A high survival rate, 75.6% at 5 years, was achieved for childhood with de novo AML in the AML99 trial. The treatment strategy was well tolerated with only 1.7% induction death rate and 3.5% remission death rate. Low-risk children were successfully treated with chemotherapy alone.

Key Points• High mortality rates are observed in patients with XIAP deficiency treated with myeloablative conditioning regimens for hematopoietic cell transplantation.

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Deficiency of X-linked inhibitor of apoptosis (XIAP) caused by XIAP/BIRC4 gene mutations is an inherited immune defect recognized as X-linked lymphoproliferative syndrome type 2. This disease is mainly observed in patients with hemophagocytic lymphohistiocytosis (HLH) often associated with Epstein-Barr virus infection. We described nine Japanese patients from six unrelated families with XIAP deficiency and studied XIAP protein expression, XIAP gene analysis, invariant natural killer T (iNKT) cell counts, and the cytotoxic activity of CD8(+) alloantigen-specific cytotoxic T lymphocytes. Of the nine patients, eight patients presented with symptoms in infancy or early childhood. Five patients presented with recurrent HLH, one of whom had severe HLH and died after cord blood transplantation. One patient presented with colitis, as did another patient's maternal uncle, who died of colitis at 4 years of age prior to diagnosis with XIAP deficiency. Interestingly, a 17-year-old patient was asymptomatic, while his younger brother suffered from recurrent HLH and EBV infection. Seven out of eight patients showed decreased XIAP protein expression. iNKT cells from patients with XIAP deficiency were significantly decreased as compared with age-matched healthy controls. These results in our Japanese cohort are compatible with previous studies, confirming the clinical characteristics of XIAP deficiency.

A B S T R A C T PurposeTo evaluate a less intensive chemotherapeutic regimen specifically designed for patients with Down syndrome (DS) and acute myeloid leukemia (AML), and to determine the prognostic factors for event-free survival. Patients and MethodsSeventy-two patients with AML-DS were treated with remission induction chemotherapy consisting of pirarubicin (25 mg/m 2 /d for 2 days), cytarabine (100 mg/m 2 /d for 7 days), and etoposide (150 mg/m 2 /d for 3 days). Patients received four courses of intensification therapy of the same regimen. Prophylaxis for CNS leukemia was not included. ResultsAll but two patients were younger than 4 years, and 67 of the 72 patients (93%) were diagnosed as acute megakaryoblastic leukemia (AMKL). Seventy of the 72 patients (97.2%) achieved a complete remission (CR), and the estimated 4-year event-free survival (EFS) rate was 83% Ϯ 9%. Nine patients relapsed, and one died as a result of pneumonia during CR. Multivariate analysis revealed that the presence of monosomy 7 was a greater risk factor of adverse outcome (odds ratio ϭ 5.67; P ϭ .027). ConclusionA less intensive chemotherapeutic regimen produces excellent outcomes in standard-risk AML-DS patient. Risk-oriented therapy should be considered for future trials in AML-DS.We would like to emphasize that the TRM in the current study was only 1.4% (one of 72 patients) which is much lower than those of previous reports. 7-9,16 On the other hand, relapse and induction failure were found in 11 of 72 patients (14%), which is more frequent than in other reports with intensive regimens. 6,8,13 On the basis of the results of the present study, we have designed a risk-oriented therapy protocol for our next trial with AML-DS. The patients with M1 marrow after induction therapy should be classified into a standard-risk group and receive the same dose of pirarubicin and cytarabine regimen. In POG 8498, daunorubicin was used only in induction, with a total dose of 135 mg/m 2 , and high-dose cytarabine in consolidation. Although this study included only small cohort of 14 DS patients, all were alive as last updated in 2005. 31 We will include high-dose cytarabine for patients with M2 or M3 marrow after induction therapy, classified into a high-risk group, who might have adverse prognostic factors such as age older than 3 and the presence of monosomy 7. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTERESTThe author(s) indicated no potential conflicts of interest.

X-linked lymphoproliferative syndrome (XLP) is a rare primary immunodeficiency characterized by increased vulnerability to Epstein-Barr virus infection. XLP type 1 is caused by mutations in SH2D1A, whereas X-linked inhibitor of apoptosis (XIAP) encoded by XIAP/BIRC4 is mutated in XLP type 2. In XIAP deficiency, hemophagocytic lymphohistiocytosis (HLH) occurs more frequently and recurrence is common. However, the underlying mechanisms remain mostly unknown. We describe the characteristics of the cytokine profiles of serum samples from 10 XIAP-deficient patients. The concentration of interleukin (IL)-18 was strikingly elevated in the patients presented with HLH, and remained high after the recovery from HLH although levels of other pro-inflammatory cytokines approached the normal range. Longitudinal examination of two patients demonstrated marked exacerbation of IL-18 levels during every occasion of HLH. These findings may suggest the association between HLH susceptibility and high serum IL-18 levels in XIAP deficiency.3

A novel leukemic cell line with an 8;21 chromosome translocation, designated as Kasumi-1, was established from the peripheral blood of a 7-year-old boy suffering from acute myeloid leukemia (AML). The Kasumi- 1 cells were positive for myeloperoxidase showing a morphology of myeloid maturation. The response in proliferation assay was observed in the culture with interleukin-3 (IL-3), IL-6, granulocyte colony- stimulating factor (G-CSF), and granulocytemacrophage CSF (GM-CSF), but not with IL-1 or IL-5. Neither granulocytic nor eosinophilic maturation was observed in the liquid culture by the addition of dimethyl sulfoxide, G-CSF, or IL-5, respectively. In contrast, induction of macrophagelike cells was seen by the addition of phorbol ester. This is the first report of a human AML cell line with t(8;21) that has characteristics of myeloid and macrophage lineages. The cell line could be a useful tool for elucidating the pathophysiology of AML with t(8;21).

The outcomes of children with relapsed acute myeloid leukemia (AML) are known to be poor, but remain obscure. We retrospectively analyzed 71 patients who had relapsed following first-line treatment under the AML99 protocol. We investigated the time and site of recurrence, response to re-induction therapy, and performance of hematopoietic stem cell transplantation (HSCT) in relapsed cases, and performed a multivariate analysis to identify prognostic factors. The 5-year overall-survival (OS) rate after relapse was 37 %. Of 71 patients, three died without any anti-leukemic therapy and two underwent allogeneic HSCT. The remaining 66 patients received re-induction chemotherapy, and 33 (50 %) achieved second CR (CR2). Twenty-two of 25 (88 %) late relapse patients and 11 of 41 (27 %) early relapse patients achieved CR2 (P < 0.001). Twenty-nine CR2 cases and 35 non-CR2 cases underwent allogeneic HSCT. The 5-year OS rate was significantly higher in patients who underwent HSCT in CR2 than those in non-CR2 (66 vs. 17 %, P < 0.000001). Multivariate analysis indicated that early relapse (P < 0.05) and the positivity of the FMS-like tyrosine kinase 3--internal tandem duplication (P < 0.05) were adverse prognostic factors for survival. In conclusion, the etiology of relapsed pediatric AML needs to be elucidated and effective chemotherapy should be administered to obtain CR2.