Juvenile Myelomonocytic Leukemia in a Child: A Case Report of Palliative Chemotherapy and Literature Review Applied to Limited Resources Centers.

Juvenile myelomonocytic leukemia (JMML) is a rare hematopoietic malignancy in children, with an incidence of 1.2 per million children per year. At this moment, we present a case report and a brief literature review of JMML in a child, primarily focused on its applicability in low-middle income countries. A 3.5-year-old male was referred to our tertiary center due to pallor, enlarging abdomen and neck mass, recurrent fever, and chronic diarrhea. Initial laboratory workup showed hemoglobin of 6.4 g/dl, white blood cell of 315.62 × 103/µL, and platelet of 17 × 103/µL. Blood smears showed 10% suspected blasts, 17% myelocytes, and 17% metamyelocytes with thrombocytopenic crisis. The HbF level was 5.8%. BCR-ABL gene tested negative. The patient was diagnosed with juvenile myelomonocytic leukemia. Considering that HSCT could not be done in our center and lack other financial possibilities to seek treatment abroad, the family agreed to do the palliative treatment. The patient was treated with oral 6-mercaptopurine and subcutaneous cytarabine. Four weeks after receiving 6-mercaptopurine, the white blood cell count decreased to 10.6 × 103/µL and the spleen size was half of the original size. The patient continued chemotherapy until week 15, chemotherapy was stopped, but 16 weeks after the diagnosis of JMML, he developed severe thrombocytopenia, endophthalmitis, and sepsis and passed away. As a conclusion, in JMML cases in developing countries without HSCT, palliative chemotherapy is acceptable, and palliative care is an important aspect.

Childhood acute lymphoblastic leukemia: Four years evaluation of protocols 2013 and 2016 in a single center in Indonesia, a lower-middle-income country.

BACKGROUND: The prognosis of childhood acute lymphoblastic leukemia (ALL) in Indonesia, a lower-middle-income country (LMIC), is lower than in high income countries (HICs). The Indonesian ALL2013 protocol resulted in too many toxic deaths (21%) and abandonments (11%). Therefore, we drafted an adapted protocol, ALL2016. Main changes: no anthracyclines in standard risk (SR), prednisone replaced dexamethasone at induction in high risk (HR), and anthracyclines and cyclophosphamide were rescheduled in HR. PROCEDURE: Patients (aged: 1-18 years) were stratified into SR and HR. HR was defined as age over 10 years, leucocyte count over 50 × 109 /L, central nervous system (CNS) involvement, mediastinal mass, T-cell phenotype, testicular involvement, or poor prednisone response. RESULTS: ALL2013 included 174 patients (106 SR and 68 HR) and ALL2016 188 (91 SR and 97 HR). Although the number of HR patients was significantly higher in ALL2016 (51.6% vs. 39.1%; p = .017), the outcome of ALL2016 improved over ALL2013 (4-year-probable overall survival (pOS) 60.1% vs. 50.0%; p = .042 and 4-year-probable event-free survival (pEFS) 49.5% vs. 36.8%; p = .018). ALL2016 showed a nonsignificant advantage for SR patients (4-year-pEFS 56.0% vs. 47.2%; p = .220 and 4-year-pOS 70.3% vs. 61.3%; p = .166), but less toxic deaths (7% vs. 20%; p = .011). In HR group, the outcomes were significantly better in ALL2016 (4-year-pEFS 43.3% vs. 20.6%; p = .004; 4-year-pOS 50.5% vs. 32.4%; p = .014) especially due to less relapses (31% vs. 62%; p = .001). Isolated CNS relapses went down from 18 to 8% in HR (p = .010) and 11 to 5% in SR (p = .474). Both SR and HR showed lower numbers of abandonment in ALL2016 (6% vs. 14%; p = .039). CONCLUSIONS: Overall ALL2016 results improved over ALL2013. Modest changes in protocol resulted in less initial toxicity and abandonments.

Comparing Health-Care Providers' Perspectives on Complementary and Alternative Medicine in Childhood Cancer Between Netherlands and Indonesia.

BACKGROUND: Use of complementary and alternative medicine (CAM) is common among patients with childhood cancer. Health-care providers (HCP) should address this need properly. Geographical and cultural differences seem likely. This study explores perspectives on CAM of HCP involved in the care of children with cancer in Netherlands and Indonesia. Health beliefs, components of CAM, encouraging or discouraging CAM, and knowledge about CAM were assessed. PROCEDURE: We conducted a cross-sectional study using semi-structured questionnaires at a Dutch and Indonesian academic hospital. RESULTS: A total of 342 HCP participated: 119 Dutch (response rate 80%) and 223 Indonesian (response rate 87%). Chemotherapy can cure cancer according to more Dutch than Indonesian HCP (87% vs. 53% respectively, P < 0.001). Combination of chemotherapy and CAM is the best way to cure cancer according to more Indonesian than Dutch HCP (45% vs. 25%, P < 0.001). Dutch and Indonesian HCP recommend and discourage CAM use differently. Most Dutch (77%) and Indonesian HCP (84%) consider their knowledge about CAM to be inadequate (P = ns). Fewer Dutch doctors than other HCP want to learn more about CAM (51% vs. 76%, P = 0.007), whereas there is no significant difference in eagerness to learn about CAM between Indonesian doctors (64%) and other HCP (72%). CONCLUSIONS: Indonesian HCP have more positive views about CAM than their Dutch colleagues. Both Dutch and Indonesian HCP consider their knowledge about CAM to be inadequate. Therefore, education programs about CAM tailored to the needs of HCP are recommended, knowing that CAM is used frequently.

Aggravated bone density decline following symptomatic osteonecrosis in children with acute lymphoblastic leukemia.

Osteonecrosis and decline of bone density are serious side effects during and after treatment of childhood acute lymphoblastic leukemia. It is unknown whether osteonecrosis and low bone density occur together in the same patients, or whether these two osteogenic side-effects can mutually influence each other's development. Bone density and the incidence of symptomatic osteonecrosis were prospectively assessed in a national cohort of 466 patients with acute lymphoblastic leukemia (4-18 years of age) who were treated according to the dexamethasone-based Dutch Child Oncology Group-ALL9 protocol. Bone mineral density of the lumbar spine (BMDLS) (n=466) and of the total body (BMDTB) (n=106) was measured by dual X-ray absorptiometry. Bone density was expressed as age- and gender-matched standard deviation scores. Thirty patients (6.4%) suffered from symptomatic osteonecrosis. At baseline, BMDLS and BMDTB did not differ between patients who did or did not develop osteonecrosis. At cessation of treatment, patients with osteonecrosis had lower mean BMDLS and BMDTB than patients without osteonecrosis (respectively, with osteonecrosis: -2.16 versus without osteonecrosis: -1.21, P<0.01 and with osteonecrosis: -1.73 versus without osteonecrosis: -0.57, P<0.01). Multivariate linear models showed that patients with osteonecrosis had steeper BMDLS and BMDTB declines during follow-up than patients without osteonecrosis (interaction group time, P<0.01 and P<0.01). We conclude that bone density status at the diagnosis of acute lymphoblastic leukemia does not seem to influence the occurrence of symptomatic osteonecrosis. Bone density declines from the time that osteonecrosis is diagnosed; this suggests that the already existing decrease in bone density during acute lymphoblastic leukemia therapy is further aggravated by factors such as restriction of weight-bearing activities and destruction of bone architecture due to osteonecrosis. Osteonecrosis can, therefore, be considered a risk factor for low bone density in children with acute lymphoblastic leukemia.

The negative impact of being underweight and weight loss on survival of children with acute lymphoblastic leukemia.

Body mass index and change in body mass index during treatment may influence treatment outcome of pediatric patients with acute lymphoblastic leukemia. However, previous studies in pediatric acute lymphoblastic leukemia reported contradictory results. We prospectively collected data on body composition from a cohort of newly diagnosed Dutch pediatric patients with acute lymphoblastic leukemia (n=762, age 2-17 years). Patients were treated from 1997-2004 and the median follow-up was 9 years (range, 0-10). Body mass index at diagnosis was expressed as age- and gender-matched standard deviation scores and on the basis of these scores the patients were categorized as being underweight, of normal weight or overweight. Multivariate analyses showed that patients who were underweight (8%) had a higher risk of relapse [hazard ratio: 1.88, 95% confidence interval (1.13-3.13)], but similar overall survival and event-free survival as patients who had a normal weight or who were overweight. Patients with loss of body mass index during the first 32 weeks of treatment had a similar risk of relapse and event-free survival, but decreased overall survival [hazard ratio: 2.10, 95% confidence interval (1.14-3.87)] compared to patients without a loss of body mass index. In addition, dual X-ray absorptiometry scans were performed in a nested, single-center cohort. Data from these scans revealed that a loss of body mass consisted mainly of a loss of lean body mass, while there was a gain in the percentage of fat. In conclusion, being underweight at diagnosis is a risk factor for relapse, and a decrease in body mass index early during treatment is associated with decreased survival. In addition, loss of body mass during treatment seems to consist mainly of a loss of lean body mass. This study was approved by the Medical Ethical Committee in 1996 (trial number NTR460/SNWLK-ALL-9).

Bone mineral density at diagnosis determines fracture rate in children with acute lymphoblastic leukemia treated according to the DCOG-ALL9 protocol.

PURPOSE: To elucidate incidence and risk factors of bone mineral density and fracture risk in children with Acute Lymphoblastic Leukemia (ALL). METHODS: Prospectively, cumulative fracture incidence, calculated from diagnosis until one year after cessation of treatment, was assessed in 672 patients. This fracture incidence was compared between subgroups of treatment stratification and age subgroups (Log-Rank test). Serial measurements of bone mineral density of the lumbar spine (BMDLS) were performed in 399 ALL patients using dual energy X-ray absorptiometry. We evaluated risk factors for a low BMD (multivariate regression analysis). Osteoporosis was defined as a BMDLS≤-2 SDS combined with clinical significant fractures. RESULTS: The 3-year cumulative fracture incidence was 17.8%. At diagnosis, mean BMDLS of ALL patients was lower than of healthy peers (mean BMDLS=-1.10 SDS, P<0.001), and remained lower during/after treatment (8months: BMDLS=-1.10 SDS, P<0.001; 24months: BMDLS=-1.27 SDS, P<0.001; 36months: BMDLS=-0.95 SDS, P<0.001). Younger age, lower weight and B-cell-immunophenotype were associated with a lower BMDLS at diagnosis. After correction for weight, height, gender and immunophenotype, stratification to the high risk (HR)-protocol arm and older age lead to a larger decline of BMDLS (HR group: ß=-0.52, P<0.01; age: ß=-0.16, P<0.001). Cumulative fracture incidences were not different between ALL risk groups and age groups. Patients with fractures had a lower BMDLS during treatment than those without fractures. Treatment-related bone loss was similar in patients with and without fractures (respectively: ΔBMDLS=-0.36 SDS and ΔBMDLS=-0.12 SDS; interaction group time, P=0.30). Twenty of the 399 patients (5%) met the criteria of osteoporosis. CONCLUSION: Low values of BMDLS at diagnosis and during treatment, rather than the treatment-related decline of BMDLS, determine the increased fracture risk of 17.8% in children with ALL.

Accelerated aging, decreased white matter integrity, and associated neuropsychological dysfunction 25 years after pediatric lymphoid malignancies.

PURPOSE: CNS-directed chemotherapy (CT) and cranial radiotherapy (CRT) for childhood acute lymphoblastic leukemia or lymphoma have various neurotoxic properties. This study aimed to assess their impact on the maturing brain 20 to 30 years after diagnosis, providing a much stronger perspective on long-term quality of life than previous studies. PATIENTS AND METHODS: Ninety-three patients treated between 1978 and 1990 at various intensities, with and without CRT, and 49 healthy controls were assessed with magnetic resonance diffusion tensor imaging (DTI) and neuropsychological tests. Differences in fractional anisotropy (FA)-a DTI measure describing white matter (WM) microstructure-were analyzed by using whole brain voxel-based analysis. RESULTS: CRT-treated survivors demonstrated significantly decreased FA compared with controls in frontal, parietal, and temporal WM tracts. Trends for lower FA were seen in the CT-treated survivors. Decreases in FA correlated well with neuropsychological dysfunction. In contrast to the CT group and controls, the CRT group showed a steep decline of FA with age at assessment. Younger age at cranial irradiation and higher dosage were associated with worse outcome of WM integrity. CONCLUSION: CRT-treated survivors show decreased WM integrity reflected by significantly decreased FA and associated neuropsychological dysfunction 25 years after treatment, although effects of CT alone seem mild. Accelerated aging of the brain and increased risk of early onset dementia are suspected after CRT, but not after CT.

A medication diary-book for pediatric patients with acute lymphoblastic leukemia in Indonesia.

BACKGROUND: Event-free survival of pediatric patients with acute lymphoblastic leukemia (ALL) in Yogyakarta, Indonesia was low (20%). The aim of the study was to evaluate the effectiveness of using a medication diary-book on the treatment outcome of childhood ALL. PROCEDURE: A randomized study was conducted with 109 pediatric patients with ALL in a pediatric oncology center in Yogyakarta, Indonesia. Both intervention and control groups received a structured parental education program and donated chemotherapy. The intervention group received a medication diary-book to remind parents and families to take oral chemotherapy and present for scheduled appointments or admissions. Event-free survival estimate (EFS) at 3 years was assessed. RESULTS: Among pediatric patients with ALL with highly educated mothers (senior high school or higher), the EFS-estimate at 3 years of the intervention group was significantly higher than the EFS-estimate at 3 years of the control group (62% vs. 29%, P = 0.04). Among pediatric patients with ALL with low-educated mothers, no significant difference was found in the EFS-estimates at 3 years between the intervention and control group (26% vs. 18%, P = 0.86). CONCLUSIONS: We conclude that a medication diary-book might be useful to improve the survival of pediatric patients with ALL in resource-limited settings, particularly in patients with highly educated mothers.

L-asparaginase: long-term results of a randomized trial of the effect of additional 3 doses during consolidation treatment in the Indonesian WK-ALL-2000 protocol.

We conducted a randomized trial to compare the influence of 3 additional doses of L-asparaginase on clinical outcome of newly diagnosed childhood acute lymphoblastic leukemia (ALL). Patients were treated using Indonesian WK-ALL-2000 protocol between 1999 and 2005 and randomized to receive (3A arm, n=61) or not to receive (0A arm, n=56) an additional 3 weekly doses of 6000 IU/m(2)/dose of Escherichia coli L-asparaginase during consolidation treatment on top of 2 doses (standard-risk patients) or 5 doses (high-risk patients). Events after remission included relapse (37.6%), death (16.2%), and abandonment of therapy (15.4%). There was no significant difference in relapses between the 2 arms. Patients in arm 3A versus 0A tended to have a lower 5 years disease-free survival (47.4±7.9% vs. 51.7±7.9%, P=0.72) and lower 5 years event-free survival (29.5±5.8% vs. 35.7±6.4%, P=0.61). We conclude that in our setting the use of 3 additional doses of L-asparaginase during consolidation therapy did not result in survival advantage. Contrariwise, adverse effects from this drug included higher treatment cost and systemic toxicity.

Myeloid Antigen Expression in Childhood Acute Lymphoblastic Leukemia and Its Relevance for Clinical Outcome in Indonesian ALL-2006 Protocol.

The frequency of acute lymphoblastic leukemia (ALL) patients expressing myeloid antigens on their ALL cells varies between 5 and 36% in several different studies. The clinical relevance of myeloid antigen expression in childhood ALL is controversial. In Indonesian patients, no data were present. Therefore, in Yogyakarta, Indonesia, we analyzed 239 ALL patients who were immunophenotyped including myeloid markers (CD13, CD33, CD117, and/or cMPO). Myeloid antigen expression was found in 25% of patients. Expression of myeloid antigen in B-lineage leukemia was 27%, and in T-lineage leukemia, it was 18% (P = 0.15). No association was found between myeloid antigen expression and clinical or biological features. In the whole cohort of patients we did not find a significant association between myeloid antigen expression and survival, although leukemia-free survival at 3 years was higher in the myeloid-negative patients (73% ± 6%) compared to myeloid-positive patients (67% ± 8%). Interestingly, in T-ALL patients, expression of myeloid antigens was an independent adverse prognostic factor (hazard ratio: 3.26, 95% CI: 1.06-9.98, P = 0.04). Kaplan-Meier analysis for event-free survival was also significant (log rank P = 0.03) in this subgroup. In conclusion, in the Indonesian ALL population, in particular, myeloid antigen-expressing T-ALL patients had a higher chance of having induction failure.

Early Response to Dexamethasone as Prognostic Factor: Result from Indonesian Childhood WK-ALL Protocol in Yogyakarta.

Early response to treatment has been shown to be an important prognostic factor of childhood acute lymphoblastic leukemia (ALL) patients in Western studies. We studied this factor in the setting of a low-income province in 165 patients treated on Indonesian WK-ALL-2000 protocol between 1999 and 2006. Poor early response, defined as a peripheral lymphoblasts count of ≥1000/µL after 7 days of oral dexamethasone plus one intrathecal methotrexate (MTX), occurred in 19.4% of the patients. Poor responders showed a higher probability of induction failures compared to good responders (53.1% versus 23.3%, P < 0.01), higher probability of resistant disease (15.6% versus 4.5%, P = 0.02), shorter disease-free survival (P = 0.034; 5-year DFS: 24.9% ± 12.1% versus 48.6% ± 5.7%), and shorter event-free survival (P = 0.002; 5-year EFS: 9.7% ± 5.3% versus 26.3% ± 3.8%). We observed that the percentage of poor responders in our setting was higher than reported for Western countries with prednisone or prednisolone as the steroids. The study did not demonstrate a significant additive prognostic value of early response over other known risk factors (age and white blood cell count) for DFS and only a moderately added value for EFS.

The significance of PTEN and AKT aberrations in pediatric T-cell acute lymphoblastic leukemia.

BACKGROUND: PI3K/AKT pathway mutations are found in T-cell acute lymphoblastic leukemia, but their overall impact and associations with other genetic aberrations is unknown. PTEN mutations have been proposed as secondary mutations that follow NOTCH1-activating mutations and cause cellular resistance to γ-secretase inhibitors. DESIGN AND METHODS: The impact of PTEN, PI3K and AKT aberrations was studied in a genetically well-characterized pediatric T-cell leukemia patient cohort (n=146) treated on DCOG or COALL protocols. RESULTS: PTEN and AKT E17K aberrations were detected in 13% and 2% of patients, respectively. Defective PTEN-splicing was identified in incidental cases. Patients without PTEN protein but lacking exon-, splice-, promoter mutations or promoter hypermethylation were present. PTEN/AKT mutations were especially abundant in TAL- or LMO-rearranged leukemia but nearly absent in TLX3-rearranged patients (P=0.03), the opposite to that observed for NOTCH1-activating mutations. Most PTEN/AKT mutant patients either lacked NOTCH1-activating mutations (P=0.006) or had weak NOTCH1-activating mutations (P=0.011), and consequently expressed low intracellular NOTCH1, cMYC and MUSASHI levels. T-cell leukemia patients without PTEN/AKT and NOTCH1-activating mutations fared well, with a cumulative incidence of relapse of only 8% versus 35% for PTEN/AKT and/or NOTCH1-activated patients (P=0.005). CONCLUSIONS: PI3K/AKT pathway aberrations are present in 18% of pediatric T-cell acute lymphoblastic leukemia patients. Absence of strong NOTCH1-activating mutations in these cases may explain cellular insensitivity to γ-secretase inhibitors.

Sequential gain of mutations in severe congenital neutropenia progressing to acute myeloid leukemia.

Severe congenital neutropenia (SCN) is a BM failure syndrome with a high risk of progression to acute myeloid leukemia (AML). The underlying genetic changes involved in SCN evolution to AML are largely unknown. We obtained serial hematopoietic samples from an SCN patient who developed AML 17 years after the initiation of G-CSF treatment. Next- generation sequencing was performed to identify mutations during disease progression. In the AML phase, we found 12 acquired nonsynonymous mutations. Three of these, in CSF3R, LLGL2, and ZC3H18, co-occurred in a subpopulation of progenitor cells already in the early SCN phase. This population expanded over time, whereas clones harboring only CSF3R mutations disappeared from the BM. The other 9 mutations were only apparent in the AML cells and affected known AML-associated genes (RUNX1 and ASXL1) and chromatin remodelers (SUZ12 and EP300). In addition, a novel CSF3R mutation that conferred autonomous proliferation to myeloid progenitors was found. We conclude that progression from SCN to AML is a multistep process, with distinct mutations arising early during the SCN phase and others later in AML development. The sequential gain of 2 CSF3R mutations implicates abnormal G-CSF signaling as a driver of leukemic transformation in this case of SCN.

Different outcome in older children with acute lymphoblastic leukemia with different treatment protocols in the Netherlands.

BACKGROUND: From 1991 until 2004 children with acute lymphoblastic leukemia (ALL) in the Netherlands were treated according to protocols ALL-8 and ALL-9 which were based on different principles. An earlier study showed that the outcome of adolescents highly differed on these protocols. PROCEDURE: In this retrospective study, we analyzed whether the outcome of older children 10-15 years of age at diagnosis differed between the Berlin-Frankfurt-Münster (BFM)-based ALL-8 regimen and the ALL-9 regimen. Two hundred fifty-four older children who were treated according to protocol ALL-8 (n = 82) or ALL-9 (n = 172) were included in the analysis. RESULTS: A higher 5-year event-free survival (EFS) rate was found for patients treated according to ALL-8 compared to ALL-9 (79 ± 5% vs. 65 ± 4%, P = 0.02). Patient characteristics did not differ except for a slightly higher age in ALL-8. Therefore, additional analyses were done including only patients who were 12-15 years of age. In this age group there was also a difference in the 5-year EFS (82 ± 5% vs. 61 ± 5%, P = 0.00) as well as in the 5-year overall survival rate; 89 ± 4% compared to 68 ± 5%, respectively (P = 0.01). Major difference between protocols was the use of a consolidation and reinduction/intensification course and higher cumulative doses of asparaginase, methotrexate, and anthracyclines in ALL-8. CONCLUSIONS: Children 10-15 years of age have been undertreated with the ALL-9 regimen and benefit by intensive treatment components as used in ALL-8. We recommend using BFM-based protocols for these older children with ALL.

Prospective study on incidence, risk factors, and long-term outcome of osteonecrosis in pediatric acute lymphoblastic leukemia.

PURPOSE: We studied cumulative incidence, risk factors, therapeutic strategies, and outcome of symptomatic osteonecrosis in pediatric patients with acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Cumulative incidence of osteonecrosis was assessed prospectively in 694 patients treated with the dexamethasone-based Dutch Child Oncology Group-ALL9 protocol. Osteonecrosis was defined by development of symptoms (National Cancer Institute grade 2 to 4) during treatment or within 1 year after treatment discontinuation, confirmed by magnetic resonance imaging. We evaluated risk factors for osteonecrosis using logistic multivariate regression. To describe outcome, we reviewed clinical and radiologic information after antileukemic treatment 1 year or more after osteonecrosis diagnosis. RESULTS: Cumulative incidence of osteonecrosis at 3 years was 6.1%. After adjustment for treatment center, logistic multivariate regression identified age (odds ratio [OR], 1.47; P < .01) and female sex (OR, 2.23; P = .04) as independent risk factors. Median age at diagnosis of ALL in patients with osteonecrosis was 13.5 years, compared with 4.7 years in those without. In 21 (55%) of 38 patients with osteonecrosis, chemotherapy was adjusted. Seven patients (18%) underwent surgery: five joint-preserving procedures and two total-hip arthroplasties. Clinical follow-up of 35 patients was evaluated; median follow-up was 4.9 years. In 14 patients (40%), symptoms completely resolved; 14 (40%) had symptoms interfering with function but not with activities of daily living (ADLs; grade 2); seven (20%) had symptoms interfering with ADLs (grade 3). In 24 patients, radiologic follow-up was available; in six (25%), lesions improved/disappeared; in 13 (54%), lesions remained stable; five (21%) had progressive lesions. CONCLUSION: Six percent of pediatric patients with ALL developed symptomatic osteonecrosis during or shortly after treatment. Older age and female sex were risk factors. After a median follow-up of 5 years, 60% of patients had persistent symptoms.

Incidence of childhood leukemia in Yogyakarta, Indonesia, 1998-2009.

BACKGROUND: In most developing countries, incidence data for childhood cancers are less reliable, because very few population-based registries exist. The aim of this study was to present the epidemiology of childhood leukemia in the Dr. Sardjito Hospital (DSH) region, which catchment area extends beyond the boundaries of the Yogyakarta Special Province (YSP). PROCEDURE: Health records of children, 0-14 years of age, who were diagnosed with leukemia between January 1998 and December 2009, were reviewed. Diagnosis of leukemia was confirmed by morphological and histochemical examination of marrow samples. RESULTS: The estimated average annual incidence rate (AAIR) of childhood acute leukemia in DSH was 46.2 per million per year. Interestingly, the annual incidence rate (AIR) of childhood acute leukemia from the catchment area of DSH significantly increased from 35 in 1999 to 70 in 2009 (ANOVA, P = 0.003). The YSP population data, analyzed separately, showed an increase in AIR from 15.7 to 32.9 (ANOVA, P = 0.325) and an AAIR of 28.8. Remarkably, a relatively high frequency (25.5% in DSH and 27.7% in YSP) of children with AML was found in the group of acute leukemias. CONCLUSION: The DSH incidence calculations may be overestimated due to an underestimation of the population number. Since the population count for YSP is more precise, the data of YSP were used for comparison with developed countries. AAIR of ALL (20.8) is relatively low compared to Western countries (22.4-37.9). The AAIR of AML (8.0) is similar to Western countries (5.0-8.0) resulting a relatively high percentage of AML versus ALL (27.7%) in YSP.

Immunophenotypic patterns of childhood acute leukemias in Indonesia.

BACKGROUND: Immunophenotyping, as suggested by WHO, may improve diagnosis of childhood leukemia since it offers a better classification of the hematopoietic lineage of malignant cells as compared to morphology. Therefore, we aimed to determine the proportion of the immunophenotypic subtypes of acute leukemia in Indonesian children. METHODS: Samples were obtained from patients (0-14 years of age) in 4 hospitals in Indonesia. We analyzed 541 suspected leukemia samples presented over a 4-year period (March 2006 - July 2010) by flow cytometry. Immunophenotyping allowed classification into acute myeloid leukemia (AML) and ALL (B-lineage and T-lineage ALL). RESULTS: Of 541 samples, 136 were tested using a single color method and 405 with a three-color method. Concordance with morphology was very good (?=0.82) using the three-color method with a panel of 15 monoclonal antibodies (n=387). A relatively high percentage of acute leukemia was classified as AML (23%). Of the ALL samples 83% were B-lineage ALL and 17% T- lineage ALL. Nine out of 239 morphological ALL were labeled AML, and 12/79 morphological AML were in fact ALL. CONCLUSION: Immunophenotyping in a multi-center study proved feasible and appears particularly important for prognostic assessment of childhood leukemia in low income countries such as Indonesia.

Treatment refusal and abandonment in childhood acute lymphoblastic leukemia in Indonesia: an analysis of causes and consequences.

BACKGROUND: Treatment refusal and abandonment are common causes of treatment failure in childhood acute lymphoblastic leukemia (ALL) in many developing countries. In most studies reasons for abandonment were based on the opinion of health-care providers (HCP), very few studies have focused on the parental point-of-view. Aims of the study were to analyze the parents' reasons of abandonment and to ascertain the fate of children who abandoned treatment in a pediatric oncology centre in Yogyakarta, Indonesia. METHODS: We conducted home-visits to interview families of ALL patients, diagnosed between January 2004 and August 2007, who refused or abandoned treatment. RESULTS: From January 2004 to August 2007, 159 patients were diagnosed with ALL of which 40 children (25%) refused or abandoned therapy. Thirty-seven (93%) of these children were home-visited. Reasons for abandonment were complex. Most parents mentioned several reasons. Financial and transportation difficulties were not the only, or even the main reasons, for abandonment. Belief of ALL incurability, experience of severe side effects and dissatisfaction with HCP were also important considerations. Most patients (64%) abandoned treatment during the diagnostic-evaluation or remission-induction phase. Of the 37 patients who refused or abandoned treatment, 26 (70%) children died, and 11 (30%) children were still alive, 2 of them more than 2 years after abandonment. CONCLUSIONS: Reducing treatment abandonment of childhood ALL in developing countries requires not only financial and transportation support, but also parental education, counseling and psychosocial support during therapy, improvement of quality-of-care and adequate management of side effects.

Intrathecal vincristine: 3 fatal cases and a review of the literature.

We report 3 cases of accidental intrathecal vincristine administration. All 3 patients died between 8 and 18 days after the incident because of decerebration. In the literature, we found 41 cases of accidental intrathecal injection of vincristine. These reports represent only a fraction of the existing problem. New in our report is the fact that the first 2 cases were attributed to viral infection, only after the detection of high levels of vincristine in the cerebrospinal fluid was the real cause of death ascertained. The third case occurred during the implementation of rules by the Dutch Childhood Oncology Group on how to handle intrathecal triple therapy; and despite sequential safety measures, the accident still occurred. In the Netherlands no more accidents of this nature have occurred in children after the introduction of a quadruple syringe system 8 years ago. In our opinion the best fail-safe solution would be the development of a unique connection that is incompatible with a standard Luer syringe.