Outcomes in children with first-relapsed acute lymphoblastic leukemia in Japan: Results from JCCG Study JPLSG-ALL-R08.

BACKGROUND/OBJECTIVES: The Berlin-Frankfurt-Münster (BFM)-S classification is a crucial prognostic indicator in children experiencing first-relapsed acute lymphoblastic leukemia (ALL). Early molecular response to therapy, evaluated by measurable/minimal residual disease (MRD), has a significant impact on the survival of patients with childhood ALL. Applying risk stratification based on the BFM-S classification and MRD response after induction, the first nationwide prospective multicenter study, ALL-R08, was conducted in children with first-relapsed ALL in Japan. METHODS: The ALL-R08 study comprised two parts: ALL-R08-I, an observational study aimed at obtaining an overall picture of outcomes in first-relapsed childhood ALL, and ALL-R08-II, a clinical trial for the non-T-ALL S2 risk group. In ALL-R08-II, patients with an MRD level of ≥10-3 at the end of induction therapy were assigned to undergo allogeneic hematopoietic stem cell transplantation (allo-HCT), whereas those with an MRD level less than 10-3 and isolated extramedullary relapse continued to receive chemotherapy. RESULTS: In total, 163 patients were enrolled in the ALL-R08 study, and 82 and 81 patients were enrolled in the ALL-R08-I and the ALL-R08-II, respectively. In ALL-R08-I, the probability of 3-year event-free survival (EFS) for patients with S1, S2, S3, S4, and post-HCT groups was 83% ± 15%, 37% ± 11%, 28% ± 8%, 14% ± 7%, and 0%, respectively. In the ALL-R08-II trial, 3-year EFS in patients with post-induction MRD less than 10-3 and ≥10-3 was 70% ± 9% (n = 27) and 68% ± 8% (n = 31) (p = .591), respectively. CONCLUSIONS: ALL-REZ BFM-type treatment is equally effective for children with first-relapsed ALL treated according to the Japanese frontline protocols and for children with first-relapsed ALL treated according to the BFM-type frontline protocols.

[Experience with an international study on standard-risk relapsed childhood acute lymphoblastic leukemia (IntReALL SR 2010 study) in Japan].

Many effective new agents for relapsed childhood acute lymphoblastic leukemia (ALL) are now becoming available, and international standard chemotherapy should be developed to optimize use of these agents. Randomized controlled trials (RCTs) are needed to establish a standard treatment, but few have been conducted for relapsed childhood ALL in Japan due to the small patient population. Participation in international RCTs is necessary to access sufficient patients for informative study results, but differences in approved drugs and healthcare systems between countries make this challenging. In 2014, the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) participated in an international study on standard-risk relapsed childhood ALL (IntReALL SR 2010) involving two RCTs and multiple drugs not approved in Japan, which was addressed by replacing the unapproved drugs with alternative approved drugs with the same or similar efficacy. This article discusses the historical background of treatment development for relapsed childhood ALL, our experience in participating in the IntReALL SR 2010 trial, and prospects for treating relapsed childhood ALL.

Phase III study of palonosetron for prevention of chemotherapy-induced nausea and vomiting in pediatric patients.

BACKGROUND: Palonosetron has demonstrated non-inferiority to ondansetron for prevention of chemotherapy-induced nausea and vomiting in pediatric patients in the United States and Europe. We conducted a single-arm registration study to evaluate the efficacy, safety and pharmacokinetics of palonosetron in pediatric patients in Japan. METHODS: Key inclusion criteria were age of 28 days to 18 years and malignant disease for which initial highly emetogenic chemotherapy or moderately emetogenic chemotherapy was planned. Patients received palonosetron at 20 µg/kg over at least 30 s intravenously before the start of highly emetogenic chemotherapy or moderately emetogenic chemotherapy and received dexamethasone on Days 1-3. The primary endpoint was the proportion of patients achieving a complete response in the overall phase (0-120 h) in Course 1, and its threshold was set at 30%. RESULTS: From December 2016 to June 2019, 60 patients were enrolled, and 58 received at least one dose of palonosetron. The proportion of patients achieving a complete response during the overall phase was 58.6% (95% confidence interval, 44.9%-71.4%), showing the primary endpoint was met (P < 0.0001). Treatment-related adverse events occurred in two patients (3.4%). Regarding the pharmacokinetics of palonosetron, neither the plasma concentration immediately after administration nor the area under the plasma concentration-time curve from time 0 to infinity differed significantly among the age groups. CONCLUSION: We demonstrated the efficacy of palonosetron in pediatric patients receiving highly emetogenic chemotherapy or moderately emetogenic chemotherapy and confirmed the appropriateness of the 20 µg/kg dose, regardless of age, considering the safety and pharmacokinetic profiles. TRIAL REGISTRATION: JapicCTI-163305, registered 6 June 2016.

Wnt3a stimulates maturation of impaired neutrophils developed from severe congenital neutropenia patient-derived pluripotent stem cells.

The derivation of induced pluripotent stem (iPS) cells from individuals of genetic disorders offers new opportunities for basic research into these diseases and the development of therapeutic compounds. Severe congenital neutropenia (SCN) is a serious disorder characterized by severe neutropenia at birth. SCN is associated with heterozygous mutations in the neutrophil elastase [elastase, neutrophil-expressed (ELANE)] gene, but the mechanisms that disrupt neutrophil development have not yet been clarified because of the current lack of an appropriate disease model. Here, we generated iPS cells from an individual with SCN (SCN-iPS cells). Granulopoiesis from SCN-iPS cells revealed neutrophil maturation arrest and little sensitivity to granulocyte-colony stimulating factor, reflecting a disease status of SCN. Molecular analysis of the granulopoiesis from the SCN-iPS cells vs. control iPS cells showed reduced expression of genes related to the wingless-type mmtv integration site family, member 3a (Wnt3a)/ß-catenin pathway [e.g., lymphoid enhancer-binding factor 1], whereas Wnt3a administration induced elevation lymphoid enhancer-binding factor 1-expression and the maturation of SCN-iPS cell-derived neutrophils. These results indicate that SCN-iPS cells provide a useful disease model for SCN, and the activation of the Wnt3a/ß-catenin pathway may offer a novel therapy for SCN with ELANE mutation.

Effect of ABO blood group incompatibility on the outcome of single-unit cord blood transplantation after myeloablative conditioning.

ABO blood group incompatibility between donor and recipient has been associated with poor transplant outcomes in allogeneic hematopoietic stem cell transplantation. However, its effect on the outcome of cord blood transplantation (CBT) has yet to be clarified. We retrospectively analyzed 191 adult patients who received single-unit CBT after myeloablative conditioning for malignant disease in our institute. Major mismatch showed a significantly lower incidence of platelet engraftment compared with ABO match as a reference (hazard ratio, .57; P = .01). Nevertheless, there was no increase in graft-versus-host disease, transplant-related mortality, and overall mortality after ABO-incompatible CBT. These data suggested that donor-recipient ABO incompatibility does not have a significant impact on outcome after myeloablative CBT for hematological malignancies.

Single-unit cord blood transplantation after granulocyte colony-stimulating factor-combined myeloablative conditioning for myeloid malignancies not in remission.

High disease burden in myeloablative allogeneic hematopoietic stem cell transplantation is associated with adverse outcomes in patients with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). Quiescent leukemia stem cells could be induced to enter cell cycle by granulocyte colony-stimulating factor (G-CSF) administration and become more susceptible to chemotherapy. We report on the outcome of unrelated cord blood transplantation (CBT) using a conditioning regimen of 12 Gy total body irradiation, G-CSF-combined high-dose cytarabine, and cyclophosphamide in 61 adult patients with AML or advanced MDS not in remission. With a median follow-up of 97 months, the probability of overall survival and cumulative incidence of relapse at 7 years were 61.4% and 30.5%, respectively. In multivariate analysis, poor-risk cytogenetics and high lactate dehydrogenase values at CBT were independently associated with inferior survival. These data demonstrate that CBT after G-CSF-combined myeloablative conditioning is a promising curative option for patients with myeloid malignancies not in remission.

Successful Bone Marrow Transplantation in a Patient with Acute Myeloid Leukemia Developed from Severe Congenital Neutropenia Using Modified Chemotherapy and Conditioning Regimen for Leukemia.

Severe congenital neutropenia (SCN) is characterized by chronic neutropenia with recurrent infections from early infancy and a predisposition to myelodysplastic syndrome/acute myeloid leukemia (AML). Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment for patients with SCN who develop myelodysplastic syndrome/AML. We report an 8-year-old girl with SCN carrying an ELANE mutation that had been refractory to granulocyte colony-stimulating factor. The patient experienced recurrent infections and then developed AML. The counts of leukemic blasts that harbored both CSF3R and RUNX1 mutations spontaneously decreased with antimicrobial therapy, leading to partial remission. After AML recurrence, HSCT was successfully performed using modified chemotherapy and a conditioning regimen. Serial donor lymphocyte infusions against mixed chimerism induced complete donor chimerism over 4 years without any infections or AML relapse. This case suggests the importance of carefully managing neutropenia-related infections, leukemia progression, and HSCT in patients with SCN developing AML.

Treatment of relapsed acute lymphoblastic leukemia in children: an observational study of the Japan Children's Cancer Group.

The Japan Children's Cancer Group Relapsed Acute Lymphoblastic Leukemia (ALL) Committee conducted a prospective observational study (ALL-R14) to explore promising reinduction therapy regimens for relapsed ALL to investigate in future trials. In Japan, clofarabine- and bortezomib-based regimens were of interest since they were newly introduced for ALL in the study period (2015-2018). Seventy-five pediatric patients were enrolled in total. The 2-year event-free/overall survival rates in patients with first (n = 59) or second (n = 11) relapse were 40.1% (95% confidence interval [CI]: 25.5-52.3%)/66.3% (95% CI 52.3-77.0%) and 34.1% (95% CI 9.1-61.6%)/62.3% (95% CI 27.7-84.0%), respectively. Clofarabine- or bortezomib-based regimens were used only in patients with high-risk disease. The first reinduction therapy used in the 41 patients with early or multiple relapsed B-cell precursor ALL was clofarabine in 7 patients and bortezomib in 9 patients. The odds ratio for reinduction failure risk with a clofarabine- or bortezomib-based regimen compared with other regimens was 9.0 (95% CI 0.9-86.4, P = 0.057) or 1.9 (95% CI 0.4-8.7, P = 0.42), respectively. Thus, clofarabine- or bortezomib-based regimens had no obvious advantage as reinduction therapy for relapsed ALL in children.

TBI, etoposide, and cyclophosphamide conditioning for intermediate-risk relapsed childhood acute lymphoblastic leukemia.

BACKGROUND: In children with intermediate-risk relapsed acute lymphoblastic leukemia (ALL), allogeneic hematopoietic stem cell transplantation (allo-HSCT) has markedly improved the outcome of patients with an unsatisfactory minimal residual disease (MRD) response. Total body irradiation (TBI), etoposide (ETP), and cyclophosphamide (CY) have been shown to be equivalent to or better than TBI + ETP for conditioning, so we hypothesized that even greater survival could be achieved due to recent advances in HSCT and supportive care. PROCEDURE: We prospectively analyzed the efficacy and safety of allo-HSCT with a unified conditioning regimen of TBI + ETP + CY in children with intermediate-risk relapsed ALL, based on MRD in the bone marrow after induction, from the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) ALL-R08-II nationwide cohort (UMIN000002025). RESULTS: Twenty patients with post-induction MRD ≥ 10-3 and two not evaluated for MRD underwent allo-HSCT. Engraftment was confirmed in all patients, and no transplantation-related mortality was observed. The 3-year event-free survival and overall survival rates after transplantation were 86.4% ± 7.3% and 95.5% ± 4.4%, respectively. CONCLUSION: Allo-HSCT based on post-induction MRD with TBI + ETP + CY conditioning was feasible in Japanese children with intermediate-risk relapsed ALL.

Differential dose response of mTOR signaling to oral administration of leucine in skeletal muscle and liver of rats.

Phosphorylation of eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) and 70-kDa ribosomal protein S6 kinase (S6K1) in the rat liver increased in proportion to the amount of leucine administered, ranging from 0.169 to 1.35 g/kg of body weight. In the skeletal muscle, phosphorylation of these factors reached a plateau at 0.675 g/kg of body weight. The sensitivity of mammalian target of rapamycin (mTOR) signaling to leucine in the skeletal muscle appeared to be higher than that in the liver.

Phase 2 study of combination chemotherapy with bortezomib in children with relapsed and refractory acute lymphoblastic leukemia.

Treatment outcomes for children with relapsed and refractory acute lymphoblastic leukemia (R/R-ALL) remain poor, and the optimal induction therapy has not been determined. Bortezomib is a proteasome inhibitor that acts synergistically and additively with standard chemotherapy for ALL. We evaluated the efficacy and safety of combination chemotherapy with bortezomib in children with R/R-ALL. This single-arm, multicenter, phase 2 study was conducted in Japan between 2016 and 2020. Eligible patients were divided into two cohorts: a high-risk first-relapse cohort of untreated patients with high-risk first-relapsed ALL and an expansion cohort of patients with refractory ALL, including multiple relapses, relapse after allogeneic hematopoietic cell transplantation, and induction failure. All patients received a single course of chemotherapy as induction therapy. Sixteen patients (10 in the high-risk first-relapse cohort, six in the expansion cohort) were evaluable. The overall remission rate after induction therapy was 60% in the high-risk first-relapse cohort and 16.7% in the expansion cohort. All patients had minimal residual disease. Adverse events were acceptable except for interstitial lung disease and hypoxia in a patient in the expansion cohort, but addition of bortezomib to conventional chemotherapy did not produce obvious improvement in children with R/R-ALL.

Successful Treatment with Antibiotics Alone for Infant Rib Osteomyelitis.

Pediatric rib osteomyelitis is a rare disease occurring predominantly in the neonatal period and early childhood and accounting for about 1% of all pediatric osteomyelitis. Compared to osteomyelitis in other parts of the body, pediatric rib osteomyelitis shows few localized findings (such as redness and swelling) and often an indolent lesion as well either of which may delay diagnosis and thus make treatment more difficult. A previously healthy one-year-old girl came to our department with a chief complaint of fever lasting for three days. She was admitted to our department to investigate her fever. At the time of admission, radiographs showed decreased permeability in the left lung field; so, we started antimicrobial therapy on the assumption of pneumonia. On the second day of admission, methicillin-susceptible Staphylococcus aureus was detected in the blood culture. A further, more detailed physical examination revealed some slight left anterior chest swelling. We performed a contrast-enhanced CT scan and an MRI and diagnosed her with rib osteomyelitis complicated with a chest wall abscess. She was given intravenous cefazolin for two weeks, switched to oral cephalexin for four weeks, and then recovered completely. She was treated without surgical intervention, having showed a good response to antimicrobial therapy. Osteomyelitis of the ribs in children is reported to be more common in the lower ribs and to occur more frequently in infants. In many cases, the earliest symptoms are nonspecific, so careful examination to detect any subtle abnormalities-such as swelling or mass-is of key importance for early diagnosis in infants. Regarding treatment, most cases of hematogenous osteomyelitis resolve with antimicrobial therapy alone-although surgical intervention may be required in cases of poor response to antimicrobial therapy. Therefore, early diagnosis of rib osteomyelitis through careful physical examination may reduce the chances of requiring surgical intervention.

Analysis of the Stimulative Effect of Tryptophan on Hepatic Protein Synthesis in Rats.

Tryptophan is an essential amino acid important as a protein building block, but it also serves as substrate for the generation of several bioactive compounds with important physiological roles. Furthermore, tryptophan has been reported to have a unique role as a nutritional signaling molecule that regulates protein synthesis in mouse and rat liver. In the present study, the acute effects of tryptophan on protein synthesis were confirmed and compared with those of leucine in rats. Eighteen hours fasted rats were orally administered of tryptophan or leucine at a dose of 135 mg/100 g body weight by gavage and then sacrificed 1 h after administration. The effects of tryptophan and leucine on the rate of protein synthesis were evaluated by the surface sensing of translation (SUnSET) method. We also examined the ability of tryptophan to induce activation of the mTOR pathway by measuring phosphorylation of 4E-BP1 and S6K1. Oral administration of tryptophan led to a stimulation of the rate of protein synthesis concomitant with activation of mTOR pathway in the liver, but not in skeletal muscle. We also investigated the sensitivity of liver protein synthesis to tryptophan administration. The half-maximal effective doses (ED50) of tryptophan in stimulating 4E-BP1 and S6K1 phosphorylation were both about 60% of daily intake. The effect of tryptophan on hepatic protein synthesis was similar to that of leucine on muscle protein synthesis, and the sensitivity of liver protein synthesis to tryptophan administration appeared to be almost the same or slightly lower than that of muscle protein synthesis to leucine administration.

Adapting pediatric health care responses to the COVID-19 pandemic in Japan: A clinical perspective.

The COVID-19 pandemic required our pediatric health care staff to adjust to many irregularities and solve serious issues in our routine clinical practice. In outpatient clinics, many children exhibited common cold symptoms that mimic COVID-19, thus we initially screened patients via an interview form, then later via SARS-CoV-2 antigen test. Cluster infections were entirely avoided by following systematic, everyday precautions. Patientsquality of life has been difficult to maintain during the pandemic, due to social and staffing restrictions. Other unexpected repercussions - such as an unexpected lack of seasonal virus infections, then a respiratory syncytial (RS) virus outbreak - required agile management of hospital resources. While we must continue to adapt our treatment programs in response to the evolving COVID-19 crisis, it remains essential to support the well-being of children through regular health check-ups, mental health support, educational opportunities, proper socialization, and close communication with parents and families.

Bone marrow transplantation from a human leukocyte antigen-mismatched unrelated donor in a case with C1q deficiency associated with refractory systemic lupus erythematosus.

Human C1q deficiency is frequently associated with systemic lupus erythematosus (SLE), which requires long-term systemic corticosteroid administration. We report the case of a 12-year-old female patient with C1q deficiency presenting with intractable SLE who successfully underwent bone marrow transplantation from a human leukocyte antigen (HLA)-mismatched unrelated donor with an immunosuppressive conditioning regimen based on fludarabine, melphalan, and anti-thymocyte globulin. She developed Grade I graft-versus-host disease, but did not have any transplantation-related morbidity. Complete donor chimerism has been maintained for 2 years after transplantation, leading to the restoration of C1q levels and the resolution of SLE symptoms. Normal C1q mRNA expression was observed in CD14 + cells. Hematopoietic stem cell transplantation from an HLA-mismatched donor is a feasible treatment for patients with C1q deficiency with refractory SLE that is dependent on systemic corticosteroid treatment who do not have an HLA-matched donor.

Two brothers with ataxia-telangiectasia-like disorder with lung adenocarcinoma.

We report on 2 brothers with ataxia-telangiectasia-like disorder with lung adenocarcinoma. They both had ataxia with cerebellar atrophy and mental retardation. They had the same mutation of the MRE11 gene, which has not been reported previously (c.727T>C and g.24994G>A).

Ethionine-induced ATP depletion represses mTOR signaling in the absence of increases in AMP-activated protein kinase activity in the rat liver.

Administration of ethionine to female rats caused a rapid and severe decline in liver ATP and inhibited hepatic protein synthesis in association with hypophosphorylation of eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) and 70-kDa ribosomal protein S6 kinase (S6K1), two key regulatory proteins involved in initiation of mRNA translation. Phosphorylation of both regulatory proteins is mediated through a signaling pathway that involves the mammalian target of rapamycin (mTOR). Recent studies indicate that AMP-activated protein kinase (AMPK) plays a role in the cellular response to environmental stresses, which deplete ATP, and suppresses protein synthesis through downregulated mTOR signaling. We investigated the possible involvement of AMPK in the ethionine-induced inhibition of protein synthesis. The administration of ethionine surprisingly decreased AMPK activity compared with controls despite ATP depletion. We conclude that inhibition of protein synthesis by ethionine is due to AMPK-independent inhibition of mTOR signaling following ATP depletion.

Acute encephalopathy with human parvovirus B19 infection in hereditary spherocytosis.

A 9-year-old girl with hereditary spherocytosis developed aplastic crisis and encephalopathy associated with human parvovirus B19 (PVB19) infection. During the clinical course, we followed PVB19 DNA in her plasma and cerebrospinal fluid by real-time polymerase chain reaction and found that her symptoms of encephalopathy had occurred at the peak viral load. PVB19-associated encephalopathy might occur as a result of direct invasion by PVB19.