Ichiro Tsukimoto

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.

The second nation-wide survey in Japan of vitamin K deficiency in infancy.

Throughout Japan a total of 543 cases of vitamin K deficiency occurring in infants over 2 weeks of age were reported from January 1981 to June 1985. Of these cases, 427 showed no obvious reasons for vitamin K deficiency; this sort of case is known as “idiopathic vitamin K deficiency in infancy”. Another 57 cases had bleeding episodes due to vitamin K deficiency associated with obvious hepatobiliary lesions, chronic diarrhoea, long-term antibiotic therapy, etc; this sort is called “secondary vitamin K deficiency in infacy”. The third group, consisting of 59 cases, was made up of the socalled “near miss” type, in which a haemorrhagic tendency, without any obvious clinical haemorrhage, was discovered by Normotest, at the time of mass screening in most cases. In the idiopathic group, 269 cases (63.0%) developed bleeding episodes between the 1st and 2nd months of age, and 387 cases (90.0%) were entirely breast-fed. Intracranial baemorrhage was observed in 353 cases (82.7%) of this group. Moreover, slight elevation of serum transaminase and direct type bilirubin levels were observed in the idiopathic group. Liver dysfunction of unknown origin may play some role in the onset of vitamin K deficiency in infancy.

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.

An effective chemotherapeutic regimen for acute myeloid leukemia and myelodysplastic syndrome in children with Down's syndrome

In recent pediatric collaborative studies of acute myeloid leukemia (AML), patients with Downs syndrome (DS) have better outcome than other patients when they were treated according to their intensive AML protocols. This may be attributed to enhanced sensitivity of DS AML cells to selected chemotherapeutic agents. We evaluated a less intensive chemotherapeutic regimen which was specifically designed for children with AML-DS. Remission induction chemotherapy consisted of daunorubicin (25 mg/m2/day for 2 days), cytosine arabinoside (100 mg/m2/day for 7 days), and etoposide (150 mg/m2/day for 3 days). Patients received one to seven courses of consolidation therapy of the same regimen. Thirty-three patients were enrolled on the study and their clinical, hematologic and immunophenotypic features were analyzed. Of the 33 patients, all were younger than 4 years and diagnosed as having acute megakaryoblastic leukemia or myelodysplastic syndrome. All patients achieved a complete remission and estimated 8 year event-free survival rate was 80 ± 7%. Three patients relapsed and two died due to cardiac toxicity and one due to septic shock. The results of our study showed that patients with AML-DS constitute a unique biologic subgroup and should be treated according to a less intensive protocol designed for AML-DS.

Extramedullary infiltration at diagnosis and prognosis in children with acute myelogenous leukemia

Extramedullary infiltration (EMI) is an occasional clinical symptom in childhood acute myelogenous leukemia (AML), but there is considerable controversy regarding the prognostic significance of EMI in AML.

Long-term follow-up of childhood acute lymphoblastic leukemia in Tokyo Children's Cancer Study Group 1981-1995.

The objectives were as follows: Firstly, to estimate the overall probability of event-free survival (EFS) and isolated CNS relapse in the studies for children with acute lymphoblastic leukemia (ALL) during the 1980s and 1990s. Secondly, to report the EFS according to presenting features and lineage. Thirdly, to evaluate the treatment results re-classified by the risks of NCI criteria. Four consecutive protocol studies were performed in the Tokyo Childrens Cancer Study Group: L81–10 protocol (1981–1984, 189 patients), L84–11 (1984–1989, 484 patents), L89–12 (1989–1992, 418 patients) and L92–13 (1992–1995, 347 patients). Overall EFS at 5 years in each protocol was 56.5 ± 3.8(1 s.e.)%, 71.0 ± 2.1%, 67.8 ± 2.3%, and 63.4 ± 2.7%, respectively. The cumulative isolated CNS relapse rate at 5 years was 8.1 ± 2.1%, 3.5 ± 0.9%, 3.6 ± 1.0%, 1.0 ± 0.6. The EFS in SR/HR (standard risk/high risk) according to the NCI criteria in B-precursor ALL at 5 years was 61.9 ± 4.3%/41.4 ± 7.4% (lineage was not confirmed.), 72.5 ± 2.6%/63.4 ± 5.0%, 77.4 ± 2.7%/56.3 ± 4.7%, and 67.8 ± 3.4%/56.7 ± 5.4% in each protocol. Also EFSs according to NCI SR/HR at 5 years of T-ALL in protocols L84–11, L89–12 and L92–13 were 55.6 ± 16.6%/60.9 ± 10.1%, 72.7 ± 13.4%/51.6 ± 9.1%, and 77.1 ± 14.4%/53.6/10.1%, respectively. The truncation of maintenance therapy to 6 months resulted in a decreased EFS in L92–13, particularly due to an increase of bone marrow relapse after cessation of therapy in SR and HR. The NCI risk criteria work properly even in the patients treated by different intensities, so that it makes the comparison possible among the patients in various groups. The overall EFSs in childhood ALL improved in 1980s, but it seemed stable or decreased in 1990s. The short maintenance therapy resulted in poor outcome in SR on the L92–13 protocol. Many of these late relapsers were effectively rescued and overall survival remained at a high level. The proportion of patients who received cranial irradiation reduced without any increase of the CNS events.

Risk-directed treatment of infant acute lymphoblastic leukaemia based on early assessment of MLL gene status: results of the Japan Infant Leukaemia Study (MLL96).

Summary.  We studied the effectiveness of risk‐directed therapy for infants younger than 13 months of age with acute lymphoblastic leukaemia (ALL). Fifty‐five infants were assigned to different treatment programs (from December 1995 to December 1998) on the basis of their MLL gene status at diagnosis. Forty‐two cases (76·3%) had a rearranged MLL gene (MLL+) and were treated with remission induction therapy followed by sequential intensive chemotherapy, including multiple genotoxic agents (MLL9601 protocol). Haematopoietic stem cell transplantation (HSCT) was attempted if suitable donors were available. Thirteen infants (23·7%) were classified as MLL– and treated for 2·5 years with intensive chemotherapy for high‐risk B‐ALL (MLL9602 protocol). Complete remission was induced in 38 of the 42 infants (90·5%) with MLL+ ALL and in all 13 patients (100%) with MLL– disease. In the MLL+ subgroup, the estimated event‐free survival (EFS) rate at 3 years post diagnosis was 34·0% ± 7·5%, compared with 92·3% ± 7·4% in the MLL– subgroup (overall comparison, P = 0·001 by log‐rank analysis). Both age less than 6 months (hazard ratio = 6·87, 95% CI = 0·91–52·3; P = 0·013) and central nervous system (CNS) involvement at diagnosis (hazard ratio = 2·92 95% CI = 1·29–6·63; P = 0·015) were significant independent predictors of an inferior outcome. These findings indicate a strategic advantage in classifying infant ALL as either MLL+ or MLL– early in the clinical course and selecting therapy accordingly. Standard chemotherapy for high‐risk B‐lineage ALL appeared adequate for MLL– cases. Novel therapeutic initiatives are warranted for infants with MLL+ disease, particularly those with initial CNS leukaemic involvement or age less than 6 months, or both.

Repetitive cycles of high-dose cytarabine are effective for childhood acute myeloid leukemia: Long-term outcome of the children with AML treated on two consecutive trials of Tokyo Children's Cancer Study Group

Various methods of intensive chemotherapy have contributed to an improved survival in pediatric acute myeloid leukemia (AML). We here report the long‐term results of the two consecutive trials of Tokyo Childrens Cancer Study Group (TCCSG), incorporating repetitive use of high‐dose cytarabine (HD‐Ara‐C) based combination chemotherapy in post‐remission phase.

NUP98-NSD1 gene fusion and its related gene expression signature are strongly associated with a poor prognosis in pediatric acute myeloid leukemia.

The cryptic t(5;11)(q35;p15.5) creates a fusion gene between the NUP98 and NSD1 genes. To ascertain the significance of this gene fusion, we explored its frequency, clinical impact, and gene expression pattern using DNA microarray in pediatric acute myeloid leukemia (AML) patients. NUP98‐NSD1 fusion transcripts were detected in 6 (4.8%) of 124 pediatric AML patients. Supervised hierarchical clustering analyses using probe sets that were differentially expressed in these patients detected a characteristic gene expression pattern, including 18 NUP98‐NSD1‐negative patients (NUP98‐NSD1‐like patients). In total, a NUP98‐NSD1‐related gene expression signature (NUP98‐NSD1 signature) was found in 19% (24/124) and in 58% (15/26) of cytogenetically normal cases. Their 4‐year overall survival (OS) and event‐free survival (EFS) were poor (33.3% in NUP98‐NSD1‐positive and 38.9% in NUP98‐NSD1‐like patients) compared with 100 NUP98‐NSD1 signature‐negative patients (4‐year OS: 86.0%, 4‐year EFS: 72.0%). Interestingly, t(7;11)(p15;p15)/NUP98‐HOXA13, t(6;11)(q27;q23)/MLL‐MLLT4 and t(6;9)(p22;q34)/DEK‐NUP214, which are known as poor prognostic markers, were found in NUP98‐NSD1‐like patients. Furthermore, another type of NUP98‐NSD1 fusion transcript was identified by additional RT‐PCR analyses using other primers in a NUP98‐NSD1‐like patient, revealing the significance of this signature to detect NUP98‐NSD1 gene fusions and to identify a new poor prognostic subgroup in AML.

Preceding immunosuppressive therapy with antithymocyte globulin and ciclosporin increases the incidence of graft rejection in children with aplastic anaemia who underwent allogeneic bone marrow transplantation from HLA-identical siblings

The incidence of graft rejection was determined in 66 children with acquired aplastic anaemia (AA) following bone marrow transplantation (BMT) from a related donor. Eleven of 65 evaluable patients experienced either early or late rejection. Multivariate analysis identified previous immunosuppressive therapy with antithymocyte‐globulin (ATG) and ciclosporin (CsA) as a risk factor for graft rejection (relative risk: 16·6, P = 0·001). Patients who received ATG and CsA had a significantly lower probability of failure‐free survival than those who did not (69·7 ± 6·2% vs. 87·9 ± 8·0%, P = 0·044). These results suggest that BMT should be instituted immediately in children with severe AA who have human leucocyte antigen‐identical siblings.