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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.

Leukocyte-adhesion deficiency-1 is a recessively inherited disorder associated with recurrent bacterial infections, severe periodontitis, peripheral leukocytosis, and impaired wound healing. We diagnosed moderate-type leukocyte-adhesion deficiency-1 in a 7-year-old girl who developed a necrotizing ulcer after Bacillus Calmette-Guerin vaccination. The patient showed moderate expression of CD18 in neutrophils with a homozygous splice mutation with c.41_c.58+2dup20 of ITGB2 and experienced recurrent severe infections complicated with systemic lupus erythematosus. She received hematopoietic stem cell transplantation from a matched elder brother with heterozygous mutation of ITGB2, and has since remained free of infection and systemic lupus erythematosus symptoms without immunosuppression therapy.

In the treatment of childhood acute lymphoblastic leukemia (ALL), excess shortening of maintenance therapy resulted in high relapse rate, as shown by our previous trial, TCCSG L92-13, in which maintenance therapy was terminated at 1 year from initiation of treatment. In this study, we aimed to confirm the long-term outcome of L92-13, and to identify who can or cannot be cured by shorter duration of maintenance therapy. To obtain sentinel cytogenetics information that had been missed before, we performed genetic analysis with genomic microarray and target intron-capture sequencing from diagnostic bone marrow smear. Disease-free survival (DFS) at 10 years from the end of therapy was 66.0±2.8%. Females (n=138) had better DFS (74.6±3.7%) than males (n=142, 57.5±4.2%, P=0.002). Patients with TCF3-PBX1 (n=11) and ETV6-RUNX1 (n=16) had excellent DFS (90.9±8.7% and 93.8±6.1%, respectively), whereas high hyperdiploidy (n=23) was the most unfavorable subgroup, with 56.6±10.3% of DFS. Short duration of therapy can cure more than half of pediatric ALL, especially females, TCF3-PBX1 and ETV6-RUNX1. Our retrospective observations suggest a gender/karyotype inhomogeneity on the impact of brief therapy.

Viridans streptococcal bacteremia is a prognostic factor in pediatric patients with malignant disease accompanied by severe neutropenia. Here the authors describe 4 patients with viridans streptococcal bacteremia-related encephalopathy who showed serious complications, which included seizures and loss of consciousness. Therapy for relief of brain edema on seizures was started quickly, and included the administration of midazolam, dexamethasone, and mannitol with antimicrobial therapy. The treatment was successfully completed without sequelae. The authors registered 28 episodes of viridans streptococcal bacteremia in their hospital. The peak of serum C-reaction protein was higher in viridans streptococcal bacteremia patients with encephalopathy than in those without encephalopathy. The authors concluded that viridans streptococcal bacteremia can induce encephalopathy in pediatric patients with malignancy and that it is crucial to establish an accurate diagnosis and initiate therapy as soon as possible.

EBV-infected T-/NK cells play an important role in the pathogenesis of mosquito allergy, and the prognosis of most patients with mosquito allergy is poor without proper treatment. We describe a 13-yr-old boy who had CAEBV with mosquito allergy and was successfully treated with BMT from an unrelated donor after reduced-intensity preconditioning. Because combination chemotherapy failed to achieve CR, we performed unrelated BMT to reconstitute normal immunity and eradicate any residual EBV-infected cells. To reduce complications after BMT, we selected a reduced-intensity preconditioning regimen consisting of fludarabine, l-phenylalanine mustard, and antithymocyte Ig instead of a conventional myeloablative preconditioning. Although grade II acute GVHD developed, it was successfully controlled with immunosuppressive therapy. After 27 months, the patient has been well without any signs of CAEBV, and the EBV DNA has been undetectable with real-time PCR analysis. We conclude that RIST from the bone marrow of an unrelated donor is indicated for some patients who have CAEBV that is refractory to chemotherapy and who have no HLA-matched related donors or cord blood as a source of stem cells.

RATIONALE Central nervous system (CNS) leukemia is a frequent diagnosis in pediatric acute myeloblastic leukemia (AML) and includes neural symptoms. However, CNS leukemia is rarely associated with central hypsothyroidism. PATIENT CONCERNS AND DIAGNOSES A 2-year-old female with AML with MLL rearrangement presented with CNS infiltration. Laboratory tests suggested the presence of central hypothyroidism (thyroid-stimulating hormone [TSH]: 0.48 mIU/ml, normal range 0.7-6.4 mIU/ml; serum free thyroxine [FT4]: 0.62 ng/dl, normal range 0.8-2.2 ng/dl; free triiodothyronine: 1.57 pg/ml, normal range 2.7-5.6 pg/ml). Magnetic resonance imaging detected no lesions in the hypothalamus, pituitary, or thyroid. INTERVENTIONS AND OUTCOMES Levothyroxine (2.5 mg/kg/day) was administered together with chemotherapy and intrathecal injection of methotrexate, cytarabine, and hydrocortisone into the cerebrospinal fluid. The FT4 concentration increased after levothyroxine treatment, but later decreased after relapse of CNS leukemia. The TSH concentrations remained low. After remission of CNS leukemia, the TSH and FT4 concentrations quickly recovered to their normal ranges. LESSONS We believe that the CNS leukemia directly affected TSH and thyroid hormone secretion in our patient.

Hematopoietic stem cell transplantation for X-linked thrombocytopenia from a mild symptomatic carrier

Burkitt-type acute lymphoblastic leukemia (B-ALL) is thought as a variant of Burkitt lymphoma/leukemia and derived from mature B-cell lymphoblast.B-ALL was developed in a 10-year-old girl. Two characteristics were apparent in this case. First, the lymphoblastic cells were positive for CD10, CD19, CD20, and CD22, but negative for terminal deoxynucleotidyl transferase and surface immunoglobulins, indicating a B-cell immunophenotype. The detection of t(8;14)(q24;q32) with a chromosomal analysis is required for a diagnosis of B-ALL. Second, der(1)(pter → q32.1::q32.1 → q21.1::q11 → qter) was detected, in which 1q21.1 to 1q32.1 was inverted and inserted. Finally, partial tetrasomy of 1q was also present. Because B-ALL with abnormal chromosome 1 has been reported poor outcome, the usual chemotherapy for stage 4 Burkitt lymphoma with added rituximab was administered for our patient.We report B-ALL with precursor B-cell immunophenotype and interesting partial tetrasomy of 1q.

Myeloproliferative diseases (MPDs) in childhood are quite rare. Although pediatric and adult MPDs exhibit similar hematologic findings, JAK2V617F mutations and clonality status of MPDs in the DNA of neutrophils are evaluated less frequently in children than in adults. Increased incidence of venous thrombosis at uncommon sites is associated with JAK2V617F mutation in MPDs and thrombotic complications are more common in essential thrombocythemia (ET). Here, we describe 6-year-old girl with clonal myelopoiesis and JAK2V617F-positive ET associated with cerebral venous sinus thrombosis. To our knowledge, this is the first report of pediatric monoclonal and JAK2V617F-positive ET with cerebral venous sinus thrombosis.

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.

Iodine-131-metaiodiobenzylguanidine (131I-MIBG) therapy combined with allogeneic cord blood stem cell transplantation (SCT) was used to treat a 4-year-old girl with recurrent neuroblastoma. The patient experienced relapse 2 years after receiving first-line therapies, which included chemotherapy, surgical resection, irradiation, and autologous peripheral SCT. Although 131I-MIBG treatment did not achieve complete remission, the size of the tumor was reduced after treatment. Based on our findings, we suggest that 131I-MIBG treatment with myeloablative allogeneic SCT should be considered as first-line therapy for high-risk neuroblastoma patients when possible.