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.

Executive Dysfunction 25 Years after Treatment with Cranial Radiotherapy for Pediatric Lymphoid Malignancies.

The first cohorts to survive childhood lymphoid malignancies treated with cranial irradiation are now aging into adulthood, and concerns are growing about the development of radiotherapy-induced cognitive deficits in the aging brain. These deficits are hypothesized to increase over time. Their impact on daily functioning of older survivors, and the accompanying need for interventions, should be anticipated. By describing a detailed profile of executive function deficits and their associations with age, specific targets for neuropsychological intervention can be identified. Fifty survivors of childhood lymphoid malignancies and 58 related controls were assessed with the Amsterdam Neuropsychological Tasks program. The survivors were on average 31.1 (4.9) years old, treated with 22.5 (6.8) Gy cranial irradiation, and examined on average 25.5 (3.1) years after diagnosis. The survivors showed significantly decreased response speed, irrespective of the task at hand. Furthermore, we found deficits in working memory capacity, inhibition, cognitive flexibility, executive visuomotor control, attentional fluctuations, and sustained attention. Older age was associated with poorer performance on executive visuomotor control and inhibition. On executive visuomotor control, 50% of female survivors performed more than 1.5 SD below average, versus 15.4% of male survivors. The combination of visuospatial working memory problems and decreasing executive visuomotor control could result in difficulty with learning new motor skills at older ages, like walking with a cane. Deterioration of executive control and inhibition may result in decreased behavioral and emotional regulation in aging survivors. Especially the deficiency in executive visuomotor control in female survivors should be considered for (prophylactic) intervention.

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).

Parents' and health-care providers' perspectives on side- effects of childhood cancer treatment in Indonesia.

BACKGROUND: Efficacy of childhood cancer treatment in low-income countries may be impacted by parents' and health-care providers' perspectives on chemotherapy-related side-effects. This study explores prevalence and severity of side-effects in childhood cancer, and compares health beliefs about side-effects between parents and health-care providers, and between nurses and doctors in Indonesia. MATERIALS AND METHODS: Semi-structured questionnaires were filled in by 40 parents and 207 health-care providers in an academic hospital. RESULTS: Parents exporessed a desire to receive more information about side-effects (98%) and worried about this aspect of treatment (90%), although side-effects were less severe than expected (66%). The most frequent was behavior alteration (98%) and the most severe was hair loss. Only 26% of parents consulted doctors about side-effects. More parents, compared to health-care providers, believed that medicines work better when side-effects are more severe (p<0.001), and accepted severe side-effects (p=0.021). More health-care providers, compared to parents, believed that chemotherapy can be stopped or the dosage altered when there are side-effects (p=0.011). More nurses, compared to doctors, stated that side-effects were unbearable (p=0.004) and made them doubt efficacy of treatment (p<0.001). CONCLUSIONS: Behavior alteration is the most frequent and hair loss the most severe side-effect. Apparent discrepancies in health beliefs about side-effects exist between parents and health-care providers. A sustainable parental education program about side-effects is recommended. Health-care providers need to update and improve their knowledge and communication skills in order to give appropriate information. Such measures may improve outcome of childhood cancer treatment in low-income countries, where adherence to therapy is a major issue.

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.

Randomized double blind trial of ciprofloxacin prophylaxis during induction treatment in childhood acute lymphoblastic leukemia in the WK-ALL protocol in Indonesia.

OBJECTIVES: Toxic death is a big problem in the treatment of childhood acute lymphoblastic leukemia (ALL), especially in low-income countries. Studies of ciprofloxacin as single agent prophylaxis vary widely in success rate. We conducted a double-blind, randomized study to test the effects of ciprofloxacin monotherapy as prophylaxis for sepsis and death in induction treatment of the Indonesian childhood ALL protocol. METHODS: Patients were randomized to the ciprofloxacin arm (n = 58) and to the placebo arm (n = 52). Oral ciprofloxacin monotherapy or oral placebo was administered twice a day. All events during induction were recorded: toxic death, abandonment, resistant disease, and complete remission rate. RESULTS: Of 110 patients enrolled in this study, 79 (71.8%) achieved CR. In comparison to the placebo arm, the ciprofloxacin arm had lower nadir of absolute neutrophil count during induction with median of 62 (range: 5-884) versus 270 (range: 14-25,480) × 10(9) cells/L (P < 0.01), greater risks for experiencing fever (50.0% versus 32.7%, P = 0.07), clinical sepsis (50.0% versus 38.5%, P = 0.22), and death (18.9% versus 5.8%, P = 0.05). CONCLUSION: In our setting, a reduced intensity protocol in a low-income situation, the data warn against using ciprofloxacin prophylaxis during induction treatment. A lower nadir of neutrophil count and higher mortality were found in the ciprofloxacin group.

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.

Long-term effects of cranial irradiation and intrathecal chemotherapy in treatment of childhood leukemia: a MEG study of power spectrum and correlated cognitive dysfunction.

BACKGROUND: Prophylaxis to prevent relapses in the central nervous system after childhood acute lymphoblastic leukemia (ALL) used to consist of both intrathecal chemotherapy (CT) and cranial irradiation (CRT). CRT was mostly abolished in the eighties because of its neurotoxicity, and replaced with more intensive intrathecal CT. In this study, a group of survivors treated with CRT before 1983 and another group treated without CRT thereafter are investigated 20-25 years later, giving a much stronger perspective on long-term quality of life than previous studies. The outcomes will help to better understand these groups' current needs and will aid in anticipating late effects of prophylactic CRT that is currently applied for other diseases. This study evaluates oscillatory neuronal activity in these long-term survivors. Power spectrum deviations are hypothesized to correlate with cognitive dysfunction. METHODS: Resting state eyes-closed magnetoencephalography (MEG) recordings were obtained from 14 ALL survivors treated with CT + CRT, 18 treated with CT alone and 35 controls. Relative spectral power was calculated in the δ, θ, α1, α2, ß and γ frequency bands. The Amsterdam Neuropsychological Tasks (ANT) program was used to assess cognition in the executive functions domain. MEG data and ANT scores were correlated. RESULTS: In the CT + CRT group, relative θ power was slightly increased (p = 0.069) and α2 power was significantly decreased (p = 0.006). The CT + CRT group performed worse on various cognitive tests. A deficiency in visuomotor accuracy, especially of the right hand, could be clearly associated with the deviating regional θ and α2 powers (0.471 < r < 0.697). A significant association between decreased regional α2 power and less attentional fluctuations was found for CT + CRT patients as well as controls (0.078 < r < 0.666). Patients treated with CT alone displayed a power spectrum similar to controls, except for a significantly increased level of left frontal α2 power (p = 0.030). CONCLUSIONS: The tendency towards global slowing of brain oscillatory activity, together with the fact that dementia has been reported as a late effect of CRT and the neuropsychological deficiencies currently present, suggest that the irradiated brain might be aging faster and could be at risk for early-onset dementia. The CT group showed no signs of early aging.

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.

Socio-economic status plays important roles in childhood cancer treatment outcome in Indonesia.

BACKGROUND: The influence of parental socio-economic status on childhood cancer treatment outcome in low-income countries has not been sufficiently investigated. Our study examined this influence and explored parental experiences during cancer treatment of their children in an Indonesian academic hospital. MATERIALS AND METHODS: Medical charts of 145 children diagnosed with cancer between 1999 and 2009 were reviewed retrospectively. From October 2011 until January 2012, 40 caretakers were interviewed using semi-structured questionnaires. RESULTS: Of all patients, 48% abandoned treatment, 34% experienced death, 9% had progressive/ relapsed disease, and 9% overall event-free survival. Prosperous patients had better treatment outcome than poor patients (P<0.0001). Odds-ratio for treatment abandonment was 3.3 (95%CI: 1.4-8.1, p=0.006) for poor versus prosperous patients. Parents often believed that their child's health was beyond doctor control and determined by luck, fate or God (55%). Causes of cancer were thought to be destiny (35%) or God's punishment (23%). Alternative treatment could (18%) or might (50%) cure cancer. Most parents (95%) would like more information about cancer and treatment. More contact with doctors was desired (98%). Income decreased during treatment (55%). Parents lost employment (48% fathers, 10% mothers), most of whom stated this loss was caused by their child's cancer (84% fathers, 100% mothers). Loss of income led to financial difficulties (63%) and debts (55%). CONCLUSIONS: Treatment abandonment was most important reason for treatment failure. Treatment outcome was determined by parental socio-economic status. Childhood cancer survival could improve if financial constraints and provision of information and guidance are better addressed.

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.