NUDT15 gene polymorphism related to mercaptopurine intolerance in Taiwan Chinese children with acute lymphoblastic leukemia.

A recent study identified a variant of the NUDT15 gene (rs116855232 C>T) associated with intolerance to thiopurine in Korean patients with Crohn's disease. This study prompted us to substantiate the finding in a Taiwanese population. Four hundred and four children with acute lymphoblastic leukemia (ALL), and 100 adults with chronic immune thrombocytopenic purpura or localized lymphoma having normal bone marrow were examined. Two candidate gene approaches, pyrosequencing for NUDT15 and TaqMan assay for thiopurine methyltransferase (TPMT) genotyping (rs1142345 A>G), were performed. We showed a risk allele frequency of NUDT15 of 11.6% in children with ALL and 15.5% in adults. By contrast, the risk allele frequency of TPMT was only 1.6% in children with ALL and 0.5% in adults. The high frequency of risk variant for NUDT15, but not the very low frequency of risk variant for TPMT, was closely associated with the intolerance to mercaptopurine in children with ALL in Taiwan, contrast to that of European descent. In regard to NUDT15 polymorphism, the maximal tolerable daily doses of mercaptopurine in homozygotes, heterozygotes and wild-type groups were 9.4 mg m-2, 30.7 mg m-2 and 44.1 mg m-2, respectively. The outcomes did not differ significantly among the different genotypes.

Unrelated cord blood transplantation for thalassaemia: a single-institution experience of 35 patients.

Our study was designed to prospectively determine whether or not unrelated cord blood transplantation (CBT) can produce outcomes comparable to related donor transplantation for children with ß-thalassaemia. In 35 patients, 40 transplants were performed between October 2003 and September 2009. HLA matching at enrolment was 6/6 (n=8), 5/6 (n=16), 4/6 (n=27), or 3/6 (n=1) by low-resolution HLA-A, -B, and high-resolution DRB1. These patients received non-manipulated grafts without ex vivo expansion or T-cell depletion. The median number of nucleated and CD34+ cells infused was 7.8 × 10(7)/kg (range, 2.8-14.7 × 10(7)/kg) and 4.0 × 10(5)/kg (range, 1.7-19.9 × 10(5)/kg), respectively. The 5-year OS and thalassaemia-free survival after the first transplant were 88.3 and 73.9%, respectively. The cumulative incidence of TRM at 2 years was 11.7%. Fourteen patients developed chronic skin GVHD. Thirty patients were alive and transfusion-independent with a Lansky performance score ≥80% achieved between 6 and 76 months post transplant (median, 36 months). These data compare acceptably with the survival rates of related-donor BMT for thalassaemia and suggest that patients without an available HLA-compatible sibling but who have well-matched unrelated donors should also be considered for CBT.

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.

Evaluation of readmission in children receiving allogeneic hematopoietic stem cell transplantation: an institutional experience.

BACKGROUND: Use of unrelated cord blood (UCB) has become increasingly popular as a stem cell source, given the rapid availability and decreased potential of graft-versus-host disease. We sought to ascertain whether the use of UCB transplantation for pediatric patients changed the rates of unscheduled readmission. METHODS: We analyzed the rate, causes, and evolution of hospitalization among patients receiving UCB versus matched sibling bone marrow. A retrospective analysis of the data from 54 patients who received a matched sibling hematopoietic stem cell transplantation (HSCT; n = 25; 46.3%) versus an unrelated cord blood transplantation (CBT; n = 29; 53.7%) was performed on subjects treated between 1998 and 2006. Patients who died before discharge (n = 4) were excluded from the readmission analysis. RESULTS: A total of 50 patients were recruited for the analyses. Their median age was 6.7 years (range = 0.2-17 years). The median duration of hospitalization was 18 days shorter in the sibling HSCT group than in the unrelated CBT group. There were 89 readmissions in 25 patients (50%): 49 readmissions (55%) in the related HSCT and 40 (45%) in the unrelated CBT cohorts. Forty-two percent of readmissions were due to infections. Mortality following transplantation in 10 patients (19%) included sepsis (n = 3), intracranial hemorrhage (n = 1), pulmonary hemorrhage (n =1), and relapse (n = 5). Seven patients received HSCT from HLA-identical sibling donors and three from a cord blood donor. CONCLUSION: For both groups, infection was the most common reason for readmission followed by graft failure and extramedullary relapse. Although the median hospital stay was shorter in the sibling donor group, some uncertainty exists as to whether the increased risk for readmission was related to proportionally more malignancies or to the severity of the illness. After HSCT, there was a frequent use of hospital resources: 46% of patients were hospitalized for a median of 11 days. The resulting health expenses seem to be useful, since 81% of subjects survived at 36-month follow-up.

Cooperating mutations of receptor tyrosine kinases and Ras genes in childhood core-binding factor acute myeloid leukemia and a comparative analysis on paired diagnosis and relapse samples.

c-KIT mutations have been described in core-binding factor (CBF) acute myeloid leukemia (AML) at diagnosis. The role of c-KIT mutations in the relapse of CBF-AML is not clear. The role of CSF1R mutation in the pathogenesis of AML remains to be determined. We analyzed receptor tyrosine kinases (RTKs) and Ras mutations on 154 children with AML. Also, we examined the paired diagnosis and relapse samples in CBF-AML. CBF-AML accounted for 27% (41/154). c-KIT mutations were detected in 41.5% of CBF-AML at diagnosis (6 in exon 8, 10 in exon 17 and 1 in both exons 8 and 17) , FLT3-TKD 2.7%, N-Ras mutations 7.3% and K-Ras mutations 4.9%. FLT3-LM and CSF1R mutations were not found in CBF-AML. The mutations of RTKs and Ras were mutually exclusive except for one patient who had both c-KIT and N-Ras mutations. Eight of the 41 CBF-AML patients relapsed; four patients retained the identical c-KIT mutation patterns as those at diagnosis, the remaining four without c-KIT mutations at diagnosis did not acquire c-KIT mutations at relapse. Our study showed that 54% of childhood CBF-AML had RTKs and/or Ras mutations; c-KIT but not CSF1R mutations play a role in the leukemogenesis of childhood CBF-AML.

Transplantation of unrelated donor umbilical cord blood utilizing double-unit grafts for five teenagers with transfusion-dependent thalassemia.

To augment graft cell dose, we evaluated the safety of the combined transplantation of two partially HLA-matched umbilical cord blood (UCB) units. Five patients with transfusion-dependent thalassemia, median age 11.1 years (range 10-13.1), received 2 UCB units after myeloablative conditioning. Cord blood units were a 4/6-HLA-match or better with the recipient, and contained a minimum combined pre-freeze CD34 cell dose of 3.0 x 10(5)/kg. All patients engrafted at a median of 15 days (range 12-19). Four patients with durable trilineage engraftment showed acute grade I-III GVHD; none developed extensive chronic GVHD until the date of last contact. The median times to red blood cell transfusion independence and platelet engraftment were 32 and 49 days after transplant, respectively. With a median follow-up of 18.5 months (range 11-32), four patients transplanted with UCB from two different partially HLA-matched donors were transfusion-independent. Therefore, transfusion of two partially HLA-matched UCB units is safe, and may overcome the cell-dose barrier that limits the use of UCB in long-term recipients of multiple transfusions for thalassemia.

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.

CEBPalpha mutations in childhood acute myeloid leukemia.

CEBPalpha: mutations have been described in adult acute myeloid leukemia (AML) and conferred a favorable prognosis. However, CEBPalpha mutation has not been reported in children. We investigated 117 children with de novo AML using DNA PCR assay followed by sequencing for each PCR product. CEBPalpha mutations were detected in seven patients, four had FAB M2, two M1 and one M4. CEBPalpha mutations only occurred in patients with intermediate cytogenetics and not in 56 children with AML1-ETO, CBFbeta-MYH11, PML-RARalpha or MLL rearrangements. Five patients had mutations occurred in both N-terminal part and basic-leucine zipper (bZIP) domain, one had an N-terminal frameshift mutation and the remaining one had an inframe insertion in the bZIP domain. Cloning analysis on five samples carrying more than one mutations demonstrated one homozygous combined mutations and four heterozygous biallelic mutations. Four of seven CEBPalpha mutation(+) patients had cooperating mutations with FLT3-ITD or N-ras mutations compared to 27 in 109 CEBPalpha mutation(-) patients. Our results showed that CEBPalpha mutations occurred in 6% of childhood AML and most exhibited combined mutations in both N-terminal part and bZIP domain.

FLT3-TKD mutation in childhood acute myeloid leukemia.

Mutations of receptor tyrosine kinases are implicated in the constitutive activation and development of human hematologic malignancies. An internal tandem duplication (ITD) of the juxtamembrane domain-coding sequence of the FLT3 gene (FLT3-ITD) is found in 20-25% of adult acute myeloid leukemia (AML) and at a lower frequency in childhood AML. FLT3-ITD is associated with leukocytosis and a poor prognosis, especially in patients with normal karyotype. Recently, there have been three reports on point mutations at codon 835 of the FLT3 gene (D835 mutations) in adult AML. These mutations are located in the activation loop of the second tyrosine kinase domain (TKD) of FLT3 (FLT3-TKD). The clinical and prognostic relevance of the TKD mutations is less clear. To the best of our knowledge, there has been no report to describe FLT3-TKD mutations in childhood AML. In this pediatric series, FLT3-TKD mutations occurred in three of 91 patients (3.3%), an incidence significantly lower than that of FLT3-ITD (14 of 91 patients, 15.4%) in the same cohort of patients. None of them had both FLT3-TKD and FLT3-ITD mutations. Sequence analysis showed one each of D835 Y, D835 V, and D835 H. Of the three patients carrying FLT3-TKD, two had AML-M3 with one each of L- and V-type PML-RARalpha, and another one had AML-M2 with AML1-ETO. None of our patients with FLT3-TKD had leukocytosis at diagnosis. At bone marrow relapse, one of the four patients examined acquired FLT3-ITD mutation and none gained FLT3-TKD mutation.

Tumor lysis syndrome in an infant with Langerhans cell histiocytosis successfully treated using continuous arteriovenous hemofiltration.

Langerhans cell histiocytosis (LCH) is an enigmatic disease usually occurring in children. Tumor lysis syndrome (TLS) is a clinical syndrome associated with severe metabolic derangement and oliguric acute renal failure. In this report, we present the clinical course of an infant with advanced LCH who had TLS develop after chemotherapy. Treatment with continuous arteriovenous hemofiltration resulted in effective control of serum uric acid, potassium, creatinine, phosphorus, and blood urea nitrogen levels in the blood.

A comparison of oral ondansetron syrup or intravenous ondansetron loading dose regimens given in combination with dexamethasone for the prevention of nausea and emesis in pediatric and adolescent patients receiving moderately/highly emetogenic chemotherapy.

This double-blind, parallel-group, multicenter study compared the efficacy and safety of intravenous (i.v.) ondansetron with oral syrup ondansetron plus oral dexamethasone in the prevention of nausea and emesis in pediatric patients receiving moderately/highly emetogenic chemotherapy. On each day of chemotherapy, patients were administered ondansetron 5 mg/m2 i.v. and placebo syrup orally (n = 215) or ondansetron 8 mg syrup orally and placebo i.v. (n = 223) plus dexamethasone 2-4 mg p.o. Ondansetron 4 mg syrup p.o. was administered twice daily for 2 days following the cessation of chemotherapy. Complete or major control of emesis was obtained in 89% patients in the i.v. group and 88% patients in the oral syrup group during the worst day of chemotherapy treatment (90% CI: -6, 4) and in 85% and 82% patients, respectively, during the worst day of the study period (90% CI: -8, 3). Intravenous or oral syrup ondansetron plus dexamethasone was well tolerated and effective in preventing chemotherapy-induced emesis in pediatric patients.

Cytogenetic pattern of childhood leukemia in Taiwan.

BACKGROUND: Cytogenetic analyses of leukemic cells can be used to define specific subgroups of leukemia with different prognoses and, thereby, indicate appropriate treatment for individual cases. In this study, we investigated the cytogenetic pattern of childhood leukemia in Taiwanese patients. METHODS: A modified trypsin method of Seabright was used for G-banding of metaphase cells. RESULTS: From October 1996 to January 1999, 111 children with a diagnosis of leukemia were enrolled in the study. Of these, 73 patients had a diagnosis of acute lymphoblastic leukemia (ALL) and 63 of these patients had successful karyotyping of their leukemic cells. Among them, 20 (30.3%) had a normal karyotype, five had hypodiploidy (all had 45 chromosomes), five had low hyperdiploidy (47-50 chromosomes), 16 (24.2%) had high hyperdiploidy (> 50 chromosomes), and 20 had pseudodiploidy. Chromosomal translocation was identified in 24 (36.4%) of the ALL patients, 17 of whom had recurrent translocations including 10 with CD10+ B-precursor ALL [4 with t(9;22), 5 with t(1;19), and 1 infant with t(8;14)(q24;q11)], one neonate with CD10- early pre-B ALL with t(4;11), three B-cell cases with t(8;14), and three T-cell cases [2 with t(11;19)(q23;p13), and 1 (11;14)(p13;q11)]. One B-precursor patient had dic (9;12). Karyotypes of the 30 patients with acute myeloid leukemia (AML) included eight with t(8;21); seven with the French-American-British-M2 subtype (FAB-M2) and one with M1. All four of the patients with M3 had t(15;17), one patient with M4 had inv(16) and 7q-, one with M4Eo (M4 with eosinophilia) had t(7;16)(q21;q22), one with M0 had t(4;11)(q21;q23), and the remaining 11 had a normal karyotype. Three of the five adult-type chronic myeloid leukemia patients had standard Philadelphia chromosome, and the other two had a variant-form of Philadelphia chromosome. Both of the patients with juvenile myelomonocytic leukemia and one patient with myelodysplastic syndrome had a normal karyotype. CONCLUSIONS: Most findings were similar to previous reports. Although the high proportion of FAB-M2 patients (7/8) with t(8;21) and the consequently higher frequency (26.7%) of this translocation in the 30 AML cases in this study might have significance, a larger series of cases is needed to establish this finding.

Prenatally detected tumor mass in the adrenal gland.

BACKGROUND/PURPOSE: Screening programs using urinary vanillylmandelic acid have detected neuroblastomas in early infancy with some success. With the widespread use of ultrasonography in modern obstetric practice, use of ultrasonography to screen for fetal neuroblastoma seems to be reasonable and practical. METHODS: Seven fetuses had suprarenal masses detected by maternal ultrasound scan at 32 to 37 weeks' gestation between 1993 and 1998. They were delivered normally if the pregnancy was uncomplicated, especially if it was without maternal preeclampsia or fetal hydrops. Each mass was further confirmed by ultrasound scan, computed tomography, or magnetic resonance imaging in the neonatal period. Tumor excision was performed at the age of 6 to 38 days of life. RESULTS: The size of the masses measured ranged from 2.0x2.0 cm to 4.5x4.5 cm. The diagnosis was adrenal hemorrhage in 1 neonate, Evan's stage I neuroblastoma in 3, and stage IV-S neuroblastoma in 3. All of the specimens with a diagnosis of neuroblastoma showed a favorable histology by the Shimada classification system. Infants with stage I disease were treated with tumor excision only, and they had survived without disease by 14, 18, and 25 months of follow-up. One infant with stage IV-S neuroblastoma was treated further with minimal chemotherapy and has survived without disease at the 66-month follow-up examination. Another child with stage IV-S neuroblastoma has survived with local recurrence and increasing liver metastasis and was still on chemotherapy at the 2-month follow-up examination. The third child with stage IV-S disease presented with massive hepatomegaly and bone marrow involvement, and disseminated intravascular coagulopathy had developed. The patient died on the 5th day of life without surgical intervention. CONCLUSIONS: The increasing use of obstetric ultrasonography has made the prenatal screening of neuroblastomas possible. The prognosis of infants with a suprarenal mass may be improved with this early detection and early surgical intervention.

Acute monoblastic leukemia in a child following chemotherapy for neuroblastoma.

The long-term effects of childhood cancer and its therapy are serious problems that deserve attention. One of the most important late effects is the development of secondary malignancy. We encountered a girl with neuroblastoma who developed acute monoblastic leukemia as a secondary malignancy, 32 months after starting treatment for the primary tumor at the age of 4 years and 10 months. For the primary tumor, she had received cyclophosphamide, ifosphamide, etoposide, epirubicin, cisplatin, and vincristine during a period of 20 months; no radiotherapy was given. Cytogenetic analysis of the leukemic cells showed no specific changes, but a rearrangement of the mixed lineage leukemia gene (chromosome 11q23 translocation) was subsequently found by reverse transcription polymerase chain reaction. The survival time after onset of the secondary malignancy was brief. The leukemogenic hazards of cancer treatment should be weighed against their therapeutic benefits.

Successfully treated central nervous system Burkitt's lymphoma with minimal extraneural disease in a child.

Burkitt's lymphoma, the most common childhood non-Hodgkin's lymphoma, usually presents with abdominal tumors. Central nervous system (CNS) involvement in Burkitt's lymphoma is mostly secondary to advanced systemic disease, rarely with brain parenchymal lesions, and was previously recalcitrant to treatment. We report an unusual case of CNS Burkitt's lymphoma with minimal extraneural disease. This 10-year-old immunocompetent boy presented with increased intracranial pressure and seizures and was found to have multifocal intracerebral lesions on brain imaging studies. Cerebrospinal fluid studies confirmed the presence of Burkitt's lymphoma cells. Abdominal computed tomography showed bilateral nephromegaly with left intrarenal lesions that disappeared after three doses of intravenous dexamethasone. The patient was treated for 6.5 months according to the LMB 89 group C protocol of the French Pediatric Oncology Society. The response was brisk and complete. The patient has been disease free for more than 4 years, and is believed to be cured.

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 x 10(9)/l and were aged between 1 and 2 or 7 and 10 years, or a leukocyte count <50 x 10(9)/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.

Subcutaneous panniculitic T-cell lymphoma developing in a child with idiopathic myelofibrosis.

PURPOSE: Subcutaneous panniculitic T-cell lymphoma is reported in a child with idiopathic myelofibrosis. Both disease entities are rarely seen in children. PATIENT AND METHODS: A girl aged 5 years and 9 months had pancytopenia and severe constitutional symptoms. Idiopathic myelofibrosis was subsequently diagnosed. RESULTS: A transient response was achieved after treatment with a course of high-dose methylprednisolone therapy. However, proptosis and skin nodules developed during tapering of steroid therapy. A computed tomography scan of the orbit also revealed a mass lesion in the right lacrimal gland region. A skin biopsy specimen showed a subcutaneous panniculitic T-cell lymphoma. The clinical course was marked by high fever, profound pancytopenia, massive gastrointestinal bleeding, and severe, recurrent infections. Her condition rapidly deteriorated, and she died from polymicrobial sepsis 4 months after her initial examination. CONCLUSIONS: Subcutaneous panniculitic T-cell lymphoma is a distinctive clinicopathologic entity that is rarely seen in children. The association of myelofibrosis and peripheral T-cell lymphoma as seen in this has been rarely reported.

Leukemia cutis as the initial manifestation of acute nonlymphocytic leukemia in a young child.

A 15-month-old boy was well except for asymptomatic, erythematous, wheal-like papuloplaques, macules, and nodules on his face and four extremities. It was misdiagnosed by a pediatrician and treated as urticaria for six months. Later, he was sent to our hospital for evaluation of prolonged fever. Acute nonlymphocytic leukemia (M5) with leukemia cutis was diagnosed by results of hematologic examination and examination of a skin biopsy specimen. After one course of chemotherapy, all of the skin lesions completely resolved and had not recurred. Five months after acute nonlymphocytic leukemia was diagnosed, bone marrow relapse and central nervous system involvement were noted.