Jiann Shiuh Chen

Long-term results of Taiwan Pediatric Oncology Group studies 1997 and 2002 for childhood acute lymphoblastic leukemia

The long-term outcome of 1390 children with acute lymphoblastic leukemia (ALL), treated in two successive clinical trials (Taiwan Pediatric Oncology Group (TPOG)-ALL-97 and TPOG-ALL-2002) between 1997 and 2007, is reported. The event-free survival improved significantly (P=0.0004) over this period, 69.3±1.9% in 1997–2001 to 77.4±1.7% in 2002–2007. A randomized trial in TPOG-97 testing L-asparaginase versus epidoxorubicin in combination with vincristine and prednisolone for remission induction in standard-risk (SR; low-risk) patients yielded similar outcomes. Another randomized trial, in TPOG-2002, showed that for SR patients, two reinduction courses did not improve long-term outcome over one course. Decreasing use of prophylactic cranial irradiation in the period 1997–2008 was not associated with increased rates of CNS relapse, prompting complete omission of prophylactic cranial irradiation from TPOG protocols, beginning in 2009. Decreased use of etoposide and cranial irradiation likely contributed to the low incidence of second cancers. High-risk B-lineage ALL, T-cell, CD10 negativity, t(9;22), infant, and higher leukocyte count were consistently adverse factors, whereas hyperdiploidy >50 was a consistently favorable factor. Higher leukocyte count and t(9;22) retained prognostic significance in both TPOG-97 and TPOG-2002 by multivariate analysis. Although long-term outcome in TPOG clinical trials is comparable with results being reported worldwide, the persistent strength of certain prognostic variables and the lower frequencies of favorable outcome predictors, such as ETV6-RUNX1 and hyperdiploidy >50, in Taiwanese children warrant renewed effort to cure a higher proportion of patients while preserving their quality of life.

IKZF1 deletions predict a poor prognosis in children with B‐cell progenitor acute lymphoblastic leukemia: A multicenter analysis in Taiwan

Despite current risk‐directed therapy, approximately 15–20% of pediatric patients with acute lymphoblastic leukemia (ALL) have relapses. Recent genome‐wide analyses have identified that an alteration of IKZF1 is associated with very poor outcomes in B‐cell progenitor ALL. In this study, we determined the prognostic significance of IKZF1 deletions in patients with childhood ALL. This study analyzed 242 pediatric B‐cell progenitor ALL patients in Taiwan. We developed a simple yet sensitive multiplex quantitative PCR coupled with capillary electrophoresis to accurately determine the allele dose of IKZF1, and high resolution melting was used for mutation screening for all coding exons of IKZF1. Twenty‐six (10.7%) pediatric B‐cell progenitor ALL patients were found to harbor these deletions. Most of the deletions were broader deletions that encompassed exon 3 to exon 6, consistent with previous reports. Genomic sequencing of IKZF1 was carried out in all cases and no point mutations were identified. Patients with IKZF1 deletions had inferior event‐free survival (P < 0.001), and overall survival (P = 0.0016). The association between IKZF1 deletions and event‐free survival was independent of age, leukocyte count at presentation, and cytogenetic subtype by multivariate Cox analysis (P = 0.003, hazard ratio = 2.45). This study indicates that detection of IKZF1 deletions upon diagnosis of B‐cell progenitor ALL may help to identify patients at risk of treatment failure. IKZF1 deletions could be incorporated as a new high‐risk prognostic factor in future treatment protocols. To the best of our knowledge, this is the first study to examine the poor prognosis of IKZF1 deletions in an Asian population. (Cancer Sci 2011; 102: 1874–1881)

Improved treatment results for childhood acute myeloid leukemia in Taiwan

To improve treatment results for children with de novo acute myeloid leukemia (AML), we introduced a novel protocol, Taiwan Pediatric Oncology Group-AML-97A, for AML other than acute promyelocytic leukemia (APL), for which modified conventional protocols were used. From January 1, 1997, to December 31, 2002, 141 children younger than 17 years old with de novo AML were enrolled. In total, 117 patients with non-APL AML were treated with induction therapy of idarubicin and cytarabine (Ara-C), postremission therapy with high-dose Ara-C – containing regimens for four monthly courses, and moderate-dose therapy with idarubicin and Ara-C for four monthly courses. The first 19 patients with APL were treated with all-trans retinoic acid, idarubicin and Ara-C, with the remaining five patients receiving all-trans retinoic acid and idarubicin, followed by maintenance therapy for 2 years. Stem cell transplantation was performed in 29 patients in first remission with a similar outcome as chemotherapy alone. The remission rate in the AML-97A study was 90%, the 5-year survival 51±5.3% (s.e.) and the 5-year event-free survival 50±4.8%; for APL, these were 100%, 86±7.0, and 75±9.8%. For the whole group, the 5-year survival was 57±4.7% and the 5-year event-free survival 54±4.4%. The AML-97A regimen was well tolerated.

Unexpected mortality from the use of E. coli L-asparaginase during remission induction therapy for childhood acute lymphoblastic leukemia: A report from the Taiwan Pediatric Oncology Group

The relative efficacy and toxicity of E. coli L-asparaginase and epidoxorubicin used in remission induction therapy for childhood acute lymphoblastic leukemia (ALL) were assessed in a randomized trial conducted in Taiwan. All patients had standard-risk ALL, defined as a leukocyte count <10 × 109/l and were aged between 1 and 2 or 7 and 10 years, or a leukocyte count <50 × 109/l and were aged between 2 and 7 years, without evidence of a T cell or mature B cell immunophenotype, central nervous system leukemia or expression of two or more myeloid-associated antigens. Ninety-three patients were randomized to receive E. coli L-asparaginase at 10 000 IU/m2 thrice weekly for nine doses and 108 to receive epidoxorubicin at 20 mg/m2 weekly for two doses during remission induction with daily prednisolone, weekly vincristine and, on day 22, a dose of etoposide plus cytarabine. Patients treated with L-asparaginase had a significantly higher rate of fatal infection with or without hemorrhage than did those who received epidoxorubicin during remission induction (six of 93 vs none of 108, P = 0.009), resulting in a lower rate of complete remission in the former group (93.6 vs 99.1%, P = 0.05). In addition, patients treated with L-asparaginase had a higher frequency of hyperglycemia and hypoalbuminemia. The overall rate of event-free survival was lower in patients treated with L-asparaginase than in other patients (P = 0.06); estimated 3-year rates were 72% (95% confidence interval, 55–89%) and 87.2% (78–96%), respectively. We conclude that L-asparaginase (Leunase) given at 10 000 IU/m2 for nine doses was poorly tolerated and resulted in excessive toxicity, both through its effects as a single agent and possibly through potentiation of etoposide.

Longitudinal observation and outcome of nonfamilial childhood haemophagocytic syndrome receiving etoposide-containing regimens

The long‐term outcome of 22 children treated with etoposide‐containing regimens for haemophagocytic syndrome (HS) were longitudinally studied; none of them had a family history of the disease. All patients received etoposide‐containing (150 mg/m2/d) regimens, combined, in 16 cases, with intravenous immunoglobulin (IVIG) and prednisolone. Complete remission (CR) was achieved in 12 patients, partial remission in seven, and early mortality occurred in three. Of the 12 CR patients, only four remain alive and disease‐free, with a median follow‐up of 47.4 months; one CR patient died due to infection and the remaining seven had relapsed diseases. Three patients with a partial response or with relapsed disease progressed to T‐cell lymphoma, characterized, in the two cases tested, by clonal chromosomal abnormalities. Epstein‐Barr virus (EBV) infection was implicated in disease pathogenesis in 15/22 patients. The overall survival was 45.5%, 40.9% and 40.9% at 1, 3 and 5 years, respectively, and disease‐free survival for CR patients at these same times was 45.5%, 36.4% and 36.4%. The etoposide‐containing regimen would appear to be an effective initial therapeutic option for childhood HS. However, in view of the frequency of partial remissions and relapsed disease, a more intensive chemotherapy or bone marrow transplantation should be applied. The progression to EBV‐containing T‐cell lymphoma in three patients is consistent with the previous observation that EBV‐associated HS is a potentially malignant disease.

Pulsed high-dose dexamethasone therapy in children with chronic idiopathic thrombocytopenic purpura

Purpose The effectiveness of pulsed high-dose oral dexamethasone therapy in children with refractory chronic idiopathic thrombocytopenic purpura (ITP) is evaluated. Patients and Methods Seven children (5 to 16 years old) who were refractory to 2 to 5 conventional standard therapies were included in the study. Dexamethasone was administered orally at a dosage of 40 mg/m2 per day (maximum 40 mg/day) for 4 consecutive days as a cycle. The cycle was repeated once a month for 6 months. Results One month after the first cycle, partial responses of platelet counts (>50±109/L and <150±109/L) were observed in three patients (43%). At the end of the sixth cycle, two patients (29%) had complete responses (>150±109/L) and one had a partial response. However, only one patient (14%) remained partially responsive 1 year after completion of therapy. Conclusions In contrast to what was observed in adults, this preliminary study suggests that pulsed high-dose oral dexamethasone therapy was not uniformly effective in children with chronic ITP.

The etiology and treatment outcome of iron deficiency and iron deficiency anemia in children.

This study aimed to evaluate the frequency of the diverse causes of iron deficiency (ID) and iron deficiency anemia (IDA) and to investigate the treatment outcomes in children. ID was defined as a serum ferritin level<12μg/L and a transferrin saturation<10%. IDA was established as ID combined with a low hemoglobin level judged by age and gender-specific reference intervals. A total of 116 ID patients were categorized into 4 groups: group I:<2 years old (n=45), group II: 2 to 10 years old (n=13), group III:>10 years old, male (n=18), and group IV: >10 years old, female (n=40). One hundred of them (86.2%) were diagnosed with IDA. The most common causes of ID were inadequate intake in group I (55.6%) and blood loss in groups II (46.1%) and IV (37.5%). Helicobacter pylori-associated ID mainly occurred in children more than 10 years old. Forty-five of 57 (78.9%) IDA patients who had underlying diseases treatment and/or iron supplementation for 3 months recovered their hemoglobin levels (follow-up range: 6–27 mo). In conclusion, the peak incidences of childhood ID were ages under 2 years old and 10–18 years old. Different age groups and sexes showed characteristic etiologies. The outcomes of childhood ID were good.

Expression and prognostic significance of the apoptotic genes BCL2L13, Livin, and CASP8AP2 in childhood acute lymphoblastic leukemia

Improved treatment of childhood acute lymphoblastic leukemia (ALL) depends on the identification of new molecular markers that are able to predict treatment response and clinical outcome. The development of impaired apoptosis in leukemic cells is one factor that may influence their response to treatment. We investigated the expression of three apoptosis related genes, BCL2L13, CASP8AP2, and Livin, as well as their prognostic significance, in a retrospective study of 90 pediatric ALL patients diagnosed between 1996 and 2007 in Taiwan. Univariant analysis revealed that high expression of BCL2L13 was associated with inferior event-free survival and overall survival (p<0.001 and 0.005, respectively). Multivariate analysis for EFS and OS demonstrated that high expression of BCL2L13 was an independent prognostic factor for childhood ALL in this ethnic group.

Papillary Cystic Tumor of the Pancreas in Children

Papillary cystic tumor of the pancreas, so-called Frantz tumor, is a very rare tumor in children. Only 157 cases had been reported since 1959. The clinical manifestations of this disease are usually a slowly growing abdominal mass with or without abdominal pain. It occurs predominantly in young females, and its pathogenesis is still unknown. Surgical resection is usually curative, and its prognosis is excellent. Four adolescent girls with acute or chronic abdominal pain were found to have papillary cystic tumor of the pancreas at our hospital in the past 4 years. They all have a variable clinical presentation. Papillary cystic tumor of the pancreas should therefore be considered one of the differential diagnoses of abdominal pain or abdominal mass in adolescent girls.

Invasion of the cardiovascular system in childhood malignant hepatic tumors.

Purpose To evaluate the utility of transthoracic echocardiography for the early detection of subclinical cardiac metastasis in childhood malignant hepatic tumors. Patients and Methods From April 1995 until February 2000, 12 consecutive children with malignant hepatic tumor were enrolled in this study. To determine the degree of invasion of the cardiovascular system, transthoracic echocardiography was performed for all patients at the time of initial diagnosis and also at subsequent follow-up investigations every 6 months until the patient was deemed to be disease-free, or until the patient died. Results There were seven patients diagnosed with hepatocellular carcinoma (six boys, one girl) and five patients diagnosed with hepatoblastoma (three boys, two girls). Most tumors were multiple (7/12) and involved both lobes of the liver (7/12). Inferior vena cava thrombi were observed in four patients. Three patients exhibited intracardiac tumor metastasis, and lung metastasis was noted in four patients. Lung metastasis was significantly more common in children with cardiovascular involvement (4/4) compared with those without (0/8). The ages of the patient, levels of alpha-fetoprotein, and types of tumor did not differ between the two groups. Conclusions Echocardiography may be useful for the early detection of cardiovascular metastases of malignant hepatic tumors in children; this was the case for 33% of the patients in this series. The frequent occurrence of cardiovascular tumor involvement and the high degree of association between lung metastasis and cardiovascular involvement observed in this small series suggest that transthoracic echocardiography should be studied prospectively in a large series of children with hepatic tumors.