SURVIVAL OF CHILDREN WITH ACUTE LEUKAEMIA: A SINGLE CENTRE EXPERIENCE

Introduction: Acute leukaemia in children accounts for 25-30% of malignant diagnosis. Survival from acute leukaemia continue to improve. Treatment outcome depends on factors like gender, age at diagnosis, parental education, the initial total white cell count (TWC), cerebrospinal fluids (CSF) infiltration, immunophenotype and treatment response. Objectives: The objectives were to evaluate the survival of children with acute leukaemia who received chemotherapy and identify relevant factors. Methodology: The study was a retrospective record review at the Paediatric Oncology Unit, Hospital Universiti Sains Malaysia (Hospital USM). The data collected depending on pre-set research proforma from the year 1990 to 2010. Survival analysis of each type of leukaemia was completed using multiple Cox regression model. Results: A total of 334 cases were identified, only 283 patients received treatment at Hospital USM. There were 224 patients with acute lymphoblastic leukaemia (ALL) and 59 with acute myeloid leukaemia (AML). Overall survival (OS) rate at 3 months for ALL and AML were 89.3% and 72.9% respectively. The event-free survival (EFS) rate for ALL at 1, 3, and 5 years were 69.6%, 54.1% and 47.8% respectively. For AML, the EFS rate at 1, 3, and 5 years were 52.0%, 42.4% and 38.1% respectively. Multiple Cox regression model showed children’s age at diagnosis and early response to steroid therapy were the most significant prognostic factors for ALL survival, whereas the spleen size and treatment protocol were the most significant prognostic factors for AML. Conclusion: Survival rate in this study was comparable to developing countries. ALL had better outcome compared to AML.


Introduction
Acute lymphoblastic leukaemia representing approximately 80% of childhood leukaemia. The worldwide incidence has gradually increased annually. Untreated diseases are associated with early childhood mortality. The survival rate has improved significantly with the modern treatment modalities [1,2]. The survival rate of children with acute lymphoblastic leukaemia (ALL) is better than acute myeloid leukaemia (AML) with overall survival (OS) at 83% (95% CI: 80-85) for ALL, and 54% (95% CI: 46-62) for AML in Northern Europe (3). A recent study stated that ALL survival rate has been improved significantly with 5-year-survival rate of 83.7% in 1990-1994 to 90.4% in 2000-2005 [4]. In Malaysia, the 2-yearsurvival rate for ALL from 1980-1995 was 67% [5].
A 5-year-survival rate for ALL was the highest in age group 1-4 years old with 87% and at 60% for AML in the similar age group. Advancement in chemotherapy has been shown to favourably increase the curative rate in ALL. More than 95% achieved complete remission (CR) with 5-year disease free survival rates at 63-83% [6]. The risk of relapse mostly depends on previously identifiable risk factors. Standard risk (SR) factors are age between 1-10 years old, initial TWC < 50 x 10⁹/L, absence of central nervous system and testicular involvement, T cell immunophenotype, M3 marrow on Day 15 or M2/M3 marrow on Day 36 and DNA index 1.16-1.6 (2). Risk stratification has been modified into 4 groups as per Children's Oncology Group (COG) findings [7]. Younger age group and low TWC at diagnosis usually have better prognosis in AML patients. Children with Down Syndromes especially if the age less than 4 years old at the time of diagnosis tends to have a better outcome. The gender factor showed that females had a better survival rate than males [2,8].
The objective of the study is to determine the survival of children with acute leukaemia (ALL and AML) who received chemotherapy in Paediatric Oncology Unit at Hospital USM from the 1 st January 1990 -31 st December 2010. Kaplan-Meier survival curves were used to calculate OS, event free survival (EFS) and log rank test were used to compare the survival curves of the subgroups. The factors investigated were age at the time of diagnosis, gender, immunophenotype, type of leukaemia, size of spleen and liver, early treatment response and CSF involvement. The proportion of events (resistance, relapse, death, complication) were compared using chi-square test. Univariate and Multivariate cox proportional hazard model were used to explore predictors of OS and EFS. The p value of < 0.05 is considered as significant. For the purpose of the study, definition below (Table 1) was used to calculate the parameters listed above. Duration of survival is taken from the date of diagnosis 2.

The study was conducted in Paediatric Oncology
Overall survival is taken from the time diagnosis to death or last contact 3.
Event free survival is time from diagnosis to the date of any event or to the date when patient was confirmed to be well, at the date of censor which ever occurred first 4.
Event is considered as resistance disease, relapse, defaultment, death or major complications (major complication is defined as presence of any recorded complications or secondary cancers) 5.
Median survival is the time when half of patients are expected to be alive (the chance of surviving beyond that time is 50%) 6.
Disease free survival is measured from time of completed treatment until remission or no disease 7.
Initial total white cell is the documented TWC at presentation, before starting treatment 8.
Complete remission is presence of less than 5% blast cells in bone marrow in the absence of leukemic blast cells in the peripheral blood and cerebrospinal fluid, normal peripheral blood count and absence of localized disease 9.
Relapse is any disease recurs in bone marrow, central nervous system or testis 10. Bone marrow relapse is presence of 25% blast cells in bone marrow 11. Central nervous system (CNS) relapse is presence of any CNS manifestation without any other explanation with or without presence of blast in cerebrospinal fluid 12. Testicular relapse is presence of testicular mass on examination or ultrasound 13. Good early response is absence of blast in peripheral blood on day 8 of treatment with steroid 14. Poor early response is presence of blast cells in peripheral blood on day 8 of treatment with steroid 15. Undetermined early response is uncertainty of blast cells in peripheral blood on day 8    Relapse was one of the main concern for both ALL and AML patients. The most common site of relapse was isolated bone marrow (BM) findings in both cases. BM relapse occurred in 52 children with ALL and 14 children with AML. There were 7 cases with CNS relapse, 1 for testicular relapse and 3 for both bone marrow and testicular relapse in ALL patients. For bone marrow and CNS relapse, 7 ALL cases and 1 AML case were identified.
Simple Cox regression analysis that showed poor prognostic factors for ALL in this study were age group, aged 10 years old and above, high TWC at the time of diagnosis (more than 100.0 x 10 9 /L), CSF involvement at diagnosis, poor or undetermined early response to oral steroid and those in high risk group. Hazard ratio was high in children more than 10 years (HR 3.07; 95% CI:  and 2005 -2010. The Hospital USM Oncology Unit has been set up in 1990 to accept referrals from neighbouring states which led to increase in number of cases. Many parents delayed seeking treatment, especially in 1990 -1994 and seeking for an alternative therapy after clinical and laboratory diagnosis [9]. In literature, the incidence of acute leukaemia has increased due to various environmental factors such as chemical, benzene and air pollutants [10]. The demographic variables for ALL and AML, such as gender and age distribution in our study, were almost similar to other reported studies [1,3]. The incidence in male was 1.5 times higher than female [11]. Kelantanese were homogenously inhabited by Malay and Siamese and reflected in our demographic capture that the predominant race group was Malay (97.4%), followed by Siamese (1.1%), Chinese (1.1%) and Indian (0.5%).
For the ALL subtype, B-cell subtype was the commonest followed by T-cell and mixed (biphenotype). These findings were almost similar as reported previously [12,13,14]. For AML, FAB classification was used and majority of patients had M2, M3, M4, M6, and M7, which was similar to Goubin et al. [1].
Treatment protocol has evolved from year 1990 to 2010 for both ALL and AML. The EORTC protocol was changed to UKALL protocol in ALL. Response to steroid, TWC at presentation > 100 x 10 9 /L, age ≥ 10 years at diagnosis, T-cell subtype, CSF involvement at diagnosis and male gender were considered a high risk group. Unfortunately, minimal residual disease (MRD) and cytogenetics tests were not performed locally as part of the risk assessment. Those who died were due to acute event such as septicaemia in 108 patients (87%), followed by intracranial bleeding in 10 cases (8%) and major complications such as disseminated intravascular coagulation (DIVC) in 6 cases (5%).

Overall Survival Rates for ALL and AML
The immediate OS rate for acute leukaemia in Hospital USM at 3 months after diagnosis was 85.9%. For ALL, immediate OS rate at 3 months after diagnosis was 89.3%. The immediate OS rate for AML at 3 months after diagnosis was 78.0%. Overall median survival time was 20 (95% CI: 1.4 -38.5) months. ALL had better OS rate compared to AML. These finding were also comparable to the other studies in developing countries [2,5,15,16] but considered lower to developed countries [13].

Event Free Survival (EFS) for ALL and AML
There were a few reasons for relatively lower survival of both ALL and AML in our study compared to developed countries. Our patients' cohort had different biological features. There was higher incidence of T-cell subtype (20.5%) compared to EORTC 58881 trial which possessed 7.6-15% patients with T-cell immunophenotype [1,2,17,18]. Many patients from our cohort had high TWC at the time of diagnosis. There were 21.4% with initial TWC > 100 x 10 9 /L compared to 13% in EORTC 58881 study [17], and 19% in ALL-BFM 90 protocol study [19]. Thirty-seven percent of our patients had initial TWC > 50 x 10 9 /L. The rate of CSF involvement at presentation was also high (4%) as compared to other studies 1.8 -2% [5,19]. Hence, lower proportion of children with good early response at 46.4%.
Lower survival rates in AML patients were seen in our study. The subtype M7 (18.6%) were higher compared to other study (6 -10.6%) [1]. Cytogenetic analysis was not routinely performed and the data was not available for analysis except for Down Syndrome group. Simple Cox regression analysis showed significant prognostic factors for ALL were older age at diagnosis, higher TWC count at diagnosis, CSF involvement at diagnosis, poor and undetermined early response and high risk treatment group. In multiple Cox regression analysis, only older age group at diagnosis and undetermined early response were the significant factors. For simple Cox regression analysis of AML, the significant prognostic factors were bigger spleen size at diagnosis and treatment group AML BFM 87. These 2 factors showed significant results after multiple logistic regression analysis.
The present study possessed a few limitations. Firstly, the total numbers of sample size are low. About 15% (n=51) cases were excluded due to multiple reasons. As this was a retrospective record review, poor documentation in the case notes resulted in the unavailability of important information for the study. Secondly, prognostic factors such as cytogenetic abnormality especially in AML were not analysed in this study due to unavailability of cytogenetic test in the first 10year study period. We did not investigate the MRD status after induction course. Other factors such as determination of platelet, haemoglobin counts, uric acid level, nutritional status during treatment, risk of getting infection and the distance from hospital could be considered important information for data capture in our settings. These factors might contribute to Malaysian Journal of Paediatrics and Child Health ISSN (print): 1511-4511 treatment interruption which lead to poor disease outcome. Thirdly, obtaining the data retrospectively were challenging due to extensive data search in each patient treated for leukaemia. It was time consuming to recover the data accuracy for one study subject.
It is hoped that with more passionate explanation by the treating specialist, more awareness about leukaemia among family members and availability of cytogenetic study will improve patients'survival.

Conclusion
Survival rate in this study was comparable to developing countries but remained low compared to developed countries. ALL had better outcome compared to AML. Majority of ALL cases relapsed within 2 to 3 years, in contrast to AML relapse occurred within a year after diagnosis. Multifactorial causes have been attributed to the lower survival in our area.