Yuri Okimoto

No Advantage of Dexamethasone Over Prednisolone for the Outcome of Standard- and Intermediate-Risk Childhood Acute Lymphoblastic Leukemia in the Tokyo Children's Cancer Study Group L95-14 Protocol

PURPOSE To evaluate whether dexamethasone (DEXA) yields a better outcome than prednisolone (PRED) in a prospective, randomized, controlled trial for the treatment of childhood acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS Two hundred thirty-one standard-risk (SR) patients and 128 intermediate-risk (IR) non-B-cell ALL patients were registered from March 1995 to March 1999. After random assignment in each group, the PRED arm patients received PRED 60 mg/m2 during induction followed by PRED 40 mg/m2 over four intensifications in the SR group and three intensifications in the IR group. DEXA arm patients received DEXA 8 mg/m2 during induction and DEXA 6 mg/m2 during the intensifications. The maintenance phase was continued until week 104. RESULTS Event-free survival rates at 8 years in the DEXA and PRED arms were 81.1% +/- 3.9% (n = 117) and 84.4% +/- 5.2% (n = 114), respectively, in the SR group (P = .217) and 84.9% +/- 4.6% (n = 62) and 80.4% +/- 5.1% (n = 66), respectively, in the IR group (P = .625). The primary reason for treatment failure was marrow relapse. Only two extramedullary relapses occurred in the DEXA arm compared with seven relapses in the PRED arm. Although complications were more prevalent in the DEXA arm than in the PRED arm, fatal toxicity was rare both groups. CONCLUSION DEXA administered at 8 mg/m2 during induction and 6 mg/m2 during intensification showed no advantage over PRED administered at 60 mg/m2 during induction and 40 mg/m2 during intensification in both the SR and IR groups.

Six Months of Maintenance Chemotherapy After Intensified Treatment for Acute Lymphoblastic Leukemia of Childhood

PURPOSE We postulated that intensification of chemotherapy immediately after remission induction might reduce the leukemic cell burden sufficiently to allow an abbreviated period of antimetabolite therapy. PATIENTS AND METHODS Three hundred forty-seven children (ages 1 to 15 years) with previously untreated acute lymphoblastic leukemia (ALL) were enrolled onto the Tokyo L92-13 study, which excluded patients with mature B-cell ALL and patients less than 1 year old. One hundred twenty-four patients were classified as standard risk, 122 as high risk, and 101 as extremely high risk, according to age, peripheral-blood leukocyte count, selected genetic abnormalities, and immunophenotype. All subjects received four drugs for remission induction, followed by a risk-directed multidrug intensification phase and therapy for presymptomatic leukemia in the CNS. Maintenance chemotherapy with oral mercaptopurine and methotrexate was administered for 6 months, with all treatment stopped by 1 year after diagnosis. RESULTS The mean (+/- SD) event-free survival (EFS) and overall survival rates for all patients were 59.5% +/- 3.4% and 81.5% +/- 2.2%, respectively, at 5. 5 years after diagnosis. EFS rates by risk category were similar (60. 2% +/- 6.0% for standard risk, 57.7% +/- 5.6% for high risk, and 62. 5% +/- 5.7% for extremely high risk), whereas overall survival rates differed significantly (91.2% +/- 2.7%, 80.0% +/- 4.1%, and 72.1% +/- 4.5%, respectively, P <.0001 by the log-rank test). There were 107 relapses. Eighty-five (79.4%) of these 107 patients achieved second complete remissions, with subsequent EFS rates of 61.5% +/- 7. 9% (standard risk), 42.6% +/- 8.1% (high risk), and 9.6% +/- 6.4% (extremely high risk). Of the five risk factors analyzed, only the response to prednisolone monotherapy among extremely high-risk patients proved important. CONCLUSION Early treatment intensification did not compensate for a truncated phase of maintenance chemotherapy in children with standard- or high-risk ALL. However, 6 months of antimetabolite treatment seemed adequate for extremely high-risk patients who were good responders to prednisolone and received intensified chemotherapy that included high-dose cytarabine early in the clinical course.

Identification of Severe Combined Immunodeficiency by T-Cell Receptor Excision Circles Quantification Using Neonatal Guthrie Cards

OBJECTIVE To assess the feasibility of T-cell receptor excision circles (TRECs) quantification for neonatal mass screening of severe combined immunodeficiency (SCID). STUDY DESIGN Real-time PCR based quantification of TRECs for 471 healthy control patients and 18 patients with SCID with various genetic abnormalities (IL2RG, JAK3, ADA, LIG4, RAG1) were performed, including patients with maternal T-cell engraftment (n = 4) and leaky T cells (n = 3). RESULTS TRECs were detectable in all normal neonatal Guthrie cards (n = 326) at the levels of 10(4) to 10(5) copies/microg DNA. In contrast, TRECs were extremely low in all neonatal Guthrie cards (n = 15) and peripheral blood (n = 14) from patients with SCID, including those with maternal T-cell engraftment or leaky T cells with hypomorphic RAG1 mutations or LIG4 deficiency. There were no false-positive or negative results in this study. CONCLUSION TRECs quantification can be used as a neonatal mass screening for patients with SCID.

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.

Long-term results of Tokyo Children's Cancer Study Group trials for childhood acute lymphoblastic leukemia, 1984–1999

We report the long-term results of Tokyo Childrens Cancer Study Groups studies L84-11, L89-12, L92-13, and L95-14 for 1846 children with acute lymphoblastic leukemia, which were conducted between 1984 and 1999. The value of event-free survival (EFS)±s.e. was 67.2±2.2% at 10 years in L84-11, which was not improved in the following two studies, and eventually improved to 75.0±1.8% at 10 years in L95-14 study. The lower EFS of the L89-12 reflected a high rate of induction failure because of infection and delayed remission in very high-risk patients. The L92-13 study was characterized by short maintenance therapy; it resulted in poor EFS, particularly in the standard-risk (SR) group and boys. Females did significantly better than males in EFS in the early three studies. The gender difference was not significant in overall survival, partly because >60% of the males survived after the testicular relapse. Randomized studies in the former three protocols revealed that intermediate- or high-dose methotrexate therapy significantly reduced the testicular relapse rate. In the L95-14 study, gender difference disappeared in EFS. Contrary to the results of larger-scale studies, the randomized control study in the L95-14 reconfirmed with updated data that dexamethasone 8 mg/m2 had no advantage over prednisolone 60 mg/m2 in the SR and intermediate-risk groups. Prophylactic cranial irradiation was assigned to 100, 80, 44, and 44% of the patients in the studies, respectively. Isolated central nervous system relapse rates decreased to <2% in the last two trials. Secondary brain tumors developed in 12 patients at 8–22 years after cranial irradiation. Improvement of the remission induction rates and the complete omission of irradiation are currently main objectives in our studies.

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.

Genetic Basis of Patients with Bacille Calmette-Guérin Osteomyelitis in Japan: Identification of Dominant Partial Interferon-γ Receptor 1 Deficiency as a Predominant Type

Interferon (IFN)-gamma-mediated immunity plays an important role in host defense against intracellular pathogens, especially mycobacteria. Six Japanese children with bacille Calmette-Guérin (BCG) osteomyelitis were evaluated (1 disseminated, 3 multiple, and 2 solitary types) for mutations of genes involved in interleukin-12-dependent, IFN-gamma-mediated immunity. Heterozygous small deletions with frameshift (818del4 and 811del4) that are consistent with the diagnosis of partial dominant IFN-gamma receptor 1 (IFN-gammaR1) deficiency were detected in 3 unrelated patients. Expression of IFN-gammaR1 on monocytes was significantly increased in all 3 patients. Screening of family members with recurrent and disseminated mycobacterial infections found the identical deletion in 1 of the fathers. Antimycobacterial treatment was effective in these patients and resulted in good clinical outcome. This study demonstrated that partial dominant IFN-gammaR1 deficiency was the most common in Japanese patients who showed predisposition to curable BCG osteomyelitis.

Moyamoya syndrome following childhood acute lymphoblastic leukemia.

Long‐term survivors of childhood acute lymphoblastic leukemia (ALL) sometimes suffer from adverse long‐term sequelae. We analyzed the incidence, clinical course and prognosis of moyamoya syndrome (MoS) following childhood ALL.

Nationwide survey of single‐system single site Langerhans cell histiocytosis in Japan

Since neither a standard treatment nor a protocol study for single‐system single site (SS‐s)‐type Langerhans cell histiocytosis (LCH) exists, we conducted a nationwide survey in Japan to clarify the epidemiology and clinical outcome of this subtype.

Detection of chimeric mRNAs by reverse transcriptase‐polymerase chain reaction for diagnosis and monitoring of acute leukemias with 11q23 abnormalities

Recurrent translocations involving chromosome band 11q23 are often found in human acute leukemias. Recently, the MLL gene on 11q23 and 10 partner genes involved in these translocations have been cloned and characterized. We performed a reverse transcriptase-polymerase chain reaction (RT-PCR) to detect the resultant der(11) chimeric mRNAs of the 3 types of 11q23 translocations including t(4;11), t(9;11), or t(11;19), in 14 leukemia patients with MLL gene rearrangements. At diagnosis or relapse, chimeric mRNA could be detected in all of the 4 patients with t(4;11), 2 of 3 with t(9;11), 2 of 3 with t(11;19), and 1 of 4 with unsuccessful karyotype. In 5 patients, we could monitor minimal residual disease (MRD) serially through the clinical course. One patient, in whom chi-meric mRNA was detected during complete remission (CR) just after the induction chemotherapy, relapsed within 2 months and died, while 2 patients in which chimeric mRNA was not detected remained in CR from 10-23 months. These findings suggest that RT-PCR is a useful approach for detecting which partner gene is involved in the translocation and monitoring MRD in patients with MLL gene rearrangement. Nonetheless, the clinical relevance of MRD evaluation by RT-PCR monitoring remains controversial. Long-term and prospective investigation of a larger series of patients is needed to confirm the clinical significance of monitoring MRD by RT-PCR method.