Kazuko Hamamoto

Risk-Stratified Therapy and the Intensive Use of Cytarabine Improves the Outcome in Childhood Acute Myeloid Leukemia: The AML99 Trial From the Japanese Childhood AML Cooperative Study Group

PURPOSE To improve the prognosis in children with newly diagnosed acute myeloid leukemia (AML) by introducing a dose-dense intensive chemotherapy regimen and an appropriate risk stratification system. PATIENTS AND METHODS Two hundred forty children with de novo AML were treated with continuous cytarabine-based induction therapy and stratified to three risk groups based on the initial treatment response, age, and WBC at diagnosis and cytogenetics. All of the patients were treated with intensive consolidation chemotherapy including three or four courses of high-dose cytarabine. Allogeneic hematopoietic stem-cell transplantation (HSCT) was indicated for only the intermediate-risk patients with matched related donors and for all the high-risk subsets. RESULTS Two hundred twenty-seven children (94.6%) achieved a complete remission (CR). Four children demonstrated induction death. The median follow-up of the live patients was 55 months (range, 37 to 73 months). The 5-year overall survival of all 240 children was 75.6% (95% CI, 70.3% to 81.4%) and event-free survival was 61.6% (95% CI, 55.8% to 68.1%). The 5-year disease-free survival in each risk group were 71.3% (95% CI, 63.4% to 80.2%) in the low-risk group (n = 112), 59.8% (95% CI, 50.6% to 70.7%) in the intermediate-risk group (n = 92), and 56.5% (95% CI, 39.5% to 80.9%) in the high-risk group (n = 23). Eight children died during the first CR, including four after HSCT. CONCLUSION 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.

Prospective Study of a Pirarubicin, Intermediate-Dose Cytarabine, and Etoposide Regimen in Children With Down Syndrome and Acute Myeloid Leukemia: The Japanese Childhood AML Cooperative Study Group

PURPOSE To 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 METHODS Seventy-two patients with AML-DS were treated with remission induction chemotherapy consisting 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 received four courses of intensification therapy of the same regimen. Prophylaxis for CNS leukemia was not included. RESULTS All 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% +/- 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 = 5.67; P = .027). CONCLUSION A 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.

Distinct Impact of Imatinib on Growth at Prepubertal and Pubertal Ages of Children with Chronic Myeloid Leukemia

OBJECTIVE To determine the extent of growth impairment resulting from imatinib treatment in children with chronic myeloid leukemia (CML). STUDY DESIGN Clinical records of 48 chronic-phase CML children administered imatinib as the first-line therapy between 2001 and 2006 were analyzed retrospectively. Cumulative change in height was assessed using the height height-SDS and converted height data from age- and sex-adjusted Japanese norms. RESULTS A decrease in height-SDS was observed in 72.9% of children, with a median maximum reduction in height-SDS of 0.61 during imatinib treatment. Median follow-up time was 34 months (range, 10-88 months). Growth impairment was seen predominantly in children who started imatinib at a prepubertal age compared with those who started at pubertal age. Growth velocity tended to recuperate in prepubertal children with growth impairment, as they reached pubertal age, suggesting that imatinib had little impact on growth during puberty. CONCLUSIONS Growth impairment was a major adverse effect of long-term imatinib treatment in children with CML. We report the distinct inhibitory effect of imatinib on growth in prepubertal and pubertal children with CML. We should be aware of growth deceleration in children, especially in young children given imatinib before puberty and subjected to prolonged exposure.

Sustained elevation of serum interleukin-18 and its association with hemophagocytic lymphohistiocytosis in XIAP deficiency

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.

Low plasma levels of hemostatic proteins during the induction phase in children with acute lymphoblastic leukemia: A retrospective study by the JACLS

Background : Thromboembolic and bleeding events are serious complications associated with the administration of L‐asparaginase (ASP) during the induction phase in children with acute lymphoblastic leukemia (ALL). Prophylactic supplementation of plasma‐derived coagulation products remains controversial. The purposes of this study were to examine the plasma levels of hemostatic proteins during the induction phase and the efficacy of prophylactic replacement of plasma‐derived products.

Fluorescence in situ Hybridization Analysis of 12;21 Translocation in Japanese Childhood Acute Lymphoblastic Leukemia

Fluorescence in situ hybridization (FISH) analysis was applied to detect t(12;21) using two yeast artificial chromosome probes and cosmid probes covering the TEL(ETV6) and the AML1 gene to clarify the incidence of abnormality of t(12;21) in Japanese childhood acute lymphoblastic leukemia (ALL). We detected seven TEL/AML1 fusion positive patients (9.5%), all of whom were diagnosed as B‐lineage ALL, among 74 childhood ALL. On the other hand, no TEL/AML1 fusion positive patients were found among 37 adult ALL. The incidence among Japanese seemed to be lower than that among other nations. Of the seven patients with the TEL/AML1 fusion, five exhibited normal karyotype, one was t(8;12)(q11;p13), i(21q) and the remaining one exhibited a near‐triploid karyotype in conventional G‐banding. The FISH method clearly demonstrated that all patients with the TEL/AML1 fusion had subpopulations of leukemic cells with deletion of the normal TEL allele, which is significant for understanding the progression of leukemia with t(12;21).

Prospective study of a therapeutic regimen with all-trans retinoic acid and anthracyclines in combination of cytarabine in children with acute promyelocytic leukaemia: the Japanese childhood acute myeloid leukaemia cooperative study.

In childhood acute promyelocytic leukaemia (APL), the efficacy of therapy combining cytarabine with all‐trans retinoic acid (ATRA) and anthracyclines remains unclear in terms of long‐term prognosis. Between August 1997 and March 2004, 58 children with APL (median age: 11 years) were enrolled into an acute myeloid leukaemia (AML) study (AML99‐M3) and followed up for a median time of 86 months. The regimen included ATRA and anthracyclines combined with cytarabine in both induction and consolidation. In induction, two patients died of haemorrhage and four patients developed retinoic acid syndrome. Of 58 patients, 56 (96·6%) achieved complete remission, two of whom relapsed in the bone marrow after 15 and 19 months respectively. Sepsis was a major complication, with an incidence of 5·6–10·9% in the consolidation blocks, from which all but one of patients recovered. Consequently, 7‐year overall and event‐free survival rates were 93·1% and 91·4% respectively, and cumulative incidence of relapse plateaued at 3·6% after 2 years. Follow‐up survey of 54 patients revealed no patients with late cardiotoxicity or secondary malignancy, except one with asymptomatic prolongation of QTc interval. This study suggests that the combination of cytarabine with ATRA and anthracycline‐based therapy may have useful implications in the perspective of long‐term prognosis and late adverse effects for childhood APL.

Outcome of 125 Children with Chronic Myelogenous Leukemia Who Received Transplants from Unrelated Donors: The Japan Marrow Donor Program

Because of a small number of patients, only a few studies have addressed the outcome of bone marrow transplantation (BMT) in children with Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML), who receive graft from a volunteer-unrelated donor (VUD), especially after practical application of imatinib mesylate. The outcomes of BMT from a VUD in 125 children with Ph+ CML were retrospectively reviewed. Patients were identified through the Japan Marrow Donor Program as having undergone BMT between 1993 and 2005 and were aged 1-19 years at the time of transplant (median age, 14 years). The probabilities of 5-year overall survival (OS) and leukemia-free survival (LFS) were 59.3% and 55.5%, respectively. Multivariate analysis identified the following unfavorable survival factors: infused total nucleated cell dose<314 x 10(6) /kg (relative risk [RR]=2.43; 95% confidence interval [CI]=1.33-4.44; P=.004), advanced phase (RR=2.43; 95% CI=1.37-4.31; P=.004), and no major cytogenetic response (MCyR) at the time of BMT (RR=6.55; 95% CI=1.98-21.6; P=.002). Of the 17 patients treated with imatinib, 15 (88%) achieved MCyR at the time of BMT, and this group had an excellent 5-year OS of 81.9%. Disease phase, infused total nucleated cell dose, and cytogenetic response were independent risk factors for survival of unrelated BMT. These findings provide important information for assessing the indications for and improving outcome in unrelated BMT for the treatment of pediatric CML.

Outcome of childhood acute lymphoblastic leukemia with induction failure treated by the Japan Association of Childhood Leukemia study (JACLS) ALL F-protocol.

Children with acute lymphoblastic leukemia (ALL) who fail to achieve complete remission (CR) after induction therapy (induction failure: IF) have a poor prognosis; however, there have been few prospective studies in patients with IF.

Clinical features and outcome of X-linked lymphoproliferative syndrome type 1 (SAP deficiency) in Japan identified by the combination of flow cytometric assay and genetic analysis

To cite this article: Kanegane H, Yang Xi, Zhao M, Yamato K, Inoue M, Hamamoto K, Kobayashi C, Hosono A, Ito Y, Nakazawa Y, Terui K, Kogawa K, Ishii E, Sumazaki R, Miyawaki T. Clinical features and outcome of X‐linked lymphoproliferative syndrome type 1 (SAP deficiency) in Japan identified by the combination of flow cytometric assay and genetic analysis. Pediatric Allergy Immunology 2012: 23: 488–493.