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Acute lymphoblastic leukemia (ALL) is the most common cancer during childhood, and some high-risk patients with ALL require hematopoietic stem cell transplantation (HSCT). Mainly due to small patient numbers, studies focusing specifically on children and adolescents with T-cell ALL (T-ALL) are limited. Using a nationwide registry, we retrospectively analyzed data from patients under 20 years old who underwent their first HSCT for T-ALL between 2000 and 2018. As a result, total 484 patients were included, and their median follow-up period was 6.9 years after HSCT for survivors. While patients receiving HSCT at first complete remission (CR) showed relatively good 5-year leukemia free survival (5yLFS, 73.5%), once relapse occurred, their prognosis was much worse (44.4%) even if they attained second remission again (p 0.001). Among patients receiving HSCT at CR1, grade II-IV acute graft versus host disease was associated with worse overall and LFS than grade 0-I (5yLFS 69.5% vs. 82.1%, p = 0.026) mainly due to high non-relapse mortality. Among those patients, patients receiving related bone marrow transplantation, unrelated bone marrow transplantation, or unrelated cord blood transplantation showed similar survival (5yLFS, 73.2%, 76.3%, and 77.0%, respectively). For patients undergoing cord blood transplantation at CR1, total-body irradiation-based myeloablative conditioning was associated with better 5yLFS than other conditioning regimens (85.4% vs. 62.2%, p = 0.044), as it reduced the risk of relapse. These results indicate that relapsed patients have much less chance of cure, and that identifying patients who require HSCT for cure and offering them HSCT with optimal settings during CR1 are crucial for children and adolescents with T-ALL.

Currently, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered to be indicated for children and adolescents with high-risk or relapsed T-cell acute lymphoblastic leukemia (T-ALL); however, the outcomes are unsatisfactory. Killer cell immunoglobulin-like receptors (KIRs) are the main receptors on natural killer (NK) cells that play an important role in the graft-versus-leukemia effect after allo-HSCT. In allo-HSCT, when the recipient lacks a donor KIR-ligand (KIR-ligand mismatch in the graft-versus-host [GVH] direction), donor NK cells will be activated against recipient cells. KIR-ligand mismatch in the GVH direction improves outcomes after unrelated cord blood transplantation (UCBT) with acute myeloid leukemia, but the effect in T-ALL is unclear. We evaluated the impact of KIR-ligand mismatch in the GVH direction on the transplantation outcomes of children and adolescents with T-ALL who received UCBT. We conducted a retrospective study using a nationwide registry of the Japanese Society for Transplantation and Cellular Therapy. Patients diagnosed with T-ALL, aged 0 to 19 years, and who underwent first UCBT between 1999 and 2017 were included. A total of 91 patients were included in this study. In all, 23 (25.3%) percent of patients had KIR-ligand mismatch in the GVH direction. The 5-year leukemia-free survival (LFS) and overall survival (OS) rates after UCBT were 65.8% and 69.6%, respectively. In a multivariate analysis, KIR-ligand mismatch in the GVH direction was associated with a significant reduction in the relapse rate (hazard ratio [HR], 0.19; P = .002), resulting in better LFS (HR, 0.18; P =.010) and OS (HR, 0.26; P = .048) without increasing non-relapse mortality (NRM; HR, 1.90; P = .264). The cumulative incidence of GVH disease (GVHD) did not differ between patients with and without KIR-ligand mismatch (grade II-IV acute GVHD, 39.1% versus 36.8%, P = .648, grade III-IV acute GVHD, 13.0% versus 11.8%, P =.857, and chronic GVHD, 26.1% versus 22.9%, P =.736, respectively). Furthermore, acute and chronic GVHD were not associated with good patient outcomes. Notably, no relapse was observed in patients who received KIR-ligand mismatched UCBT in complete remission. KIR-ligand mismatch in the GVH direction improved LFS and decreased relapse rates without increasing NRM in children and adolescents with T-ALL who received UCBT, which was not mediated by GVHD.

Background Single-dose i.v. fosaprepitant has been approved as an alternative to 3 day oral aprepitant, a neurokinin-1 receptor antagonist, and improves prevention of chemotherapy-induced nausea and vomiting (CINV). Because fosaprepitant has shown similar efficacy to aprepitant in adult patients only, this study compared the efficacy and safety of aprepitant and fosaprepitant in pediatric patients. Methods Children younger than 18 years who received aprepitant or fosaprepitant to manage CINV between January 2015 and March 2018 at the National Cancer Center Hospital (Tokyo) were recruited to this study. The primary endpoint was complete response (CR; no vomiting/rescue medication) between 0 and 120 h after the start of chemotherapy. Secondary endpoints were safety based on the frequency of severe adverse events, and evaluation of patient characteristics as risk factors (effect of age and sex). Results A total of 125 chemotherapy cycles were evaluated. In the aprepitant group, CR was observed in 36 of 80 treatment cycles (45.0%), whereas in the fosaprepitant group, it was observed in 19 of 45 cycles (42.2%; P = 0.852). No treatment-related severe adverse events were observed in either group. The number of non-CR was greater than that of CR in patients aged 6-14 years. The difference in CR rate between male and female patients was not statistically significant (47.1% vs 40.0%, respectively; P = 0.471). Conclusions Aprepitant and fosaprepitant were safely used and may be equally useful for pediatric patients receiving highly emetogenic chemotherapy. CR rate may be associated with patient age.

The effect of genetic variation on second malignant neoplasms (SMNs) remains unclear. First, we identified the pathogenic germline variants in cancer-predisposing genes among 15 children with SMNs after childhood leukemia/lymphoma using whole-exome sequencing. Because the prevalence was low, we focused on the association between SMNs and NUDT15 in primary acute lymphoblastic leukemia (ALL) cases. NUDT15 is one of the 6-mercaptopurine (6-MP) metabolic genes, and its variants are common in East Asian individuals. The prevalence of NUDT15 hypomorphic variants was higher in patients with SMNs (n = 14; 42.9%) than in the general population in the gnomAD database (19.7%; P = .042). In the validation study with a cohort of 438 unselected patients with ALL, the cumulative incidence of SMNs was significantly higher among those with (3.0%; 95% confidence interval [CI], 0.6% to 9.4%) than among those without NUDT15 variants (0.3%; 95% CI, 0.0% to 1.5%; P = .045). The 6-MP dose administered to patients with ALL with a NUDT15 variant was higher than that given to those without SMNs (P = .045). The 6-MP–related mutational signature was observed in SMN specimens after 6-MP exposure. In cells exposed to 6-MP, a higher level of 6-MP induced DNA damage in NUDT15-knockdown induced pluripotent stem cells. Our study indicates that NUDT15 variants may confer a risk of SMNs after treatment with 6-MP in patients with ALL.

Cytogenetic abnormalities are a major risk factor for relapse after hematopoietic stem cell transplantation (HSCT) for myelodysplastic syndrome (MDS). We aimed to evaluate the value of the five-group cytogenetic classification according to the revised International Prognostic Scoring System (R-IPSS) for predicting the outcome after HSCT in pediatric patients with MDS. We retrospectively analyzed the Japanese registration data of 242 pediatric patients with MDS. According to the R-IPSS classification, 112 (45.5%) patients had good, 55 (22.7%) had intermediate, 64 (26.4%) had poor, and 11 (4.6%) had very poor cytogenetics. The 5-year overall survival (5yOS) was 72%, 69%, 59%, and 30% in the good, intermediate, poor, and very poor cytogenetic subgroups (p = 0.026), respectively. The very good, good, and intermediate subgroups were grouped into a "standard" subgroup and reclassified into three subgroups (standard, poor, and very poor). Patients with very poor risk had worse 5yOS (hazard ratio 2.17, 95% confidence interval (CI) 1.02-4.61; p = 0.04) and a much higher 5yCIR (hazard ratio 2.52, 95% CI 1.05-6.04; p = 0.04) than those of patients in the standard group in the multivariate analysis, indicating that very poor risk cytogenetic characteristics independently predicted worse outcome after HSCT in pediatric patients with MDS.

The role of allogeneic hematopoietic stem cell transplantation (HSCT) for infants with acute lymphoblastic leukemia (ALL) and KMT2A gene rearrangement (KMT2A-r) is controversial in terms of both its efficacy and potential for acute and late toxicities. In Japanese Pediatric Leukemia/Lymphoma Study Group trial MLL-10, by introducing intensive chemotherapy, indication of HSCT was restricted to patients with high-risk (HR) features only (KMT2A-r and either age

We report a case of a 16-year-old woman who achieved her third complete remission of acute lymphoblastic leukemia after undergoing allogeneic stem cell transplantation for the second time from an unrelated donor. On post-transplantation day 30, she showed weight gain, hepatomegaly, right hypochondriac pain, and ascites. On day 35, ultrasonography (US) revealed portal vein regurgitation. She was subsequently diagnosed with late-onset sinusoidal obstruction syndrome (SOS) and was transferred to the intensive care unit (ICU) on day 36 for multiple organ dysfunction syndrome (MODS) and disseminated intravascular coagulation, requiring mechanical ventilation. Her SOS was graded as very severe upon ICU admission. Recombinant human soluble thrombomodulin (380 U/kg/day) and methylprednisolone (2 mg/kg/day) therapies were initiated. Additionally, her intra-abdominal pressure had increased to 19 mmHg, which was thought to be the cause of MODS. Ascites drainage (1,000 ml/day), according to the treatment for abdominal compartment syndrome, improved her SOS and MODS. She was weaned from mechanical ventilation on the 10th day after ICU transfer, and US showed resolution of the portal vein regurgitation. She was transferred to the general ward on the 14th day. She had not experienced disease recurrence at her last visit (527 days after the second transplantation).

Histiocytic sarcoma in advanced clinical stages is typically an aggressive neoplasm, with poor response to conventional chemotherapy. An 18-year-old male with refractory histiocytic sarcoma that had transformed from Rosai-Dorfman disease was admitted to our hospital. A pathogenic variant of MAP2K1 was detected by next-generation sequencing of tumor specimens. Affected regions showed excellent responses to the MEK inhibitor trametinib. It has been reported that RAS/MEK/ERK pathway is activated in many cases of histiocytic sarcoma. MEK inhibition may represent a useful treatment option in histiocytic sarcoma.

Background KMT2A-rearranged acute lymphoblastic leukemia (KMT2A-r ALL) is a rare and dismal disease in infants. Despite restriction of the indication of allogeneic hematopoietic stem cell transplantation to the high-risk group (patients aged Methods We analyzed and compared the MM expression (defined as at least one positive marker [with a positive blast subset ≥ 10%] among CD117, CD13, CD33, and CD65/CD15) by using flow cytometry (FCM) in infants with KMT2A-r ALL who were registered in the JPLSG MLL-10 trial. We also compared the results of immunoglobulin/T-cell receptor (Ig/TCR) gene-based polymerase chain reaction (PCR)-MRD analyses or 4-color FCM-MRD assay between the MM-positive and MM-negative groups at EOI and end of early consolidation. The Ig/TCR-MRD results were classified as negative if Results and Discussion Among the patients with KMT2A-rALL, 74 were included in this study, excluding one who was not evaluated with FCM at diagnosis. Of these patients, 42 were MM-positive and 32 were MM-negative. The 3-year EFS rates of the MM-positive and MM-negative patients were 62.3% (95% confidence interval [CI], 45.5-75.3) and 70.0% (95% CI, 50.3-83.1), respectively (p = 0.61). Their 3-year overall survival rates were 80.6% (95% CI, 65.0-89.8) and 87.5% (95% CI, 70.0-95.1), respectively (p = 0.74). The numbers of MM-positive and MM-negative patients according to age group are summarized in Table 1, and the difference in age distribution between the two groups was not significant. The MRD statuses of the patients at EOI in the two groups are also summarized in Table 1. No significant difference in MRD clearance was found between the MM-positive and MM-negative groups. Conclusion In this study, we found no significant difference in survival rate between the MM-positive and MM-negative groups. The MM expression was not a prognostic marker in the infants with KMT2A-r ALL in the MLL-10 cohort. We believe that rapid MRD clearance in the early phase of treatment with enhanced chemotherapy would have the greatest contribution to the improvement of prognosis. In this study, the MM-positive patients from the MLL-10 cohort might have benefited from early-phase treatment intensification in terms of MRD clearance. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Objective Parents of children with cancer are susceptible to psychological distress; however, many parents also report posttraumatic growth (PTG). The objective of this study was to explore the variables associated with PTG in parents of children with cancer who were either on treatment or off treatment. Methods One hundred and nineteen parents (71 mothers and 48 fathers) of children with cancer completed self-report questionnaires including the Posttraumatic Growth Inventory (PTGI), Center for Epidemiologic Studies Depression Scale (CES-D), State-Trait Anxiety Inventory (STAI), and Impact of Event Scale-Revised (IES-R). Demographic data and children's medical information were also collected. Multivariate linear regression analyses were conducted to investigate the variables associated with PTG. Results The mean age of participants was 41.4 years (SD = 6). Higher PTGI scores were associated with parents’ lower trait anxiety (p = 0.028), parents’ sex (female) (p = 0.004), treatment status (within 12 months from treatment end compared with on-treatment) (p = 0.048), surgery (p = 0.007), and late effects (p = 0.01). Conclusions Parents’ PTG was associated with children's clinical characteristics, parents’ sex, and parents’ anxiety levels. When dealing with PTG, the parents’ psychological characteristics and children's clinical characteristics should be considered. Particularly for parents with high trait anxiety, it is important to reduce anxiety first before addressing PTG. This article is protected by copyright. All rights reserved.

Background Rearrangements of chromosome 8q24/MYC (8q24/MYC-r), resulting from t(8;14)(q24;q32), t(2;8)(p11;q24), or t(8;22)(q24;q11), are mainly associated with Burkitt lymphoma/leukemia (BL) and rarely observed in patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL). The characteristics of BCP-ALL with 8q24/MYC-r are poorly understood. Procedure A retrospective nationwide study of data from patients with pediatric BCP-ALL with 8q24/MYC-r in Japan was conducted to clarify the clinical and biological characteristics associated with 8q24/MYC-r BCP-ALL. Results Ten patients with BCP-ALL with 8q24/MYC-r, including three with double-hit leukemia (DHL) (two with t(8;14)(q24;q32) and t(14;18)(q32;q21) and one with t(8;14) and t(3;22)(q27;q11)), were identified. Patients with BCP-ALL with 8q24/MYC-r had higher median age and uric acid and lactate dehydrogenase levels, than those without 8q24/MYC-r. All patients were initially treated with ALL-type chemotherapy; however, four, including one with DHL, were switched to BL-type chemotherapy, based on cytogenetic findings. One patient relapsed after standard-risk ALL-type chemotherapy, and two patients with DHL did not attain complete remission with chemotherapy; all three died within 11 months. The other seven patients treated with BL-type or high-risk ALL-type chemotherapy are alive without disease. Conclusions The clinical and laboratory features of BL with IG-MYC rearrangement, displaying a BCP immunophenotype (Wagener et al. and Herbrueggen et al. termed it as pre-BLL), are similar to those of BCP-ALL with 8q24/MYC-r. Low-risk ALL-type chemotherapy may not be appropriate for them, and further studies are required to establish an adequate therapeutic strategy. Further studies of DHL to identify new treatment strategies are also needed.

Hemoglobin Evans is an unstable variant caused by a single nucleotide mutation that produces a valine-to-methionine substitution at residue 62 of the α-globin chain. It has not been reported in the Asian population and only three cases have been reported worldwide. We diagnosed a Japanese boy with chronic hemolytic anemia with hemoglobin Evans after genetic testing. This is the first familial case of hemoglobin Evans in an Asian population.

Background The UDP-glucuronosyltransferase 2 family, polypeptide B17 (UGT2B17) gene encodes an enzyme that modifies carcinogens, C19 steroids, xenobiotics, and anticancer chemotherapeutic agents by glucuronidation. Pediatric cancers are much more sensitive to anticancer agents than adult cancers. Therefore, we examined the effects of a deletion polymorphism in the UGT2B17 gene on prognosis in pediatric cancer. Methods A total of 145 DNA samples were collected from children with malignant diseases. Copy number variants (CNVs) of the UGT2B17 gene were determined using polymerase chain reaction (PCR). Survival analyses were computed to analyze effects of UGT2B17 gene deletion on relapse-free rates in lymphoblastic and nonlymphoblastic malignancies. Results The UGT2B17 gene was deleted in 64% of children with lymphoblastic malignancies but in 83% of children with nonlymphoblastic malignancies. Moreover, in nonlymphoblastic malignancies, children without deletion polymorphism in the UGT2B17 gene had significantly higher relapse rates than those with the deletion polymorphism (hazard ratio, 16.1; 95% confidence interval [CI], 1.67–154; P = 0.016), which remained significant (P = 0.032) after adjustment for age, sex, underlying diseases, advanced stage, and adverse events (HR, 22.4; 95% CI, 1.10–454; P = 0.043). There was a significant interaction between UGT2B17 gene deletion and nonlymphoblastic malignancies. In the early subgroup, i.e., stage 1–3 or standard/intermediate risk, children without a deletion polymorphism in the UGT2B17 gene showed higher relapse rates than children with more advanced disease (log-rank test: P = 0.0004). Conclusions Deletion polymorphism in the UGT2B17 gene may improve the relapse-free rate in children with nonlymphoblastic malignancies. This article is protected by copyright. All rights reserved.

Parents of children with cancer are susceptible to psychological distress; however, many parents also report posttraumatic growth (PTG). The objective of this study was to explore the variables associated with PTG in parents of children with cancer who were either on treatment or off treatment.One hundred and nineteen parents (71 mothers and 48 fathers) of children with cancer completed self-report questionnaires, including the PTG Inventory, Center for Epidemiologic Studies Depression Scale, State-Trait Anxiety Inventory, and Impact of Event Scale-Revised. Demographic data and children's medical information were also collected. Multivariate linear regression analyses were conducted to investigate the variables associated with PTG.The mean age of participants was 41.4 years (SD = 6). Higher PTG Inventory scores were associated with parents' lower trait anxiety (P = .028), parents' sex (female; P = .004), treatment status (within 12 months from treatment end compared with on-treatment; P = .048), surgery (P = .007), and late effects (P = .01).Parents' PTG was associated with children's clinical characteristics, parents' sex, and parents' anxiety levels. When dealing with PTG, the parents' psychological characteristics and children's clinical characteristics should be considered. Particularly for parents with high trait anxiety, it is important to reduce anxiety first before addressing PTG.

Hemoglobin Evans is an unstable variant caused by a single nucleotide mutation that produces a valine-to-methionine substitution at residue 62 of the α-globin chain. It has not been reported in the Asian population and only three cases have been reported worldwide. We diagnosed a Japanese boy with chronic hemolytic anemia with hemoglobin Evans after genetic testing. This is the first familial case of hemoglobin Evans in an Asian population.

Background L-asparaginase is important in successfully treating childhood acute lymphoblastic leukemia (ALL). However, some patients experience hypersensitivity, mechanisms for which have not been fully elucidated. Previous studies, predominately based on populations of European ancestry, have described L-asparaginase hypersensitivity associations with genetic variant tagging the NFATC2, GRIA1, ASNS, and HLA-DRB1genes. The aim of this study was to evaluate the association between L-asparaginase hypersensitivity and genetic variants in Japanese childhood ALL patients. Methods This study included 472 Japanese children with ALL who received E. coli derived L-asparaginase comprising 6000 U/m2 intravenously or 10000 U/m2 subcutaneously according to the Tokyo Children's Cancer Study Group (TCCSG) L84-11, L89-12, L92-13, L95-14, L99-15, L04-16, and more recent protocols. L-asparaginase hypersensitivity was defined as experience of fever, rash, and other allergic reaction after L-asparaginase infusion. Through an ongoing genome-wide association study, patient DNA from saliva were genotyped using the Illumina platform and genome-wide single nucleotide polymorphism (SNP) imputation was performed using the 1000 Genomes Project Phase I Version 3 as the reference population. Tests of association between childhood ALL and SNP genotypes across the candidate loci, NFATC2, GRIA1, and ASNS, were performed using logistic regression and assuming a log-additive model of inheritance. Results We observed 47 (10%) hypersensitivity patients, of which 32 patients could not be infused again. These L-asparaginase hypersensitivities were not associated with patients' gender and age in this population. SNPs previously reported in NFATC2 rs6021191, GRIA1 rs4958351, and ANSN rs3832526 were not significantly associated with L-asparaginase hypersensitivity (P = 0.76, 0.99, and 0.53, respectively). For confirmation, the NFATC2 rs6021191 SNP was directly genotyped in a large subset of the ALL patients, but no association was observed (P = 0.44; 377 patients). Evaluation of other variants within those genes and flanking regions showed evidence of association with rs11482430 (NFATC2, P = 0.01), rs558550699 (GRIA1, P = 0.02), and rs7803055 (ANSN, P= 0.04), although not significant after correction for multiple testing. Conclusion This lack of association with variants reported in populations of European ancestry may be influenced by ethnic specific differences in genetic structure surrounding these variants as exemplified by differences in observed minor allele frequency of the reported NFATC2 rs6021191 and GRIA1 rs4958351 SNPs in Japanese (0.11 and 0.01) and Europeans (< 0.01 and 0.36). Moreover, the type of L-asparaginase, and/or differences in therapeutic protocol may also contribute to inconsistencies with the previous reports. There is indication of an involvement of genetic variation of NFATC2 in L-asparaginase hypersensitivity, but whether the signal is representing the same regions as the previous reports needs to be further examined. Disclosures No relevant conflicts of interest to declare.

Recent studies revealed that a substantial proportion of patients with high-risk B-cell precursor acute lymphoblastic leukemia (BCP-ALL) harbor fusions involving tyrosine kinase and cytokine receptors, such as ABL1, PDGFRB, JAK2 and CRLF2, which are targeted by tyrosine kinase inhibitors (TKIs). In the present study, transcriptome analysis or multiplex reverse transcriptase–PCR analysis of 373 BCP-ALL patients without recurrent genetic abnormalities identified 29 patients with kinase fusions. Clinically, male predominance (male/female: 22/7), older age at onset (mean age at onset: 8.8 years) and a high white blood cell count at diagnosis (mean: 94 200/μl) reflected the predominance of National Cancer Institute high-risk (NCI-HR) patients (NCI-standard risk/HR: 8/21). Genetic analysis identified three patients with ABL1 rearrangements, eight with PDGFRB rearrangements, two with JAK2 rearrangements, three with IgH-EPOR and one with NCOR1-LYN. Of the 14 patients with CRLF2 rearrangements, two harbored IgH-EPOR and PDGFRB rearrangements. IKZF1 deletion was present in 16 of the 22 patients. The 5-year event-free and overall survival rates were 48.6±9.7% and 73.5±8.6%, respectively. The outcome was not satisfactory without sophisticated minimal residual disease-based stratification. Furthermore, the efficacy of TKIs combined with conventional chemotherapy without allogeneic hematopoietic stem cell transplantation in this cohort should be determined.

10032 Background: Standard duration of maintenance therapy for childhood acute lymphoblastic leukemia (ALL) is generally considered as one year or longer. In our previous clinical trial, the TCCSG L92-13 (1992 – 1995, n = 347), maintenance therapy was shortened to 6 months and it resulted in decreased EFS of 59.5% at 5.5 years (Toyoda Y, et al. J Clin Oncol 2000), indicating that excess shortening of maintenance therapy could lead to high relapse rate. Conversely, it should be noted that about 60% of ALL achieved continuous complete remission with this short maintenance therapy. Thus, to confirm long-term outcome of ALL with short maintenance therapy, and to identify subgroups which do or do not require the standard duration of maintenance therapy, we conducted L92-13E study, an extended follow up of patients enrolled on the L92-13 study. Methods: In the L92-13 trial, children (15 years or younger) with ALL were enrolled, and were assigned to three risk groups, standard-risk (SR), high-risk (HR) and extre...

Maintenance therapy is a key component of ALL treatment. Although maintenance with 6-mercaptopurine (6-MP) and methotrexate (MTX) is generally less hemato-toxic, it occasionally causes severe complications such as infections, and too long maintenance is possibly associated with lower adherence. Thus, the duration of maintenance should be as short as possible, but excess shortening of maintenance therapy leads to high relapse incidence, as shown in our previous clinical trial, the Tokyo Children's Cancer Study Group (TCCSG) L92-13 (1992 - 1995, n = 347). In this study, the shortened maintenance therapy to 6 months resulted in EFS of 59.5% at 5.5 years although OS was as good as 81.5%. Especially, higher relapse rate in standard-risk (SR) resulted in EFS of as low as 60.2% (Toyoda Y, et al. J Clin Oncol 2000). However, it should be noted that about 60% of ALL achieved continuous complete remission (CCR) with short maintenance therapy. Thus, to confirm long-term outcome of ALL with this short maintenance therapy, we conducted an extended follow up study of patients enrolled on the TCCSG L92-13. In the L92-13 trial, previously untreated children (15 years or younger) with ALL were enrolled, and were assigned to three risk groups, standard-risk (SR), high-risk (HR) and extremely high-risk (HEX), according to age at diagnosis, immunephenotype, sentinel cytogenetics and initial leukocyte count. All patients received four-drug induction, followed by consolidation therapy including re-induction. Maintenance therapy with daily 6-MP and weekly MTX was shortened to 6 months, and all treatment was discontinued at 12 months after diagnosis. The data was analyzed as of 2014 July. A median of follow up period of this extended study was 14.8 years, and the survival curve is shown in Figure 1A. Relapse was reported in 128 patients, with a median time of relapse was 1.8 years from diagnosis. EFS at 12 years for all patients was 58.7 +- 2.7% (59.2% for SR [n = 127], 57.8% for intermediate-risk [IR, n = 122], and 59.2% for high-risk [HR, n = 101]) and OS was 78.7 +- 2.2% (85.4% for SR, 80.0% for IR, and 69.0% for HR). Incidences of relapse and non-relapse mortality were 37.2 +- 2.6% and 3.2 +- 0.9%, respectively. Five patients (0 in SR group, 3 in HR group, and 2 in HEX group) developed secondary malignant neoplasms before relapse, which resulted in cumulative incidence of secondary malignancy of 0.9 +- 0.5% at 12 years. Patient gender was associated with the outcome, and female had better EFS (65.3 +- 3.7%) compared to male (52.2 +- 3.8%) (p = 0.04, Figure 1B). High-hyperdiploid (HHD) patients had relatively worse prognosis, with EFS of 50.0 +- 11.8%, although it is generally considered as good prognostic factor, and most of the relapsed HHD patients were salvaged and OS was 94.4 +- 5.4%. It is confirmed that 6 months maintenance therapy is insufficient for male, HHD, and standard risk patients. In contrast, most of patients who had been in first CR at previous analysis maintained CCR status. Our results demonstrate that short maintenance therapy can cure a substantial portion of ALL with extremely low non-relapse mortality, and that it may be possible to shorten the duration of maintenance therapy for female and non-HHD patients. This study provides precise information of leukemia biology and highlights the role of maintenance therapy. Ongoing molecular characterization of the cured patients will clarify the subset of patients who can be cured with short maintenance therapy. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Background: Using clinical samples and tumor cell lines, chromosomal aberrations and somatic mutations have been well explored in the field of pediatric oncology. However, genes susceptible to pediatric acute lymphoblastic leukemia (ALL) as well as lymphoblastic lymphoma (LBL) have not been delineated yet. Therefore, we examined copy number variations (CNVs) of genomic DNA by means of high-resolution comparative genomic hybridization (CGH) microarray to find significant susceptible genes to ALL and LBL. Methods: We investigated CNVs by array CGH in genomic DNA derived from a total of 58 children with ALL and LBL as case, and compared with control I (n=67): acute myeloid leukemia (AML)(n=10), other type of leukemia (n=4), non-LBL (n=7) and solid tumors such as neuroblastoma (n=46) as well as control II (N=301): adults patients with diabetic nephropathy and receiving dialysis (n=86), with neurological diseases (n=76) and with esophageal, gastric and colon cancers (n=72) plus control I (n=67). Normalization was performed using the Log2 signal ratio (sample DNA/control DNA) for individual 180K probes distributed throughout the whole genome. Control DNA was obtained from a single Japanese person. To compare data between two groups (e.g., ALL+LBL vs. control I or control II), an unpaired t test was used and subsequently corrected by the Benjamini-Hochberg false-discovery rate using GeneSpringGX v.11.5.1. Probes with a corrected p-value (=q-value) less than 0.05 and fold change greater than 1.8 or less than -1.8 were considered statistically significant. Significant gene was confirmed using real time polymerase chain reaction (PCR). Results: CNV of uridine diphospho glucuronosyltansferase 2B17 (UGT2B17) gene was statistically less deleted in children with ALL+LBL, compared with control I (q-value=5.51 x 10-12) and with control II (q-value=6.58 x 10-6). Presence or absence of UGT2B17 gene was reconfirmed by real time PCR. CNVs of other genes were similar in cases and controls. UGT2B17 glucuronidates several endogenous and exogenous compounds in particular steroid hormones as well as several pharmaceutical drugs such as anthraquinones and histone deacetylase inhibitor. As previously reported in some paper of adult solid tumors, CNV of UGT2B17 gene showed significant correlation to drug response. The frequency of CNV shows exceptional differences between populations from Africa, Europe, and Asia. Interindividual variability in UGT2B17 allele-frequency is accompanied by pronounced differences in gene expression characterized by more than 29 times higher mRNA levels in Caucasian compared with Japanese. Conclusion: These results suggest that homozygous or heterozygous gains of the UGT2B17 gene may be associated with a significant risk for pediatric ALL and LBL. Citation Format: Sae Ishimaru, Yuya Saito, Yuichi Yokokawa, Yuki Yuza, Takashi Kaneko, Mitsuyoshi Urashima. Uridine diphospho glucuronosyl-transferase 2B17 genotype and a risk of acute lymphoblastic leukemia and lymphoblastic lymphoma among Japanese children. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr A9.