Publications by authors named "Keizo Horibe"

191 Publications

Droplet digital polymerase chain reaction assay for the detection of the minor clone of KIT D816V in paediatric acute myeloid leukaemia especially showing RUNX1-RUNX1T1 transcripts.

Br J Haematol 2021 Jun 13. Epub 2021 Jun 13.

Department of Pediatrics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

KIT D816V mutation within exon 17 has been particularly reported as one of the poor prognostic factors in pediatric acute myeloid leukemia (AML) with RUNX1-RUNX1T1. The exact frequency and the prognostic impact of KIT D816V minor clones at diagnosis were not examined. In this study, the minor clones were examined and the prognostic significance of KIT D816V mutation in pediatric patients was investigated. Consequently, 24 KIT D816V mutations (7.2%) in 335 pediatric patients were identified, and 12 of 24 were only detected via the digital droplet polymerase chain reaction method. All 12 patients were confined in core binding factor (CBF)-AML patients. The 5 year event-free survival of the patients with KIT D816V mutation was significantly inferior to those without KIT D816V mutation (44.1% [95% confidence interval (CI), 16.0%-69.4%] vs. 74.7% [95% CI, 63.0%-83.2%] P-value = 0.02, respectively). The 5 year overall survival was not different between the two groups (92.9% [95% CI, 59.0%-NA vs. 89.7% [95% CI, 69.6%-96.8%] P-value = 0.607, respectively). In this study, KIT D816V minor clones in patients with CBF-AML were confirmed and KIT D816V was considered as a risk factor for relapse in patients with RUNX1-RUNX1T1-positive AML.
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http://dx.doi.org/10.1111/bjh.17569DOI Listing
June 2021

Clinical significance of RAS pathway alterations in pediatric acute myeloid leukemia.

Haematologica 2021 Mar 18. Epub 2021 Mar 18.

Department of Hematology/Oncology, Gunma Children's Medical Center, Gunma, Japan; Institute of Physiology and Medicine, Jobu University, Gunma.

RAS pathway alterations have been implicated in the pathogenesis of various hematological malignancies. However, their clinical relevance in pediatric acute myeloid leukemia (AML) is not well characterized. We analyzed the frequency, clinical significance, and prognostic relevance of RAS pathway alterations in 328 pediatric patients with de novo AML. RAS pathway alterations were detected in 80 (24.4%) out of 328 patients: NF1 (n = 7, 2.1%), PTPN11 (n = 15, 4.6%), CBL (n = 6, 1.8%), NRAS (n = 44, 13.4%), KRAS (n = 12, 3.7%). Most of these alterations were mutually exclusive and were also mutually exclusive with other aberrations of signal transduction pathways such as FLT3-ITD (p = 0.001) and KIT mutation (p = 0.004). NF1 alterations were frequently detected in patients with complex karyotype (p = 0.031) and were found to be independent predictors of poor overall survival (OS) in multivariate analysis (p = 0.007). At least four of seven patients with NF1 alterations had bi-allelic inactivation. NRAS mutations were frequently observed in patients with CBFB-MYH11 and were independent predictors of favorable outcomes in multivariate analysis [OS, p = 0.023; event-free survival (EFS), p = 0.037]. Patients with PTPN11 mutations more frequently received stem cell transplantation (p = 0.035) and showed poor EFS than patients without PTPN11 mutations (p = 0.013). Detailed analysis of RAS pathway alterations may enable a more accurate prognostic stratification of pediatric AML and may provide novel therapeutic molecular targets related to this signal transduction pathway.
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http://dx.doi.org/10.3324/haematol.2020.269431DOI Listing
March 2021

Prednisolone poor response is not an indication for HSCT in pediatric B-cell precursor acute lymphoblastic leukemia in first remission: results from JACLS ALL-02 study.

Int J Hematol 2021 Jun 28;113(6):893-902. Epub 2021 Feb 28.

Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465, Kajiichou, Hirokouji Kawaramachidori, Kamigyo-ku, Kyoto, 602-8566, Japan.

Approximately 90% of pediatric acute lymphoblastic leukemia (ALL) cases are curable with intensified chemotherapy, but very high-risk patients may require hematopoietic stem cell transplantation (HSCT). A suitable indication for HSCT in the first complete remission (CR1) should be defined to protect patients from long-term complications. We report the outcomes of HSCT in CR1 from the Japan Association of Childhood Leukemia Study (JACLS) ALL-02 study and reassess indications for HSCT. Of 1114 patients, 71 (6.4%) received HSCT in CR1. Indications included high-risk cytogenetic abnormalities and non-CR on day 33. Patients with B-cell precursor (BCP) ALL and a prednisolone poor response (PPR) received HSCT when leukocyte antigen-matched siblings were available. The 4-year overall survival (OS) of transplanted patients was 78.8% (confidence interval 67.3-86.6). Multivariate analysis revealed that cord blood transplantation was associated with poor OS. For BCP-ALL patients with PPR who achieved CR1 after induction therapy, HSCT in CR1 showed excellent outcomes (4-year OS 90.9%) but demonstrated no survival advantage as the outcome with chemotherapy was also excellent (4-year OS 97.0%). This study suggests that in BCP-ALL patients PPR is not an indication for HSCT in CR1. Precise evaluation of treatment responses would increase sophistication of indications for HSCT in CR1.
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http://dx.doi.org/10.1007/s12185-021-03110-0DOI Listing
June 2021

Landscape of driver mutations and their clinical impacts in pediatric B-cell precursor acute lymphoblastic leukemia.

Blood Adv 2020 10;4(20):5165-5173

Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Recent genetic studies using high-throughput sequencing have disclosed genetic alterations in B-cell precursor acute lymphoblastic leukemia (B-ALL). However, their effects on clinical outcomes have not been fully investigated. To address this, we comprehensively examined genetic alterations and their prognostic impact in a large series of pediatric B-ALL cases. We performed targeted capture sequencing in a total of 1003 pediatric patients with B-ALL from 2 Japanese cohorts. Transcriptome sequencing (n = 116) and/or array-based gene expression analysis (n = 120) were also performed in 203 (84%) of 243 patients who were not categorized into any disease subgroup by panel sequencing or routine reverse transcription polymerase chain reaction analysis for major fusions in B-ALL. Our panel sequencing identified novel recurrent mutations in 2 genes (CCND3 and CIC), and both had positive correlations with ETV6-RUNX1 and hypodiploid ALL, respectively. In addition, positive correlations were also newly reported between TCF3-PBX1 ALL with PHF6 mutations. In multivariate Cox proportional hazards regression models for overall survival, TP53 mutation/deletion, hypodiploid, and MEF2D fusions were selected in both cohorts. For TP53 mutations, the negative effect on overall survival was confirmed in an independent external cohort (n = 466). TP53 mutation was frequently found in IGH-DUX4 (5 of 57 [9%]) ALL, with 4 cases having 17p LOH and negatively affecting overall survival therein, whereas TP53 mutation was not associated with poor outcomes among NCI (National Cancer Institute) standard risk (SR) patients. A conventional treatment approach might be enough, and further treatment intensification might not be necessary, for patients with TP53 mutations if they are categorized into NCI SR.
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http://dx.doi.org/10.1182/bloodadvances.2019001307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594377PMC
October 2020

Association between sites and severity of eczema and the onset of cow's milk and egg allergy in children.

PLoS One 2020 19;15(10):e0240980. Epub 2020 Oct 19.

Department of Pediatrics, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.

Background: Cow's milk allergy (CMA) and egg allergy (EA) are common and can reduce quality of life in children. Infantile eczema is a well-established risk factor for the onset of food allergy via transdermal sensitization; however, various types of infantile eczema have not yet been evaluated. Therefore, we assessed the association between CMA and EA and the sites and the severity of infantile eczema.

Methods: This retrospective study was based on data from patients aged 2-19 years with atopic disease who were treated between July 2015 and March 2019 in a pediatric allergy clinic in Japan. Data regarding the history of IgE-mediated symptoms, eczema in the first year of life, parental history of atopic diseases, and infantile nutrition were collected.

Results: A total of 289 patients were included in the study, of which 81 and 111 children had IgE-mediated CMA and EA, respectively. The rates of CMA and EA were higher in the children with infantile eczema than in those without (30% vs. 9% and 42% vs. 21%). The rate of CMA was also higher in children with eczema on the face. Significant differences were noted in the rate of CMA among children with facial eczema of exudation (adjusted odds ratio 2.398; P = 0.017) and papules (adjusted odds ratio 2.787; P = 0.008), using multivariate analysis.

Conclusion: The rate of IgE-mediated CMA was high among children with atopic disease having severe facial eczema during infancy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240980PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571679PMC
December 2020

Alectinib for relapsed or refractory anaplastic lymphoma kinase-positive anaplastic large cell lymphoma: An open-label phase II trial.

Cancer Sci 2020 Dec 28;111(12):4540-4547. Epub 2020 Oct 28.

Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.

Anaplastic lymphoma kinase (ALK) inhibition is expected to be a promising therapeutic strategy for ALK-positive malignancies. We aimed to examine the efficacy and safety of alectinib, a second-generation ALK inhibitor, in patients with relapsed or refractory ALK-positive anaplastic large cell lymphoma (ALCL). This open-label, phase II trial included patients (aged 6 years or older) with relapsed or refractory ALK-positive ALCL. Alectinib 300 mg was given orally twice a day (600 mg/d) for 16 cycles, and the duration of each cycle was 21 days. Patients who weighed less than 35 kg were given a reduced dose of alectinib of 150 mg twice a day (300 mg/d). Ten patients were enrolled, and the median age was 19.5 years (range, 6-70 years). Objective responses were documented in eight of 10 patients (80%; 90% confidence interval, 56.2-95.9), with six complete responses. The 1-year progression-free survival, event-free survival, and overall survival rates were 58.3%, 70.0%, and 70.0%, respectively. The median duration of therapy was 340 days. No unexpected adverse events occurred. The most common grade 3 and higher adverse event was a decrease in neutrophil count in two patients. Alectinib showed favorable clinical activity and was well tolerated in patients with ALK-positive ALCL who had progressed on standard chemotherapy. Based on the results of the current study, the Ministry of Health, Labour and Welfare of Japan approved alectinib for the treatment of recurrent or refractory ALK-positive ALCL in February 2020.
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http://dx.doi.org/10.1111/cas.14671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734006PMC
December 2020

Prognostic Factors in Childhood Anaplastic Large Cell Lymphoma: Long Term Results of the International ALCL99 Trial.

Cancers (Basel) 2020 Sep 24;12(10). Epub 2020 Sep 24.

Pediatric Hematology, Oncology and Stem Cell Transplant Division, Padua University Hospital, 35128 Padua, Italy.

With the aim of describing the long-term follow-up and to define the prognostic role of the clinical/pathological/molecular characteristics at diagnosis for childhood, adolescent and young adults affected by anaplastic large cell lymphoma (ALCL), we analyzed 420 patients aged up to 22 years homogeneously treated within the international ALCL99 trial. The 10-year progression free survival (PFS) was 70% and overall survival was 90%, rare late relapses occurred but no secondary malignancies were reported. Among clinical/pathological characteristics, only patients presenting a small cell/lymphohistiocytic (SC/LH) pattern were independently associated with risk of failure (hazard ratio = 2.49). Analysis of minimal disseminated disease (MDD), available for 162 patients, showed that both SC/LH pattern (hazard ratio = 2.4) and MDD positivity (hazard ratio = 2.15) were significantly associated with risk of failure in multivariate analysis. Considering MDD and SC/LH results, patients were separated into three biological/pathological (bp) risk groups: a high-risk group (bpHR) including MDD-positive patients with SC/LH pattern; a low-risk group (bpLR) including MDD-negative patients without SC/LH pattern; and an intermediate-risk group (bpIR) including remaining patients. The 10-year PFS was 40%, 75% and 86% for bpHR, bpIR and bpLR, respectively ( < 0.0001). These results should be considered in the design of future ALCL trials to tailor individual treatments.
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http://dx.doi.org/10.3390/cancers12102747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598675PMC
September 2020

Attempts to optimize postinduction treatment in childhood acute myeloid leukemia without core-binding factors: A report from the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG).

Pediatr Blood Cancer 2020 12 4;67(12):e28692. Epub 2020 Sep 4.

Human Health Sciences, Kyoto University, Kyoto, Japan.

We previously reported that risk-stratified therapy and intensive postremission chemotherapy (PRC) contributed to the improved survival of childhood acute myeloid leukemia (AML) in the AML99 study, which led us to consider a reduction in the number of PRC courses with more restrictive indications for stem cell transplantation (SCT) in the successor AML-05 study. We here report the outcome of AML patients without core-binding factor mutation (non-CBF AML) in the AML-05 study. Two-hundred eighty-nine children (age < 18 years old) with non-CBF AML were eligible. Patients with unfavorable cytogenetics and/or poor bone marrow response to the first induction course were candidates for SCT in the AML-05 study. After two courses of induction, a further three courses of PRC were given in AML-05, while four courses were given in the AML99 study. The 3-year event-free survival (EFS) rate in the AML-05 study (46.7%, 95% CI: 40.6-52.6%) was comparable to that of non-CBF AML in the AML99 study (51.5%, 95% CI: 42.7-59.6%) (P = .16). However, the 3-year overall survival (OS) rate in the AML-05 study (62.9%, 95% CI: 56.3-68.8%) was slightly lower than that in the AML99 study (71.6%, 95% CI: 63.2-78.5%) (P = .060), mainly due to decreased remission induction rate and increased nonrelapsed mortality. In conclusion, reductions in the number of PRC courses from four to three, together with repetitive cycles of high-dose cytarabine, were acceptable for non-CBF childhood AML.
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http://dx.doi.org/10.1002/pbc.28692DOI Listing
December 2020

In-Hospital Management Might Reduce Induction Deaths in Pediatric Patients With Acute Lymphoblastic Leukemia: Results From a Japanese Cohort.

J Pediatr Hematol Oncol 2021 03;43(2):39-46

Department of Pediatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima.

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.
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http://dx.doi.org/10.1097/MPH.0000000000001926DOI Listing
March 2021

A risk-stratified therapy for infants with acute lymphoblastic leukemia: a report from the JPLSG MLL-10 trial.

Blood 2020 10;136(16):1813-1823

Department of Hematology/Oncology, Saitama Children's Medical Center, Saitama, Japan.

The prognosis for infants with acute lymphoblastic leukemia (ALL), particularly those with KMT2A gene rearrangement (KMT2A-r), is dismal. Continuous efforts have been made in Japan to investigate the role of hematopoietic stem cell transplantation (HSCT) for infants with KMT2A-r ALL, but improvement in outcome was modest. In the Japanese Pediatric Leukemia/Lymphoma Study Group MLL-10 trial, infants with ALL were stratified into 3 risk groups (low risk [LR], intermediate risk [IR], and high risk [HR]) according to KMT2A status, age, and presence of central nervous system leukemia. Children's Oncology Group AALL0631 modified chemotherapy with the addition of high-dose cytarabine in early intensification was introduced to KMT2A-r patients, and the option of HSCT was restricted to HR patients only. The role of minimal residual disease (MRD) was also evaluated. Ninety eligible infants were stratified into LR (n = 15), IR (n = 19), or HR (n = 56) risk groups. The 3-year event-free survival (EFS) rate for patients with KMT2A-r ALL (IR + HR) was 66.2% (standard error [SE], 5.6%), and for those with germline KMT2A (KMT2A-g) ALL (LR), the 3-year EFS rate was 93.3% (SE, 6.4%). The 3-year EFS rate was 94.4% (SE, 5.4%) for IR patients and 56.6% (SE, 6.8%) for HR patients. In multivariable analysis, female sex and MRD ≥0.01% at the end of early consolidation were significant factors for poor prognosis. Risk stratification and introduction of intensive chemotherapy in this study were effective and were able to eliminate HSCT for a subset of infants with KMT2A-r ALL. Early clearance of MRD seems to have translated into favorable outcomes and should be incorporated into risk stratifications in future trials. This trial was registered at the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) as #UMIN000004801.
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http://dx.doi.org/10.1182/blood.2019004741DOI Listing
October 2020

FLEND (nelarabine, fludarabine, and etoposide) for relapsed T-cell acute lymphoblastic leukemia in children: a report from Japan Children's Cancer Group.

Int J Hematol 2020 Nov 6;112(5):720-724. Epub 2020 Aug 6.

Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Mie, Japan.

Nelarabine is a key drug for T-cell acute lymphoblastic leukemia (T-ALL). Fludarabine and etoposide might have synergistic effect with nelarabine by inhibiting ribonucleotide reductase and by preparing cell cycle for G1/S phase, respectively. We had started phase 1/2 multicenter clinical trial of combination chemotherapy consisted of nelarabine, fludarabine, and etoposide (FLEND therapy) for children with relapsed/refractory T-ALL which has been conducted since October 2011. Although we could not complete this trial because of recruitment difficulties, we treated five children with first-relapsed T-ALL which were enrolled in the phase 1 dose escalation study of fludarabine and etoposide with nelarabine. No dose-limiting toxicity occurred, and frequent grade 3-4 toxicity was hematological toxicity and febrile neutropenia, as expected. There was no neurotoxicity. All 2 patients who received the target dose of FLEND, in which nelarabine (650 mg/m), fludarabine (30 mg/m), and etoposide (100 mg/m) were administered for 5 consecutive days, were induced to complete remission. We concluded that FLEND might be safe and one of the promising combination chemotherapies to relapsed/refractory T-ALL.
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http://dx.doi.org/10.1007/s12185-020-02962-2DOI Listing
November 2020

Neuro-meningeal relapse in anaplastic large-cell lymphoma: incidence, risk factors and prognosis - a report from the European intergroup for childhood non-Hodgkin lymphoma.

Br J Haematol 2021 Mar 9;192(6):1039-1048. Epub 2020 Jul 9.

Department of Children and Adolescents Oncology, Gustave Roussy Cancer Center, Paris-Saclay University, Villejuif, France.

Relapses involving the central nervous system (CNS) are rare in children and adolescents with ALK+ anaplastic large cell lymphoma (ALCL) treated with regimens including CNS prophylaxis. Early identification of patients at high-risk for CNS relapse would enable stratification and better adaptation of initial treatment especially in the light of the upcoming targeted therapies with limited CNS penetration. We analyzed clinical and histological data of all ALK+ALCL patients with CNS relapse registered in ALCL99-database with the aim to describe risk factors and outcome. Characteristics of patients with no relapse, relapse without CNS involvement and CNS relapse were compared. At a median follow-up of 8 years (0.05-18 years), a CNS involvement was reported at first or subsequent relapse in 26/618 patients. Median interval between initial diagnosis and first CNS relapse was 8 months (IQR 5.55-10.61/range 1.31-130.69). The 5-year cumulative risk of CNS relapse was 4% (95% CI 2.9-5.5). Bone marrow involvement, peripheral blasts and CNS involvement at diagnosis were more frequent in patients with CNS relapse than in patients with no relapse or with relapse with no CNS involvement. The treatment of CNS relapse was heterogeneous. The median survival after CNS relapse was 23.7 months. Eleven patients were alive at last follow-up. Three-year overall survival after CNS relapse was 48.70% (95% CI 30.52-67.23).
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http://dx.doi.org/10.1111/bjh.16755DOI Listing
March 2021

Clinical utility of target capture-based panel sequencing in hematological malignancies: A multicenter feasibility study.

Cancer Sci 2020 Sep 17;111(9):3367-3378. Epub 2020 Jul 17.

Department of Hematology, Atomic Bomb Disease and Hibakusha Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.

Although next-generation sequencing-based panel testing is well practiced in the field of cancer medicine for the identification of target molecules in solid tumors, the clinical utility and clinical issues surrounding panel testing in hematological malignancies have yet to be fully evaluated. We conducted a multicenter prospective clinical sequencing study to verify the feasibility of a panel test for hematological tumors, including acute myeloid leukemia, acute lymphoblastic leukemia, multiple myeloma, and diffuse large B-cell lymphoma. Out of 96 eligible patients, 79 patients (82%) showed potentially actionable findings, based on the clinical sequencing assays. We identified that genetic alterations with a strong clinical significance were found at a higher frequency in terms of diagnosis (n = 60; 63%) and prognosis (n = 61; 64%) than in terms of therapy (n = 8; 8%). Three patients who harbored a germline mutation in either DDX41 (n = 2) or BRCA2 (n = 1) were provided with genetic counseling. At 6 mo after sequencing, clinical actions based on the diagnostic (n = 5) or prognostic (n = 3) findings were reported, but no patients were enrolled in a clinical trial or received targeted therapies based on the sequencing results. These results suggest that panel testing for hematological malignancies would be feasible given the availability of useful diagnostic and prognostic information. This study is registered with the UMIN Clinical Trial Registry (UMIN000029879, multiple myeloma; UMIN000031343, adult acute myeloid leukemia; UMIN000033144, diffuse large B-cell lymphoma; and UMIN000034243, childhood leukemia).
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http://dx.doi.org/10.1111/cas.14552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469806PMC
September 2020

A phase 1b study of blinatumomab in Japanese children with relapsed/refractory B-cell precursor acute lymphoblastic leukemia.

Int J Hematol 2020 Aug 20;112(2):223-233. Epub 2020 Jun 20.

Department of Pediatric Oncology, National Cancer Center Hospital, Chūō, Tokyo, Japan.

Novel therapies are needed for children with relapsed/refractory (R/R) B-cell precursor acute lymphoblastic leukemia (ALL). Blinatumomab is a bispecific T-cell engager immunotherapy that simultaneously binds to CD3-positive cytotoxic T cells and CD19-positive B cells and redirects the patient's T cells to lyse malignant and normal B cells. We conducted an open-label phase 1b study to determine the safety, pharmacokinetics, efficacy, and recommended dose of blinatumomab in Japanese children with R/R B-cell precursor ALL. Patients received induction blinatumomab for 4 weeks (5 μg/m/day week 1; 15 μg/m/day weeks 2-4), followed by a 2-week treatment-free interval (6-week cycle). In subsequent cycles, patients received blinatumomab 15 μg/m/day. The primary end point was the incidence of dose-limiting toxicities. Nine patients received blinatumomab. Since no dose-limiting toxicities were reported, the maximum tolerated dose was 5 μg/m/day for week 1, followed by 15 μg/m/day weeks 2-4 (5-15 μg/m/day, the global recommended dose of blinatumomab). All patients had ≥ 1 grade ≥ 3 adverse events; 89% had grade ≥ 3 treatment-related adverse events. M1 remission rate within the first two cycles of treatment was 56%; one patient had a minimal residual disease response. Consistent with global studies, blinatumomab appeared to be safe with preliminary evidence of efficacy in Japanese children with R/R B-cell precursor ALL.
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http://dx.doi.org/10.1007/s12185-020-02907-9DOI Listing
August 2020

Genomic analysis of multiple myeloma using targeted capture sequencing in the Japanese cohort.

Br J Haematol 2020 12 9;191(5):755-763. Epub 2020 May 9.

Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Japan.

Previous genomic studies have revealed the genomic landscape of myeloma cells. Although some of the genomic abnormalities shown are believed to be correlated to the molecular pathogenesis of multiple myeloma and/or clinical outcome, these correlations are not fully understood. The aim of this study is to elucidate the correlation between genomic abnormalities and clinical characteristics by targeted capture sequencing in the Japanese multiple myeloma cohort. We analysed 154 patients with newly diagnosed multiple myeloma. The analysis revealed that the study cohort consisted of a less frequent hyperdiploid subtype (37·0%) with relatively high frequencies of KRAS mutation (36·4%) and IGH-CCND1 translocation (26·6%) compared with previous reports. Moreover, our targeted capture sequencing strategy was able to detect rare IGH-associated chromosomal translocations, such as IGH-CCND2 and IGH-MAFA. Interestingly, all 10 patients harboured MAX mutations accompanied by 14q23 deletion. The patients with del(17p) exhibited an unfavourable clinical outcome, and the presence of KRAS mutation was associated with shorter survival in patients with multiple myeloma, harbouring IGH-CCND1. Thus, our study provides a detailed landscape of genomic abnormalities, which may have potential clinical application for patients with multiple myeloma.
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http://dx.doi.org/10.1111/bjh.16720DOI Listing
December 2020

Predisposition to prolonged neutropenia after chemotherapy for paediatric acute myeloid leukaemia is associated with better prognosis in the Japanese Paediatric Leukaemia/Lymphoma Study Group AML-05 study.

Br J Haematol 2021 Apr 26;193(1):176-180. Epub 2020 Apr 26.

Division of Leukemia and Lymphoma, Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan.

The variability in myelosuppression after chemotherapy for acute myeloid leukaemia (AML) can affect its prognosis; however, the underlying mechanism remains controversial. In the Japanese Paediatric Leukaemia/Lymphoma Study Group AML-05 study, we showed that prolonged neutropenia was associated with high overall survival (P = 0·011) and low frequency of relapse (P = 0·042) in patients without granulocyte-colony stimulating factor (G-CSF) who completed the indicated treatment protocol. Our data indicate that predisposition to prolonged neutropenia after chemotherapy is correlated with a better outcome of AML treatment. Our results promote the usage of individualised drug dosing strategies to improve the therapeutic outcome in AML patients.
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http://dx.doi.org/10.1111/bjh.16656DOI Listing
April 2021

Nationwide study of pediatric B-cell precursor acute lymphoblastic leukemia with chromosome 8q24/MYC rearrangement in Japan.

Pediatr Blood Cancer 2020 07 23;67(7):e28341. Epub 2020 Apr 23.

Department of Hematology/Oncology, Saitama Children's Medical Center, Saitama, Japan.

Background: Rearrangements of chromosome 8q24/MYC (8q24/MYC-r), resulting from t(8;14)(q24;q32), t(2;8)(p11;q24), or t(8;22)(q24;q11), are mainly associated with Burkitt lymphoma/leukemia (BL) and rarely observed in patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL). The characteristics of BCP-ALL with 8q24/MYC-r are poorly understood.

Procedure: A retrospective nationwide study of data from patients with pediatric BCP-ALL with 8q24/MYC-r in Japan was conducted to clarify the clinical and biological characteristics associated with 8q24/MYC-r BCP-ALL.

Results: Ten patients with BCP-ALL with 8q24/MYC-r, including three with double-hit leukemia (DHL) (two with t(8;14)(q24;q32) and t(14;18)(q32;q21) and one with t(8;14) and t(3;22)(q27;q11)), were identified. Patients with BCP-ALL with 8q24/MYC-r had higher median age and uric acid and lactate dehydrogenase levels, than those without 8q24/MYC-r. All patients were initially treated with ALL-type chemotherapy; however, four, including one with DHL, were switched to BL-type chemotherapy, based on cytogenetic findings. One patient relapsed after standard-risk ALL-type chemotherapy, and two patients with DHL did not attain complete remission with chemotherapy; all three died within 11 months. The other seven patients treated with BL-type or high-risk ALL-type chemotherapy are alive without disease.

Conclusions: The clinical and laboratory features of BL with IG-MYC rearrangement, displaying a BCP immunophenotype (Wagener et al. and Herbrueggen et al. termed it as pre-BLL), are similar to those of BCP-ALL with 8q24/MYC-r. Low-risk ALL-type chemotherapy may not be appropriate for them, and further studies are required to establish an adequate therapeutic strategy. Further studies of DHL to identify new treatment strategies are also needed.
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http://dx.doi.org/10.1002/pbc.28341DOI Listing
July 2020

Risk-adjusted therapy for pediatric non-T cell ALL improves outcomes for standard risk patients: results of JACLS ALL-02.

Blood Cancer J 2020 02 27;10(2):23. Epub 2020 Feb 27.

Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.

This study was a second multicenter trial on childhood ALL by the Japan Childhood Leukemia Study Group (JACLS) to improve outcomes in non-T ALL. Between April 2002 and March 2008, 1138 children with non-T ALL were enrolled in the JACLS ALL-02 trial. Patients were stratified into three groups using age, white blood cell count, unfavorable genetic abnormalities, and treatment response: standard risk (SR), high risk (HR), and extremely high risk (ER). Prophylactic cranial radiation therapy (PCRT) was abolished except for CNS leukemia. Four-year event-free survival (4yr-EFS) and 4-year overall survival (4yr-OS) rates for all patients were 85.4% ± 1.1% and 91.2% ± 0.9%, respectively. Risk-adjusted therapy resulted in 4yr-EFS rates of 90.4% ± 1.4% for SR, 84.9% ± 1.6% for HR, and 66.5% ± 4.0% for ER. Based on NCI risk classification, 4yr-EFS rates were 88.2% in NCI-SR and 76.4% in NCI-HR patients, respectively. Compared to previous trial ALL-97, 4yr-EFS of NCI-SR patients was significantly improved (88.2% vs 81.2%, log rank p = 0.0004). The 4-year cumulative incidence of isolated (0.9%) and total (1.5%) CNS relapse were significantly lower than those reported previously. In conclusion, improved EFS in NCI-SR patients and abolish of PCRT was achieved in ALL-02.
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http://dx.doi.org/10.1038/s41408-020-0287-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046744PMC
February 2020

Phase I study of brentuximab vedotin (SGN-35) in Japanese children with relapsed or refractory CD30-positive Hodgkin's lymphoma or systemic anaplastic large cell lymphoma.

Int J Hematol 2020 May 20;111(5):711-718. Epub 2020 Jan 20.

Department of Pediatrics, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.

Data on the treatment of pediatric patients with brentuximab vedotin are limited. The aims of the present study were to assess the safety and tolerability of brentuximab vedotin in Japanese children with relapsed or refractory Hodgkin's lymphoma (HL) or systemic anaplastic large-cell lymphoma (sALCL). Pediatric patients, aged 2-17 years, with relapsed or refractory HL or sALCL were recruited. Brentuximab vedotin were administered at 1.8 mg/kg via intravenous infusion once every 3 weeks. Primary endpoints were dose-limiting toxicity and safety. Between September 2016, and March 2018, six patients (median age 11.5, range 5-14 years), four with relapsed or refractory HL and two with relapsed or refractory sALCL were enrolled. Dose limiting toxicity was not observed in any of the six patients. Although three of six patients (50%) experienced at least one grade ≥ 3 adverse event, no patient experienced a serious adverse event. The pharmacokinetic profile of brentuximab vedotin in pediatric patients was comparable to that reported in adults. The proportion of patients who achieved overall response was 60% (95% confidence interval 14.7-94.7). Brentuximab vedotin at 1.8 mg/kg once every 3 weeks was considered tolerable in children with relapsed or refractory HL or sALCL.
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http://dx.doi.org/10.1007/s12185-020-02820-1DOI Listing
May 2020

A female patient with retinoblastoma and severe intellectual disability carrying an X;13 balanced translocation without rearrangement in the RB1 gene: a case report.

BMC Med Genomics 2019 12 5;12(1):182. Epub 2019 Dec 5.

Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan.

Background: Female carriers of a balanced X; autosome translocation generally undergo selective inactivation of the normal X chromosome. This is because inactivation of critical genes within the autosomal region of the derivative translocation chromosome would compromise cellular function. We here report a female patient with bilateral retinoblastoma and a severe intellectual disability who carries a reciprocal X-autosomal translocation.

Case Presentation: Cytogenetic and molecular analyses, a HUMARA (Human androgen receptor) assay, and methylation specific PCR (MSP) and bisulfite sequencing were performed using peripheral blood samples from the patient. The patient's karyotype was 46,X,t(X;13)(q28;q14.1) by G-banding analysis. Further cytogenetic analysis located the entire RB1 gene and its regulatory region on der(X) with no translocation disruption. The X-inactivation pattern in the peripheral blood was highly skewed but not completely selected. MSP and deep sequencing of bisulfite-treated DNA revealed that an extensive 13q region, including the RB1 promoter, was unusually methylated in a subset of cells.

Conclusions: The der(X) region harboring the RB1 gene was inactivated in a subset of somatic cells, including the retinal cells, in the patient subject which acted as the first hit in the development of her retinoblastoma. In addition, the patient's intellectual disability may be attributable to the inactivation of the der(X), leading to a 13q deletion syndrome-like phenotype, or to an active X-linked gene on der (13) leading to Xq28 functional disomy.
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http://dx.doi.org/10.1186/s12920-019-0640-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896736PMC
December 2019

Transcriptome analysis offers a comprehensive illustration of the genetic background of pediatric acute myeloid leukemia.

Blood Adv 2019 10;3(20):3157-3169

Department of Hematology/Oncology, Gunma Children's Medical Center, Shibukawa, Japan.

Recent advances in the genetic understanding of acute myeloid leukemia (AML) have improved clinical outcomes in pediatric patients. However, ∼40% of patients with pediatric AML relapse, resulting in a relatively low overall survival rate of ∼70%. The objective of this study was to reveal the comprehensive genetic background of pediatric AML. We performed transcriptome analysis (RNA sequencing [RNA-seq]) in 139 of the 369 patients with de novo pediatric AML who were enrolled in the Japanese Pediatric Leukemia/Lymphoma Study Group AML-05 trial and investigated correlations between genetic aberrations and clinical information. Using RNA-seq, we identified 54 in-frame gene fusions and 1 RUNX1 out-of-frame fusion in 53 of 139 patients. Moreover, we found at least 258 gene fusions in 369 patients (70%) through reverse transcription polymerase chain reaction and RNA-seq. Five gene rearrangements were newly identified, namely, NPM1-CCDC28A, TRIP12-NPM1, MLLT10-DNAJC1, TBL1XR1-RARB, and RUNX1-FNBP1. In addition, we found rare gene rearrangements, namely, MYB-GATA1, NPM1-MLF1, ETV6-NCOA2, ETV6-MECOM, ETV6-CTNNB1, RUNX1-PRDM16, RUNX1-CBFA2T2, and RUNX1-CBFA2T3. Among the remaining 111 patients, KMT2A-PTD, biallelic CEBPA, and NPM1 gene mutations were found in 11, 23, and 17 patients, respectively. These mutations were completely mutually exclusive with any gene fusions. RNA-seq unmasked the complexity of gene rearrangements and mutations in pediatric AML. We identified potentially disease-causing alterations in nearly all patients with AML, including novel gene fusions. Our results indicated that a subset of patients with pediatric AML represent a distinct entity that may be discriminated from their adult counterparts. Based on these results, risk stratification should be reconsidered.
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http://dx.doi.org/10.1182/bloodadvances.2019000404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849955PMC
October 2019

Patients aged less than 3 years with acute myeloid leukaemia characterize a molecularly and clinically distinct subgroup.

Br J Haematol 2020 02 14;188(4):528-539. Epub 2019 Oct 14.

Department of Haematology and Oncology, Gunma Children's Medical Centre, Shibukawa, Japan.

Although infants (age <1 year) with acute myeloid leukaemia (AML) have unique characteristics and are vulnerable to chemotherapy, children aged 1-2 years with AML may have characteristics similar to that of infants. Thus, we analysed 723 paediatric AML patients treated on the Japanese AML99 and AML-05 trials to identify characteristics of younger children. We identified patients aged <3 years (the younger group) as a distinct subgroup. KMT2A-rearrangement (KMT2A-R), CBFA2T3-GLIS2, CBFB-MYH11 and NUP98-KDM5A were frequently found in the younger group. Prognostic analyses revealed poor 5-year overall survival (OS), event-free survival (EFS) and cumulative incidence of relapse (CIR) in patients with CBFA2T3-GLIS2 (42%, 17% and 83%, respectively) and those with NUP98-KDM5A (33%, 17% and 83%, respectively). Additionally, we identified KMT2A-R and CBFB-MYH11 as age-specific prognostic markers. Regarding KMT2A-R, the younger group had significantly better OS, EFS and CIR than the older group (aged 3 to <18 years) (P = 0·023, 0·011 and <0·001, respectively). Conversely, concerning CBFB-MYH11, the younger group had significantly poor EFS and CIR than the older group (each P < 0·001), suggesting that certain molecular markers are linked to different prognoses according to age. Therefore, we characterized patients <3 years as a distinct subgroup of paediatric AML.
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http://dx.doi.org/10.1111/bjh.16203DOI Listing
February 2020

Highly sensitive detection of GATA1 mutations in patients with myeloid leukemia associated with Down syndrome by combining Sanger and targeted next generation sequencing.

Genes Chromosomes Cancer 2020 03 21;59(3):160-167. Epub 2019 Oct 21.

Department of Pediatrics, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.

Myeloid leukemia associated with Down syndrome (ML-DS) is characterized by a predominance of acute megakaryoblastic leukemia, the presence of GATA1 mutations and a favorable outcome. Because DS children can also develop conventional acute myeloid leukemia with unfavorable outcome, detection of GATA1 mutations is important for diagnosis of ML-DS. However, myelofibrosis and the significant frequency of dry taps have hampered practical screening of GATA1 mutations using bone marrow (BM) samples. In response to those problems, 82 patients were enrolled in the Japanese Pediatric Leukemia/Lymphoma Study Group AML-D11 study. GATA1 mutations were analyzed by Sanger sequencing (SS) using genomic DNA (gDNA) from BM and cDNA from peripheral blood (PB) followed by targeted next-generation sequencing (NGS) using pooled diagnostic samples. BM and PB samples were obtained from 71 (87%) and 82 (100%) patients, respectively. GATA1 mutations were detected in 46 (56%) and 58 (71%) patients by SS using BM gDNA and PB cDNA, respectively. Collectively, GATA1 mutations were identified in 73/82 (89%) patients by SS. Targeted NGS detected GATA1 mutations in 74/82 (90%) patients. Finally, combining the results of SS with those of targeted NGS, GATA1 mutations were identified in 80/82 (98%) patients. These results indicate that SS using BM gDNA and PB cDNA is a rapid and useful method for screening for GATA1 mutations in ML-DS patients. Thus, a combination of SS and targeted NGS is a sensitive and useful method to evaluate the actual incidence and clinical significance of GATA1 mutations in ML-DS patients.
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http://dx.doi.org/10.1002/gcc.22816DOI Listing
March 2020

[Precision medicine in hematological malignancies].

Rinsho Ketsueki 2019 ;60(9):1386-1395

Nagoya Medical Center, Clinical Research Center.

Precision medicine is a type of medical care designed to optimize the therapeutic efficiency or benefit for particular groups of patients with the use of genetic profiling. The application of precision medicine in cancer treatment is prospected because cancer is reported to be the leading cause of death in Japan. Consequently, Japanese cancer genome medicine will be launched within this fiscal year. In this study, we focus on precision medicine specifically in the field of hematological malignancies with an overview of its clinical utility. We further discuss how precision medicine should be developed in this field, based on our experience of a feasibility study for clinical sequencing in hematological malignancies.
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http://dx.doi.org/10.11406/rinketsu.60.1386DOI Listing
October 2019

Nationwide survey of pediatric hypodiploid acute lymphoblastic leukemia in Japan.

Pediatr Int 2019 Nov 21;61(11):1103-1108. Epub 2019 Nov 21.

Department of Hematology/Oncology, Saitama Children's Medical Center, Saitama, Japan.

Background: Ploidy is a highly significant prognostic factor for pediatric acute lymphoblastic leukemia (ALL). Children with hypodiploid ALL have poor outcomes despite current intensive chemotherapy. Little has been investigated with regard to hypodiploid ALL in Japanese children.

Methods: We retrospectively collected clinical data on hypodiploid ALL cases from the registries of prospective multicenter trials conducted by the four independent clinical study groups in Japan between 1997 and 2012.

Results: A total of 117 ALL patients with hypodiploidy were analyzed in this study. There were 101, eight, and eight patients with 45, 44, and fewer than 44 chromosomes, respectively. The 5 year overall survival rates differed significantly: 86.0%, 87.5%, and 62.5% for patients with 45, 44, and fewer than 44 chromosomes, respectively (P = 0.037). Of the eight patients with 44 chromosomes, seven were alive, including five patients who maintained complete remission without undergoing hematopoietic stem cell transplantation (HSCT). Of the eight patients with fewer than 44 chromosomes, six were good responders to prednisolone and none had induction failure, but the relapse rate was high (5/8). No patients had central nervous system relapse. Four patients underwent HSCT after relapse, but only one survived.

Conclusions: Outcomes of Japanese ALL patients with fewer than 44 chromosomes were poor, as previously reported in other countries. Although the sample size was small, patients with 44 chromosomes had better prognoses than those previously reported. Further studies including international collaboration are needed to improve outcomes for pediatric ALL patients with fewer than 44 chromosomes.
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http://dx.doi.org/10.1111/ped.14006DOI Listing
November 2019

Bortezomib-containing therapy in Japanese children with relapsed acute lymphoblastic leukemia.

Int J Hematol 2019 Nov 10;110(5):627-634. Epub 2019 Aug 10.

Department of Pediatric Oncology, National Cancer Center Hospital, Tokyo, Japan.

Outcomes of children treated for relapsed acute lymphoblastic leukemia (ALL) remain poor. Bortezomib (BZM), a proteasome inhibitor, has shown promising activity against lymphoid malignancies. We conducted a phase I study to evaluate the safety and tolerability of multidrug chemotherapy including BZM in Japanese children with relapsed ALL. Three of five children with relapsed ALL enrolled in the study between November 2014 and April 2016 were evaluated. BZM (1.3 mg/m) was administered on days 8, 11, 15, and 18 of multidrug induction chemotherapy. Pharmacokinetic studies were performed. Age at study entry was 5, 7, and 7 years old, respectively. Two patients had hyperdiploid B-precursor ALL, and one had T cell ALL. Although all patients experienced grade 3-4 hematologic toxicity and grade 3 elevation of aminotransferases, no dose-limiting toxicities were observed. The maximum tolerated dose was defined as 1.3 mg/m. Peripheral neuropathy and respiratory complications were not observed. Complete remission was achieved in all three patients. The mean maximum plasma concentration and area under the concentration-time curve was 74.0 ng/mL and 73.9 ng h/mL, respectively. Thus, adding BZM to 5-drug induction chemotherapy appears safe and well-tolerated in Japanese children with relapsed ALL.
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http://dx.doi.org/10.1007/s12185-019-02714-xDOI Listing
November 2019