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BACKGROUND The quality of end-of-life (Q-EOL) care is influenced by various factors such as resources for palliative care (PC). We introduced a multi-professional expert team (MET) in 2014, which provides home-based care for children and adolescents with incurable cancer. This study investigated the impacts of the outreach activities by the MET on Q-EOL care of pediatric oncology patients. METHODS This observational study retrospectively examined 112 patients receiving end-of-life care between 1989 and 2018 at a pediatric cancer center in Japan. Some of the indicators of Q-EOL care before and after the introduction of the outreach activities by the MET were compared. The subjects were 92 in pre-MET and 20 in post-MET periods. RESULTS The median number of days for which the patients stayed at home during the final seven or 30 days were significantly prolonged in the post-MET period (0.0 vs 1.5 days, P = 0.020, 3.0 vs 12.0 days, P = 0.042). The change was more significant in hematologic malignancies than solid and central nervous system tumors. Patients receiving longer PC before their deaths could stay at home longer during the last 7 days. The ratio of patients receiving PC for more than 2 months was significantly increased in post-MET period (60.9 vs 90.0%, P = 0.014). More patients also greeted their deaths at home in the post-MET period (3.3 vs 25.0%, P < 0.001). CONCLUSIONS The activities of the MET transformed the end-of-life care of children and adolescents with incurable cancer. Earlier transitions to PC from curative treatment were associated with longer home-based care and more deaths at home.

Myeloid leukemia of Down syndrome (ML-DS) is associated with good response to chemotherapy, resulting in favorable outcomes. However, no universal prognostic factors have been identified to date. To clarify a subgroup with high risk of relapse, the role of minimal residual disease (MRD) was explored in the AML-D11 trial by the Japanese Pediatric Leukemia/Lymphoma Study Group. MRD was prospectively evaluated at after induction therapy and at the end of all chemotherapy, using flow cytometry (FCM-MRD) and GATA1-targeted deep sequencing (GATA1-MRD). A total of 78 patients were eligible and 76 patients were stratified to the standard risk (SR) group by morphology. In SR patients, FCM-MRD and GATA1-MRD after induction were positive in 5/65 and 7/59 patients, respectively. Three-year event-free survival (EFS) and overall survival (OS) rates were 93.3% and 95.0% in the FCM-MRD-negative population, and 60.0% and 80.0% in the positive population. Three-year EFS and OS rates were both 96.2% in the GATA1-MRD-negative population, and 57.1% and 71.4% in the positive population. Adjusted hazard ratios for associations of FCM-MRD or GATA1-MRD with EFS were 10.98 (p = 0.01) and 27.68 (p < 0.01), respectively. Detection of MRD by either FCM or GATA1 after initial induction therapy represents a significant prognostic factor for predicting ML-DS relapse.

Li-Fraumeni syndrome (LFS) is a rare inherited disease characterized by a high and early-onset cancer risk. A cancer surveillance program is important to reduce cancer-related morbidity and mortality in individuals with LFS. We report 2 pediatric cases with LFS-related malignancy in a family. Eight-year-old elder brother was diagnosed with adrenocortical carcinoma and was found to have a heterozygous missense germline mutation c.736A>G: p.Met246Val in the TP53 gene. Cancer screening led to the diagnosis of rhabdomyosarcoma at a curable stage in his 2-year-old younger brother. Comprehensive surveillance resulted in early tumor detection and improved survival.

Patient: Female, 14 Final Diagnosis: Nasopharyngeal carcinoma Symptoms: Fever • neck swelling • trismus Medication: — Clinical Procedure: Biopsy Specialty: Oncology Objective: Challenging differential diagnosis Background: Clinical presentation of nasopharyngeal carcinoma (NPC) is correlated with the extent of primary and nodal disease. Hence, depending on the anatomical structures affected, the clinical presentation varies accordingly, ranging from non-specific symptoms of epistaxis, unilateral nasal obstruction, and auditory complaints, to cranial nerve palsies. Nodal metastasis in the neck is a frequent clinical finding in nasopharyngeal carcinoma. Case Report: A female was admitted to the hospital because of fever and trismus with painful swelling in the right neck. Computed tomography (CT) revealed a mass in the nasopharynx with heterogeneous enhancement and multiple swollen lymph nodes in the corresponding neck. Initial biopsies of nasopharyngeal mass and lymph node of the neck revealed nonspecific lymphoid hyperplasia; we administered antibiotics with the provisional diagnosis of bacterial infection, including Lemierre syndrome that is typically defined by the constellation of septic internal jugular vein thrombophlebitis, pulmonary and other septic emboli, and sterile site bacterial infection. However, the patient was refractory to antibiotics over a month of treatments. The third biopsy of the throat lesion revealed NPC and bacterial cultures using the biopsy specimen were negative. She received intensity-modulated radiation therapy and chemotherapy for NPC stage II (TNM staging: T2N1M0). She never developed Lemierre syndrome-like symptoms after chemoradiotherapy. Conclusions: We report a unique case of NPC presenting with Lemierre syndrome-like symptoms, including prior sore throat, trismus, painful swollen neck, and high fever. Since these symptoms have not been reported in NPC, we included NPC as a differential diagnosis.

Patients with SMID (severe motor and intellectual disabilities) have severe limb disorders and severe mental disabilities. More than half of their deaths are due to respiratory disorders. Therefore, respiratory rehabilitation is important. The effect of respiratory rehabilitation is generally determined by measuring respiratory volume and rate with an expired gas analyzer. However, the equipment is expensive and requires direct contact, making it difficult to use. The purpose of this research is to develop a non-contact measurement system for respiratory function to assess the effect of respiratory rehabilitation in patients with SMID. The proposed method detects respiration by depth change of the abdomen measured using a three-dimensional camera designed to identify body tremor /motion and respiration based on respiratory parameters and individually adapted parameters. Finally, we verify the rehabilitation effect of an RTX respirator on patients with SMID and the effectiveness of the proposed method in an experiment.

BACKGROUND The prognosis of children with acute myeloid leukemia (AML) has improved with the efficacy of hematopoietic cell transplantation (HCT) as a second-line therapy and improvements in supportive care following anthracycline- and cytarabine-based chemotherapy; however, the outcomes of children with relapsed AML still remain unsatisfactory. PROCEDURE In order to identify prognostic factors and improve their prognosis, we analyzed 111 patients who relapsed after treatment with the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05 protocol and who were registered in the retrospective JPLSG AML-05R study. RESULTS The 5-year overall survival rate was 36.1%. The major determinant of survival was duration from the diagnosis to relapse. The mean duration in the nonsurviving group (10.1 ± 4.1 months) was shorter than that in the surviving group (16.3 ± 8.3 months) (P

The variability in myelosuppression after chemotherapy for acute myeloid leukaemia (AML) can affect its prognosis; however, the underlying mechanism remains controversial. In the Japanese Paediatric Leukaemia/Lymphoma Study Group AML-05 study, we showed that prolonged neutropenia was associated with high overall survival (P = 0·011) and low frequency of relapse (P = 0·042) in patients without granulocyte-colony stimulating factor (G-CSF) who completed the indicated treatment protocol. Our data indicate that predisposition to prolonged neutropenia after chemotherapy is correlated with a better outcome of AML treatment. Our results promote the usage of individualised drug dosing strategies to improve the therapeutic outcome in AML patients.

Acute myeloid leukemia harboring internal tandem duplication of FMS-like tyrosine kinase 3 (AMLFLT3-ITD) is associated with poor prognosis. We evaluated the results of the AML-05 study, in which all AMLFLT3-ITD patients were assigned to receive hematopoietic stem cell transplantation (HSCT) in the first remission (1CR). We also investigated the effects of additional genetic alterations on FLT3-ITD. The 5-year overall survival (OS) and event-free survival (EFS) rates among the 47 AMLFLT3-ITD patients were 42.2 and 36.8%, respectively. The 5-year disease-free survival rate among 29 patients without induction failure was 58.4%. We defined the allelic ratio (AR) of FLT3-ITD to WT > 0.7 as high. Significant differences were found in OS (AR-high, 20% vs. AR-low, 66%, p 0.7 and expression of the NUP98-NSD1 chimera strongly impacted OS and EFS. Although all the AMLFLT3-ITD patients received HSCT at 1CR, the treatment outcome of AMLFLT3-ITD patients did not improve compared with those in a previous study. Heterogeneity was observed among AMLFLT3-ITD patients.

Although prognosis in patients with localized osteosarcoma has been dramatically improved by the introduction of multiple chemotherapy agents known as combination chemotherapy, there is growing concern about the development of secondary malignant neoplasms. We report the case of a 13-year-old girl in whom the diagnosis of Ewing sarcoma of bone localized on the shaft of left femur was made 2 years after successful treatment without radiotherapy for osteosarcoma of right proximal femur. EWS-FLI1 fusion gene was detected by reverse transcriptase-polymerase chain reaction. To our knowledge, this is the first case with Ewing sarcoma of the bone as a secondary malignant neoplasm developed in osteosarcoma survivor. We collected 15 cases, included this case, with secondary Ewing sarcoma family of tumor by utilizing the PubMed search and might consider the causes of this secondary cancer.

We previously reported that risk-stratified therapy and intensive postremission chemotherapy (PRC) contributed to the improved survival of childhood acute myeloid leukemia (AML) in the AML99 study, which led us to consider a reduction in the number of PRC courses with more restrictive indications for stem cell transplantation (SCT) in the successor AML-05 study. We here report the outcome of AML patients without core-binding factor mutation (non-CBF AML) in the AML-05 study. Two-hundred eighty-nine children (age < 18 years old) with non-CBF AML were eligible. Patients with unfavorable cytogenetics and/or poor bone marrow response to the first induction course were candidates for SCT in the AML-05 study. After two courses of induction, a further three courses of PRC were given in AML-05, while four courses were given in the AML99 study. The 3-year event-free survival (EFS) rate in the AML-05 study (46.7%, 95% CI: 40.6-52.6%) was comparable to that of non-CBF AML in the AML99 study (51.5%, 95% CI: 42.7-59.6%) (P = .16). However, the 3-year overall survival (OS) rate in the AML-05 study (62.9%, 95% CI: 56.3-68.8%) was slightly lower than that in the AML99 study (71.6%, 95% CI: 63.2-78.5%) (P = .060), mainly due to decreased remission induction rate and increased nonrelapsed mortality. In conclusion, reductions in the number of PRC courses from four to three, together with repetitive cycles of high-dose cytarabine, were acceptable for non-CBF childhood AML.

Children with severe motor and intellectual disabilities experience chronic pain but cannot communicate verbally. However, no Japanese tool currently exists for assessing pain in this population. This study aimed to develop and evaluate the reliability and validity of a Japanese version of the Paediatric Pain Profile, which is a behavioral rating scale to assess pain in children with severe neurological disabilities. The sample comprised 30 children with severe motor and intellectual disabilities at three hospitals in Japan. Three specialist nurses rated low and high pain video scenes of the children (twice at 1-week intervals) using the Face, Legs, Activity, Cry, Consolability behavioral scale and a translated Japanese version of the Paediatric Pain Profile. On the basis of their ratings, we calculated the internal consistency, test–retest reliability, and intra- and inter-observer reliabilities of the Paediatric Pain Profile. Additionally, we assessed concurrent validity using the Face, Legs, Activity, Cry, Consolability behavioral scale and construct validity using low versus high pain scenes. Both internal consistency (low pain: alpha = 0.735; high pain: alpha = 0.928) and test–retest reliability (r = 0.846) of the Japanese version of the Paediatric Pain Profile were good. Intra-observer reliability was substantial (r = 0.748), whereas inter-observer reliability was only moderate (r = 0.529). However, the concurrent validity with Face, Legs, Activity, Cry, Consolability scores was good (r = 0.629) and construct validity was confirmed (p < 0.001). We confirmed the validity of the Japanese version of the Paediatric Pain Profile, but reliable pain assessment may require repeated ratings by the same person. To accurately assess pain in children with severe motor and intellectual disabilities, healthcare staff must be properly trained and become more skilled in using the Japanese version of the Paediatric Pain Profile.

Background:The current event-free survival rates of children with acute myeloid leukemia (AML) approach 60%, with hematopoietic cell transplantation (HCT) as an effective second-line therapy and improvements in supportive care; however, the overall survival rates of children with relapsed AML still remains 70%, which is an unsatisfactory situation that urgently needs to be solved. Patients & Methods:In order to identify prognostic factors and improve their prognosis, we analyzed 111 patients with relapsed disease after treatment with the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05 protocol, who were registered in the retrospective JPLSG AML-05R study. We collected the following data: age at relapse, time from the diagnosis to relapse, site of relapse, FAB classification, chromosomal analysis results, reinduction chemotherapy regimen, rate of achieving a second complete remission (CR2) after initial reinduction therapy, detailed information on HCT, outcome and cause of death. Moreover, ninety-three leukemic samples obtained from 111 patients at the time of their diagnosis were available for a genetic analysis. Mutational analyses ofFLT3-ITD,KIT, N-andK-RAS, NPM1,WT1,andKMT2A-partial tandem duplication were performed. Screening ofNUP98-NSD1was also performed. The high or low expression ofMECOMandPRDM16were determined based on theABL1ratio. Results:The 5-year overall survival rate was 36.1%. t(8;21) was found in 27 patients and inv(16) was found in 5 patients.KMT2Arearrangement was found in 23 patients (24.7%).KITmutations were found in 17 patients (17.5%). The following mutations were also detected:FLT3-ITD (n=10),N-RAS(n=10),WT1(n=7),K-RAS(n=4),NUP98-NSD1(n=2),KMT2A-PTD (n=2), andNPM1(n=2). The high expression ofMECOMandPRDM16was found in 24 (25.8%) and 32 (34.4%) patients, respectively. A genetic analysis revealed the prognostic significance ofFLT3-ITD as a poor prognostic marker (p=0.04) and core binding factor-AML, t(8;21) and inv(16), as a good prognostic marker (p Conclusions:Achieving CR2 prior to HCT by intensive reinduction chemotherapy, ECM, or FLAG, is important for improving the prognosis of patients with relapsed pediatric AML. Liposomal daunorubicin or 3 fractionated doses of gemtuzumab ozogamicin is an attractive option which is under consideration for addition to FLAG. Moreover, recent molecular targeted therapeutics, such as FLT3 inhibitors, may contribute to improving the prognosis of these patients. Larger prospective investigations are needed in order to establish individualized treatment strategies for patients with relapsed childhood AML. Disclosures No relevant conflicts of interest to declare.

The prognosis of paediatric acute myeloid leukaemia (AML) with primary induction failure (PIF) is extremely poor, and effective treatment strategies have not been established. We investigated the clinical and biological features of paediatric AML patients with PIF registered to the Japanese Paediatric Leukaemia/Lymphoma Study Group AML-05 study. The 3-year overall survival rate of the 41 PIF patients was 19.0%. High leucocyte count, M7 morphology, and unfavourable genetic aberrations, such as FLT3-internal tandem duplication, NUP98-NSD1 and high MECOM or PRDM16 expression, were risk factors for PIF. More effective treatment strategies based on leukaemia biology need to be urgently explored.

Background On the basis of results of previous Japanese trials for myeloid leukemia in Down syndrome (ML-DS), the efficacy of risk-oriented therapy was evaluated in the Japanese Pediatric Leukemia/Lymphoma Study Group AML-D05 study. Procedure All patients received induction chemotherapy that consisted of pirarubicin, intermediate-dose cytarabine, and etoposide. Patients who achieved complete remission (CR) after initial induction therapy were stratified to the standard risk (SR) group and received four courses of reduced-dose intensification therapy. Patients who did not achieve CR were stratified to the high risk (HR) group and received intensified therapy that consisted of continuous or high-dose cytarabine. Results A total of 72 patients were eligible and evaluated. One patient died of sepsis during initial induction therapy. Sixty-nine patients were stratified to SR and two patients to HR. No therapy-related deaths were observed during intensification therapy. The 3-year event-free and overall survival rates were 83.3% ± 4.4% and 87.5% ± 3.9%, respectively. Age at diagnosis less than 2 years was a significant favorable prognostic factor for risk of relapse (P = 0.009). Conclusions The attempt of risk-oriented prospective study for ML-DS was unsuccessful, but despite the dose reduction of chemotherapeutic agents, the overall outcome was good, and further dose reduction might be possible for specific subgroups.

As past studies of adolescent and young adults (AYA) with acute myeloid leukemia (AML) reported conflicting results, we conducted a retrospective analysis using data from three Japanese pediatric AML studies. Among the 782 patients with de novo AML, 44 were classified as AYA (age ≥15 years at diagnosis), 164 as infants (0-1 year), 413 as younger children (2-11 years), and 161 as older children (12-14 years). While the 5-year event-free survival rate of AYA was not different among the groups, the five-year survival rate (54.7 %) was significantly lower than that of the other three groups (P = 0.019): 68.7 % for infants, 73.2 % for younger children, and 75.5 % for older children. No difference in the 5-year cumulative incidence of relapse was observed, but treatment-related death (TRD) of AYA was significantly higher (29.4 %) than that in infants (14.8 %), younger children (10.2 %), and older children (13.8 %). Multivariate analysis showed age ≥15 years old at diagnosis was associated with both poor survival rate and high TRD. Adolescents with AML had inferior survival due to a higher incidence of TRD, especially after failure of initial frontline treatment.

Eculizumab, terminal complement inhibitor, has become the frontline treatment for atypical hemolytic uremic syndrome (aHUS). However, the optimal treatment schedule has not yet been established. We describe here an aHUS patient with a mutation of C3 I1157T who achieved remission with eculizumab and suffered a recurrence after eculizumab discontinuation, a clinical situation that has not been previously described in patients with C3 mutation. A 9-year-old male experienced an onset of aHUS after viral gastroenteritis and was treated with hemodialysis. At 13 years of age he developed bacterial enterocolitis due to Campylobacter jejuni and experienced a recurrence of aHUS. Eculizumab was initiated on day 4 after disease onset resulting in recovering laboratory parameters. The patient received eculizumab for 5 months before its discontinuation. Second relapse induced by bacterial pharyngitis was confirmed 4 months after eculizumab discontinuation and prompt eculizumab reinitiation resulted in rapid remission. The patients carrying mutations in CFH or C3 have a high frequency of relapse and worse prognosis. More than 50% of aHUS relapses occurred during the first year after the onset. Therefore, long-term treatment with eculizumab is appropriate in patients with aHUS who have experienced a relapse or have mutations associated with poor prognosis.

Background The combination of fludarabine (Flu), high-dose cytarabine (Ara-C) and granulocyte colony-stimulating factor (G-CSF; FLAG), with anthracyclines has become standard chemotherapy for refractory acute myeloid leukemia (AML) in European children and adults. To clarify the efficacy and the safety of FLAG-idarubicin (IDA) for children prospectively, we planned a multicenter phase II study (AML-R11) by the Japanese Pediatric Leukemia/Lymphoma Study Group. Methods Patients with AML aged between 2 and 20 years old, who had the first bone marrow (BM) relapse or induction failure, were enrolled. The FLAG-IDA regimen consisted of Flu 30 mg/m2 for 5 days, Ara-C 2 g/m2 for 5 days, G-CSF (lenograstim) 5 μg/kg for 6 days and IDA 10 mg/m2 for 3 days. The primary endpoint was remission rate after therapy. Results Due to drug supply issues, the trial was suspended after the inclusion of seven eligible patients. There were six cases of early relapse within 1 year of the first remission. All seven patients completed the therapy and no early death was observed. Hematological toxicity was common, and one patient developed grade 4 non-hematological toxicity of bacterial meningitis. Although only one patient with late relapse achieved complete remission, minimal residual disease was positive on both flow cytometry and Wilms' tumor 1 mRNA. Two patients were alive in remission following hematopoietic stem cell transplantation, whereas the other five patients died of either the disease or treatment-related causes. Conclusion FLAG-IDA might be tolerable for children with refractory AML although the efficacy should be further investigated.

Background: Myeloid leukemia in Down syndrome (ML-DS) is associated with good response to chemotherapy thus results in a favorable outcome. However, relapsed and refractory cases are rarely salvageable, regardless of receiving hematopoietic stem cell transplantation. Several factors such as certain chromosomal abnormalities and age at diagnosis are somewhat prognostic, but no universal prognostic factor has been found to date. In order to identify a subgroup with high risk of treatment failure, the role of minimal residual disease (MRD) with three methods were explored in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) trial AML-D11. Procedure: AML-D11 is a nationwide single-arm clinical trial for children (4 months to 17 years old) with ML-DS. All patients received an identical chemotherapy to the previous AML-D05 study (Taga T. Pediatr Blood Cancer 2016). MRD was evaluated at two time points, one after the induction therapy and another at the end of whole chemotherapy, using 3 different methods; flow cytometric MRD (FCM-MRD), deep sequencing MRD of mutant GATA1 (GATA1-MRD) and PCR MRD of WT1 mRNA expression (WT1-MRD). WT1-MRD was measured in both bone marrow (BM) and peripheral blood (PB) samples, while FCM- and GATA1-MRD were measured only in BM samples. Results: A total of 78 patients were eligible and followed-up with a median of 47.6 months (range, 8 to 68.8 months). Seventy-six patients were stratified to the standard risk (SR) and one patient to the high risk (HR) group by morphological response. One patient died of sepsis during initial induction therapy. Three-year event-free survival (EFS) and overall survival (OS) rates were 87.2% (95%CI, 77.5 to 92.9%) and 89.7% (95%CI, 80.5 to 94.7%), respectively. FCM-MRD and GATA1-MRD after initial induction therapy were positive in 5/65 and 7/59 patients, respectively, which were both significantly prognostic (Fig.1). Prognostic significance of WT1-MRD could not be evaluated due to a limited number of collected samples. Conclusions: MRD detections by FCM and targeted deep sequencing of GATA1 after initial induction therapy are both significant prognostic factors for predicting relapse. Risk stratification using FCM-MRD is currently incorporated in the on-going Japan Children's Cancer Group ML-DS trial (AML-D16; jrct.niph.go.jp, jRCTs041190047). Figure 1 Disclosures No relevant conflicts of interest to declare.

Introduction: Transient abnormal myelopoiesis (TAM) in neonates with Down syndrome (DS) is characterized by the transient appearance of blast cells that harbor somatic GATA1 gene mutation. Although most patients show spontaneously resolution without therapeutic interventions, approximately 20% of TAM cases result in early deaths within 9 months and 20% of survivors develop acute megakaryoblastic leukemia (AMKL) within 4 years. Although the risk factors associated with early deaths are known, the definite clinical predictive indicators of AMKL onset in patients with TAM remain unclear. Therefore, we analyzed 167 TAM patients with DS enrolled in the TAM-10 prospective observational study conducted by the Japan Pediatric Leukemia/Lymphoma Study Group (JPLSG) to determine the clinical characteristics of TAM and predictive factors of leukemia development. Patients and Methods: Between May 2011 and February 2014, 167 neonates (89 boys and 78 girls) diagnosed with TAM were prospectively registered in the TAM-10 study. Somatic GATA1 gene mutations were confirmed in 163 (98%) patients using Sanger and/or next-generation sequencing. Minimal residual disease using flow cytometry (FCM-MRD; cut-off level, ≥0.1%) was monitored at 1 (n = 133) and 3 months (n = 104). Results: Median (range) gestational age, birth body weight, white blood cell (WBC) count, and percentage of blasts at diagnosis were 37 (29-40) weeks, 2,612 (1,066-3714) g, 38.3 (2.4-478.7) × 109 cells/L, and 37% (0.5%-95.5%), respectively. Systemic edema and organ hemorrhage was observed in 31/167 (19%) and 14/167 (8%) patients, respectively; 68/167 (41%) patients received some therapeutic interventions, including low-dose cytarabine (LDCA; n = 52), exchange blood transfusion (n = 20), and systemic steroid therapy (n = 31). Early death ( Among 145/167 patients without early death, 28 (19%) developed AMKL. FCM-MRD positivity at 1 month [positive, n = 107; negative, n = 26; cumulative incidence ratio (CIR) (95% CI) = 25.2% (17.3-33.9%) vs 3.8% (0.3%-16.8%), P = 0.022] and 3 months (positive, n = 20; negative, n = 84; CIR (95% CI), 45.0% (22.3%-65.4%) vs. 16.0% (9.0%-24.8%), P = 0.002] was significantly associated with leukemia development. However, other clinical covariates, including sex, birth weight, gestational age, WBC count, blast percentage, and GATA1 gene mutational types, could not predict AMKL development. Considering their severe clinical conditions, 13/31 (42%) patients who received systemic steroid therapy died before AMKL development; interestingly, none of the remaining 18 patients developed AMKL but they showed significantly lower CIR than those who did not receive this therapy [CIR (95% CI), 0% vs. 19.4% (10.9%-29.6%), P = 0.010]. Other therapeutic interventions, including LDCA and exchange blood transfusion, were not associated with AMKL development. Conclusion: FCM-MRD positivity at 1 month and 3 months might be a useful marker to predict leukemia development in patients with TAM. Although LDCA therapy significantly decreased the rate of early deaths, it did not suppress leukemia development. Interestingly, systemic steroid therapy might suppress leukemia development. These results pave the way to design clinical trials for developing MRD-directed leukemia prevention therapy for patients with TAM. Disclosures No relevant conflicts of interest to declare.

Infants (

Gastric antral vascular ectasia (GAVE) leading to upper gastrointestinal bleeding is a heterogeneous disorder that is not commonly recognized in hematopoietic stem cell transplantation (HSCT). Protein-losing enteropathy (PLE) is noted as another gastrointestinal complication in the context of chronic graft-versus-host disease (GVHD) after HSCT. The possibility of a relationship between these two distinct gastrointestinal disorders, however, remains obscure. A 6-year-old boy with acute myelogenous leukemia developed severe hematemesis 4 months after myeloablative HSCT from a human leukocyte antigen-matched sibling donor. The diagnosis of GAVE was made by upper endoscopy and histological examination. The patient simultaneously developed frequent diarrhea and significant hypoproteinemia, consistent with a diagnosis of PLE. This co-occurrence of GAVE and PLE against a background of chronic GVHD was successfully treated with cyclosporin A and prednisolone. To our knowledge, this is the first report of GAVE concurrent with PLE following HSCT. The possible association of GAVE and PLE in chronic GVHD is discussed.

Myeloid leukemia in Down syndrome (ML-DS) is associated with good response to chemotherapy and favorable prognosis. Because little research has been focused on refractory/relapsed (R/R) cases, we conducted a retrospective analysis for R/R ML-DS. Among ML-DS patients diagnosed between 2000 and 2010 in Japan, 26 relapsed (25 in the BM and 1 in the skin), and 3 refractory patients were enrolled. The male/female ratio was 18/11. The median age at initial diagnosis of ML-DS was 2 years, and the median time to relapse was 8.6 months. Each patient initially had been treated with ML-DS–specific protocols. Thirteen of the 26 patients achieved complete remission with various kinds of reinduction chemotherapies; 2 of 8 survived without further recurrence after receiving allogeneic hematopoietic stem cell transplantation, and 4 of 5 maintained complete remissions with chemotherapy alone. Treatment failures mostly were associated with disease progression rather than treatment-related toxicities. The 3-year OS rate was 25.9% ± 8.5%. A longer duration from initial diagnosis to relapse was a significant favorable prognostic factor (P < .0001). We conclude that clinical outcome for patients with R/R ML-DS generally are unfavorable, even in those receiving hematopoietic stem cell transplantation. Novel methods to identify poor prognostic factors for ML-DS are necessary.

Although there are National Institutes of Health consensus criteria for the global assessment of chronic graft-versus-host disease, no validated biomarkers have been established for this disease. Furthermore, whereas the role of T cells, B cells, and dendritic cells in chronic graft-versus-host disease has been established, the contribution of monocytes has not been clearly addressed. Using an enzyme-linked immunospot assay, we measured the spot-forming cells for interferon-γ, interleukin-4, interleukin-10, and interleukin-17 in unstimulated peripheral blood of patients following allogeneic hematopoietic stem cell transplantation. Other immunological examinations, including skin biopsy, were also done. Fifty-seven patients were enrolled. Interleukin-10 spot-forming cells were evaluable for therapeutic monitoring in 16 patients with chronic graft-versus-host disease. The number of interleukin-10 spot-forming cells in patients with active chronic graft-versus-host disease was significantly higher than the number in those with no or inactive chronic graft-versus-host disease. Interleukin-10 was predominantly produced by monocytes. CD29 expression on monocytes in patients with active chronic graft-versus-host disease was elevated. The level of plasma fibronectin, a ligand of CD29, correlated with the number of interleukin-10 spot-forming cells. Immunohistochemical analysis of the skin in active chronic graft-versus-host disease showed that infiltrating CD29(+) monocytes might produce interleukin-10. A novel biomarker, interleukin-10 spot-forming cells, shows promise as both a diagnostic and prognostic indicator for chronic graft-versus-host disease, and may allow for early intervention prior to the onset of the disease. Measurement of interleukin-10 spot-forming cells would be helpful in clinical trials and in patients' management.

We evaluated the efficacy of treatment using reduced cumulative doses of anthracyclines in children with acute promyelocytic leukaemia (APL) in the Japanese Paediatric Leukaemia/Lymphoma Study Group AML-P05 study. All patients received two and three subsequent courses of induction and consolidation chemotherapy respectively, consisting of all-trans retinoic acid (ATRA), cytarabine and anthracyclines, followed by maintenance therapy with ATRA. Notably, a single administration of anthracyclines was introduced in the second induction and all consolidation therapies to minimize total doses of anthracycline. The 3-year event-free (EFS) and overall survival rates for 43 eligible children were 83·6% [95% confidence interval (CI): 68·6-91·8%] and 90·7% (95% CI: 77·1-96·4%), respectively. Although two patients died of intracranial haemorrhage or infection during induction phases, no cardiac adverse events or treatment-related deaths were observed during subsequent phases. Patients not displaying M1 marrow after the first induction therapy, or those under 5 years of age at diagnosis, showed inferior outcomes (3-year EFS rate; 33·3% (95% CI: 19·3-67·6%) and 54·6% (95% CI: 22·9-78·0%), respectively). In conclusion, a single administration of anthracycline during each consolidation phase was sufficient for treating childhood APL. In younger children, however, conventional ATRA and chemotherapy may be insufficient so that alternative therapies should be considered.

The human polyomavirus BK (BKV)-associated hemorrhagic cystitis (HC) has been a frequent and, seldom life-threatening complication after bone marrow transplantation (BMT). The authors report a male with melodysplastic syndrome, who developed BKV-associated late-onset HC 12 days after HLA-matched unrelated BMT. His urine contained epithelial cells with intranuclear inclusion bodies suggestive of BKV infection and was positive for BKV in polymerase chain reaction. He did not respond to any treatment for HC. In addition, he developed BKV-associated acute renal failure on day 26, followed by hepatic veno-occlusive disease on day 42. This is the first case in which BKV may be associated with fatal progressive renal failure.

Cord blood transplantation (CBT) has been increasingly used to treat patients with hematological diseases, but active immunizations for patients have not been described. Patients certainly need immunizations following CBT, since transplanted cord blood is naive. The authors previously reported successful hematopoietic reconstitution following cord blood transplantation from an HLA-matched sibling in a transfusion-dependent child with Diamond-Blackfan anemia. No graft-versus-host disease, either acute or chronic, has been observed so far. Here, the authors report that immunological recovery of the patient has been rapid shortly after CBT and immunization has been done successfully. Vaccines (diphtheria, pertussis, tetanus, rubella, measles, and BCG) were administered during 22-34 months post-transplant. Seroconversion to these vaccines was excellent without significant adverse effects. These results indicate that both toxoid and live vaccines have been safely administered in the patient who underwent related cord blood transplantation.

Excess treatment reduction including anthracyclines results in higher incidence of relapse in core binding factor acute myeloid leukemia in children

INTRODUCTION: Treatment outcome of pediatric acute myeloid leukemia (AML) patients has improved over the past few decades due to intensive chemotherapy. Primary induction failure (PIF), defined as failure to achieve complete remission after the second induction chemotherapy, occurs in around 10% of children with newly diagnosed AML. Effective treatment strategy for these patients is not established and their poor prognoses have been reported elsewhere. Here we investigated the clinical and biological features of pediatric AML patients with PIF who were registered in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05 Study (AML-05). METHODS: We conducted a retrospective survey of patients who were registered in the AML-05. We analyzed probabilities of overall survival (OS) according to gender, age at diagnosis, white blood cell count (WBC) at diagnosis, FAB classification, etc. Genetic analysis of primary leukemic blasts was performed. We screened fusion genes and gene mutations as follows: RUNX1-RUNX1T1, CBFB-MYH11, NUP98-NSD1, DEK-NUP214, MLL-PTD, WT1, NPM1, and MLL-rearrangements, gene mutations of KIT and FLT3-ITD. Furthermore, we evaluated the clinical and biological background of these PIF patients to define their prognostic factors statistically. RESULTS: Among the 443 patients registered in the AML-05 between November 2006 and December 2010, 43 patients (9.7%) had PIF. The observation period from the date of PIF was 5-78 months (median, 20 months). The age at diagnosis was 0.1-17 years (median, 6.1 years). There was no significant difference in gender (28 males vs15 females). The 3-year OS rate was 19.0% (95% confidence interval 1.0%-38.0%). This was extremely poor compared to the patients who achieved complete remission (CR): 66.7% for high-, 73.2% for intermediate-, and 92.6% for low-risk groups, respectively. Disease recurrence is the major cause of death (n=19, 46.3%). The mean WBC at diagnosis of PIF patients was 96 x 109/L: this is significantly higher than that of non-PIF patients (51 x 109/L, P CONCLUSIONS: The prognosis of pediatric AML patients with PIF was extremely poor. In our survey, unfavorable molecular biological background of leukemia was associated with PIF. It is necessary to explore more effective treatment strategies based on leukemia biology for these patients in the future. Disclosures No relevant conflicts of interest to declare.

The acute myeloid leukaemia (AML) 99 trial conducted previously in Japan for the treatment of de novo paediatric AML showed excellent results, with a 5-year overall survival (OS) and event-free survival (EFS) of 75·6% and 61·6%, respectively. To examine reproducibility of these results in another cohort, the outcome of 146 newly diagnosed AML paediatric patients prospectively registered in the Japan Association of Childhood Leukaemia Study (JACLS) from 2003 to 2006 was compared to that of 240 patients in the original AML 99 clinical trial. The 5-year EFS and OS achieved in the new cohort was 66·7 ± 4·0% and 77·7 ± 8·0% respectively, which were comparable to those obtained in the original AML 99 clinical trial, although less frequent core-binding factor (CBF) AML (29·5% vs. 37%) and an almost equal frequency of allogeneic haematopoietic stem cell transplantation (allo-HSCT) during first complete remission (16·5% vs. 19%) were observed. The 5-year EFS in patients with a normal karyotype (NK) (n = 35, 54·9 ± 15·1%) was inferior in the present cohort when compared to the original AML99 trial. This study confirmed the excellent outcome of the original AML99 protocol.

Lymphocytic intestinal leiomyositis is a rare entity, which causes chronic intestinal pseudo-obstruction (CIPO) in children. We present the first case of a boy who had pure red cell anemia 1 year before onset. Prolonged ileus developed after gastroenteritis and the patient was diagnosed using a biopsy of the intestinal wall. Findings from the present case indicate that there are three important factors for accurate diagnosis: history of enteritis, positive serum smooth muscle antibody, and lymphocyte infiltration with muscle destruction in the muscularis propria in the intestinal wall. Earlier diagnosis and induction of immunosuppressive therapy may be essential for a better outcome.

Although the antigen expression patterns of childhood acute lymphoblastic leukemia (ALL) are well known, little attention has been given to standardizing the diagnostic and classification criteria. We retrospectively analyzed the flow cytometric data from a large study of antigen expression in 1,774 children with newly diagnosed ALL in JPLSG. T- and B-lineage ALL accounted for 13 and 87% of childhood ALL cases, respectively. Cytoplasmic CD3 and CD7 antigens were positive in all T-ALL cases. More than 80% of T-ALL cases expressed CD2, CD5 and TdT. In B-lineage ALL, the frequencies of early pre-B, pre-B, transitional pre-B and B-ALL were 81, 15.5, 0.6 and 2.9%, respectively. More than 90% of early pre-B ALL cases expressed CD19, CD79a, CD22, CD10 and TdT. CD34 was expressed in three-fourths of early pre-B ALL cases. The frequencies of TdT and CD34 expression were lower in pre-B ALL than in early pre-B ALL. B-ALL showed less frequent expression of CD22, CD10, CD34 and TdT than other B-lineage ALL cases. Expression of CD13 and CD33, aberrant myeloid antigens, was significantly more frequently associated with B-lineage ALL than with T-ALL. Based on this retrospective study of antigen expression in 1,774 de novo childhood ALL cases in JPLSG, we propose standardized clinical guidelines for the immunophenotypic criteria for diagnosis and classification of pediatric ALL.

BACKGROUND: Acute erythroid leukemia (AEL) is a rare subtype of acute myeloid leukemia (AML) that represents less than 5% of AML in children. However, its clinical picture is not fully understood. PATIENTS & METHODS: We conducted a retrospective analysis on AEL using data from the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05 study (registered at http://www.umin.ac.jp/ctr/index.htm as UMIN000000511) in which patients were enrolled between 2006 and 2010. Morphological, immunophenotypic, cytogenetic, and molecular diagnoses were confirmed by the integrated prospective central diagnostic system. RESULTS: Among the 443 children (age 0 to 18 years old at diagnosis) with de novo AML (acute promyelocytic leukemia and Down syndrome patients are excluded), ten AEL patients (2.2%) were identified. All the cases were classified as M6 in French-American-British classification (eight as M6a, one as M6b, and one as M6). Notably, 8 were classified as AML with myelodysplasia-related changes (5 with morphological dysplasia and 3 with myelodysplasia-related cytogenetic abnormalities) and 2 as AEL in World Health Organization classification (ver.4). There were 6 males and 4 females. Median age and leukocyte count at diagnosis was 3.5 years old (range, 1-15 years old) and 4.7 x 109/L (1.1-16.1 x 109/L), respectively. Cytogenetically, 3 had complex karyotype, 2 had monosomy 7, and 5 had normal karyotype. Molecular analysis showed one case with NRAS mutation, one with both mutated KIT and WT1, and one with MLL-PTD. No case was FLT3 -ITD positive. Eight cases achieved complete remission after initial induction but 3-year event-free survival and overall survival rates were 30.0% (SE 14.4%) and 41.1% (SE 17.5%), respectively. CONCLUSIONS: AEL has distinct features such as high frequency of myelodysplasia- related features and poor risk cytogenetics. Because the outcome seems poor, further genetic analysis is required for development of effective novel therapy. Disclosures No relevant conflicts of interest to declare.

BACKGROUND: Core binding factor acute myeloid leukemia (CBF-AML), which is characterized by the chromosomal abnormalities of t(8;21) and inv(16), is the most frequent subtype of pediatric AML. Patients with CBF-AML have a better prognosis than patients with a normal karyotype when they receive chemotherapy of appropriate intensity; however, in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05 study, the excessive treatment reduction was observed to induce a higher incidence of relapse in children with CBF-AML. We investigated the outcomes of patients with relapsed CBF-AML who were registered in the JPLSG AML-05. PATIENTS & METHODS: We conducted a retrospective analysis of the JPLSG AML-05R study using a questionnaire. Furthermore, a mutation analysis was performed to identify NRAS, KRAS, KIT, WT1, NPM1, NUP98-NSD1, FLT3-ITD and MLL-PTD mutations using the available samples. We investigated the probability of overall survival (pOS) after relapse according to the patient's age, time from diagnosis to relapse, site of relapse, FAB classification, t(8;21) versus inv (16), reinduction chemotherapy regimen, obtaining a second complete remission before stem cell transplantation (SCT), the method of SCT and the presence of additional mutations. RESULTS: Forty-one of the 154 children with CBF-AML who were registered in the JPLSG AML-05 study experienced a relapse. The information from 32 of these 41 patients was collected using a questionnaire. Twenty-seven had t(8;21), and 5 had inv (16). It was possible to perform molecular analyses for 28 of the patients. KIT mutations were identified in 16 of 28 patients (57.1%). The follwing mutations were also detected: NRAS (n=4), KRAS (n=1), and WT1 (n=1). There were no cases with FLT3 -ITD, NUP98-NSD1, MLL-PTD or NPM1 mutations. Twenty-five cases achieved a complete remission after the initial reinduction (78.1%). The pOS was 65.6% (21/32) after a mean observation period of 2.7 years. The significant prognostic factors influencing pOS included a failure to obtain complete remission prior to SCT (p=0.03), reinduction chemotherapy regimen [p=0.02, a FLAG-based or ECM (etoposide, cytarabine and mitoxantrone)-based regimen was better than other modalities], donor source (p CONCLUSIONS: Relapsed childhood CBF-AML in the JPLSG AML-05 study was still associated with a better prognosis, because almost two thirds of the patients were successfully treated with SCT. Obtaining complete remission prior to SCT was associated with a good prognosis. A FLAG- or ECM-based regimen is therefore recommended for reinduction chemotherapy. Unexpectedly, cord blood transplantation and HLA-mismatched SCT were associated with a better prognosis. Further investigations are necessary to clarify the genes that are associated with a poor prognosis in patients with CBF-AML. Disclosures No relevant conflicts of interest to declare.

Introduction: Transient abnormal myelopoiesis (TAM) occurs in approximately 10% of infants with Down syndrome (DS). Although most patients achieve spontaneous remission, some develop severe organ failure and die in their infancy. Previous studies have identified several risk factors associated with early death in such cases, including a high white blood cell (WBC) count, early gestational age, and ascites (Massey GV, 2006; Muramatsu H, 2008; Klusmann JH, 2008). Although chemotherapy with low-dose cytosine arabinoside (LDCA) has been applied for severe cases, its side effect profile has not been fully demonstrated in an adequate number of patients. Here we prospectively analyzed 168 infants with DS who were diagnosed with TAM, including 52 patients treated with LDCA. We assessed the efficacy and safety of LDCA therapy in these cases. Patient and Methods: Between May 2011 and February 2014, 168 infants (90 boys and 78 girls) were diagnosed with TAM and prospectively registered in the Japan Pediatric Leukemia/Lymphoma Study Group (JPLSG) TAM-10 study. GATA1 gene mutations were identified in all except 7 patients who had a very low blast percentage. The median (range) of WBC count was 38.6 (2.4-478.7) × 109 cells/L, and the median (range) of gestational age was 37 (29-40) weeks. Thirty one (18%) patients developed anasarca at diagnosis, and 23 (14%) patients developed acute megakaryocytic leukemia. Results: The overall survival (OS) rate and the event-free survival (EFS) rate at 1 year from diagnosis [95% confidential interval (CI)] were 86.3% (80.1-90.7), and 80.2% (73.2-85.5), respectively. Univariate analysis identified the following covariates as risk factors associated with early death ( Conclusion: This prospective study confirmed that a high WBC count and anasarca are risk factors for early death in patients with DS who were diagnosed with TAM. Although LDCA therapy could significantly improve the survival rate in patients with a high WBC count, it failed to change the prognosis of patients with anasarca. A new treatment modality is required for most severe TAM patients with anasarca at diagnosis. Disclosures No relevant conflicts of interest to declare.

In childhood acute lymphoblastic leukemia (ALL), early response to treatment is a powerful prognostic indicator. To identify genes associated with this response, we analyzed gene expression of diagnostic lymphoblasts from 189 children with ALL and compared the findings with minimal residual disease (MRD) levels on days 19 and 46 of remission induction treatment. After excluding genes associated with genetic subgroups, we identified 17 genes that were significantly associated with MRD. The caspase 8–associated protein 2 (CASP8AP2) gene was studied further because of its reported role in apoptosis and glucocorticoid signaling. In a separate cohort of 99 patients not included in the comparison of gene expression profiles and MRD, low levels of CASP8AP2 expression predicted a lower event-free survival (P = .02) and a higher rate of leukemia relapse (P = .01) and were an independent predictor of outcome. High levels of CASP8AP2 expression were associated with a greater propensity of leukemic lymphoblasts to undergo apoptosis. We conclude that measurement of CASP8AP2 expression at diagnosis offers a means to identify patients whose leukemic cells are highly susceptible to chemotherapy. Therefore, this gene is a strong candidate for inclusion in gene expression arrays specifically designed for leukemia diagnosis.

Introduction: Anthracyclines (Atc) are the key drugs in the treatment of acute promyelocytic leukemia (APL) combined with all-trans retinoic acid (ATRA), however, dose-dependent risk of long-term cardiac toxicity is sometimes problematic especially in pediatric patients. To evaluate efficacy of the treatment with reduced cumulative doses of Atc in childhood APL, we conducted a nationwide non-randomized prospective study, AML-P05, in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG). Patients & Methods: Between April 2006 and March 2011, forty-six children with newly diagnosed APL were enrolled in this study. All patients received at least 3-day precedence of ATRA monotherapy (45mg/m2/d for 35 days in total), followed by chemotherapeutic agents consisted of cytarabine (200mg/m2/d for 7 days) and daunorubicin (DNR, 45mg/m2/d for 3 days) as the first induction therapy. The second induction therapy and subsequent 3 courses of consolidation therapy consisted of ATRA, either high- or intermediate-dose of cytarabine, triple intrathecal injection, and single dose of Atc; 10mg/m2 of mitoxantrone (MIT) in the first 2 courses and 45mg/m2 of pirarubicin (THP) in the last 2 courses. Finally, patients received one-year maintenance therapy with ATRA for 15 days every 3 months. Results: Among the 46 patients registered in this study, 3 were excluded because of PML/RARA negativity, and the remaining 43 patients including 2 with molecular variants were evaluated. The median age at diagnosis was 9 years (range, 11 months to 15 years old). The median follow up period was 4.47 years (0.00-7.45 years). FLT3-ITD was positive in 6 out of 40 patients examined. Two patients died during induction therapies; one of coagulopathy in first course and the other of infection in second course. Two patients developed differentiation syndrome but resolved with temporary cessation of ATRA and supportive therapies. Three patients did not achieve complete remission (CR) after 2 courses of induction therapy, and overall CR rate was 85.7% (36/42, 95%CI: 71.5-94.6%). Neither cardiac adverse events nor treatment-related death were observed during consolidation and maintenance therapies. Three patients exhibited relapse during or after maintenance therapy, and another one developed secondary acute myeloid leukemia. Consequently, the 3-year event-free (EFS) and overall survival rate were 83.6% (95%CI: 68.6-91.8%) and 90.7% (95%CI: 77.1-96.4%), respectively. Age less than 4 years old at diagnosis and non-M1 marrow after first induction therapy were associated with lower EFS. High WBC count (>10,000/μL), low platelet count ( Conclusions: According to the JPLSG criteria of Atc equivalents, cumulative Atc dose in this study was converted to 246mg/m2 of doxorubicin (for 1:0.83 for DNR, 1:4 for MIT, and 1:0.6 for THP). The dose was much lower than that in recent US or European protocols, especially in those designed primarily for adult APL patients where more than 600mg/m2 of Atc were used. Comparing with these studies, we have achieved equivalent good results with minimum does of Atc. Therefore, single administration of Atc in each consolidation phases seems sufficient in the treatment of childhood APL. This trial is registered with UMIN Clinical Trials Registry (UMIN-CTR, URL: http://www.umin.ac.jp/ctr/index.htm), number UMIN000000645 Disclosures No relevant conflicts of interest to declare.

BACKGROUND: There have been conflicting results from several large pediatric AML collaborative groups comparing survival of adolescent and young adults (AYAs) to that of younger patients with AML. We conducted a retrospective analysis using data from 3 Japanese pediatric AML studies; AML99 (2000-02), AML9805 (1998-2002), and AML-05 (2006-10), conducted by the Japanese Childhood AML Cooperative Study (consisted of Tokyo Children’s Cancer Study Group (TCCSG), Japan Association of Childhood Leukemia Study (JACLS), and Kyushu Yamaguchi Children’s Cancer Study Group (KYCCSG)), the Japanese Childhood Cancer and Leukemia Study Group (CCLSG), and the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG, the first Japanese national study group), respectively. PATIENTS & METHODS: Among the 782 patients with de novo AML (excluding acute promyelocytic leukemia and Down syndrome), 44 were AYAs (age ≥15 years), 574 were age 2 to 14 years, and 164 were infants (age RESULTS: 29.5% (13/44) of AYAs were t(8;21) (vs. 37.1% of 2 to 14 years old, P=0.315), 38.6% (17/44) were normal karyotype (vs. 22.0%, P=0.011), and 16.2% of the tested cases (6/37) were FLT3-ITD positive (vs. 9.4%, P=0.554). Complete remission (CR) rate after 2 induction courses was similar between AYAs and patients 2 to 14 years old: 88.6% vs. 88.8% (P=0.965). Five-year EFS rate was also similar between the two cohorts: 55.2% vs. 59.2% (P=0.578). However, 5-year OS rate was significantly poorer in AYAs: 54.7% vs 73.8% (P=0.005). Total 19 events were observed among the 44 AYA patients; 4 failures to achieve CR, 12 relapses, and 3 deaths. Fourteen out of the 16 patients with non-CR or relapse eventually died and 8 deaths were treatment-related. In fact, 5-year RR was similar between the 2 age groups (32.7% vs. 30.1%, P=0.819), but TRM was significantly higher in AYAs (33.2% vs. 12.4%, P=0.001). In multivariate analysis, using Cox proportional hazard regression model, age ≥15 years old at diagnosis, absence of low risk cytogenetics (t(8;21) or inv(16)), and no remission after initial induction course were associated with both poorer OS and higher TRM, while high white cell count at diagnosis (≥ 100,000/μL) and presence of high risk cytogenetics (-7, 5q-, t(16;21)(p11:q22)/FUS-ERG, Philadelphia chromosome, and/or FLT3-ITD) were not siginificant. CONCLUSIONS: AYAs with AML had inferior OS, but not EFS, due to higher incidence of TRM especially after failure of initial treatment. Disclosures No relevant conflicts of interest to declare.

Introduction: Asmyeloid leukemia in Down syndrome patients (ML-DS) is known to have higher sensitivity against cytotoxic agents, children with ML-DS are treated with less intensive ML-DS-oriented protocol in recent clinical studies. On the basis of results of previous Japanese trials for ML-DS, we have evaluated an efficacy of the risk-oriented therapy in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-D05 study. Patients and Methods: Between January 2008 and December 2010, seventy-four patients with newly diagnosed ML-DS from 122 hospitals in Japan were enrolled in this study. All patients received induction chemotherapy consisted of pirarubicin (25 mg/m2/d for 2 days), cytarabine (100 mg/m2/d for 7 days), and etoposide (150 mg/m2/d for 3 days). Patients who achieved complete remission (CR) after initial induction therapy were stratified to the Standard Risk (SR) and received four courses of reduced dose intensification therapy. Patients who did not achieve CR were stratified to the High Risk (HR) and received intensfied therapy consisted of continuous and high-dose cytarabine. Prophylaxis for CNS leukemia was not included throughout the therapy. Results: Out of 74 patients registered in this study, two patients were excluded (one because of uncontrolled cardiac failure, another of non-Down syndrome), and 72 were eligible and were evaluated. Male/Female ratio was 40/32. The median age at diagnosis was 19 months (range, 10 months and 17 years old). Median follow-up period was 3.64 years (range, 0.05 -5.96 years. One patient died of sepsis during initial induction therapy. Sixty-nine patients were stratified to SR and 2 patients to HR. Both of the two HR patients achieved CR but one relapsed. No therapy-related death was observed during intensification therapy. The 3-year event free and overall survival rate was 83.3% ± 4.4% and 87.5% ± 3.9 %, respectively. Age at diagnosis less than 2 years old was significant favorable prognostic factor for relapse (p=0.009). Sex, history of TAM, and chromosomal abnormalities (Normal karyotype or monosomy 7) did not influence the risk of relapse. Conclusion: This study succeeded the previous Japanese strategy with very low-intensive chemotherapy regimen for ML-DS, and despite the dose reduction of chemotherapeutic agents compared to the previous studies, the overall outcome was good and further dose reduction might be possible for specific subgroups. However, considering that most relapse occurred in the SR group defined by morphological treatment response and that relapsed cases are rarely salvageable, more accurate method for identification of the poor prognostic subgroup is needed. This trial is registered with UMIN Clinical Trials Registry (UMIN-CTR, URL: http://www.umin.ac.jp/ctr/index.htm), number UMIN000000989. Disclosures No relevant conflicts of interest to declare.

Background Acute myeloid leukemia harboring internal tandem duplication of fms-like tyrosine kinase 3 (AMLFLT3-ITD) is associated with poor prognosis, but the previous studies have reported that the inferior outcome is only confined to those with high allelic ratio (AR) of ITD/wild type (WT). In our previous AML99 study (2000-2002), AMLFLT3-ITD showed a poor outcome compared to the WT cases (5-year OS; 35% vs. 84%, P Patients & Methods AML-05 study, registered at http://www.umin.ac.jp/ctr/ as UMIN000000511, is a Japanese nation-wide multi-institutional study for children (age0.4 as high and AR ≤ 0.4 as low as previously reported (Meshinchi S. Blood2006). Results We found 47 patients (10.6%) with AMLFLT3-ITD in this study (30 males, 17 females, and median age of 11 years at diagnosis). The median WBC count was 65,300/ml (3,690 - 522,050/mL). FAB classification included M1 (n=10), M2 (n=9), M4 (n=9), and M5 (n=11), and AML with normal karyotype was dominant (19/47, 40.4%). Of the 29 patients (61.7%) who achieved CR, twenty-seven received HSCT in 1CR and 19 patients survived (19/27, 70.4%). On the other hand, 14/16 non-CR patients received HSCT, but only 4 survived. The only demographic difference between the 29 CR and 16 non-CR cases was the median WBC count at diagnosis (19,000 vs. 124,000/μL, P AR was analyzed in 44 patients with median ratio of 0.68 (range, 0.11 to 4.47). Median AR was not different between CR vs. non-CR cases (0.53 vs. 0.72). There were no difference in 5-year OS (52.8% vs. 42.5%, P=0.302), DFS (54.5% vs. 64.5%, P=0.524), and EFS (50.0% vs. 34.4%, P=0.283) between patients with low (n=12) and high AR (n=32), however, induction rate was significantly higher in the low AR patients (91.7% vs. 53.1%, P=0.018). It was rather surprising that all FLT3-ITDs were found only in JM domain and not in TKI domain in the current trial. In addition, six of 47 (12.8%) AMLFLT3-ITD patients had NPM1mutation simultaneously, and all received HSCT at 1CR and survived. Discussion and Conclusion We observed a different induction rate between AMLFLT3-ITD patients with low and high AR, but poor final outcomes in both. Regardless of the level of AR, patients with AMLFLT3-ITD, especially who fail to achieve remission, have dismal outcome and effective therapy combined with novel FLT3 inhibitor is urgently needed to overcome the disease. Disclosures: No relevant conflicts of interest to declare.

Abstract 2615 Background: Infants (age Patients & Methods: JPLSG AML-05 study, registered at http://www.umin.ac.jp/ctr/as UMIN000000511, is a nation-wide multi-institutional study and recruited 447 eligible children (age Results: The median follow-up period for living patients was 3.06 years (range, 0.84 – 5.36 years). Although, there was no difference in 3-year probability of event-free survival (pEFS) between infants and patients ≥1 year old [56.0% (95%CI, 38.7 – 70.1%) vs. 55.2% (49.8 – 60.2%) (p = 0.63)], 3-year probability of overall survival (pOS) in infants was inferior; 56.0% (95%CI, 37.9 – 70.7%) vs. 75.0% (70.0 – 79.4%) (p = 0.011). When the outcome of infants were compared with patients 1 - The inferiority of pOS in infants compared to the patients 1 - Conclusions: Our experience suggests that appropriate chemotherapeutic dose modification in induction therapy to avoid early deaths is essential in treating infants with de novo AML. As dose intensification approach is difficult to apply for this age subgroup, incorporation of less toxic targeted agents based on biological features is needed to attain better outcome for infants with AML. Disclosures: No relevant conflicts of interest to declare.

Abstract 3545 Background: With intensive chemotherapy and optimal risk stratification, 80–90 % of children with acute myeloid leukemia (AML) achieve complete remission (CR) which translates into a long-term disease-free survival in as many as 50–60% of patients. We have previously reported that risk stratified therapy and intensive use of cytarabine improved the outcome of childhood AML in AML99 study with 5-year event free survival (EFS) of 61.6% and 5-year overall survival (OS) of 75.6% (Tsukimoto I. J Clin Oncol 2009;27:4007–13), which gave us an additional impetus to reduce the number of consolidation courses with more restrictive indication for stem cell transplantation (SCT). We here report the outcome of successor nation-wide multi-institutional study AML-05, focusing on the AML patients without core binding factor (CBF). Patients & Methods: 47 eligible children (age Results: Three-year EFS and 3y-OS of all 444 patients was 55.3% (95%CI, 50.2 – 60.1%) and 73.2% (68.3 – 77.5%), respectively. The median follow-up period for living patients was 3.1 years (range, 0.8 – 5.4 years). Two hundred eighty-nine non-CBF-AML patients [t(9;11), N=39 (13.5%); 11q23, N=27 (9.3%); Normal, N=81 (28.0%); Others, N=137 (47.4%)] in the AML-05 and 151 patients [t(9;11), N=15 (9.9%); 11q23, N=26 (17.2%); Normal, N=53 (35.1%); Others, N=55 (36.4%)] in AML99 were compared. There were no significant differences in basic characteristics such as sex and age/WBC at diagnosis. Incidence of FLT3-ITD in AML-05 cohort were identical to that in AML99 [AML-05 cohort, N= 42/289 (14.5%); AML99, N= 15/82 (18.2%), p=0.41]. CR rate in AML-05 was inferior to that in AML99 (81.0% vs. 90.7%, p = 0.008). There was no significant differences in 3y-EFS of non-CBF AML among 2 cohort [47.5% in AML-05 (95%CI, 41.2– 53.6%) vs. 49.7% in AML99 (41.5 – 57.3%), p= 0.43], however, there was a tendency of lower 3y-OS among them [62.8% in AML-05 (95%CI, 56.2– 68.7%) vs. 70.9% in AML99 (62.9 – 77.4%), p = 0.083]. The early death within 42 days in AML-05 (2.1%) were equivalent to that of AML99 (2.0%), whereas non-relapsed mortality were significantly increased in AML-05 compared with that of AML99 [44/289 (15.2%) in AML-05; 11/151 (7.3%) in AML99, p=0.022], which was due to increased mortality among infants. SCT rate in the 1stCR was lower in the non-CBF AML-05 compared with that in AML99 [47/289 (16.3%) in AML-05; 40/151 (26.4%) in AML99, p=0.011]. Conclusions: Reduction on consolidation chemotherapy courses from four to three, together with incorporation of repetitive cycles of high-dose cytarabine were adequate for non-CBF childhood AML, and did not compromise the treatment results in AML-05 despite of adaptation of more restrictive indication for SCT in 1st CR. Non-CBF-AML is a cytogenetically heterogeneous disease, hence the mechanism underlying these prognostic differences should be studied. Disclosures: No relevant conflicts of interest to declare.

Abstract 4276 Introduction: Myeloid leukemia in Down syndrome patients (ML-DS) is known to have good sensitivity against cytotoxic agents, especially to cytarabine, and outcomes in recent clinical trials are favorable with more than 80 % probability of long-term event-free survival (EFS). However, little have been focused on refractory / relapsed cases, since most of the treatment failures consist of toxicities rather than resistant or recurrent leukemia. We present here a retrospective analysis of the patients with refractory / relapsed ML-DS. Patients and Method: Among the ML-DS patients diagnosed between 2000 and 2011 at the 120 hospitals in Japan, twenty-nine refractory / relapsed patients were enrolled in this retrospective study. Result: Median follow-up period for all 29 patients was 10.9 months (range, 2.8 –76.7 months). Male/Female ratio was 18/11. The age at initial diagnosis for ML-DS was between 7 months and 16 years old (median, 2 years old). All the patients were initially treated with one of the protocols specifically designed for ML-DS; twenty patients with AML99 Down protocol, eight with JPLSG AML-D05 protocol, and one with JCCLSG AML9805 Down protocol. There were 3 induction failures and 26 relapsed cases. Among the 26 relapsed cases, duration from initial diagnosis to relapse was 2.4 month to 71.8 months (median 8.6 months); Twenty-eight relapsed at bone marrow and one patient relapsed at skin site. Twenty-six out of the 29 patients received various re-induction chemotherapies and 13 of them achieved complete remission (CR). Eight of the 13 patients with CR subsequently received allogeneic stem cell transplantation (SCT) and 4 survived. On the other hand, five of the 13 cases with CR were treated with chemotherapy alone, and 4 were alive with no evidence of leukemia. All the 12 patients who failed to achieve CR and the 2 patients who only received palliative therapy eventually died. The 3-year overall survival rate was 22.6 ± 8.8 %. Achievement of CR with second-line chemotherapy and longer duration from initial diagnosis to relapse were significant favorable prognostic factors. SCT did not influence the prognosis even if performed after achieving further remission. Conclusion: The Japanese strategy treating ML-DS have been successful with very low-intensive chemotherapy regimen, however, rescue of refractory / relapsed patients with ML-DS seems difficult even with SCT. No relevant conflicts of interest to declare. Disclosures: No relevant conflicts of interest to declare.

Abstract 1074 Introduction: Transient leukemia (TL), which is also referred to as transient myeloproliferative disorder or transient abnormal myelopoiesis, occurs in approximately 10% of infants with Down syndrome (DS). This disorder is characterized by the appearance of blast cells with megakaryoblastic and/or erythroblastic characteristics in the peripheral blood. While most TL patients have a favorable clinical course and the blast cells disappear spontaneously, vital organ failure and early death occurs in some patients. In this group of patients, liver failure with hepatic fibrosis and cardiopulmonary failure are the major causes of death. Recently, low-dose cytosine arabinoside (Ara-C) therapy has been reported to be effective for improving the clinical outcome in TL patients with severe liver or cardiopulmonary disease. However, because the disease resolves spontaneously in most instances, it is not generally recommended that all patients receive antileukemic therapy. It is unknown whether the survival rate of certain TL patients could be improved by low-dose Ara-C. This study was conducted to clarify the safety and efficacy of low-dose Ara-C therapy for TL patients with DS. Patients and Methods: A retrospective questionnaire survey of patients diagnosed with DS between 2003 and 2009 was conducted to identify all DS neonates with TL. The eligibility criteria for the analysis were infants with DS who were younger than 3 months and had circulating blast cells in the peripheral blood. A total of 153 patients (81 male, 72 female) were identified. Results: Thirty-four of the 153 patients (22%) died. Early death occurred in 31 of 153 patients (20%); the median age at death was 47 days (range, 9–241 days). The covariates that were significantly correlated with early death were examined further. On univariate analysis, the following covariates were identified: early estimated gestational age, WBC ≥ 100 × 109/L, severe bleeding, and anasarca. On multivariate analysis, it was confirmed that WBC ≥ 100 × 109/L and anasarca were independent risk factors for early death. Twenty of the 121 patients (16.5%) who survived for more than 9 months after birth subsequently developed acute myeloid leukemia at a median age of 16 months (range, 3–45 months). All 21 patients were diagnosed as having acute megakaryoblastic leukemia (AMKL) and received low intensity chemotherapy specific for AMKL in DS patients. Eighteen of 21 (86%) patients achieved a complete remission, and they are alive and well; whereas 3 patients who had refractory or relapsed leukemia died. Twenty-eight of the 153 patients (18%) received low-dose Ara-C therapy. The median dose and duration of Ara-C were 0.95 mg/kg/day (range, 0.4–3.1 mg/kg/day) and 7 days (range, 2–15 days), respectively. The median duration of neutropenia ( While the median WBC count of early treated patients was significantly higher than that of other patients (133.5 × 109/L; range, 16.0–356.9 □L 109/L vs 31.9 × 109/L; range, 4.4–341.5 × 109/L.; p < 0.001), the probability of 1-year overall survival of patients who received low-dose Ara-C within 10 days after the initial diagnosis of TL was similar to that of patients who received Ara-C later or who did not receive Ara-C (69.4 ± 12.9%; n = 16 vs. 79.7 ± 3.5%; n = 137; p = 0.614). By subgroup analysis of patients with WBC ≥ 100 × 109/L, the probability of 1-year overall survival of patients who received early Ara-C treatment was significantly higher than that of others (66.1 ± 13.9%; n = 13 vs. 33.3 ± 8.6%; n = 30; p = 0.035). Conclusion: In summary, we found that low-dose Ara-C therapy for patients with TL and DS has a tolerable toxicity profile, and early intervention with this therapy could improve the clinical outcome of patients whose WBC count exceeds 100 × 109/L. We plan to confirm the efficacy of low dose Ara-C treatment in a prospective clinical trial for high-risk patients with DS and TL. Disclosures: No relevant conflicts of interest to declare.