Papers by Toshihiko Imamura
International Journal of Hematology
Journal of Pediatric Hematology/Oncology, 2020
Induction deaths (ID) remain a critical issue in the treatment of pediatric patients with acute l... more Induction deaths (ID) remain a critical issue in the treatment of pediatric patients with acute lymphoblastic leukemia (ALL). The reported rate of ID in this population is 1% or higher. We speculate that this proportion might be lower in Japan because of mandatory hospitalization during induction therapy to manage complications. We retrospectively analyzed the incidence of ID among children with ALL enrolled in 4 Japanese study groups between 1994 and 2013. Among 5620 children, 41 (0.73%) cases of ID were noted. The median age was 6.5 years; 24 children were female, and 7 had T-cell ALL. Infection was the most common cause of ID (n=22), but the incidence (0.39%) was lower than that reported in western countries. Mortality within 48 hours from the onset of infection was low, comprising 25% of infection-related deaths. The incidence of infections caused by Bacillus species was low. Only 1 patient died because of Aspergillus infection. Fatal infections mostly occurred during the third week of induction therapy. Our findings suggest that close monitoring, stringent infection control, and immediate administration of appropriate antibiotics through hospitalization might be important strategies in reducing the rate of infection-related ID in pediatric patients with ALL.
Journal of Pediatric Hematology/Oncology, 2021
Fanconi anemia (FA) is a rare genetic disorder that manifests as congenital abnormalities and bon... more Fanconi anemia (FA) is a rare genetic disorder that manifests as congenital abnormalities and bone marrow failure (BMF). Most patients with FA present with BMF within the first decade of life; however, neonate and early infancy BMF is rare. Recent studies have shown that a defective aldehyde dehydrogenase 2 (ALDH2) variant accelerates BMF development in patients with FA. Herein, we described an infant case of FA with compound heterozygous FANCI mutation and the defective ALDH2 variant. Our case developed BMF early probably because of ALDH2 deficiency, while the mild malformation might be because of the locus of FANCI mutation.
Blood, 2009
3111 Poster Board III-48 Backgrounds and Introduction The CCAAT/enhancer binding protein (C/EBP)α... more 3111 Poster Board III-48 Backgrounds and Introduction The CCAAT/enhancer binding protein (C/EBP)αa is a transcriptional factor of hematopoietic system and plays a key role in monocytic differentiation. Recently, several studies have reported that C/EBPαa expression is down-regulated in acute myeloid leukemia (AML), leading to block of granulocytic and monocytic differentiation. Differentiation therapy of ATRA is highly effective for acute promyelocytic leukemia (APL). The mechanism of induction of differentiation in the treatment of APL is induction of a set of transcriptional factors which are responsible for myeloid differentiation. However, ATRA alone is not sufficient to treat another type of AML. Thus, it is worth to explore the agents which intensify the efficacy of ATRA. To assess the possibility of differentiation therapy in AML, except for APL, we evaluated the efficacy of demethylation agent combined with ATRA for various AML cell lines. Materials and Methods The five AML ...
International Journal of Hematology
Recent progress in comprehensive genomic analysis and well-designed clinical trials has dramatica... more Recent progress in comprehensive genomic analysis and well-designed clinical trials has dramatically improved the treatment strategies for pediatric leukemia, resulting in better prognosis and reducing acute and late adverse events. This review series describes successes and challenges for the future in the management of pediatric leukemia.
[Rinsho ketsueki] The Japanese journal of clinical hematology, 2021
Ph-like acute lymphocytic leukemia (ALL) is a subtype of Ph-negative B precursor ALL, and its gen... more Ph-like acute lymphocytic leukemia (ALL) is a subtype of Ph-negative B precursor ALL, and its gene expression profile is similar to that of Ph+ALL. In recent decades, comprehensive genomic analyses have revealed that Ph-like ALL has two types. The first type is associated with the ABL-class tyrosine kinase fusion gene, and the second type with fusion genes involving cytokine receptors or molecules, including CRLF2, which are correlated with the activation of the JAK/STAT pathway. Based on these findings, tyrosine kinase or JAK inhibitors were found to be effective for Ph-like ALL. Genetic abnormalities identified in Ph-like ALL, except for CRLF2 rearrangement, are quite rare. Thus, functional studies regarding each genomic abnormality are relevant for establishing targeted therapies for Ph-like ALL. To develop a targeted molecular therapy, a functional study of NCOR1-LYN, which is a novel ABL-class fusion gene, was conducted on pediatric patients with Ph-like ALL.
Cancer Reports, 2021
BACKGROUND Lymphoblastic lymphoma (LBL) and acute lymphoblastic leukemia (ALL) are categorized as... more BACKGROUND Lymphoblastic lymphoma (LBL) and acute lymphoblastic leukemia (ALL) are categorized as the same entity under precursor lymphoid neoplasms in the World Health Organization classification. However, compared to B-cell ALL, the molecular genetic makeup of B-cell LBL remains to be understood, mainly due to its rarity. We performed whole exome sequencing (WES) on seven patients with TCF3-PBX1-positive B-cell LBL. METHODS WES was performed using DNA extracted from tumor specimens and paired blood samples at remission for six patients, and tumor-only analysis was performed for one patient whose remission sample was not available. For one patient, a relapsed sample was also analyzed. RESULTS KMT2D variants and 6q LOH were found as recurrent alterations. Somatic variants of KMT2D were identified in three of the seven patients. Of note, the two patients with heterozygous nonsense variant of KMT2D were at stage III, without bone marrow infiltration. 6q LOH was also identified in two others, out of the seven patients. The common 6q deleted region of the two patients ranged from 6q12 to 6q16.3. Both patients had bone marrow infiltration. Analysis of recurrent case also revealed that the relapsed clone might be derived from a minor clone of the bone marrow at diagnosis. CONCLUSION In this study, through WES for seven patients with TCF3-PBX1-positive B-LBL, we identified KMT2D mutations and 6q LOH as recurrent alterations. In order to elucidate the relationship between these recurrent alterations and disease specificity or outcomes, further studies comparing with TCF3-PBX1-positive B-ALL are required.
The Journal of Allergy and Clinical Immunology: In Practice, 2021
BACKGROUND X-linked inhibitor of apoptosis protein (XIAP) deficiency is an infrequent inborn erro... more BACKGROUND X-linked inhibitor of apoptosis protein (XIAP) deficiency is an infrequent inborn error of immunity that is often associated with refractory inflammatory bowel disease (IBD). The natural course of XIAP deficiency is typically associated with poor prognosis, and hematopoietic cell transplantation (HCT) is the only curative treatment. OBJECTIVE To study (1) the effect of HCT on patients with XIAP deficiency undergoing HCT, (2) the status of XIAP deficiency-associated IBD after HCT, and (3) the gut microbiota of XIAP deficiency-associated IBD before and after HCT. METHODS A nationwide survey of patients with XIAP deficiency was conducted. A spreadsheet questionnaire was collected from the physicians. Feces samples collected from the patients before and after HCT and their healthy family members were analyzed. RESULTS Twenty-six patients with XIAP deficiency underwent HCT by the end of March 2020, and 22 patients (84.6%) survived. All the survivors underwent a fludarabine-based reduced-intensity condition regimen. Acute graft-versus-host disease was observed in 17 patients (65.4%). Nineteen patients experienced refractory IBD before undergoing HCT. IBD improved remarkably after HCT. After HCT, the colonoscopic and pathological symptoms were restored to normal, and the pediatric ulcerative colitis activity index improved significantly. Gut microbiota indicated dysbiosis before HCT; however, it was improved to resemble that of the healthy family members after HCT. CONCLUSIONS This study revealed that HCT has a favorable outcome for XIAP deficiency. HCT rescues gut inflammation and dysbiosis in patients with XIAP deficiency.
BMC Pediatrics, 2020
Background This study aims at determining the health-related quality of life (HRQOL) of children ... more Background This study aims at determining the health-related quality of life (HRQOL) of children with acute lymphoblastic leukemia (ALL) after the induction therapy, assessing the agreement between child self-reports and family proxy-reports HRQOL, and determining the factors related to this agreement, especially child age, family attendance, and children’s social relationships beyond the family. Methods We analyzed questionnaire data (2012–2017) from the Japanese Pediatric Leukemia/Lymphoma Study Group’s clinical study (ALL-B12). Participants were children with B-cell precursor ALL aged 5–18 and their family members, who mostly took care of the child during hospitalization. Participants answered the Pediatric Quality of Life Inventory™ (PedsQL™) Generic Core Scales (PedsQL-G), and Cancer Module (PedsQL-C) to measure pediatric HRQOL. We calculated the differences between child self-reported and family proxy-reported subscale scores along with intraclass correlation coefficients (ICC...
Cancer Research, 2020
Mixed-lineage leukemia (MLL)-related leukemia which has MLL rearrangement is an intractable disea... more Mixed-lineage leukemia (MLL)-related leukemia which has MLL rearrangement is an intractable disease. Recently, bromodomain and extra-terminal (BET) inhibitors are promising agents, and clinical trials are undergone. However, drug resistance against BET inhibitors has been reported, therefore, it is important to elucidate its mechanism. In this study, we established OTX015-resistant leukemic cells with MLL-AF5q31 fusion gene (OTX015-R cells) and identified molecules that contribute to drug resistance. In addition, we evaluated whether identified molecules are effective as therapeutic target for BET inhibitor-resistant MLL-related leukemia. To generate OTX015-R cell line, we cultured MLL-AF5q31 cells in the complete medium containing OTX015 with stepwise increasing concentrations. OTX015-R cells exhibited cross-resistance to various BET inhibitors. In addition, protein expressions of bromodomain-containing protein 4 (Brd4) and Brd4-regulated molecules c-Myc, Cdk6 and Bcl-2 were remark...
Blood, 2018
Introduction: L-asparaginase (L-Asp) is one of the risk factor of thromboembolism during ALL chem... more Introduction: L-asparaginase (L-Asp) is one of the risk factor of thromboembolism during ALL chemotherapy. Although the pathogenesis has been still unclarified, L-Asp may have profound effects on hepatic synthesis of pro-, anti-coagulant and fibrinolytic factors. In addition, recent studies demonstrated that the age of over 10-years might be a risk factor for this L-Asp associated coagulopathy. In this study, we hypothesized that change of balance between coagulation and fibrinolysis contributes to hyper-coagulation condition during chemotherapy including L-Asp. In order to clarify our hypothesis, we investigated the global coagulation and fibrinolytic function during the ALL induction therapy with simultaneous thrombin and plasmin generation assay (T/P-GA). Patients: Seventy-two pediatric patients aged 1.0 to 15.2 years (43 males and 29 females) with newly diagnosed ALL were enrolled from Aug. 2014 to Mar. 2018 at four hospitals in Japan. All patients and their families had no thro...
Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis, Jan 19, 2015
Acquired haemophilia A (AHA) is a life-threatening haemorrhagic disorder that occurs with various... more Acquired haemophilia A (AHA) is a life-threatening haemorrhagic disorder that occurs with various underlying conditions such as autoimmune disease, drug reactions, lymphoproliferative diseases, solid tumours and pregnancy/postpartum status. However, in half of all reported cases, the underlying disease is unknown. Most AHA cases develop in adults paediatric/adolescent cases are extremely rare. The main clinical symptom is bleeding into the skin, muscles, soft tissues and/or mucous membranes. Here, we report the case of an otherwise healthy 12-year-old girl who presented with prolonged bleeding postexodontia. After being diagnosed with AHA, she was successfully treated with recombinant activated factor VII infusion and oral prednisolone. To avoid such unanticipated bleeding when performing dental extraction, preoperative haemostatic screening tests are recommended.
International journal of hematology, Jan 6, 2015
After allogeneic stem-cell transplantation, nonhematopoietic tissues contain donor-derived cells;... more After allogeneic stem-cell transplantation, nonhematopoietic tissues contain donor-derived cells; however, whether cells from malignant hematological disease can also be found in nonhematopoietic tissues is unclear. This report describes a juvenile myelomonocytic leukemia (JMML) case with a typical PTPN11 mutation (p.E76K) at different allele frequencies in the bone marrow mononuclear cells, buccal smear cells, and fingernails at diagnosis, which was suggestive of PTPN11 somatic mosaicism; however, the PTPN11 mutation in the buccal smear cells and fingernails was lost after unrelated cord blood transplantation. These results suggest that JMML-derived cells may migrate into and reside in nonhematopoietic tissues and furthermore that these cells can be eradicated by cord blood transplantation.
American Journal of Hematology, 2002
FL 33612 to permit rapid consideration for publication. Rituximab-Induced Serum Sickness To the E... more FL 33612 to permit rapid consideration for publication. Rituximab-Induced Serum Sickness To the Editor: Rituximab, a chimeric murine-human monoclonal anti CD20 antibody, is approved for the treatment of relapsed or refractory, CD20(+) B-cell, low-grade or follicular non-Hodgkin's lymphoma (NHL). This antibody is also being used and evaluated against other CD20expressing hematological malignancies and autoimmune disorders [1]. Recently, D'Arcy and Mannick [2] reported the first case of serum sickness occurring 10 days after the patient started a protocol of 4 weekly infusions of rituximab for refractory autoimmune polyneuropathy. The patient presented with fever, polyarthritis, and transient decrease of C3 and C4 levels. IgG antibodies directed to the murine FabЈ fragments of the rituximab were found [2]. We observed a similar clinical presentation in a 48-year-old woman with refractory immune thrombocytopenia (anti-nuclear factor negative). Six days after the second course of rituximab on a weekly protocol, the patient was admitted because of fever (38.5°C), malaise, symmetric polyarthritis of large and small joints, and a morbilliform skin eruption. At the same time, her platelet count dropped to 2,000, and she was treated with methylprednisolone 500 mg (i.v.) for 2 days. The patient responded favorably to the treatment, and less than 48 h after the treatment was started the symptoms and the signs of serum sickness resolved. Although rituximab is a chimeric murine-human antibody, only 3 patients out of more than 300 patients who were treated with rituximab and were tested for human anti-chimeric antibodies showed detectable antibodies levels [3]. None of them was reported to develop serum sickness. This is the second case reported of rituximab-induced serum sickness; both cases occurred a few days after the second course of rituximab for an autoimmune disorder, and both of them responded favorably to glucosteroid treatment. We believe that with increasing clinical experience with rituximab more cases of serum sickness will occur; therefore, the clinicians should be aware of this adverse effect.
Erythroid sarcoma is very rare form of pure erythroid leukemia with undetermined biological featu... more Erythroid sarcoma is very rare form of pure erythroid leukemia with undetermined biological features. Here, we present an infant with a multifocal erythroid sarcoma, diagnosed because the tumor cells were positive for glycophorin A. After acute myeloid leukemia-oriented chemotherapy and surgical resection followed by cord blood transplantation, he has successfully maintained complete remission without any late effects. Total transcriptome analysis of the tumor identified a novel fusion gene, RCC1-LCK, and high LCK expression levels, suggesting that LCK overexpression was involved in leukemogenesis in this case.
Blood, 2016
Introduction B-progenitor acute lymphoblastic leukemia (B-ALLs) accounts for 85% of pediatric ALL... more Introduction B-progenitor acute lymphoblastic leukemia (B-ALLs) accounts for 85% of pediatric ALL and categorized into several molecular subgroups according to their ploidy and recurrent translocations, such as ETV6-RUNX1, TCF3-PBX1, BCR-ABL1, and MLL-rearrangements. In addition, recent genetic studies using high-throughput sequencing have disclosed landscapes of gene alterations in each subgroup, however, their clinical relevance have not fully been investigated in a large cohort of B-ALL patients who are uniformly treated and enrolled in an unbiased manner. Methods We enrolled a total of 515 pediatric B-ALL patients, who had been uniformly treated according to the Japan Association of Childhood Leukemia Study (JACLS) ALL-02 protocol between 2002 and 2008. These patients were categorized into three risk groups, including standard-, high-, and extremely high-risk. Infantile ALL as well as BCR-ABL1-positive and Down syndrome-associated cases were excluded. A total of 158 known or put...
International Journal of Hematology, 2022
Recent genetic studies of pediatric acute lymphoblastic leukemia (ALL), both in B cell precursor ... more Recent genetic studies of pediatric acute lymphoblastic leukemia (ALL), both in B cell precursor and T cell ALL (B/T-ALL), clarified the landscape of genetic alterations due to great progress of comprehensive genome sequencing technologies including next generation sequencing. These studies revealed genetic alterations such as somatic structural DNA rearrangement and sequence mutations that affect multiple pathways including lymphocyte development, cytokine signaling, JAK-STAT pathway, MAP kinase and RAS signaling pathway, transcriptional, and epigenetic regulation to provide us new insight of leukemogenesis of pediatric B/T-ALL. In addition, recent comprehensive genetic studies of paired diagnostic and relapse samples clarified the mechanism of clonal evolution of leukemic cells to provide novel insights of mechanism of therapeutic resistance of pediatric ALL. Owing to huge success of genetic studies, several new subtypes of pediatric ALL have been identified, and some of them are ...
The Lancet Haematology, 2021
BACKGROUND ABL-class fusion genes other than BCR-ABL1 have been identified in approximately 3% of... more BACKGROUND ABL-class fusion genes other than BCR-ABL1 have been identified in approximately 3% of children with newly diagnosed acute lymphocytic leukaemia, and studies suggest that leukaemic cells carrying ABL-class fusions can be targeted successfully by tyrosine-kinase inhibitors. We aimed to establish the baseline characteristics and outcomes of paediatric patients with ABL-class fusion B-cell acute lymphocytic leukaemia in the pre-tyrosine-kinase inhibitor era. METHODS This multicentre, retrospective, cohort study included paediatric patients (aged 1-18 years) with newly diagnosed ABL-class fusion (ABL1 fusion-positive, ABL2 fusion-positive, CSF1R fusion-positive, and PDGFRB fusion-positive) B-cell acute lymphocytic leukaemia enrolled in clinical trials of multidrug chemotherapy done between Oct 3, 2000, and Aug 28, 2018, in which tyrosine-kinase inhibitors had not been given as a first-line treatment. Patients from 14 European, North American, and Asia-Pacific study groups of the Ponte di Legno group were included. No patients were excluded, and patients were followed up by individual study groups. Through the Ponte di Legno group, we collected data on the baseline characteristics of patients, including IKZF1, PAX5, and CDKN2A/B deletion status, and whether haematopoietic stem cell transplantation (HSCT) had been done, as well as treatment outcomes, including complete remission, no response, relapse, early death, and treatment-related mortality, response to prednisone, and minimal residual disease (MRD) at end of induction therapy. 5-year event-free survival and 5-year overall survival were estimated by use of Kaplan-Meier methods, and the 5-year cumulative incidence of relapse was calculated by use of a competing risk model. FINDINGS We identified 122 paediatric patients with newly diagnosed ABL-class fusion B-cell acute lymphocytic leukaemia (77 from European study groups, 25 from North American study groups, and 20 from Asia-Pacific study groups). 64 (52%) of 122 patients were PDGFRB fusion-positive, 40 (33%) were ABL1 fusion-positive, ten (8%) were CSF1R fusion-positive, and eight (7%) were ABL2 fusion-positive. In all 122 patients, 5-year event-free survival was 59·1% (95% CI 50·5-69·1), 5-year overall survival was 76·1% (68·6-84·5), and the 5-year cumulative incidence of relapse was 31·0% (95% CI 22·4-40·1). MRD at the end of induction therapy was high (≥10-2 cells) in 61 (66%) of 93 patients, and most prevalent in patients with ABL2 fusions (six [86%] of 7 patients) and PDGFRB fusion-positive B-cell acute lymphocytic leukaemia (43 [88%] of 49 patients). MRD at the end of induction therapy of 10-2 cells or more was predictive of an unfavourable outcome (hazard ratio of event-free survival in patients with a MRD of ≥10-2vs those with a MRD of <10-2 3·33 [95% CI 1·46-7·56], p=0·0039). Of the 36 (30%) of 119 patients who relapsed, 25 (69%) relapsed within 3 years of diagnosis. The 5-year cumulative incidence of relapse in 41 patients who underwent HSCT (17·8% [95% CI 7·7-31·3]) was lower than in the 43 patients who did not undergo HSCT (45·1% [28·4-60·5], p=0·013), but event-free survival and overall survival did not differ between these two groups. INTERPRETATION Children with ABL-class fusion B-cell acute lymphocytic leukaemia have poor outcomes when treated with regimens that do not contain a tyrosine-kinase inhibitor, despite the use of high-risk chemotherapy regimens and frequent HSCT upon first remission. Our findings provide a reference for evaluating the potential benefit of first-line tyrosine-kinase inhibitor treatment in patients with ABL-class fusion B-cell acute lymphocytic leukaemia. FUNDING The Oncode Institute, Pediatric Cancer Foundation Rotterdam, Dutch Cancer Society, Kika Foundation, Deutsche Krebshilfe, Blood Cancer UK, Associazione Italiana per la Ricerca sul Cancro, Cancer Australia, National Cancer Institute, National Institute of Health, and St Baldrick's Foundation.
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Papers by Toshihiko Imamura