.

The STATISTICAL PACKAGE FOR THE SOCIAL SCIENCES (SPSS)

software was used in the statistical analysis. The probability of Overall Survival (OS),

Events Free Survival (EFS), and Disease-free Survival (DFS) were calculated using the

Kaplan-Meier method. In the analysis of OS, events included all patients who were

surviving since at diagnosis. EFS, events included induction failure (early death, death in

aplasia and resistant disease), death in remission, relapse disease. Children who did not

achieve remission were excluded from analysis of DFS (Mantel, 1966).

Figure 1. The Outline of WK-ALL-SR protocol

Figure 2. The Outline of WK-ALL-HR protocol

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RESULTS

Patients Characteristic

WK-ALL protocol study included a total 113 patients: the clinical characteristics

are presented in Table I. One patient (0.9%) was less than 1 year of age, 14 (12.4%) were

10 to 15-years old at diagnosis. Twenty-seven patients (23.9%) of the children had WBC

> 50,000/ul.

TABLE I. Patient Characteristics

Feature Total (n= 113) Percentage (%)

Sex Male FemaleAge at diagnosis < 1 years 1-9 years 10-15 yearsWBC < 10,000/ul > 10,000-50,000/ul > 50,000-100,000/ul > 100,000/ulCNS disease Absent PresentSplenomegaly Absent PresentMediastinal mass Absent PresentTesticular enlargement Absent Present

6251

19814

58281314

1112

2390

10013

1130

5545

0.986.712.4

51.324.811.512.4

98.21.8

20.479.6

88.511.5

1000

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Tolerance to Treatment

During induction and intensification, most patients developed fever and

Neutrogena. Most of them were treated with intravenous amino glycoside and third and

fourth generation cephalosporin. If fever still persisted, oral antifungal would be added.

Response, Relapse, and Death

Induction treatment

CR was obtained in 78 (69%) of the113 children treated according to WK-ALL

protocol, 14 (12%) died; 6 (5%) had resistant disease, and 15 (13%) were dropped from

treatment. (Figure 2). Patients treated on WK-ALL protocol had a high risk of toxic death

in remission. Have remaining 87 children, 25 (29%) died from complication. 14 (16%) in

induction; 11 (13%) after induction. Septicemia was considered the causes of death in 11

(44%) (Fig.4).

Post-remission therapy

The outcome according to post-remission treatment is shown in Fig. 4. Of the 78

patients who achieved complete remission, 29 (37%) were relapse; 11(14%) died; and 11

(14%) dropped out from treatment (Figure 3). Of the 78 patients who achieved complete

remission, 29 patients (27%) relapsed. The relapses were predominantly located in the

bone marrow (59%). Eight patients (28%) suffered from CNS relapse, and 4 (13%) with

others relapsed (Fig.6). Most relapse occurred within the maintenance course.

Dropped out on WK-ALL protocol

Overall, 26/113 children (23%) dropped out from therapy, whereas 15 (58%) in

induction, and 11 (42%) after remission (Fig.5)

Table II. Main outcomes of WK-ALL

Standard Risk High Risk TotalN % N % N %

All patientsEarly deathResistant disease

6862

604333

4584

405767

113146

100

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RemissionRelapseDeath in CRCCR 12/2004

OS at 6 yearsEFS at 6 yearsDFS at 6 years

5120727

65746477

774138

27748

35263623

613926

78271135

Overall715344

0

10

20

30

40

50

60

70

80

Total

Dropped out Died Persistant disease Remission

Response

Response of Induction Treatment

Figure 3. Response of Induction Treatment

0

5

10

15

20

25

30

Total

Relapse Died Dropped out

outcome

Post-remission therapy

Figure 4. Post-remission Therapy

7

0

2

4

6

8

10

12

14

Total

Phase

Death case

Total 14 11

Induction Post Remission

Figure 5. Death Case based on Phase

Overall outcome

Table II and Figs 7, 8, and 9present the main result of the WK-ALL protocol. The

remission rate was 69%. The OS, EFS, and DFS at 6 years were 71%, 53% and 44 %

respectively. The standard risk has higher of percentage of OS, EFS, and DFS than high-

risk group.

0

2

4

6

8

10

12

14

16

18

Total

Type of Relapse

Relapse cases

Total 17 8 4

BM CNS Others

Figure 6. The type of Relapse

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Figure 7. Probability of Survival in WK-ALL protocol

Figure 8. Probability of EFS in WK-ALL Protocol

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Figure 9. Probability of DFS in WK-ALL Protocol

DISCUSSION

The treatment results of childhood ALL have steadily improved over the past 20

years. The estimated 5-7 years event-free survival were reported to be 55-78% (Eden OB,

et al 1991; Chessels JM et al, 1995, Schorin MA et al, 1994). To improve the curate of

childhood ALL, several risk factors should be considered regarding the treatment

strategy. Generally, between 1 and 9 year of age, WBC < 50000 per micro litre, absent of

mediastinal mass and CNS Leukemia are used as criteria for low-risk ALL. Based on the

concept in the current study all the ALL children patients were classified in to two

subgroup according those criteria as a high risk and standard risk patients.

Our analysis suggests that the dropout still is major reason of failure, and probable

non-compliance in the remaining passions is also big problem. Overall, 26 from 113

patients (23% were dropped out from therapy due to many problem for instant the

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financial reason, critical conditions of passions, persistence of the blood cells (more than

1000 UL after one week receive bethametason. Some of the patients develops septicemia,

so, the chemotherapy had not been given properly, eleven patients (42% were dropped

out after remission do to the relapse). Our result similar with previously study. In both

Taiwan CCG studies, protocol TCL-821 and TCL-842 reported that there were also high

dropped out rates (32% and 16.8%). The authors postulated that the inferior results were

due lack of financial support to the families, pessimistic attitudes of the families and

some medical personnel, high remission death rates, and possibly the questionable

compliance with maintenance therapy. (Kong Shing MM, et al. 1999).

The second problem is toxic death, were as almost, one third of remaining patients

the lost though complication and septicemia is mayor cause of death. In our department

most of passions come from poor family while for the several period they did not get

funding from the government. In order to cover hospitalization cost, that was most

important reason for non-compliance. Treatment related mortality in London with

national multicentre study has been analyzed for induction and first remission (including

after intensification treatment). There was 2.3% induction death, whereas 84% of these

followed a bacterial and fungal infection. Thirty-seven infective remission deaths

occurred, which including caused by Pneumocystis carinii pneumonia (Wheeler K et al,

1996).

Relapse of leukemia (37%) was the main cause of treatment failure. As compared

with the MRC UKALL X study in Hong Kong we have a higher incidence of relapses

(24.6%) (Kong Shing at al, 1999).

Large part of the improvement in survival is clearly attributable to advances in

treatment methods, particularly, the increasing efficacy of combination chemotherapy.

How ever not a children benefited equally from this development (Styler C.A., 1999).

Our analysis, six-years overall OS, EFS, and DFS, are 62/87 (71%), 33/62 (53%), and

27/62 (44%) respectively. The patterns survival for children ALL in UK, which treated

with UKALL protocol show, that 5-year survival rate was 70% during 1980-84, while in

1990-94 the rate was 70% (Stiller CA, 1999). The Hong Kong study has better result on

overall survival and EFS (75% and 66%), respectively with more aggressive treatment

(Kong Shing, et al, 1999). In Japan, one of ALL study was done in 2001 with AL90

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regimen, and the result of 5-years EFS was 67.4% (Ishii E, et al, 2001). The standard risk

group has a superior of 6-years Survival, EFS, and DFS to the high-risk group (77% vs.

61%; 41% vs. 39%; 30% vs.26%) respectively. The EUROCARE study mentioned about

Variation in survival of European children with ALL. During 1985-1989, the 5-year

survival rate from over 80 to 56% (with the exception of Estonia; 34%; various country,

90%; and European weighted was 72%. Survival was particularly favorable in (south)

Sweden, Finland, Germany and The Netherlands and rather unfavorable in Estonia

(Coebergh JW, 2001). However, the incidence of relapse was higher in standard risk to

that high-risk group (36% vs. 23%). The possibility reason for that problem was, in our

study, the criteria for classified just based on FAB (France American British) criteria,

without any better supporting examination such as immunophenotyping, karyotyping;

criteria for remission still a conventional, no minimal residual disease examination. Based

on this fact, we do not know whether the patients really include in standard risk or should

be high risk. If we looked the protocol it self, the high-risk group received more drug

(daunorubicine) and added the one phase re-induction. Those possibilities reason might

cause a higher relapse cases in standard risk group.

For high-risk ALL, the WK-ALL –HR protocol regimen including induction,

consolidation, re-induction and maintenance therapies did not improve patient outcome.

Failure to achieve remission in the high-risk group was 9%. The added once

daunorubicine 30 mg/m2, did not give better CR for HR group.

CONCLUSION

The survival of children with ALL living in developing countries is lower than

that of children in developed countries. The failure of treatment mostly due to the lack of

financial support to the families, pessimistic attitudes of the families and some medical

personnel, high remission death rates, and possibly the questionable compliance with

maintenance therapy.

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